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Modulation of gene expression rather than monoamine oxidase inhibition: (-)-Deprenyl-related compounds in controlling neurodegeneration
Neurology (USA), 1996, 47/6 SUPPL. 3 (S171-S183)
(-)-Deprenyl has been used to irreversibly inhibit monoamine oxidase B (MAO-B) in Parkinson's disease (PD) and Alzheimer's disease (AD) as a possible means of improving dopaminergic neurotransmission or of reducing neuronal necrosis caused by oxidative radical damage. Recent research in tissue culture and animal models has shown that (-)-deprenyl can reduce neuronal apoptosis caused by a variety of agents, in a variety of neuronal subtypes through a mechanism(s) that does not require MAO-B inhibition. Studies using general P450 blockers have shown that one of the principal metabolites of (-)-deprenyl, (-)-desmethyldeprenyl, mediates the antiapoptotic action. Other research has shown that (-)-deprenyl can induce altered expression of a number of genes in preapoptotic neurons both in vitro and in vivo, including the genes for superoxide dismutase (SOD) 1 and 2, BCL- 2 and BCL-x(L), nitric oxide synthase, c-JUN, and nicotinamide adenine dinucleotide dehydrogenase. Antiapoptosis by (-)-deprenyl is associated with a prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons, which has been shown to occur early in apoptosis and is likely an initiating factor. The above changes in gene expression appear to reduce oxidative radical damage to mitochondria and maintain mitochondrial permeability, thereby blocking mitochondrial 'signals' that initiate apoptosis. In situ evidence suggests that apoptosis contributes to neuronal death in a number of neurodegenerative diseases. If apoptosis is critical to the progression of one or more human neurodegenerative diseases, then transcriptionally active agents such as (-)-desmethyldeprenyl may be of value in treating the diseases. The kinetics of (-)-deprenyl metabolism, however, and its biodistribution after oral administration, make it unlikely that the antiapoptotic action has played a major role in benefits found for the drug in PD and AD to date.
L-Deprenyl protects mesencephalic dopamine neurons from glutamate receptor-mediated toxicity in vitro
Journal of Neurochemistry (USA), 1997, 68/1 (33-39)
L-Deprenyl is a relatively selective inhibitor of monoamine oxidase (MAO)-B that delays the emergence of disability and the progression of signs and symptoms of Parkinson's disease. Experimentally, deprenyl has also been shown to prevent neuronal cell death in various models through a mechanism that is independent of MAO-B inhibition. We examined the effect of deprenyl on cultured mesencephalic dopamine neurons subjected to daily changes of feeding medium, an experimental paradigm that causes neuronal death associated with activation of the NMDA subtype of glutamate receptors. Both deprenyl (0.5-50 microM) and the NMDA receptor blocker MK-801 (10 microM) protected dopamine neurons from damage caused by medium changes. The nonselective MAO inhibitor pargyline (0.5-50 microM) was not protective, indicating that protection by deprenyl was not due to MAO inhibition. Deprenyl (50 microM) also protected dopamine neurons from delayed neurotoxicity caused by exposure to NMDA. Because deprenyl had no inhibitory effect on NMDA receptor binding, it is likely that deprenyl protects from events occurring downstream from activation of glutamate receptors. As excitotoxic injury has been implicated in neurodegeneration, it is possible that deprenyl exerts its beneficial effects in Parkinson's disease by suppressing excitotoxic damage.
The natural history of Parkinson's disease
Neurology (USA), 1996, 47/6 SUPPL. 3 (S146-S152)
A large body of evidence indicates that the progression of Parkinson's disease (PD) may be fast in the preclinical stage as well as during the first years of the disease, with a subsequent slowing down of the disease process. As has been shown in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination scores declined at a rate of 8 to 9% per year in untreated patients. A subgroup of levodopa-naive DATATOP patients ('survivors') showed a much slower rate of progression, in the order of 3% per year, suggesting a more benign disease course. A number of clinical factors that may govern the rate of motor decline, such as age at onset, disease duration, gender, and clinical phenotype (akinetic-rigid versus tremulous) have been proposed; however, none of them is proven. In contrast, dopaminergic substitution undoubtedly has had a major impact on the natural history of PD, resulting in a reduction of the mortality ratio from about 3.0 to 1.5. This benefit has been noted particularly in patients in whom levodopa therapy was started early. The positive impact of levodopa is largely derived from its symptomatic action; its influence on the disease process itself remains controversial.
Effect of lazabemide on the progression of disability in early Parkinson's disease
Annals of Neurology (USA), 1996, 40/1 (99-107)
Lazabemide (Ro 19-6327) is a relatively short-acting, reversible, and selective type B monoamine oxidase inhibitor that is not metabolized to amphetamines or other active compounds. We previously found lazabemide to be safe and well tolerated at dosages of up to 400 mg/day during a 6-week study of 201 patients with early untreated Parkinson's disease (PD). We now assess whether or not lazabemide influences the progression of disability in untreated PD. Patients (N = 321) were assigned by randomization to one of five treatment groups (placebo, 25 mg, 50 mg, 100 mg, or 200 mg/day) and followed systematically for up to 1 year. The risk of reaching the primary end point (the onset of disability sufficient to require levodopa therapy) was reduced by 51% for the patients who received lazabemide compared with placebo-treated subjects. This effect was consistent among all dosages. The frequency of adverse experiences did not differ among the treatment groups. At dosages ranging from 25 to 200 mg/day, lazabemide was well tolerated and delayed the need for levodopa in early, otherwise untreated PD. The magnitude and pattern of benefits were similar to those observed after 1 year of deprenyl (selegiline) treatment in the DATATOP clinical trial.
Impact of deprenyl and tocopherol treatment on Parkinson's disease in DATATOP subjects not requiring levodopa
Annals of Neurology (USA), 1996, 39/1 (29-36)
In the controlled trial Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), 310 of the 800 enrolled subjects did not reach the primary end point of disability requiring levodopa therapy during 21 plus or minus 4 (mean plus or minus SD) months of observation or need early initiation of deprenyl (selegiline) during a 2-month withdrawal of experimental treatments. While maintaining the blindness of their original deprenyl and tocopherol treatment assignments, these 310 subjects were administered deprenyl 10 mg/day (open label) and were monitored systematically at 1- to 3-month intervals for up to 18 months (12 plus or minus 5 mo). During this extended trial, the 189 subjects who had been assigned originally to active deprenyl tended to reach the end point of disability faster than the 121 subjects who had not been assigned originally to deprenyl (hazard ratio, 1.43; 95% CI, 0.98, 2.09; p = 0.065). However, the differential rates of reaching the end point may have been due in part to the more severe baseline impairment of deprenyl-assigned subjects, who benefited originally from deprenyl but who were more likely to require levodopa during this extended period of observation. Prior treatment with deprenyl did not lead to superior survival with respect to the end point of disability requiring levodopa, suggesting that the initial advantages of deprenyl were not sustained.
New approaches to drug treatment of Parkinson's disease
Aktuelle Neurologie (Germany), 1995, 22/6 (217-223)
Although the aetiology of Parkinson's disease remains unknown, an improved understanding of the neurobiology of Parkinson's disease has opened up new avenues for pharmacological therapeutic interventions. Some of these new neuropharmacological approaches are still in the experimental preclinical phase, whereas others are currently studied in patients. In addition, experimental neuropharmacological research provides a better understanding of the mechanism of action of conventional antiparkinsonian drugs. Recent experimental evidence suggests that striatal dopamine loss leads to increased glutamatergic transmission in the basal ganglia. In animal experiments, the action of L-dopa and dopamine agonists is potentiated by glutamate antagonists. A number of weak glutamate antagonists with low specificity are available for clinical use. These compounds include amantadine, memantine and budipine. Neurotrophic factors, such as ciliary neurotrophic factor (CNTF) and glial cell line derived neurotrophic factor (GDNF) are promising new approaches for neuroprotection in Parkinson's disease. Problems of bioavailability thus far preclude their use in patients. Catechol-O-methyl-transferase (COMT) inhibitors are a new class of drugs that act on the dopaminergic system. Clinical studies show that COMT inhibitors prolong the action of L-dopa in patients with wearing off phenomenon. In spite of its haematological risk, the atypical neuroleptic clozapine is the treatment of choice for the alleviation of L-dopa-induced psychosis. Clozapine has also beneficial effects on tremor and L-dopa-induced dyskinesias. The monoamine oxidase B (MAO-B) inhibitor deprenyl blocks the oxidative metabolism of dopamine and reduces the formation of free oxygen radicals. On the basis of these properties neuroprotective actions of deprenyl have been postulated. Clinical studies, however, failed to undoubtedly prove a neuroprotective action of deprenyl in patients. New experimental studies show protective actions of deprenyl, which are independent of MAO-B inhibition and which are due to a direct effect on gene transcription.
Novel sites of action for deprenyl in MPTP-parkinsonism: Metabolite-mediated protection against striatal neurotoxicity and suppression of MPTP-induced increase of dopamine turnover in C57BL mice
Progress in Brain Research (Netherlands), 1995, 106 (155-171)
In the present study we provide further evidence for our recent finding that DEP has neuroprotective effects against dopaminergic toxicity of MPTP and its 2'-substituted analogs in mice, which are associated with the ability of its major metabolites, 1-methamphetamine and 1-amphetamine to block the neuronal uptake of the toxic pyridinium metabolites of MPTP and its analogs. Here we demonstrated that protection by a 30-min DEP posttreatment (10 mg/kg) against MPTP (40 mg/kg)-induced decrease of striatal dopamine level is reduced when mice received SKF 525A (25 mg/kg), an inhibitor of the metabolism of DEP 10 min prior to DEP treatment. For the first time, we demonstrated that a 30-min pre- or post-treatment with DEP (10 mg/kg) provided substantial protection against striatal dopamine depletion induced by 2'Et-MPTP (30 mg/kg), which is primarily bioactivated by MAO-A. A 30-min posttreatment with DEP (but not by pargyline or clorgyline), in addition to protection against dopamine depletion, also prevents the decrease in striatal mazindol binding (an indicator of the integrity of dopaminergic terminals) induced by MPTP (40 mg/kg), 2'Me-MPTP (15 mg/kg) or 2'Et-MPTP (30 mg/kg). A subacute DEP treatment of mice with severe injury in the terminal fields of the nigrostriatal dopaminergic system (80-90% loss of dopamine; 2-4-fold increase in dopamine turnover as reflected by higher metabolite/DA ratios) enhanced the recovery of striatal dopamine level and suppressed the MPTP-induced elevation of dopamine turnover. Deprenyl treatment was applied in a wide range of dose (0.01-20 mg/kg, i.p., eight times over 18 days from the 3rd day after the last MPTP injection) to mice that had received MPTP (30 mg/kg; i.p.) for 5 consecutive days. The effect of subacute DEP treatment on the recovery of striatal dopamine level was most pronounced at a cumulative dose of 0.8 mg/kg, indicating that higher dosage of DEP may be less beneficial.
Combined treatment in Parkinson's disease
Neuropsychiatrie (Germany), 1995, 9/SUPPL. 1 (S27-S29)
As a rule patients with Parkinson's disease receive combined therapy aiming at reducing the levodopa dose and achieving optimum therapeutic results regarding the target symptoms, e.g. tremor and slowing disease progression by neuroprotection. The benefits of combined treatment with levodopa and dopaminergic agonists in the treatment of dyskinesia and fluctuations in advanced disease stages have been established. It is further recommended to combine dopaminergic agonists and levodopa during early disease stages to delay the occurrence of late complications and to administer selegeline because of its possible neuroprotection. Studies on the latter aspects are controversial and discussion is in progress.
In vivo comparison of the effects of inhibition of MAO-A versus MAO-B on striataI L-DOPA and dopamine metabolism
Journal of Neural Transmission - Parkinson's Disease and Dementia Section (Austria), 1995, 10/2-3 (79-89)
Utilizing the cerebral microdialysis technique, we have compared in vivo the effects of selective MAO-A, MAO-B, and nonselective MAO inhibitors on striatal extracellular levels of dopamine (DA) and DA metabolites (DOPAC and HVA). The measurements were made in rats both under basal conditions and following L-DOPA administration. Extracellular levels of dopamine were enhanced and DA metabolite levels strongly inhibited both under basal conditions and following L-DOPA administration by pretreatment with the nonselective MAO inhibitor pargyline and the MAO-A selective inhibitors clorgyline and Ro 41-1049. The MAO-B inhibitor deprenyl had no effect on basal DA, HVA, or DOPAC levels. Nevertheless, deprenyl significantly increased DA and decreased DOPAC levels following exogenous L-DOPA administration, a finding compatible with a significant glial metabolism of DA formed from exogenous L-DOPA. We conclude that DA metabolism under basal conditions is primarily mediated by MAO-A. In contrast, both MAO-A and MAO-B mediate DA formation when L-DOPA is administered exogenously. The efficacy of newer, reversible agents which lack the 'cheese effect' such as Ro 41-1049 are comparable to the irreversible NAG-A inhibitor clorgyline. The possible relevance of these findings for the treatment of Parkinson's disease is discussed.
Selegiline: A review of its clinical efficacy in Parkinson's disease and its clinical potential in Alzheimer's disease
CNS Drugs (New Zealand), 1995, 4/3 (230-246)
Selegiline (deprenyl) increases nigrostriatal dopamine levels by several mechanisms, including selective and irreversible inhibition of cerebral monoamine oxidase type-B. Through this mechanism it may also protect neurons against damage by free radicals and possibly exogenous neurotoxins. When used alone in patients with early Parkinson's disease, oral selegiline 5 mg twice daily initially reduces symptoms severity compared with placebo. During prolonged therapy, selegiline slows the rate of symptoms progression and delays the need for levodopa therapy by 6 to 9 months. The benefits of coadministration of selegiline with levodopa as de novo therapy in early Parkinson's disease compared with levodopa monotherapy remain unclear. Studies have shown either similar disease progression in both treatment groups after 3 years or significantly slowed disease progression and reduced levodopa requirement after 14 to 54 months in patients treated with both drugs compared with levodopa monotherapy. In patients with more advanced disease who have mild levodopa response fluctuations, concomitant selegiline allows a reduction in levodopa dosage. Improvements in overall disability and 'end-of-dose' fluctuations are observed, although benefits are rarely maintained for longer than a year. Improvements in cognitive function, behaviour and activities of daily living have been observed in patients with Alzheimer's disease following administration of selegiline 10 mg/day for up to 15 months, and the drug appeared to be more effective in this regard than 1-acetylcarnitine, oxiracetam and phosphatidylserine in single-blind studies. In addition, preliminary findings suggest that selegiline may have an additive effect when coapministered with cholinergic therapy. At the dosage recommended for Parkinson's disease and Alzheimer's disease, selegiline is not associated with the tyramine ('cheese') reaction. Thus, selegiline is a valuable treatment option for de novo therapy of patients with early Parkinson's disease, improving symptoms and postponing the need for levodopa therapy. Whether it also offers clinically significant neuroprotection remains unclear. Selegiline is a useful adjunct to long term levodopa therapy in patients with more advanced disease experiencing response fluctuations, and recent findings suggest that it may offer some clinical benefit to patients with Alzheimer's disease.
Treatment of Parkinson's disease
Neurology India (India), 1995, 43/2 (77-82)
Inspite of extensive research the ideal drug therapy for idiopathic Parkinson's disease (PD) and its optimal timing remain uncertain. Levodopa still is the mainstay of therapy for PD. Little evidence exists to incriminate early institution of levodopa therapy in the development of motor fluctuations and dyskinesias in PD. These complications are probably a consequence of disease progression, and resultant inability to synthesize and store dopamine, and buffer the variability in dopamine availability. Therefore, withholding levodopa therapy until late stage of the disease is not warranted. Dopa agnoists provide only a short-term benefit. The neuroprotective effect of selegeline remains to be established. There is not enough evidence to justify the current practice of initiating treatment for PD patients with expensive polypharmacy. Research into the development of inexpensive levodopa containing preparations needs to be encouraged.
Clinical pharmacokinetics of drugs for Alzheimer's disease
Clinical Pharmacokinetics (New Zealand), 1995, 29/2 (110-129)
Pharmacological treatment of patients with Alzheimer's disease is becoming more important, as evidenced by the number of drugs being developed in different countries. It has been shown in the majority of clinical trials that cholinesterase inhibitors, such as tacrine (tetrahydroaminoacridine), are able to induce beneficial effects in cognition and memory. Tacrine, like most of the other oral antidementia agents, is rapidly absorbed from the gastrointestinal tract. It is excreted mainly through the kidney, with a terminal elimination half-life of about 3 hours. Tacrine has nonlinear pharmacokinetics and there are large interindividual differences in pharmacokinetic parameters after oral, intravenous and rectal administration. A positive relationship between cognitive changes and plasma tacrine concentrations has been recently described. Similarly, velnacrine exhibits evidence of nonlinearity in some pharmacokinetic parameters, but renal excretion is a miner route of elimination for this drug. Pharmacokinetic data pertaining to epiastigmine, a third cholinesterase inhibitor, is more limited. However, the drug is rapidly distributed to the tissues after oral administration and readily enters the central nervous system, where it can be expected to effectively inhibit acetylcholinesterase in the brain for a prolonged period. Pharmacokinetic data for the nootropic agents are more limited. However, of the 3 agents reviewed only pramiracetam penetrates the central nervous system (CNS) poorly. Indeed, oxiracetam crosses the blood-brain barrier and persists for longer in the CNS than in the serum. Selegiline (deprenyl), a neuroprotective agent, is readily absorbed from gastrointestinal tract. It is metabolised mainly in the liver; and to a minimal extent in the lung or kidneys. The steady-state concentrations of metabolites in the cerebrospinal fluid (CSF) and serum are very similar, reflecting their easy penetration into the CNS. Idebenone, another neuroprotective agent, likewise is rapidly absorbed and achieves peak concentrations in the brain comparable to those in plasma. Similarly, CSF concentrations of metabolites of ST 200 (acetyl-L-carnitine) parallel those in plasma, suggesting that they easily cross the blood-brain-barrier. Gangliosides (GM1) can be given intramuscularly or subcutaneously, but the latter route of administration provides a concentration 50% higher both in the serum and the ganglioside fraction. However, because of its longer elimination, the intramuscular route is the best form of administration when the brain is the target organ for the treatment. Absorption of nimodipine is quite rapid. The pharmacokinetics of nimodipine during multiple-dose treatment have not been studied extensively; however, the drug does not appear to accumulate during repeated administration of standard doses. Nimodipine has linear pharmacokinetics and is subject to interindividual variability. It is primarily excreted in the urine, but 32% of the dose is excreted in the faeces, possibly as a consequence of biliary excretion. To achieve adequate drug concentrations in the brain, different methods have been devised, both invasive (implantable drug infusion pumps and polymer drug-delivery systems, neural transplantation, etc.) and noninvasive (prodrugs microencapsulated within biocompatible polymers that can protect the drug from degradation, etc.) methods. These methods may provide more effective drug delivery into the CNS, and pharmacokinetic data should be determined when these methods of drug delivery are being assessed in clinical trials.
Anticonvulsant and antiepileptogenic effect of L-deprenyl (selegiline) in the kindling model of epilepsy
Journal of Pharmacology and Experimental Therapeutics (USA), 1995, 274/1 (307-314)
L-Deprenyl (selegiline) is an irreversible inhibitor of monoamine oxidase type B, but also exerts several effects on dopamine and noradrenaline systems independent of monoamine oxidase type B inhibition. Thanks to these properties, L-deprenyl has gained wide acceptance in the therapy of Parkinson's disease by using L-deprenyl both with levodopa and alone. Furthermore, L-deprenyl improves the performance of patients with Alzheimer's disease. Epilepsy, particularly temporal lobe epilepsy with complex-partial seizures, is often associated with disturbances of cognitive function and behavior, and it has been suggested that a drug combining cognition-enhancing and antiepileptic activity would be of benefit in the treatment of epileptic patients. This prompted us to study if L-deprenyl exerts anticonvulsant efficacy in amygdala-kindled rats, i.e., a useful model of complex-partial seizures in humans. In addition to anticonvulsant activity, i.e., effects on already developed seizures, we determined whether L-deprenyl exhibits antiepileptogenic properties, i.e., suppressive effects on development of kindling. In all experiments, behavioral alterations of the rats in response to L-deprenyl were monitored closely. In order to assess the role of active metabolites in the anticonvulsant and behavioral effects of L-deprenyl in the kindling model, the D-enantiomer of deprenyl, which is metabolized to more potent compounds (D-amphetamine and D-methamphetamine) than the L- enantiomer, was used for comparison. In fully kindled rats, L-deprenyl potently increased the threshold for focal afterdischarges. The most marked increase in afterdischarge threshold (up to 250% above control) was seen after a dose of 10 mg/kg, whereas the D-enantiomer was ineffective at this dosage. In contrast to the lack of anticonvulsant activity, D-deprenyl was more potent than L-deprenyl to induce amphetamine-like behavioral adverse effects such as stereotypies, thus indicating that degradation to active metabolites is involved in the behavioral but not anticonvulsant effects of deprenyl. This was substantiated by the observation that increase of dosage of L-deprenyl to 20 or 40 mg/kg induced marked amphetamine-like adverse effects, whereas the anticonvulsant effect was reduced compared to lower doses. Chronic treatment with L-deprenyl during kindling acquisition did not prevent kindling, but significantly retarded the development of some kindling parameters. The present study is the first to demonstrate potent anticonvulsant effects of L-deprenyl. In view of the neuroprotective and cognition-enhancing effects of this drug, L-deprenyl might be of clinical benefit in patients with epilepsy.
Chronic treatment with levodopa and/or selegiline does not affect behavioral recovery induced by fetal ventral mesencephalic grafts in unilaterally 6-hydroxydopamine-lesioned rats
Experimental Neurology (USA), 1994, 130/2 (261-268)
It has been suggested that levodopa (L-dopa), a dopamine precursor used to treat Parkinson's disease, may be toxic to grafted fetal neuroblasts; if so, the use of the monoamine oxidase B inhibitor selegiline might prevent such toxicity. We randomly assigned 30 unilaterally 6-hydroxydopamine-lesioned male Sprague-Dawley rats, whose lesions were verified with low-dose apomorphine-induced rotations, to one of five treatment groups: (i) L-dopa methyl ester (125 mg/kg/day) with benserazide (a peripheral decarboxylase inhibitor; 25 mg/kg/day), (ii) L-dopa methyl ester with benserazide and selegiline (L-deprenyl; 0.5 mg/kg/day), (iii) selegiline only, (iv) and (v) vehicle (ascorbate in normal saline) only. After 2 weeks of twice-daily ip injections, the rats received fetal ventral mesencephalic grafts into the lesioned striatum; one vehicle group received sham grafts. Drug therapy was continued for 2one-half months post grafting. At 1 month after grafting, and every 2 weeks thereafter, the rats were tested using low-dose apomorphine-induced rotation. A 70% decrease in rotations among all grafted groups, relative to the shams, was found. No statistical differences among groups receiving various drug therapies were seen in behavior or in counts or dimensions of tyrosine hydroxylase-positive cells. We therefore conclude that, in the unilaterally lesioned rat model of Parkinson's disease, there is no adverse effect of L-dopa nor any significant effect of selegiline, either alone or coadministered with L-dopa, on behavioral recovery induced by fetal ventral mesencephalic grafts.
What is it that l-deprenyl (selegiline) might do?
There have been many claims that l-deprenyl may have distinct properties in slowing and perhaps even in reversing the progression of Parkinson's disease and other neurodegenerative conditions. This article will consider the paucity of evidence that such is the case in humans and the more detailed results from studies with experimental animals indicating that deprenyl may indeed express such a property. The conflicting data on its mechanism of action are considered, and the concept that it may function to enhance neuronal fitness is advanced as an alternative to the neuroprotection and neurorescue hypotheses. Possible lines of experimental development that would help resolve some of the many unanswered questions regarding l-deprenyl function are outlined.
Slow recovery of human brain MAO B after L-deprenyl (selegeline) withdrawal
L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 220.127.116.11). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L-deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L- Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use.
Deprenyl enhances neurite outgrowth in cultured rat spinal ventral horn neurons
J. NEUROL. SCI. (Netherlands), 1994, 125/1 (11-13)
Deprenyl, a selective monoamine oxidase B inhibitor, is effective in Parkinson's disease, and can slow the cognitive deterioration in Alzheimer's disease. However, it is not known whether this agent has a trophic effect on spinal motor neurons. We have studied neurotrophic effects of deprenyl on spinal motor neurons, using explanted ventral spinal cord culture from 13-day-old rat embryos. Deprenyl-treated cultures significantly enhanced neurite outgrowth with cultures of ventral spinal cord. Our data suggest that deprenyl is one of the candidate for neurotrophic factors on spinal motor neurons in vitro. A possible role for deprenyl in amyotrophic lateral sclerosis remains to be defined.
Effect of L-Deprenyl, its structural analogues and some monoamine oxidase inhibitors on dopamine uptake
NEUROPHARMACOLOGY (United Kingdom), 1994, 33/6 (763-768)
The effect on dopamine uptake by L-deprenyl, its structural analogues and different types of monoamine oxidase (MAO) inhibitors was investigated. Both direct (3H)dopamine uptake into rat striatal slices and binding of a specific dopamine uptake inhibitor (3H)GBR-12935 were used in the present study. L-Deprenyl exhibits a relatively weak dopamine uptake inhibitory effect in vitro, while D-deprenyl possesses a very potent inhibitory effect. The potent effect of D-deprenyl on dopamine uptake may be responsible, at least in part, for its behavioral effects and abuse liability. L-Methamphetamine, a metabolite of L-deprenyl, does not inhibit (3H)GBR-12935 binding but it reduces the retention of (3H)dopamine in striatal tissues, suggesting that it may enhance dopamine release. The MAO-A inhibitors clorgyline and brofaromine also exhibit dopamine uptake inhibitory effects. Irreversible and reversible MAO-B inhibitors, however, such as pargyline, aliphatic N-methylpropargylamines, Ro 19-6327 and MDL-72974A and MAO-A inhibitor moclobemide do not possess any appreciable inhibitory effects on dopamine uptake. Dopamine uptake is probably unrelated to the pharmacological actions of L-deprenyl.
Neuropsychological correlates of L-deprenyl therapy in idiopathic parkinsonism
PROG. NEURO-PSYCHOPHARMACOL. BIOL. PSYCHIATRY (United Kingdom), 1994, 18/1 (115-128)
Monoaminergic neurotransmitter systems are known to play an important role in neuropsychological functions and they are impaired in dementia of DAT and PD. L-deprenyl is a monoamine-enhancing drug which at low doses selectively inhibits MAO-B, an enzyme whose brain activity has been reported to increase in normal aging and neurodegenerative dementing disorders. The authors studied the effects of L-deprenyl, 10 mg/day, on several cognitive domains in idiopathic parkinsonians without dementia. Ten out-patients, treated with levodopa plus DDI, were tested before receiving L-deprenyl and retested six months after they had been treated with the drug. A control group of ten parkinsonian out-patients treated with only levodopa plus DDI, matched for age, educational level, severity and duration of extrapyramidal disease, was tested by the same neuropsychological battery and retested after the comparable time interval. Statistically significant changes were noted in the verbal and visuospatial learning performances of PD patients treated with the combination of L-deprenyl and levodopa.
Monoamine oxidase inhibition by L-deprenyl depends on both sex and route of administration in the rat
The monoamine oxidase B (MAO-B) inhibitor L-deprenyl, widely used to treat Parkinson's disease, has frequently been studied in animal models. We have examined the effects of several variables on activity levels of MAO-A and B in rat brain and liver following chronic (3 wks) treatment with L-deprenyl. Significant effects were observed for sex (females showed lower overall MAO- B activity in the liver), dose (MAO-A and B inhibition increased with dose, with females exhibiting greater sensitivity), route of administration (subcutaneous injection was more efficient than oral dosing), and dosing interval (MAO-B was significantly inhibited when dosing interval was increased to as long as 168 hours). Our results thus indicate that the effectiveness of L-deprenyl in vivo is dependent on several factors and that these must be taken into account in studies involving the benefits or risks of this drug.
Monoamine oxidase (MAO): Relationships to foods, poisons and medicines
BIOG. AMINES (Netherlands), 1993, 9/5-6 (355-365)
Monoamine oxidase has an important role in metabolism of biogenic amines and in disposing of exogenous amines. As information about MAO and its inhibitors has unfolded, effects which are deleterious in some patients have proven therapeutically beneficial in other conditions. The central nervous system effects of an antituberculosis drug, iproniazid, led to its use as an antidepressant and to the discovery of MAO inhibitors. Understanding the role of MAO in noradrenergic neurons explained why orthostatic hypotension occurs in some patients treated with a MAO inhibitor and why MAO inhibitors found use as antihypertensive drugs. Reversal of the tranquilizing effects by MAO inhibitors was explained also. Differences among MAO inhibitors in their potency in precipitating hypertensive crises after ingestion of foods with high tyramine content was explained when subtypes MAO-A and MAO-B were defined. MAO-B inhibitors were not associated with these reactions to tyramine ingestion and were deemed 'safe'. MAO-B was found to be important for the bioactivation of MPTP to MPP+ which causes selective destruction of dopaminergic nigrostriatal neurons. In humans and in non-human primates, this results in a motor deficit almost identical to Parkinson's disease. The high levels of MAO-B in the endothelium of brain blood vessels appear to protect the brain of rats from MPTP toxicity. Trials of a 'safe' MAO-B inhibitor, deprenyl, for potentiating the antiparkinsonian effects of DOPA, suggested that this drug slowed the progression of Parkinson's disease. This observation and the demonstrated role of MAO-B in bioactivation MPTP were the bases for a large multicenter placebo-controlled clinical trial of deprenyl for treatment of early Parkinson's disease. The apparent success of this trial has stimulated searches for newer more effective agents to inhibit MAO-B and to retard the progression of degenerative diseases of the central nervous system.
Deprenyl increases survival of rat foetal nigral neurones in culture
NEUROREPORT (United Kingdom), 1993, 4/10 (1183-1186)
To study the potential of L-deprenyl to rescue dopaminergic neurones from natural death in primary cultures, foetal nigral neurones were prepared from the ventral midbrain of 16 day old rat embryos. L-deprenyl, at final concentrations of 0.1, 1 and 10 microM, or vehicle solution was added to the culture medium. The cells were allowed to survive for 1, 5 and 10 days. They were then fixed and stained for tyrosine hydroxylase (TH) immunohistochemistry, with or without histological staining. After 5 and 10 days, deprenyl at 0.1 microM increases the number of TH-positive profiles in treated cultures when compared with controls but the effect was more evident at 1 and 10 microM. This can be interpreted as increased survival of catecholaminergic neurones. We cannot however rule out the possibility that deprenyl stimulates the expression of TH by other neurones.
Chronic treatment of aged mice with L-deprenyl produces marked striatal MAO-B inhibition but no beneficial effects on survival, motor performance, or nigral lipofuscin accumulation
Male C57BL/6J mice were provided I-deprenyl (at 0, 0.5 mg/kg or 1.0 mg/kg per day) in their drinking water beginning at 18 months of age. A battery of motor tests, including open-field, tightrope, rotorod, inclined screen, runwheel, and rotodrum tests, was administered before treatment and then 6 months later at 24 months of age. A subsample of mice was retested again at 27 months of age. An untreated group of 9-month-old mice served as young controls. Deprenyl treatment reduced striatal MAO-B activity by up to 60% after 6 months on treatment but had no significant effects on striatal catecholamine levels. No significant effects of deprenyl treatment were observed on body weight, fluid intake, or survival of the mice. Chronic deprenyl treatment also did not afect motor performance in any test, except rotodrum performance at 27 months of age, which was significantly better in the 1.0 mg/kg group treated group compared to controls. No age or deprenyl effects were observed with respect to cell counts in the substantia nigra. However, nigral cells containing lipofuscin increased with age, but this neurohistochemical parameter was also unaffected by deprenyl treatment.
Effect of selegiline (deprenyl) on the progression of disability in early Parkinson's disease
ACTA NEUROL. SCAND. SUPPL. (Denmark), 1993, 87/146 (36-42)
In patients with early, otherwise untreated Parkinson's disease, the abilities of selegiline (deprenyl) and tocopherol, antioxidative agents that act through complementary mechanisms, to delay the emergence of more severe disability requiring treatment with levodopa were evaluated. Eight hundred subjects were randomly assigned in a two-by-two factorial design to receive selegiline (10 mg per day), tocopherol (2000 IU per day), selegiline and tocopherol, or placebo and were followed up to determine the frequency of development of disability requiring treatment with levodopa, the primary end point. Interim analysis performed by an independent safety monitoring committee prompted a preliminary comparison of the 401 subjects assigned to tocopherol or placebo with the 399 subjects assigned to selegiline, alone or with tocopherol. During an average of 12 months of follow-up, only 97 subjects who received selegiline reached the end point. In contrast, 176 subjects who did not receive selegiline reached the end point during this period (P < 10-8). Selegiline was also found to be well tolerated and to have a small, but statistically significant symptomatic benefit. These results indicate that use of selegiline (10 mg per day) in patients with early, otherwise untreated Parkinson's disease, delays the emergence of more severe disability.
Parkinson's disease: Past, present, and future
The development of understanding of the pathophysiology and modes of treatment of Parkinson's disease represents one of the triumphs of modern medicine, encompassing astute clinical observation, utilization of basic research findings regarding dopamine to develop the first rational treatment of a degenerative disorder of the central nervous system, and remains at the frontiers of neurologic science. After characterization of the clinical and pathologic features of Parkinson's disease, rational treatment awaited the discovery of the deficit in basal ganglia dopamine. On the basis of this observation and the known biosynthetic pathways for dopamine formation, levodopa was introduced. Use of metabolic inhibitors to prolong and potentiate the effects and avoid the deleterious side effects of levodopa enhanced the efficacy of this neurotransmitter replacement strategy. The discovery and characterization of dopamine receptor subtypes and the availability of selective dopamine agonists provided additional therapeutic approaches, but failed to address the underlying cause of the degenerative process. The discovery and disclosure of the mechanisms of toxicity of the relatively selective nigrostriatal neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), triggered a resurgence of interest in etiological factors which might contribute to the development of parkinsonism and together with the report that inhibition of monoamine oxidase B with deprenyl not only potentiated the effects of levodopa, but appeared to prolong the life of parkinsonian patients, resulted in a large-scale trial of drugs that might arrest the degenerative process. Furthermore, the MPTP primate model of Parkinson's disease has encouraged development of fetal mesencephalic and other tissue implant approaches to reversal of parkinsonism. Although much of this is still in the experimental stages, hopes are high that new and more effective therapies will be developed and that similar techniques might be applicable to a wide variety of neuropsychiatric disorders.
Short-term beneficial effect of deprenyl monotherapy in early Parkinson's disease: A quantitative assessment
It was recently shown that early treatment with deprenyl in patients with Parkinson's disease can delay the need for initiation of levodopa therapy. It was therefore suggested that deprenyl may slow down disease progression. Alternatively, the observed stabilization of clinical disability may merely reflect drug-induced symptomatic benefit. We therefore examined a possible short-term beneficial effect of deprenyl (10 mg/day) as the first and only drug in 15 consecutive de novo patients. Bradykinesia was quantitatively assessed by computerized analysis of isometric force/time curves of biceps and triceps bilaterally and by calculation of simple reaction time (RT) and maximal muscle contraction rate (MMCR). We also measured maximal muscle force, evaluated clinical status by the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, and recorded patients' subjective reports. All tests were carried out before and at 1 and 2 months of treatment. Only one patient reported a beneficial effect. No significant changes in the UPDRS or score or muscle force were observed. In contrast, MMCR and RT improved at 1 month by an average of 12.1 and 7.2%, respectively (p < 0.01, paired t test). This improvement persisted after 2 months of treatment. Study shows that deprenyl monotherapy exerts a short-term beneficial effect in de novo parkinsonian patients. This effect, however, appears to be small, subclinical, and probably cannot account for the observed delay in the need to start levodopa therapy.
Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease
Background and Methods. In 1987 we began a multicenter controlled clinical trial of deprenyl (a monoamine oxidase inhibitor) and tocopherol (a component of vitamin E that traps free radicals) in the treatment of early Parkinson's disease. We randomly assigned 800 patients to one of four treatments: placebo, active tocopherol and deprenyl placebo, active deprenyl and tocopherol placebo, or both active drugs. The primary end point was the onset of disability prompting the clinical decision to begin administering levodopa. An interim analysis showed that deprenyl was beneficial (N Engl J Med 1989;321:1364-71). We report the results of tocopherol treatment after a mean (plus or minusSD) follow-up of 14plus or minus6 months, as well as the follow-up results for deprenyl. Results. There was no beneficial effect of tocopherol or any interaction between tocopherol and deprenyl. The beneficial effects of deprenyl, which occurred largely during the first 12 months of treatment, remained strong and significantly delayed the onset of disability requiring levodopa therapy (hazard ratio, 0.50; 95 percent confidence interval, 0.41 to 0.62; P<0.001). The difference in the estimated median time to the end point was about nine months. The ratings for Parkinson's disease improved during the first three months of deprenyl treatment; the motor performance of deprenyl-treated patients worsened after the treatments were withdrawn. Conclusions. Deprenyl (10 mg per day) but not tocopherol (2000 IU per day) delays the onset of disability associated with early, otherwise untreated Parkinson's disease. The action of deprenyl that accounts for its beneficial effects remains unclear.
Enhanced hydroxyl radical generation by 2'-methyl analog of MPTP: Suppression by clorgyline and deprenyl
Sodium salicylate was infused through a microdialysis probe placed in the striatum of anesthetized rats in order to assay the formation of hydroxyl radical (.OH) in the extracellular fluid in vivo. In addition to causing sustained dopamine release, intrastriatal infusion of the 2'-methyl analog of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2'CH3-MPTP) increased the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA), the nonenzymatic .OH adduct of salicylate in the brain dialysate. Inhibition of monoamine oxidase (MAO) by clorgyline and deprenyl completely blocked the formation of 2,3-DHBA and the sustained dopamine overflow induced by 2'-CH3-MPTP. The results indicate that the enhanced formation of cytotoxic .OH by 2'-CH3-MPTP is suppressed by MAO inhibitors. These data support the hypothesis that the protective effect of MAO inhibitors on the neurotoxicity induced by MPTP analogues may be due not only to the inhibition of MPTP metabolism by MAO but also the blockade of the formation of .OH free radicals. An enhanced generation of cytotoxic .OH free radicals in the striatum which in turn leads to oxidant damage may be relevant to the development of parkinsonism- like changes in animals produced by MPTP analogues.
Neurotoxicity of levodopa on catecholamine-rich neurons
The human neuroblastoma cells NB69 are a catecholamine-rich cell line with pharmacological properties similar to dopamine neurons. This cell line was used to study the neurotoxicity of levodopa on catecholamine neurons. Levodopa, at 50 x 10-6 M or higher concentrations, produced a dose- and time-dependent reduction in the number of live cells, (3H)thymidine uptake, levels of protein and DNA, and an enhancement of the quinone formation. This is a specific effect of levodopa since it did not happen in NB69 cells incubated with equimolar concentrations of leucine and tryptophan. Treatment with deprenyl, an inhibitor of monoamine oxidase type B, partially prevented levodopa neurotoxicity, suggesting that the mechanism of toxicity was, at least in part, related to an increase in the metabolism of dopamine catalyzed by monoamine oxidase.
A review of the pharmacology of selegiline
ACTA NEUROL. SCAND. SUPPL. (Denmark), 1991, 84/136 (44-59)
Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity of MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article
Parkinson's disease: An epidemiologic method for distinguishing between symptomatic and neuroprotective treatments
Recent studies have suggested that deprenyl may exert a neuroprotective influence and thus retard progression of Parkinson's disease (PD). On the other hand, the data do not disprove that deprenyl is primarily another form of symptomatic therapy like levodopa. Longitudinal Gompertzian analysis demonstrates the absence of beneficial alteration of intrinsic or environmental influences on the epidemiology of PD mortality after the introduction of levodopa. Moreover, this method demonstrates the basis for the enhanced survival in PD that resulted from the efficacy of levodopa as symptomatic therapy. If deprenyl becomes standard therapy in PD and exerts a beneficial (neuroprotective) influence on intrinsic and environmental pathogenic mechanisms, this will become evident by a decrease in the PD mortality rate in the United States in men at age 73.4 years and in women at age 79.1 years. The ability to accurately assess the overall impact of new therapies on the general population is increasingly important in an era of upward spiraling health care costs. Longitudinal Gompertzian analysis is a simple method of detecting and distinguishing between symptomatic (competitive) and protective (intrinsic and environmental) influences on disease mortality at the population level after the introduction of new therapies.
L-Deprenyl, levodopa pharmacokinetics, and response fluctuations in Parkinson's disease
Six patients with Parkinson's disease (PD) and therapeutic response fluctuations (RF) on levodopa treatment participated in an open-label trial of L-deprenyl (Eldepryl) in conjunction with Sinemet. Deprenyl (10 mg/day) allowed a slight but not statistically significant 22% reduction of total daily levodopa intake after 4 weeks of treatment, with a significant but unsustained reduction in the number of daily 'off' periods and an increase in the portion of waking day spent 'on'. Pharmacokinetic studies revealed no effect of deprenyl on the plasma levodopa concentration vs. time curve, or the coefficient of variation (C.V.) of plasma levodopa levels measured over an 8-h period. Plasma DOPAC levels were unaffected, suggesting that the majority of peripheral DOPAC is generated by action of MAO-A. For most patients, benefit was not maintained. Two patients have continued taking the drug, and both have enjoyed significant reductions in total levodopa dose. Both have mild end-of-dose failure and little dyskinesia. Since no changes in peripheral pharmacokinetics of levodopa could be demonstrated, any therapeutic action of deprenyl in PD would appear to be due to prolongation of dopaminergic activity within the CNS.
New approaches in the use of selegiline for the treatment of Parkinson's disease
ACTA NEUROL. SCAND. SUPPL. (Denmark), 1989, 80/126 (139-145)
Selegiline hydrochloride (deprenyl) is a safe, useful adjuvant therapy in patients with Parkinson's disease treated with L-dopa. The optimum time for its introduction into the treatment regimen of a patient remains controversial. A multi-centre long-term study being conducted by the Parkinson's Disease Research Group of the United Kingdom to attempt to answer whether selegiline improves the natural history of Parkinson's disease is discussed. In a separate study we have been unable to demonstrate that higher doses of selegiline (up to 40 mg a day) produce additional therapeutic benefit above the conventional dose of 10 mg a day in levodopa-treated patients with motor fluctuations. Preliminary data from a neuropsychological study is also presented which suggests that selegiline may have beneficial effects on the speed of psychomotor responses supporting the anecdotal clinical observations of increased mental energy and alacrity.
Two weeks of treatment with deprenyl (selegiline) does not prolong L-dopa effect in parkinsonian patients: A double-blind cross-over placebo-controlled trial
We investigated the influence of 2 weeks of treatment with deprenyl on the acute effect of a single dose of 200 mg of L-dopa in a double-blind cross-over placebo-controlled trial in 16 parkinsonian patients with wearing-off phenomena. Deprenyl induced no significant benefite in the duration or the maximal improvement of L-dopa's effect. Moreover, deprenyl treatment did not improve the patient's motor status.
Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease
Deprenyl, a selective inhibitor of monoamine oxidase, type B, which is free of the 'tyramine effect', may ameliorate symptom fluctuations in advanced Parkinson's disease (PD). We randomized 96 patients with marked symptom fluctuations at three centers to receive either deprenyl 5 mg b.i.d. or placebo in parallel fashion in addition to a previously optimized levodopa/carbidopa (Sinemet) regimen. Disability was recorded hourly at home by patients 3 days weekly during the 2-week baseline and the 6-week treatment period. Disability during the 'on' state was assessed each week by examination. Mean hourly self-assessment of gait improved in 28 of 50 patients (56%) receiving deprenyl (mean degree of improvement 0.25 points on a 0-2 scale) and in 14 of 46 (30.4%) taking placebo (mean 0.15). Mean hourly overall symptom control improved in 29 (58%) taking deprenyl (mean 0.34) and in 12 (26.1%) taking placebo (mean 0.15) (p < 0.01 for each parameter). No significant improvement occurred in the objective quality of the 'on' state with deprenyl. Mean daily Sinemet dosage decreases were 17% in the deprenyl group and 7% in the placebo group. Adverse effects included nausea, light-headedness, dyskinesias, and hallucinations, all of which abated after the Sinemet dose was reduced. We conclude that deprenyl is of moderate benefit in a majority of patients with symptom fluctuations complicating PD and is generally well tolerated.
Selegiline (1-deprenyl) and low-dose levodopa treatment of Parkinson's disease. A double-blind crossover trial
Fifteen parkinsonian patients previously untreated with levodopa were treated with daily doses of 200 mg Madopar and randomized to addition of 10 mg selegiline (1-deprenyl) in a double-blind, placebocontrolled, crossover trial. According to the patients own evaluations 6 reported additional therapeutic effect from selegiline to Madopar; 2 reported possible additional effect, whereas a further 6 reported no improvement; 1 did not complete the trial. Statistically significant positive therapeutic effect of selegiline could not be found on Webster's rating sclare or on a sensimotoric test designed for parkinsonian disabilities. Side effects of selegiline were minimal. It is concluded that selegiline may be of some value in addition to levodopa in early treatment of parkinsonian patients, but positive therapeutic effect has to be tested individually. Even in these patients the additional therapeutic effect of selegiline to levodopa seems to be quantitatively small.
Neurochemical insights into monoamine oxidase inhibitors, with special reference to deprenyl (selegiline)
Monoamine oxidase (MAO) is distributed in neurons and nonneuronal tissue in the human central nervous system. It occurs there as MAO type A and MAO type B. It is not, however, established where both types are located intra- and/or extra-neuronally. Recently, the use of selective MAO-B blockers has shown beneficial effects in the treatment of Parkinson's disease (PD). Knowledge about the locus of action of MAO inhibitors is therefore of great importance. Our findings indicate that MAO-B inhibitors like deprenyl act by blocking neuronal and extra-neuronal MAO-B. This demonstrates that in the early stages of PD the action of deprenyl improves dopamine neurotransmission and hormonal action, whereas in the advanced stages of the disease, when there is progressive loss of dopaminergic neurons accompanied by gliosis, the drug seems to exert beneficial effects via the hormonal route.
Problems associated with long-term levodopa treatment of Parkinson's disease
Levodopa treatment improves significantly not only the parkinsonian disability but also the most morality rate. However, during long-term levodopa treatment the therapeutic benefit gradually declines. Furthermore, most cognitive skills improve initially, but long-term levodopa treatment is associated with declining intellectual capacity and dementia. In patients on long-term levodopa treatment there seems to be a low threshold for certain clinical side-effects, especially postural hypotension, psychiatric disturbances and various types of fluctations in disability. Low age at onset of Parkinson's disease, and at the commencement of levodopa therapy, the duration of levodopa treatment and a high dose of levodopa seem to be significant risk factors for the development of response fluctuations, but not the pretreatment duration of parkinson's disease nor disability of the patients. A readjustment of the levodopa dosage, and as an adjuvant drug treatment deprenyl, a specific inhibitor of MAO type B, or a direct-acting dopamine agonist may prove helpful in the management of fluctuation in disability. It is important, moreover, to try to prevent these phenomena by taking into account the predictive risk factors of response fluctuations in the treatment strategy of Parkinson's disease.
Overview of present day treatment of Parkinson's disease
In the light of present day knowledge, augmenting striatal dopaminergic activity is the most effective means for controlling the symptoms of parkinsonism. This is best accomplished by the administration of levodopa with a peripheral decarboxylase inhibitor. However, limitations in its benefits develop after long-term administration in a substantial number of patients. In an attempt to overcome these a number of pharmacological agents acting on striatal dopaminergic mechanisms have undergone clinical trial. Of those tried Deprenyl, an MAO-B inhibitor, given with levodopa and carbidopa has shown the most promise. Preliminary results in 35 patients indicate that it is useful in diminishing the incidence of 'on-off' phenomena - one of the most limiting reactions to levodopa - as well as enabling some patients to recoup their loss of therapeutic benefits. Though far from resolving all of the therapeutic difficulties encountered with prolonged use of levodopa, it appears to be a valuable adjunctive agent for the long-term problem patient.
The possible mechanisms of action of (-)deprenyl in Parkinson's disease
Deprenyl, a selective inhibitor of MAO-B, was found to be 60 times less potent in inhibiting intestinal MAO in the rat than clorgyline, the selective inhibitor of MAO-A. This is one of the reasons why (-)deprenyl is safe with respect to the hazards involved in combination with a variety of foods and drugs and its administration is not contraindicated in parkinsonian patients. (-)Deprenyl is a potent inhibitor of the uptake of amines into the nerve endings of catecholaminergic neurons. With the aid of N-methyl-N-propargyl-/1-indenyl/-ammonium. HC1 (J-508), a newly developed highly potent MAO inhibitor, devoid of uptake-inhibitory and releasing effects, a tyramine-uptake model for testing the effects of MAO inhibitors on uptake, using different isolated noradrenergic organs (cat nictitating membrane, perfused ear artery and strip of pulmonal artery of the rabbit, rat vas deferens), was introduced. In contrast to the nonselective and A-selective MAO inhibitors, as well as to the newly developed selective MAO-B inhibitors (J-508, U-1424), (-)deprenyl was unique in inhibiting tyramine-uptake in all the tests. (-)Deprenyl was found to inhibit the release of acetylcholine in isolated striatal slices of the rat, owing to its blocking effect on the uptake of dopamine. N-methyl-N-propargyl-/2-furyl-1-methyl/-ethylammonium (U-1424), a new selective inhibitor of MAO-B devoid of uptake-inhibitory effect did not significantly influence the ouabain induced striatal acetylcholine release. The release of dopamine from the synaptosomes of the rat striatum was found to be enhanced by clorgyline and tyramine and only slightly influenced by (-)deprenyl. The advantage of the combination of levodopa and (-)deprenyl in the treatment of Parkinson's disease was summarized as follows. Levodopa exerts its therapeutic effect by stimulating the postsynaptic dopaminergic receptors of the caudate interneurons, thereby it suppresses, by also stimulating the presynaptic 'autoreceptors', the activity of nigrostriatal dopaminergic neurons. (-)Deprenyl acts as a activator of the nigrostriatal dopaminergic neurons. As these neurons contain MAO-B in man, (-)deprenyl increases the dopamine content of the nerve terminals and as a potent inhibitor of the re-uptake of dopamine it intensifies the physiological control on the cholinergic caudate neurons.


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A spokesman for the Secretary of State's office says voter turnout "seems to be steady."
Spokesman Jared Thomas would not provide any estimates on how many people are expected to cast ballots before polls close at 7 p.m., or where turnout was heaviest. According to the agency, Georgia has 5.8 million registered voters.
Thomas said the Secretary of State's office is fielding calls about problems, though he would not provide specifics. "Every election day we get calls," he said. "We do have a team spread out across the state to physically investigate."
Thomas says the agency has set up a large call center to field calls at 404-656-2871.
July 31st, 2012
2:17 pm
Polls today didn't seem to crowded here in woodstock. My only gripe is that atleast at First Baptist Woodstock it was a MESS. They are having a huge conference at the same time so it took me a solid 5 minutes of driving around to figure out what building it was in and then i had to park FAR away. I'm physically capable of walking 1/4 mile from my car to vote (though i didn't appreciate it in the rain)but there was an older man with a cane behind me and he certainly WAS NOT. In the future, they need to reserve a row of parking spaces for voters coming in and out.
July 31st, 2012
3:47 pm
Well, the vote today is another I.Q. Test for those in the metro. Begin the process of alleveating the gridlock or postpone the process and watch commute times grow and grow.
I don't know how much people value time with their families or how seriously they take the health risks of stress related to gridlock traffic and the inhaling of exhaust fumes, so we'll see if the good folks of the metro pass the test.
But, of course, this is the age of political gridlock where politicians and voters alike are intent on being contrary and oppositional. . . . and stupid!
Sit in traffic. . . .waste $3.29 a gallon gas. . . .miss time with your wife and familly for one dang percent. Now brother, that's a dumbarse response to a serious problem if you ask me.
July 31st, 2012
5:31 pm
Or you could just walk on water

subset: commoncrawl


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There are plenty of mysteries within hot rodding, but none so vast and bewildering as car-show judging. In roadsterlandia, there is no event so steeped in tradition as the Grand National Roadster Show (GNRS), where the coveted "America's Most Beautiful Roadster" (AMBR) crown is the Holy Grail. And just as the Grail is mysterious, so, too, is the process by which the AMBR is judged. For 2013, HOT ROD was allowed into the inner sanctum of the show's secret judging to witness how the honor is conferred, pledging not to reveal the parties involved and what methods of provocation were involved.
GNRS history dates back to 1949 in Oakland, California's Exposition Building, where Al and Mary Slonaker assembled an international car show. Though primarily made up of foreign makes, sharing the floor were a dozen or so hot rods. By the end of the show, it was apparent that spectator interest mostly centered on the rods. Score one for the home team. Later that year, the newly christened National Roadster Show was being touted in the Oct. 1949 HOT ROD, and a two-page, editorial-looking advertisement for the show ran in the Jan. 1950 issue. The show was a success, according to HOT ROD's Mar. 1950 coverage and the almost 30,000 spectators who paid to see it. Bill Niekamp's track-nose 1929 Ford won the first AMBR title and was featured in the same issue.
Through the years as entries grew, new award classifications were created, dividing the field into groups of similar types of cars and making the judging more intricate. In 1958, Richard Peters' Ala Kart hit the floor and won the AMBR title for the first of two consecutive times; its level of detail, design, and finish changed the game, pushing out homebuilt, street-driven roadsters and creating more points-driven, professionally built contenders. The trend continued in the 1960s, with roadsters becoming more complex and imaginative. Fiberglass and aluminum construction allowed builders to create ever more exotic bodies that at times bordered on excessive, but creativity has no bounds, and the spectators loved it. Points were accumulated in five categories: show appeal (craftsmanship and how the car was displayed), safety (roadworthiness), condition (overall paint, engine compartment, interior, and chassis), workmanship (fit and finish), and innovation (design, ideas, and component selection).
By 1972, Al Slonaker's failing health caused him to sell the show to Harold "Baggy" Bagdasarian, a fellow car-show promoter from nearby Sacramento. He had a partnership with customizer Darryl Starbird—and later with Don Tognotti, who bought out Starbird's share—and the AMBR winner was determined by them and them alone. They would huddle with confidants throughout the 10 days of the show, but ultimately they made the pick. How the choice was made has always been somewhat of a mystery, though looking through the past AMBR list, it's hard to fault the winners. But, as the show progressed, the judging became far more like a Detroit-type show, so a little background on that is necessary.
The so-called Detroit style of judging dates back to 1961, when famed car-show promoter Bob Larivee developed the standards for his new International Championship Auto Shows circuit. In 1963, he used them for his International Show Car Association, and they were adopted the same year by the Detroit Autorama show (which dates back to 1953 and which Larivee's companies have operated for decades). Larivee devised a method of judging that used a point system based on three criteria, starting with the most important: design, engineering, then fit and finish. Over the years, the criteria have flipped, with fit and finish being the main focus of show judging. That's understandable considering that how a car or component is finished and assembled is the easiest measure to quantify. Design, on the other hand, isn't. Can you define in words why a 1965 Mustang is considered one of the best-designed cars of the era while a 1965 Fairlane sedan isn't? Same builder, same year, but a completely different design expression.
So the Detroit awards came to honor cars with the highest level of fit and finish for individual components combined with how expertly they are assembled. This method of judging gained momentum as Larivee expanded his car show empire into other markets, making it the easiest and best method in the country, and no alternative guidelines were ever deemed necessary. Though different in nature, the Detroit Autorama and GNRS continue to be the most significant shows in the country today.
In the same time frame, the GNRS—not being part of Larivee's domain—always had its own method for picking winners. It had the reputation of dealing more in the sum total of the components, with an emphasis on how pleasingly they jelled as a car—what some would say is more of an old school or traditional approach. Judging gave ample consideration to the ever-narrowing fit and finish category, but the contender still had to have "the look."
In the 1970s, as disco waned, Detroit-type judging gained at the GNRS. First came highly modified roadsters, then roadster bodies created from scratch, aiming to score extra points in the degree of difficulty category. Interestingly, the first such roadster rendered almost unrecognizable for the sheer amount of modifications came from HOT ROD's own Tex Smith and his XR-6 AMBR-winning entry in 1963. A project chronicled within HOT ROD, it was based on a 1927 T roadster body, but the Steve Swaja design was barely identifiable as such. The trend of non-OE-appearing bodies has ebbed and flowed throughout the years, hitting its peak over the last 20 years. Bodies were being created with an emphasis on being unpredictable and with less concern for how "beautiful" the car actually was. Or wasn't. But the award was still for the "most beautiful roadster." And just like in the Detroit show, you scored extra points for your display—even if the radiant roadster twirling on the display was a polished turd.
Ultimately, if the paint was puckered around chassis bolts from being too fresh during assembly, or you missed wiping a bit of rubbing compound off of the hidden portion of a component seen only by a judge with a pocket mirror and flashlight, it could mean the difference between victory and defeat. Points for perfection trumped stance, and it didn't matter if body lines were eliminated to the point that the car took on the look of a rolling egg. The beauty of the roadster became secondary—or tertiary.
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The coyote is a medium-sized member of the dog family that includes wolves and foxes. With its pointed ears, slender muzzle, and drooping bushy tail, the coyote often resembles a German shepherd or collie. Coyotes are usually a grayish brown with reddish tinges behind the ears and around the face but coloration can vary from a silver-gray to black. The tail usually has a black tip. Eyes are yellow, rather than brown like many domestic dogs. Most adults weigh between 25-35 pounds, with a few larger individuals weighing up to 42 pounds.
Current Distribution: Coyotes are native to North America and currently occur throughout most of the continent. In addition to occurring in natural areas, coyotes are also found in a range of human-populated areas, including rural farms, suburbs and cities.
Historical Distribution: Although coyotes have a current distribution that spans across most of North and Central America, their historical range prior to 1700 was restricted to the prairies and desert areas of Mexico and central North America. Since the 1700's, coyotes have dramatically expanded their range across North America and now are found in an increasing number of cities in the United States and Canada. Coyotes were initially present at the founding of the Chicago site in the 18th century but disappeared during most of the 19th and 20th centuries. This recent expansion in distribution is unique as other large carnivore populations, such as wolves and bears, were extirpated from many portions of the United States, leading to the absence of large carnivores in most urban landscapes. The emergence of coyotes in urban systems can have important ecological implications, such as through their role as an apex carnivore and subsequent effects on prey.
Natural Habitat: Although coyotes can use any habitat, they typically prefer open habitats, such as prairie and desert. In addition to occurring in natural areas, coyotes are also found in a range of human-populated areas, including rural farms, suburbs and cities. Current research, including the Cook County Urban Coyote Project, is dedicated to understanding coyote habitat selection within natural and urban areas, in order to understand if coyotes benefit from human-associated developments (i.e. are synanthropic species) or if they are merely occurring in human-populated areas due to increased sprawl and fragmentation.
Urban Habitat: In urban areas, coyotes prefer wooded patches and shrubbery, which provides shelter to hide from people. Our research has found that within the urban matrix, coyotes will avoid residential, commercial, and industrial areas but will use any remaining habitat fragments, such as those found in parks and golf courses.
Some people believe that urban coyotes primarily eat garbage and pets. Although coyotes are predators, they are also opportunistic feeders and shift their diets to take advantage of the most available prey. Coyotes are generally scavengers and predators of small prey but can shift to large prey occasionally. Researcher Paul Morey analyzed scat (fecal matter) contents at different locations within our study area. After investigating 1,429 scats, he found that diet items varied across space and time, which reflects the flexible food habits of coyotes.
The most common food items were small rodents (42%), fruit (23%), deer (22%), and rabbit (18%). (Scats often have more than one diet item; therefore, frequencies do not necessarily add up to 100%). Apparently, the majority of coyotes in our study area do not, in fact, rely on pets or garbage for their diets. Visit our new research page for information on a novel scientific procedure we are now using to further investigate diets.
Mating and Gestation: In most years, coyotes typically mate in February. Only the alpha pair in a pack will mate and subordinates will usually help raise the young. Coyotes appear to be strongly monogamous and so far, we have only seen bonds between alpha pairs broken upon the death of one of the pair. Therefore, a number of pairs have maintained bonds for multiple years (read the story about coyotes 1 and 115). In April, after a 62 to 65-day gestation period, the female will begin looking for existing dens or dig one herself.
The Den: Pup season is the only time coyotes will voluntarily use a den; otherwise, coyotes usually sleep above ground in the open or in cover. Dens may consist of a hollowed-out tree stump, rock outcrop, or existing burrow made by raccoons, skunks or other medium-sized carnivores. Coyotes will also build dens from scratch by digging a hole. They usually prefer some protective cover at the den, such as bushes or trees, and some type of slope for drainage. It is not uncommon for mothers to move their young from den to den to keep them protected or to re-use the same den in multiple years. Some coyotes select secluded areas for their dens, whereas others in more urbanized areas have less selection and may use dens near buildings or roads or even in parking lots.
The Litter: Litter sizes often range from four to seven pups, though some litters can be bigger and some smaller. The largest litter we found held 11 pups in one den. Coyotes have the ability to adjust their litter sizes based on food abundance and population density. While it is difficult for us to get reliable estimates of litter sizes in urban areas, our best estimate suggests that litter sizes are larger than average, indicating an abundant food supply. Pups stay in the den for about six weeks and then begin traveling short distances with adults. By the end of summer, pups are spending some time away from parents and attempting to hunt on their own or with siblings.
In captivity, coyotes can live 13 to 15 years but in the wild, most die before they reach three years of age. The oldest confirmed coyote so far has been an eleven-year-old alpha female, Big Mama. In our study, we found that coyotes in the Chicago area generally have a 60% chance of surviving one year. Many pups die from a variety of causes during their first few ventures away from their homes. Survival is fairly consistent among seasons, even during the winter. Survival rates of adult coyotes in the Chicago metropolitan area are similar to estimates for coyotes living in rural Illinois. However, the survival rates of juvenile coyotes in Cook County are approximately five times higher than the 13% survival rate reported for rural juvenile coyotes. Rural Illinois is dominated by row-crop agriculture and hunting of coyotes occurs year-round without any regulatory constraints, such as bag limits. Given this intensive hunting and trapping pressure found in rural Illinois, coyote vulnerability is magnified during parts of the year in which substantial cover/shelter (e.g. agricultural crops) is lost due to crop harvesting. Large metropolitan areas, on the other hand, provide more year-round protection since there is no seasonal loss of habitat via crop harvesting and a lack of intensive hunting pressure.
By far the most frequent cause of death for urban coyotes has been collisions with vehicles (50 to 70% of deaths each year). Given the large areas traversed by coyotes and the number of roads regularly crossed during their activities, this is not surprising. Some of the roads crossed by coyotes in our study have average traffic volumes of more than 100,000 vehicles every 24 hours. Other causes of death have included shootings, malnutrition, and disease (please visit our page on disease). Few coyotes make it through their full potential life spans, unlike Big Mama who died of natural causes despite existing in a heavily urbanized area.
Coyotes typically have a highly organized social system, even in urban areas. This consists of packs, or groups, of coyotes that defend territories from other coyotes. In Cook County, we have identified coyotes that live in packs as well as coyotes that live and travel alone (solitary coyotes). Packs are usually composed of an alpha male and female pair, and a few other coyotes. Genetic analysis of coyotes has revealed that nearly all pack mates are close relatives, except the alpha male and female are not closely related to each other.
Defending Territories: Our observations (during tracking, helicopter flights, and trapping) have revealed that the coyotes in our study maintain their territories as groups. Group size in protected habitats is typically five to six adults in addition to pups born that year. Territories have very little overlap, so the coyotes defend these areas from other groups. In rural areas, especially where hunting and trapping are common, the group may only consist of the alpha pair and the pups.
Hunting & Travel: Although coyotes live in family groups, they usually travel and hunt alone or in loose pairs. In this way they are different from wolves, which sometimes leads to the impression that coyotes do not form packs since they are usually seen alone.
Solitary Coyotes: In addition to resident packs, the urban population also consists of solitary coyotes that have left packs and are looking to join groups or create their own territories. Between one-third and one-half of the coyotes we study each year are solitary animals. These solitary coyotes can be either males or females and are usually young coyotes (six months to two years old), but can also be older individuals who have left packs.
If a coyote is seen running across a field, it is impossible to know if it is a solitary coyote or a member of a pack from that sighting. Solitary coyotes travel over large areas, up to 60 square miles covering many different municipalities; some coyotes may disperse to different states. These animals must travel between, and through, resident coyote territories.


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Alcoa got a raw deal
Investors who dubbed the aluminum giant's first-quarter earnings 'disappointing' didn't do any real homework.
It was like an orchestrated smear campaign -- one of the most effective I have ever seen. I am talking about the across-the-board Web-radio-TV-print campaign to use the word "disappointing" in front of Alcoa's (AA) earnings report.
I have followed Alcoa through thick and thin for many, many years, through several CEOs and many cycles. I have seen the company's fortunes wax and wane and the business get hammered beyond recognition and the business throw off amounts of cash flow that were obscene.
Every time I always had the same feeling: When is this company going to get a CEO with a worldwide vision who can take advantage of all of the fantastic growth markets for aluminum, lower its costs of production, take share and expand to where the real demand is, the emerging markets?
Finally, Alcoa has that CEO, Klaus Kleinfeld. Finally, the company has the vision, has the growth where it should be and is lowering costs and taking share. Finally, it reports a really good quarter and raises the growth rate for its end markets and therefore for itself. Finally, it is delivering what it said it would do -- or a little bit better -- on the way to opening some gigantic new plants that will be the lowest-cost smelters on earth.
And now it's "disappointing"? Now it's not what people want? Now people don't like the growth and the end markets and the projections? Now people doubt the management team?
I have to tell you, this one was a travesty, just a travesty, as anyone who reads our bulletins for Action Alerts PLUS knows.
I thought maybe I misheard something at first as I listened to it on the way home. So I then read it with the transcript. Then, when I was finished, I read the transcript again vs. what I was looking for. It only made me like the story more than the first time I heard it.
As someone who had every reason to be disappointed if the company had screwed up -- because I had hated Alcoa and its management team for several decades before recently declaring that Alcoa is finally ready to turn -- I was aghast that this quarter got smeared with a snap-judgment "disappointing" label that then infected trading to the point that there was no question the quarter was a loser.
Now, mind you, in any given quarter there are a ton of line items that both matter and could disappoint. I wanted to hear that input costs excluding oil were coming down. I wanted to hear that expansions were on time. I wanted to hear that autos, cans, construction, turbines, trucks and China were all up and going higher. I GOT EVERY ONE OF THOSE! EVERY ONE! Those were the important lines, for heaven's sake.
The commentaries on China, natural gas, autos and natural-gas turbines were actually better than I thought -- "anti-disappointing." The trucking commentary was amazing. The aerospace commentary was fabulous -- especially important, given the recent closing of the Transdigm fastener business.
Individual commentary for individual markets was even better: Higher oil prices mean more new planes that are built with fuel-efficient aluminum; worries about the environment fueling a return to more recyclable aluminum cans; CAFE standards helping auto production; the chaos of nuclear power driving increased demand for gas turbines, augmented by the low cost of natural gas. Every bullet point was hit. And improved upon.
So I kept searching and searching. Yes, there was a cash flow number that was negative that I didn't like, but it was a past-tense number that won't be the case going forward. There were some small currency issues, but I mean really small. Brent crude hurt a bit, but don't look now at what's happening with that fuel.
All of these together, if you add them all up, don't even offset the good news in Chinese growth. All of them together!
Plus, anyone who has followed Alcoa in China knows that Alcoa is the solution to one of the country's biggest and most vexing problems -- smelting pollution. If China wanted to clean its air substantially, it could just import from Alcoa. But if you read between the lines, you can see that politically it would be very difficult to close all the high-cost, dirty, offending smelters without creating a level of unemployment that the government doesn't find tolerable. My betting, though, is it will have no choice and the game will go to Alcoa.
Sure, someone can say that the supply-demand imbalances aren't perfect. To quote Kleinfeld: "The picture here basically hasn't changed. I mean, you see on the China side a slight deficit of 700,000 tons, and you see on the Western side a slight surplus of 945,000 tons. So that's pretty much unchanged and pretty much in balance." I would love to have seen that reversed. But if you look at individual premiums paid in individual markets, there are imbalances galore that are positively accruing for Alcoa.
In truth, the only thing that was disappointing was that Kleinfeld left out the iPad. He left out how much business Alcoa is doing in tablets, as Steve Jobs loves the way aluminum feels on the back of the tablet, and Alcoa has the order. But we all know how much Jobs hates letting anyone to talk about orders to Apple (AAPL), so maybe the same gag rule applies to Kleinfeld.
So I come back to motivation. Was it urban legend that determined how "bad" Alcoa was? Did shorts "influence" the commentary?
But here's what I think happened. People didn't do jack for homework. They didn't examine it. They didn't go line by line. They didn't even know what they were looking for. They affixed "disappointing" to the headline, and it stayed.
Conference calls aren't like baseball games. You don't have a winner and a loser. But they aren't plays or movies, either, where it is nothing but subjectivity. Conference calls are attempts by management to talk about what goals were met and what goals weren't and to give a vision of the future.
In that sense, this management delivered a victory, not a defeat. You could have just as easily affixed "better than expected" to this quarter. And I certainly would have done that if I were writing the headline.
Then why did the stock go down?
I can give you several answers. One, it happened to report on a day when Goldman Sachs (GS) pricked the commodity bubble, although there has not been an aluminum bubble. Two, the stock had been one of the best performers in the Dow Jones Industrial Average ($INDU), up 16% going into the quarter, and we were in the midst of a correction. Three, there is a growing consensus -- NOT BUTTRESSED BY ALCOA -- that the world's economic engine is slowing down. And, finally, Alcoa has disappointed before, and people wanted to see an amazing quarter, with earnings maybe 3, 4 or 5 cents better -- something that was never really possible this quarter, given all of the moving parts and new plants that are opening.
Oh, and the "disappointing" revenues? What a joke! Do you think this is Cisco (CSCO) or something, with dozens of revenue models out there? Alcoa failed to beat a straw man of revenues.
You know what should have happened? Alcoa should have been bought, not sold. It should have been up, not down.
And there's not only nothing wrong here, but if I could wave a wand and come up with a new term, I would say that Alcoa "appointed," which is the polar opposite of "disappointed." Owing to the homework I do, and the work I have done on so many quarters, I can tell you that "appointing" would have been the better prefix to the earnings Alcoa announced Monday night.
At the time of publication, Cramer was long Alcoa.
Jim Cramer is co-founder and chairman of TheStreet. He contributes daily market commentary for TheStreet's sites and serves as an adviser to the company's CEO.
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An important note for all prospective UIW students:
Beginning October 1, 2013, Texas law requires all students under the age of 22 to provide proof of immunization against bacterial meningitis in the preceding five years prior to registering for classes. The law, which applies to students at all higher education institutions, both public and private, is meant to protect the health and well being of all on campus. UIW's Health Services offers vaccinations against bacterial meningitis; more information may be found on the Health Services web site. Vaccinations may also be obtained from local clinics, or your primary care physician.
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A clothing optional Kehena Black Sand Beach, located across the street. Swim with the Dolphins and watch the whales in the winter. NO LIFE GUARD OR BATHROOM FACILITIES. Across our street and Only 200 ft. away down the cliff from the Bali House and Cottage!
This is a place where dozens of large pools in the lava hold a plethora of fish and coral, protected from the surf by an old lava flow. Abundant fresh water carries the nutrients that create a rich reef environment where thousands of juvenile fish can be found using these sheltered waters. The results are much like a series of large aquariums, open to anyone with a mask and snorkel to enjoy. The calm waters are accessible to swimmers of a wide range of skill levels, a friendly introduction to a reef environment.
Just a 15 minute drive from the Bali House and Cottage. Great snorkeling area.
This spring fed pool is part natural and part man-made. It is also volcanically heated to a balmy 90 degrees! The bottom of the pool is sand and mud and has a slight sulfur smell. The water is brackish but very clear and fish often swim along with the visitors. A small inlet separates the pool from the ocean and allows the fish access to the pool. The area is surrounded by palm trees, green grass and the Pacific Ocean making it a very beautiful and uncrowded tropical retreat.
Only 12 minutes away from the Bali House and Cottage. Geo-thermally heated spring fed pond.
The path to the remote new Kaimu beach, goes from Kalapana through the lava field and is about a 1/3 mile. The active Kilauea Volcano emissions are visible from the path in the distance. It has a treacherous surf, too dangerous to swim, but beautiful to see.
Only 5 minutes away from Bali House and Cottage.
(not advisable to swim)
This beach park is known to locals as Pohioki and is located at the edge of Pohoiki Bay, in the Puna district of the Big Island. Oceanfront park facilities include rest rooms and picnic areas. It's a good place for an afternoon nap but can be dangerous for swimming. Strong waves make this a popular place for local surfers, but can make it rough for swimmers. There is a boat launch ramp and a man made break water.
Only a 15 Minute drive form the Bali House and Cottage to a great surfing, swimming and sunbathing and fishing.
Green Lake is a very unique place to visit. True to its name, it's a deep green lake inside of an old volcano crater, surrounded by bamboo and other trees to jump off of into the seemingly endless lake. For years people could sneak around the fence and walk up, but it is now run by a local woman named Smiley who charges $5 a person to enter the property. 15 Minutes from Bali House and Cottage, This fresh water lake situated inside a cinder cone crater is on private land. You must call the day before to receive permission from owner. Awesome place to swim.
Akaka Falls State Park, located along the northeastern Hamakua Coast, you can see two gorgeous waterfalls on one short hike. The pleasant 0.4-mile uphill hike will take you through a lush rainforest filled with wild orchids, bamboo groves and draping ferns.
Located north of Hilo on the Hamakua Coast. The highest water fall on the Big Island of Hawaii. About a 1 hour drive from the Bali House and Cottage.
Only 2 miles from the Bali House and Cottage in Kalapana . Open 7 days a week, serving breakfast lunch and dinner and local favorites. You also can find a small corner store to get your last minute goodies or spirits here as well.
Beautiful overlook, hike, horseback and day tours available, on the Hamakua Coast only 50 minutes away from the Bali House and Cottage!
Get a cup of Kava or Awa or even a cold one from Uncle Roberts in Kalapana. Lava Walk Tours also available! Uncle Roberts also host Wed. Friday & Saturday night Farmers Market from 5-9 , Live music, Tropical Bar ! Many food and crafts vendors to choose from! Only 2 miles from the Bali Cottage.
Take a Lava Boat Tour and watch Pele create more land, on we are only minutes away from Isaac Hale Boat launch on the Puna Coast!
Kalapana Lava Viewing Area. Only a 6 minute drive away, watch Pele make new land. Open from 2-10 pm daily (Last car in at 8:00pm). Wear good hiking shoes, bring a flashlight and water. Only a 6 minute drive from the Bali House and Cottage! Lava is currently entering the ocean!
Drive up and see the Mauna Kea Summit, about an hour away, 14000 ft elevation, it snows in the winter time, but access year round with a great scenery! Off Saddle Road.
Located on the Volcano Nation Park is only a 45 min. drive from the Bali Cottage. Visit the Jaggar Museum, Stores, Kilauea Crater,Thurston Lava Tube, Hiking Trails, and Steam vents.
The Star of Sea Painted Church, located just a few minutes away from the Bali House and Cottage by Kalapana of hwy 130, images of Saint Damien, it was moved during the Lava flow from Kalapana in 1993hand painted ceilings, Saint Damien history and more .
Pahoa Town, just a short 15 minute drive, great restaurants, live music, shopping, bars, groceries, banks, post office, sushi, Chinese , Mexican, Italian, Thai, Hawaiian, pizza, burgers,natural foods store and more! The Makuu Farmers Market is open on Sundays from 8-2. Crafts produce, live music Ono foods and more.
The most Eastern point in Hawaii the Tidal Ponds at the Kumukahi Light House area, only a 20 min drive from the Bali House and Cottage, great for sunbathing, wave watching and fishing!
The Botanical Gardens, located right outside Hilo, a beautiful self guided tour to see 3 waterfalls and a wide variety of exotic flowers. This is a must if you want to see examples of tropical paradise on the East Side of the Big Island on the Hamakua Coast.
The Merrie Monarch Festival, held every year in Hilo, it is a celebration of the Hawaiian tradition of Hula! A week long event in the Spring with parades, crafts, free shows and competition!
Rainbow Falls is located in Hilo only 40 minutes away from the Bali House and Cottage.
Hilo Town, is great place for shopping, malls, dining, rental cars, airport, farmers market, museum's, Mac Nut Factories, Big Island Candies Factory, Zoos, Kayaking, sailing, Bay front shopping and live entertainment and so more!
Visit the Volcano National Park only 45 minutes from the Bali House and Cottage and see the most active Volcano in World Kilauea!
Maku'u Farmers Market is located outside Pahoa on Hwy 130, offering fresh produce local gifts, food court, and live entertainment. Open on Sundays 8-2 pm.
Hilo Farmer's market offers food, fun, shops, food courts and local flair, open Wed. from 8-3 and Sat. from 8-3 pm in downtown Hilo Bayfront .


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The Mommy Files
A local mom's take on raising kids by the Bay.
Posts filtered on Tag
High school sophomore catches teacher stealing students' money
A California high school student decided to play Nancy Drew when money was being repeatedly stolen from backpacks during gym class, according to ABC News. Justine Betti, a sophomore at Linden High School outside Stockton, conducted her own sting by hiding in a locker to try to spot the thief. After all of the students […] [Read More]


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Jun 21, 2013 | 12:40 PM
| Frank Haflich
steel tube,
West Coast tube producers,
price increase,
coil prices,
American Tubular Products,
Schaeffer Industries,
Evraz Inc. North America,
Frank Haflich
NEW YORK Key West Coast tubing producers continue to hold back from joining a price hike, but some buyers think rising coil prices could trigger an increase despite a weak market.
Tubing mills east of the Rockies have already announced hikes of $30 per ton, scaled back from an initial $50 per ton, but California tubers balked at joining their counterparts in the East and Midwest as a lagging construction-dependant market has failed so far to show convincing signs of improvement.....
NEW YORK Key West Coast tubing producers continue to hold back from joining a price hike, but some buyers think rising coil prices could trigger an increase despite a weak market.
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Are you stocking more inventory today than 18 months ago?
We actually don't know who his investors are. At the point when we are ready, we will investigate further. There are just so many things to handle and there are a lot of items to be considered with the project."
-- Charles C. Mitchell, Barstow city manager