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PD SCIENCE HIGHLIGHTS, 1996 by Joe Bruman p. 1 of 2 There were no dramatic breakthroughs, but modest progress in most areas: DRUG THERAPY: The reason why PD drugs take so long to reach the market is that, in a slowly progressive disease, trial subjects must be tracked for years to ensure that (a) the benefits are lasting, and (b) long-latency adverse effects don't sneak in. SELEGILINE (Deprenyl, Eldepryl): Despite more numerous and thorough trials than any other PD drug, the transatlantic debate over efficacy and safety rages on, probably until its action is fully understood (not soon). The most convincing opinion is that the drug really is beneficial, and that the mortality scare was premature. LAZEBEMIDE, an MAO-B inhibitor like selegiline, has shown equal merit in trials, but doesn't metabolize to harmful amphetamine. TOLCAPONE, ENTACAPONE: inhibit Catechol-O-Methyl Transferase (COMT), a natural enzyme that destroys dopamine. In trials, they prolonged the effect and reduced the required dosage of levodopa. PRAMIPEXOLE, another dopamine agonist, completed formal trials and awaits FDA approval. CABERGOLIINE, a long-acting dopamine agonist, has passed its trial for effectiveness; exceptionally well tolerated and offers the prospect of reducing levodopa dosage to once daily. GLUTAMATE ANTAGONISTS: Glutamates are a family of neurotransmitter enzymes that in excess may be toxic to neurons and also may cause symptoms of PD. Inhibitors of those substances, particularly of the glutamate NMDA (N-Methyl-D-Aspartate), may offer the same beneficial effects as pallidotomy, without the surgery, if one can be found that lacks intolerable side effects. AMANTADINE (Symmetrel) in a large cohort of PD patients over 15 years, seems to have slowed progression and prolonged lifespan; and was recently found to be an NMDA inhibitor. LEVODOPA ETHYLESTER (LDEE) is an injectable form which avoids the wearing-off fluctuations due to poor solubility of the oral form, as well as the nausea that bothers many PD patients. DIET SUPPLEMENTS often are natural enzymes thought to be deficient in PD, and sometimes get formal trials in the attempt to join the profitable mainstream of PD drugs. If results aren't advertised it may mean they didn't do so well. I believe there are clinical trials (current or recent) of NADH, DHEA, and ganglioside GM-1. SURGERY: PALLIDOTOMY became increasingly popular and available, and at least one large-scale trial report should be helpful in getting coverage. THALAMOTOMY is due for a revival, following discovery that the sub- thalamic nucleus is a source not only of tremor but other major PD symptoms. DEEP-BRAIN STIMULATION (DBS) of the pallidum or ventral intermediate nucleus of the thalamus) by a controllable, implanted electrical generator is gaining favor due to its success. FETAL CELL TRANSPLANTS continue as experimental, with at least one controlled trial underway. To overcome ethical objections and the scarcity of aborted human cells, Workers report success with pig cells, and are looking at ways to culture human cells in vitro, or to convert cells from the adult host, in any case removing limits of supply. ELECTROCONVULSIVE THERAPY (ECT), which used to be the sovereign tactic for schizophrenia, was tried on PD patients, with mixed results. PD SCIENCE HIGHLIGHTS, 1996 P. 2 of 2 ETIOLOGY OF PD: Workers still looking for environmental factors such as geography, lifestyle, diet, exposure to toxins, and so forth, came up with various statistical correlations, but nothing definite and conclusive. One of the most striking correlations (negative) is between PD and smoking. Familial clusters, some impressively large, suggest a genetic origin, but then the vast majority of PD patients have no known family linkage. Some think therefore that familial PD is a distinct type of the disease; for example, young-onset or juvenile PD seems to have more linkage than the more common form which presents in the 7th or 8th decade. ESSENTIAL TREMOR: ET is getting much more attention, aimed both at etiology and the site of its origin in the CNS. It seems to be much more frequent than PD, and is thought to be often misdiagnosed as PD. From the number of family links, workers are pretty sure that ET is hereditary. While the thalamus has long been seen as the origin of tremor, recent work implicates other sites, particularly the cerebellum. The influence of alcohol on the cerebellum and on the tremor of ET supports the notion. DIAGNOSTIC AND STUDY TOOLS: Clinical diagnosis should get much more sophisticated than the traditional "classic triad" symptoms of rigidity, bradykinesia, and tremor. Subtle tests of cognition such as memory, smell, or color perception may detect PD long before movement troubles appear. But favorable response to levodopa remains the most useful sign, because it affects directly the choice of treatment whether the presenting disorder is really PD or not. Noninvasive scanning techniques such as Positron-Emission Tomography (PET) and Single-Photon-Emission Computed Tomography (SPECT), while still very costly, find rapidly growing use, by means of a variety of injected radioactive tracers, in detailed mapping of activity in the brain. In this way workers can measure the function of specific areas known to be affected by PD or by therapeutic drugs, during actual performance of psychological tasks by the subject. NEURAL REGENERATION: A cure for PD must include restoration of the lost function and prevention of subsequent loss. Toward this end, workers are exploring the mediation of apoptosis, or programmed cell death in response to the cellular environment. They also are finding that neurons of the CNS, contrary to former belief, can regenerate in the presence of certain growth factors. If the neural failure of PD can be traced to a particular mutant gene, there is then the possibility of grafting new cells lacking the mutant, which can be made to grow and restore the deficient neural pathway, and which will be exempt from the degeneration of PD. We aren't there yet, but a step in that direction is the current trial in humans of a directly (stereotactically) injected Glial-cell-Derived Neurotrophic Factor (GDNF) which has shown promise so far in rats and monkeys. J. R. Bruman (818) 789-3694 3527 Cody Road Sherman Oaks CA 91403