Design of selegiline-loaded bio-nanosuspension for the management of depression using novel bio-retardant from Manilkara zapota.

Objective: Depression is one of the most frequent psychiatric and potentially life-threatening disorders. This research work can offer a potential for delivery of selegiline moiety via ocular route in bio-nanosuspension mode for the effective management of depression after preclinical performance screening. Methods: The selegiline-loaded bio-nanosuspension was prepared using novel bio-retardant isolated from fruit pulp of Manilkara zapota (Sapodilla) by sonication solvent evaporation method with different ratios (0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, and 1%) and with standard polymer HPMC (0.1%, 0.2%, 0.3%, 0.4%, and 0.5%). The prepared formulations were evaluated for pH stability studies, %entrapment efficiency, in vitro drug release, particle size, polydispersity index (PDI), zeta potential, and stability studies. Results: The prepared bio-nanosuspension was subjected to the best formulation based on comparison of above-mentioned evaluation parameters, so Fb2 (0.1%) formulation was found to be the best formulation showing an R2 value of 0.9814, T50% of 29.7 h, and T80% of 65.25 h. According to the release kinetics, the best fit model was found to be the Korsmeyer-Peppas with the Fickian diffusion (Higuchi matrix) as the mechanism of drug release. Manilkara zapota (Sapodilla) provided excellent stability for the formulation and resulting particle size for the best formulation was found to be 252 nm. The bio-nanosuspension had PDI of 0.35 with zeta potential of -8.91 mV. Conclusion: The prepared bio-nanosuspension was found to be safe and compatible with the ophthalmic delivery for treatment of depression.

Adjuvant potential of selegiline in treating acute toxicity of aluminium phosphide in rats.

Aluminium phosphide (AlP) is a highly toxic substance with a high mortality rate and no effective antidote. Once exposed to the moisture and acidic conditions of the stomach, AlP releases toxic phosphine (PH3 ) gas, which results in severe toxicity in poisoned subjects. Selegiline is a monoamine oxidase inhibitor with antioxidant and anti-apoptotic properties, which is mostly prescribed for the treatment of mood disorders and Parkinson's disease. Since AlP has detrimental effects on cardiac physiology and mitochondrial function, we tested the protective effects of acute selegiline treatment on cardiac mitochondrial function, redox status and electrocardiographic parameters in rats after AlP poisoning. To do this, AlP was given to rats by gavage to induce toxicity. Selegiline was injected intraperitoneally in the treatment groups 1 hour after AlP poisoning. Selegiline treatment after AlP intoxication was not associated with a significant difference in the mortality rate of animals. However, selegiline reduced oxidative stress (decreased the reactive oxygen species and malondialdehyde) and increased glutathione in the cardiac tissue of rats exposed to AlP. Further, the mitochondrial membrane potential (ΔΨm) collapse reversed after treatment with selegiline. Selegiline also improved the electrocardiographic (ECG) parameters and enhanced heart rate. The histopathological evaluation revealed that selegiline eliminated the inflammation and injuries induced by AlP in the stomach and duodenum, as well as cardiac tissue. In conclusion, selegiline treatment can ameliorate the AlP-induced cardiac and gastrointestinal injuries in rats via boosting redox status and mitochondrial function with no significant effect on survival. We suggest that using selegiline, apart from other clinical treatments, may improve the quality of treatment process for AlP toxicity.

The effect of R-(-)-deprenyl administration on antioxidant enzymes in rat testis.

The aim of the study was to investigate the effect of R-(-)-deprenyl administration on the activity and localization of superoxide dismutases (SODs) and catalase (CAT) in rat testis. After 30 days of intraperitoneal administration of either saline (control) or R-(-)-deprenyl dissolved in saline at concentrations of 0.0025mg/kg (low dose of deprenyl, LDD) or 0.25mg/kg (high dose of deprenyl, HDD), males were killed by thiopental, and their testes were collected. We found that deprenyl administration significantly increased the activity of antioxidant enzymes, and this effect varied by dosage. LDD caused significant elevation of all monitored enzymes, but HDD did not increase the activity of SOD2. Employing immunohistochemistry, we detected enzymes predominantly in Leydig cells (SOD1, SOD2, CAT), in late spermatids and residual bodies (SOD1, SOD2), and in primary spermatocytes (SOD2). Histopathological examination did not reveal testicular damage in experimental groups compared to control. Deprenyl proved to be a potent stimulator of antioxidant enzymes in rat testes; therefore, it could be used in the therapy of male infertility. On the other hand, it is crucial to choose a proper dose, since lower dose was more competent compared to a dosage that was one hundred times higher.

Inhibition of monoamine oxidase isoforms modulates nicotine withdrawal syndrome in the rat.

AIMS: There have been many reports of monoamine oxidase (MAO) inhibition by non-nicotine ingredients in tobacco smoke, persisting for days after smoking cessation. This study determined the effect of inhibiting MAO and its isoforms on nicotine withdrawal syndrome. MAIN METHODS: Rats were rendered nicotine-dependent by seven days of subcutaneous (s.c.) 9 mg/kg/day infusion of nicotine bitartrate. Twenty-two hours after termination of infusion, they were observed over 20 min for somatically expressed nicotine withdrawal signs. Three hours before observation, rats were injected intraperitoneally (i.p.) with 4 mg/kg each of the MAO A antagonist clorgyline and the MAO B antagonist deprenyl, or with saline alone. A similar experiment was performed with non-dependent, saline-infused rats. Another experiment compared nicotine-dependent rats that received injections of either saline or 4 mg/kg clorgyline alone. A further experiment compared rats receiving either saline or 4 mg/kg deprenyl alone. KEY FINDINGS: Combined treatment with both MAO inhibitors markedly and significantly exacerbated somatically expressed nicotine withdrawal signs in nicotine infused rats, while having no significant effects in saline-infused rats. Rats injected s.c. with 4 mg/kg clorgyline alone had significantly more withdrawal signs than saline-injected rats, while deprenyl-injected rats had significantly fewer signs than saline controls. Assays confirmed that clorgyline thoroughly reduced MAO A enzymatic activity and deprenyl thoroughly reduced MAO B activity. SIGNIFICANCE: The results suggest that inhibition of MAO A may contribute to the intensity of withdrawal syndrome in smoking cessation.

Supplementation of deprenyl attenuates age associated alterations in rat cerebellum.

Aging, a multifactorial process of enormous complexity is characterised by physio-chemical and biological aspects of cellular functions. It is closely associated with changes in metabolism of various biological molecules in the system. In the present study, we have investigated the effect of deprenyl on cerebellum during ageing process in male Wistar rats with respect to the changes in levels of protein, glycoproteins and amino acids in experimental rats of three age groups (6, 12 and 18 months old). Intraperitoneal administration of liquid deprenyl (2 mg/kg body weight/day for a period of 15 days i.p., significantly P < 0.05) attenuated age-associated alterations in the levels of amino acids (taurine, aspartate, glutamate, arginine, hydroxy proline and homocysteine), protein content and glycoprotein components (hexose and hexosamine) in the rat cerebellum. The results of the present investigation indicate that the protective effect of deprenyl is probably related to its ability to strengthen the neuronal membrane by its membrane stabilizing action or to a counteraction of free radicals by its antioxidant property.

Orally disintegrating selegiline for the treatment of Parkinson's disease.

The selective monoamine oxidase type B inhibitor selegiline is commonly administered as medical treatment to patients suffering from Parkinson's disease. The clinical value of conventional selegiline is, however, compromised by extensive first-pass metabolism, which reduces its bioavailability and leads to the production of possibly harmful methamfetamine metabolites. This review aims to evaluate a novel, orally disintegrating formulation of selegiline by examining scientific evidence from previous pharmacological and clinical studies. As a result of improved bioavailability, orally disintegrating selegiline can be administered at lower doses than conventional selegiline with similar clinical effect. It also leads to less variable selegiline blood concentrations and produces significantly less methamfetamine metabolites. We conclude that this novel formulation offers an interesting treatment option, especially for patients who report adverse events after initial treatment with conventional selegiline or who suffer from swallowing difficulties.

[A case of interval form of carbon monoxide poisoning with a remarkable recovery].

A 69-year-old woman was admitted to our hospital due to an interval form of carbon monoxide (CO) poisoning one month after acute CO poisoning. On admission, she had disorientation, memory disturbance, apathy, masked face, muscle rigidity, bradykinesia and parkisonian gait. An MRI (FLAIR image) revealed high signal intensity lesions in the bilateral globus pallidus and the white matter of the frontal lobe. Hyperbaric oxygen (HBO) therapy at 2 atmospheres for 60 min was given every day, in addition to citicoline, levodopa/DCI and selegiline hydrochloride. Cognitive disturbance and parkinsonism gradually decreased, and abnormal signals in the bilateral globus pallidus and the cerebral white matter were attenuated after the treatment. Neuropsychiatric abnormalities except for a slight gait disturbance disappeared one and a half month after starting the treatment. In addition to HBO therapy, administration of citicoline, lovodopa and selegiline may be useful in the case of the interval form of CO poisoning.

Effect of repeated treatment with high doses of selegiline on behaviour, striatal dopaminergic transmission and tyrosine hydroxylase mRNA levels.

The anti-parkinsonian drug selegiline is a monoamine oxidase B (MAO-B) inhibitor and a potential neuroprotective agent which facilitates dopaminergic transmission. Its metabolites (-)-amphetamine and (-)-metamphetamine might contribute to the pharmacological effects as they are also able to increase dopaminergic transmission and in addition might lead to behavioural sensitization after repeated administration. We investigated the effects of acute and repeated treatment with a high dose of selegiline on dopamine overflow in the striatum as well as on behaviour and on tyrosine hydroxylase (TH) mRNA levels in midbrain. Two experiments were performed. In the first one, rats were implanted with microdialysis probes into the striatum and received daily injections of selegiline (10 mg/kg, i.p.) for 1 or 8 days or a single dose of saline. In vivo microdialysis was carried out on days 1, 8 or 17 (after withdrawal of 9 days) to measure dopamine overflow. Motility was measured at the same time. In the second experiment, rats were injected daily with selegiline (10 mg/kg, i.p.) or saline over a time period of 6 weeks or only once before the brains were processed for in situ hybridization with a (35)S-radiolabelled probe for TH. Repeated treatment led to higher levels in motility scores than acute administration after administration of the same dose, indicating behavioural sensitization, which was still manifest after an interruption of 9 days in the supply of selegiline. In contrast, acute administration of selegiline increased dopamine levels to a similar degree as the same dose after subchronic treatment, with or without interruption of 9 days. The dopamine metabolite DOPAC was reduced by more than 50% after acute administration of selegiline and even more so on day 8 by the same dose, after repeated administration. The basal concentrations of dopamine (before challenge with selegiline) were not altered by the repeated administration, whereas the basal concentrations of DOPAC were decreased by more than 80% by the repeated administration of selegiline, suggesting a decrease in dopamine turnover. Acute administration did not have any influence on TH mRNA levels, whereas chronic treatment significantly reduced TH mRNA levels in substantia nigra and ventral tegmental area. In conclusion, repeated administration of selegiline leads to behavioural sensitization independent of altered dopamine levels. In addition, it leads to a decrease, probably due to a down-regulation, of dopamine turnover and tyrosine hydroxylase.

Chronic daily administration of selegiline and EGb 761 increases brain's resistance to ischemia in mice.

Brief cerebral ischemia is reported to cause selective neuronal necrosis, apoptotic cell death, silent infarcts and, when recurrent, cognitive decline. Acute administration of selegiline and EGb 761 have been shown to have anti-apoptotic and neuroprotective effects in experimental ischemia. Their daily use is currently advised to slow down cognitive decline in patients with vascular dementia. Hence, unlike previous studies, we studied the neuroprotective action of chronic daily administration of these drugs in Swiss mice subjected to 30-min middle cerebral artery occlusion and 72 h of reperfusion since this model was reported to induce a slowly evolving infarct with profuse apoptotic cell death. Infarct area was evaluated by H&E staining on coronal brain sections and, apoptotic cells were identified by histological criteria, terminal transferase-mediated d-UTP nick-end labeling (TUNEL) and by immunohistochemical detection of caspase-cleaved actin fragments (fractin). Fifty-one mice received daily intraperitoneal injections of 10 mg/kg selegiline (n=18) or 50 mg/kg EGb 761 (n=17) or equal volume of saline (n=16) for 10-14 days before but not on the day of insult. The infarct volume, number of TUNEL- and fractin-positive cells were significantly reduced in treatment groups by 30, 42 and 51% (selegiline) and, 27, 27 and 29% (EGb 761), respectively. These data suggest that prophylactic use of selegiline and EGb 761 could increase the brain's resistance to mild ischemic injury.

[Current strategies of pathogenetic therapy of Alzheimer's disease]. / Sovremennye strategii patogeneticheskoi terapii bolezni Al'tsgeimera.

This is a review of the data available in the literature and the authors' own findings on pathogenetical rationale for the use and clinical study of current treatments for Alzheimer's disease (AD) (synonym: Alzheimer-type dementia). In the past decade many attempts have been made at targeting different links of the pathogenesis of a neurodegenerative process that underlie AD. Several areas of pathogenetical therapy for AD have been developed on the basis of experimental studies and pilot clinical tests. The most developed areas are as follows: various compensatory (replacement) treatments aimed at overcoming neurotransmitter deficit in different neuronal systems that are damaged in AD to a greater or lesser extent; neuroprotective therapy promoting increased viability (survival) of neurons and their plasticity, and vasoactive therapy. Rather new directions of AD pathogenetic therapy, such as antiinflammatory and hormonal therapy along with antiamyloid therapeutic strategies are still under study.

A high dose of long term treatment with deprenyl loses its effect on antioxidant enzyme activities as well as on survivals of Fischer-344 rats.

The survival rate of male Fischer-344/Du rats treated chronically with high doses of deprenyl was investigated. Eighteen month old rats were treated with 1 mg/kg s.c. deprenyl 3 times per week for 13 months. At the age of 31 months, treated rats showed a greater mortality rate with three of 12 rats surviving, while in saline-treated control animals seven of 12 animals survived. No significant differences in superoxide dismutase (SOD) or catalase (CAT) activities in brain regions of control and treated animals were seen at 31 months of age. In contrast, when 27 month old rats were treated in the same manner for one month, significant increases in SOD (both Cu,Zn- and Mn-) and CAT activities were found in substantia nigra, striatum and cerebral cortex, but not in hippocampus. This effect was produced with a wide range of deprenyl doses (0.25-2 mg/kg, but not 4 mg/kg). Although a causal relationship between the two different effects of the drug, i.e. 1) increases in antioxidant enzyme activities and 2) the prolongation of survival of animals, has not been directly demonstrated, the loss of both effects with the high dose of the drug in the present experiment may be taken as circumstantial evidence for their causal relationship.

Practice guidelines for the diagnosis and treatment of Alzheimer's disease in a managed care setting: Part II--Pharmacologic therapy. Alzheimer's Disease (AD) Managed Care Advisory Council.

The progressive loss of social and physical functioning associated with Alzheimer's disease (AD) results in extensive social and economic costs to society. The early diagnosis and treatment of AD may reduce cognitive and behavioral symptoms of this disease and may slow disease progression, thereby alleviating some of these social and economic costs. The Alzheimer's Disease Managed Care Advisory Council, a panel of experts from managed care, academic medicine, and the Los Angeles chapter of the Alzheimer's Association was convened to synthesize current evidence-based recommendations for AD diagnostic and treatment guidelines and to integrate these guidelines for use in MCOs. This paper presents conclusions from this panel and provides an algorithm for the treatment of AD specifically for managed care settings. When combined with other necessary efforts to educate providers, these guidelines should improve the cost-effectiveness and quality of care for individuals with dementia in managed care.

Region-specific alterations in the concentrations of catecholamines and indoleamines in the brains of young and old F344 rats after L-deprenyl treatment.

The effects of L-deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, on the concentrations of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-hydroxytryptamine), and 5-hydroxyindoleacetic acid (5-HIAA) in medial basal hypothalamus (MBH), substantia nigra (SN), striatum (Str), and nucleus accumbens (NAc) of young (3 month) and old (21 month) male F344 rats were examined after a 7-day wash-out period following 1, 15, or 30 days of deprenyl treatment in young rats and a 9-day wash-out period after a 10-week deprenyl treatment in old rats. The brain areas were microdissected and the concentrations of neurotransmitters were measured by High Performance liquid chromatography with electrochemical detection (HPLC-EC). Deprenyl administration following the drug wash-out period increased the concentrations of DOPAC in the SN, Str, and in the NAc of young rats but it was decreased in the NAc of old rats. The concentration of HVA was lower in the Str of young deprenyl-treated rats, and in the Str and NAc of old deprenyl-treated rats, but it was higher in the SN of young deprenyl-treated rats. The concentration of 5-HIAA was increased in the MBH, SN, and in the NAc of young deprenyl-treated rats, but it was decreased in the Str and NAc of old deprenyl-treated rats. The concentration of NE was increased in the MBH, SN, Str, and in the NAc of young rats treated with deprenyl and in the MBH of old deprenyl-treated rats. The concentration of 5-HT was increased in the SN of young deprenyl-treated rats. The concentration of DA increased in the Str of both young and old deprenyl-treated rats. We concluded that a drug wash-out period after deprenyl treatment differentially affects the metabolism of catecholamines and indoleamine depending on the region of the brain and that this effect may be due to variation in the kinetics of MAO inhibition.

L-deprenyl reduces brain damage in rats exposed to transient hypoxia-ischemia.

BACKGROUND AND PURPOSE: L-Deprenyl (Selegiline) protects animal brains against toxic substances such as 1-methyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine. Experiments were conducted to test whether L-deprenyl prevents or reduces cerebral damage in a transient hypoxia/ischemia rat model. METHODS: Rats were treated for 14 days with 2 mg/kg and 10 mg/kg L-deprenyl or saline. After surgery a 20-minute hypoxia/ischemia period was induced by simultaneous occlusion of the left common carotid artery and reduction of the percentage of oxygen in the gas mixture to 10%. Rats were killed 24 hours later. Silver staining was used to reveal damage in several brain regions. RESULTS: In the brain, both L-deprenyl dosages reduced damage up to 78% compared with the controls. Total brain damage was decreased from 23%-31% to 5%-9% with the L-deprenyl treatment (2 mg/kg: F1.13 = 6.956, P < .05; 10 mg/kg: F1.13 = 5.731, P < .05). In the striatum, significant treatment effects were found between both the L-deprenyl groups (2 mg/kg and 10 mg/kg, respectively) and the saline group (F1.13 = 14.870, P < .005; and F1.13 = 8.937, P = .01; respectively). In the thalamus, significant treatment effects were seen in the 2-mg/kg L-deprenyl group (F1.13 = 11.638, P < .005) and the 10-mg/kg group (F1.13 = 8.347, P < .05) compared with the control group. No significant damage decrease was seen in the hippocampus and the cortex. CONCLUSIONS: The results show that L-deprenyl is effective as a prophylactic treatment for brain tissue when it is administered before hypoxia/ischemia. Mechanisms responsible for the observed protection remain unclear. The regional differences in damage, however, are in accordance with the reported regional increase in superoxide dismutase and catalase activities after L-deprenyl treatment, suggesting the involvement of free radicals and scavenger enzymes.

The distribution of orally administered (-)-deprenyl-propynyl-14C and (-)-deprenyl-phenyl-3H in rat brain.

Using alternatively labelled (-)-deprenyl (3H label in the ring and 14C in the propargyl group) the distribution of the compound was studied in 15 brain regions and the plasma of rats over a period of 96 h, after oral administration of 1.5 mg/kg of (-)-deprenyl. The compound is rapidly absorbed (within 15-30 min) from the gastrointestinal tract, as indicated by its high plasma level. It penetrates to the central nervous system, where it reaches a peak level within 45-60 min. During the first 2 h in the plasma the 14C label, whilst in cerebral tissues during the whole period of the experiment the 3H tracer dominates. The difference in the ratio of 3H to 14C radioactivity (compared to the 0 time relation) develops as early as in the first 15 min, which indicates the operation of a rapid "first pass" biotransformation of the compound. Our data represent the tissue molar concentration -time curves of (-)-deprenyl calculated from both the 3H and 14C radiolabels. A ratio of 1 of the concentrations of the two tracers would indicate that the molecule remained unchanged. The changes in the ratio, therefore, suggest the formation of considerable quantities of metabolites (methylamphetamine and amphetamine) and their presence in the brain. The difference between the area under the curves (AUC0-t for 3H and AUC0-t for 14C) represents the amount of metabolites expected to be formed during the experiment. The concentration of the metabolites should be taken into account while evaluating the pharmacological effect of (-)-deprenyl. We proved earlier that a dose of 1.5 mg/kg of (-)-deprenyl completely blocks MAO-B activity in the central nervous system. The fast metabolism of the inhibitor indicates that a minor part of the orally administered (-)-deprenyl is sufficient to produce a high level of selective MAO-B inhibition in the brain.

(-)Deprenyl-medication: a strategy to modulate the age-related decline of the striatal dopaminergic system.

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. (1) It is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-)Deprenyl, the first selective inhibitor of MAO-B described in literature, has become the universally used research tool for selectively blocking B-type MAO. It is the only MAO-B inhibitor in clinical use. (2) (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron in a way similar to the physiological substances transported through the axonal end organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives, it does not displace the transmitter from storage, ie, it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine, and, at present, is the only safe MAO inhibitor that can be administered without dietary precautions. (3) Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to its effect on MAO-B and the inhibitory effects of the drug on neurotransmitter uptake. (4) Maintenance on (-)deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity, and this effect, too, is unrelated to either its effects on MAO or on neurotransmitter uptake. (5) Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. All in all, (-)deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline. Maintenance of male rats on (-)deprenyl delays the loss of the capacity to ejaculate, slows the decline of learning and memory, and significantly lengthens the life-span as compared with saline-treated rats. Parkinson's disease patients on levodopa plus (-)deprenyl (10 mg daily) live significantly longer than those on levodopa alone. (-)Deprenyl is the first drug that retards the progress of Parkinson's disease. Newly diagnosed Parkinson's disease patients maintained on (-)deprenyl need levodopa significantly later than their placebo-treated peers. Maintenance on (-)deprenyl improves significantly the performance of patients with Alzheimer's disease. It is concluded that Parkinson's disease and Alzheimer's disease patients need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of deprenyl on the progression of disability in early Parkinson's disease.

In a clinical trial that is still in progress, we studied the ability of deprenyl and tocopherol, antioxidative agents that act through complementary mechanisms, to delay the onset of disability necessitating levodopa therapy (the primary end point) in patients with early, untreated Parkinson's disease. Eight hundred subjects were randomly assigned in a two-by-two factorial design to receive deprenyl, tocopherol, a combination of both drugs, or placebo, and were followed up to determine the frequency of development of the end point. The interim results of independent monitoring prompted a preliminary comparison of the 401 subjects assigned to tocopherol or placebo with the 399 subjects assigned to deprenyl, alone or with tocopherol. Only 97 subjects who received deprenyl reached the end point during an average 12 months of follow-up, as compared with 176 subjects who did not receive deprenyl (P less than 10(-8). The risk of reaching the end point was reduced by 57 percent for the subjects who received deprenyl (Cox hazard ratio, 0.43; 95 percent confidence limits, 0.33 and 0.55; P less than 10(-10]. The subjects who received deprenyl also had a significant reduction in their risk of having to give up full-time employment (P = 0.01). We conclude from these preliminary results that the use of deprenyl (10 mg per day) delays the onset of disability associated with early, otherwise untreated cases of Parkinson's disease.

Interactions between relatively selective monoamine oxidase inhibitors and an inhibitor of 5-hydroxytryptamine re-uptake, clomipramine.

Features of interactions with combined antidepressants in man were evoked by clomipramine in rats pretreated with both the relatively selective monoamine oxidase (MAO) inhibitors clorgyline and deprenyl, but not when clomipramine was given to rats pretreated with deprenyl or clorgyline alone, i.e. inhibition of both MAO A and B was a likely prerequisite for clomipramine to elicit the syndrome (with the larger dose of clorgyline and deprenyl, MAO A and B inhibition exceeded 95%). The features evoked were myoclonic--forelimb flexor-extensor movements, wet dog shakes and head and body twitches; hyperthermia and ECG anomalies also developed, and locomotor activity was augmented. Myoclonic phenomena were prevented when the above pretreatment also included p-chlorophenyl-alanine, but were unaffected or even intensified when pretreatment instead included alpha-methyl-p-tyrosine; these phenomena were attenuated or abolished by pirenperone, a 5HT2 antagonist. Relevance of these findings to safer combinations of antidepressants is discussed.