Multivariate statistical analysis of L-dopa esters as potential anti-parkinsonian prodrugs.

This paper reports a QSAR study of thirteen L-DOPA esters previously synthesised and examined for their physicochemical, biochemical and behavioural properties. Multivariate statistical analysis (principal component analysis, cluster analysis, simple and multiple linear regression) reveals favourable and unfavourable structural features of L-DOPA prodrugs. Some of the many biochemical and behavioural activities investigated are shown to be redundant.

An immunohistochemical study of the acute and long-term effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the marmoset.

Administration of the drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induces a parkinsonian syndrome in primates. Intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the common marmoset (Callithrix jacchus) produced symptoms of rigidity, akinesia and tremor which persisted for at least one month. However, after this time, considerable behavioural recovery occurred, although animals were still severely bradykinetic compared with controls.

Review of the experience with nabumetone in clinical trials outside of the United States.

Nabumetone, a new nonsteroidal anti-inflammatory agent, has undergone extensive clinical evaluation in a number of countries. There have been over 4,000 patients treated, including nearly 1,000 elderly patients and over 1,100 patients who have received nabumetone for more than one year. A total of 2,400 of these patients with a variety of rheumatic disorders have been investigated in studies outside of the United States.

Nabumetone in the treatment of skin and soft tissue injury.

Nabumetone, a new nonsteroidal anti-inflammatory agent, has been evaluated for the treatment of skin and soft tissue injury, including sports injury, in clinical trials involving nearly 1,000 patients. Its efficacy, safety, and tolerance in these patients is reviewed. The efficacy of nabumetone in the treatment of soft tissue injury has been demonstrated to be similar to that of soluble aspirin, ibuprofen, and naproxen.

Pilocarpine-induced purposeless chewing behaviour in rats is dependent on intact central stores of 5-HT.

Pilocarpine-induced purposeless chewing behaviour in rats was partially antagonised by pretreatment with reserpine, tetrabenazine or p-chlorophenylalanine (PCPA). In contrast, pretreatment with alpha-methyl-p-tyrosine (AMPT) had no effect on pilocarpine-induced chewing. These data suggest that enhancement of purposeless chewing by pilocarpine is dependent, in part, on intact central stores of 5-HT.

Selegiline in narcolepsy.

We examined the effect of the specific monoamine oxidase-B (MAO-B) inhibitor selegiline (deprenyl, Eldepryl), 20-30 mg p.o. daily, in 21 subjects with the narcoleptic syndrome for 4 weeks.

L-dopa esters as potential prodrugs: effect on brain concentration of dopamine metabolites in reserpinized mice.

The intraperitoneal administration of L-dopa and a series of ester prodrugs of L-dopa to reserpinized mice produced elevations of striatal and tuberculum olfactorium homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Differences in the pattern of change produced by individual drugs, compared with L-dopa, were observed. Only the phenoxyethyl ester caused elevations of both striatal and tuberculum olfactorium HVA and DOPAC, greater than those measured following L-dopa administration.

Neuroleptic-induced tardive dyskinesia.

Prolonged exposure to neuroleptic drugs induces tardive dyskinesia which may be persistent or permanent. Predisposing factors to tardive dyskinesia are not apparent although the aging brain appears more vulnerable. The drug treatment of tardive dyskinesia is at present unsatisfactory.

Effects of continuous administration for 12 months of amine-depleting drugs and chlorpromazine on striatal dopamine function in the rat.

Rats received either chlorpromazine (33-36 mg/kg/day), oxypertine (6.3-7.3 mg/kg/day), tetrabenazine (6.

L-dopa esters as potential prodrugs: behavioural activity in experimental models of Parkinson's disease.

Intraperitoneal administration of the 2-tetrahydropyranylmethyl, phenoxyethyl, ethyl, 2-hydroxypropyl and methyl ester prodrugs of L-dopa produced locomotor activity in reserpine-pretreated mice with equal intensity and duration to that observed following administration of L-dopa itself. Administration of the 2-(1-methoxy)propyl ester produced a more prolonged effect while the p-methoxyphenylethyl, n-propyl, phenylethyl, m-trifluoromethylbenzyl, cyclohexyl, p-chlorophenylethyl and benzyl ester prodrugs were less active than L-dopa itself. On oral administration, the ethyl and methyl ester prodrugs were more effective than L-dopa in reversing reserpine-induced akinesia in mice.

Chronic pharmacological manipulation of dopamine receptors in brain.

Dopamine receptors in the brain play an important role in the treatment of schizophrenia and in the development of tardive dyskinesia. In Parkinson's disease the loss of dopamine innervation and the use of chronic administration of L-DOPA or therapy with dopamine agonists also affects the function of dopamine receptors in brain. Subacute administration of neuroleptic drugs to rodents for a few weeks followed by the withdrawal of the drug induces supersensitivity of dopamine receptors in the striatum.

Localization of neurotensin receptors in the forebrain of the common marmoset and the effects of treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

The distribution of neurotensin binding sites was mapped in the brain of the common marmoset using [3H]neurotensin as the ligand. Autoradiographic techniques show that the density of receptors is particularly high in the substantia nigra, ventral tegmental area, olfactory tubercle and cerebral cortex and that the distribution of neurotensin receptors in the cerebral cortex and striatum is heterogenous. In the cerebral cortex neurotensin receptors are concentrated in layers I, II, III and V, whilst receptor density is generally less in all layers of middle temporal cortex.

Chronic trifluoperazine treatment does not induce lipid peroxidation in the rat cortex.

Rats received continuous chronic trifluoperazine hydrochloride (4.4-4.9 mg/kg/day) treatment for 15 months via their drinking water.

Analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as monoamine oxidase substrates: a second ring is not necessary.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is oxidised to a neurotoxic metabolite by monoamine oxidase B (MAO B). Using two colorimetric assays, we have examined a range of its structural analogues as possible further substrates of this enzyme in order to identify the types of environmental or endogenous compounds that might also be neurotoxic. Compounds with fully saturated or unsaturated pyridine rings were not substrates; nor were a range of tetrahydro-beta-carbolines or isoquinolines.

In vitro characterisation of dopamine receptors in the superior colliculus of the rat.

In membrane preparations of superior colliculus of the rat, the binding of [3H]spiperone (0.15 nM) was displaced by the incorporation of (+)-butaclamol, haloperidol, apomorphine and (+/-)-sulpiride, but not by (-)-butaclamol, prazosin, propranolol, ketanserin or cinanserin. The Ki values for the displacement of [3H]spiperone by (+/-)-sulpiride, (+)-butaclamol and haloperidol were similar in tissue preparations from superior colliculus and striatum.

Age-related decreases in the concentration of Met- and Leu-enkephalin and neurotensin in the basal ganglia of rats.

Previous studies using radioimmunoassay procedures have failed to show age-related changes in the concentration of Met- and Leu-enkephalin or neurotensin in rat basal ganglia. In contrast, using a combined high-pressure liquid chromatography (HPLC)-radioimmunoassay (RIA) technique we now report considerable decreases in the levels of these neuropeptides in areas of basal ganglia of 22 months old-compared to 3 months-old male Wistar rats. The concentration of Met-enkephalin was greatly reduced in the striatum and nucleus accumbens, but not in substantia nigra, of old compared to young animals.

Comparison of changes in locomotor activity with striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations following the bilateral intranigral injection of dopamine agonist drugs in rats.

Bilateral injection of apomorphine (2.5 micrograms) into the substantia nigra zona reticulata of rats reduced both locomotor activity and striatal HVA and DOPAC concentrations. Bilateral injection of dopamine (10 micrograms) did not affect locomotor activity whereas a higher dose of dopamine (50 micrograms) enhanced locomotor activity.