Synthesis and toxicity toward nigrostriatal dopamine neurons of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analogues.

Six compounds having structural features in common with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and tested in mice for the ability to produce a prolonged decrease in nigrostriatal dopamine (DA) and DA metabolites. The compounds that were prepared and tested include the ester elimination products of the analgetic drugs alpha-prodine and trimeperidine. None of the compounds in this study, except for MPTP, produced significant neurotoxic effects in the mouse model. The study shows that minor changes in the tetrahydropyridine ring of MPTP result in a marked decrease in neurotoxicity.

Two different dose regimens of cisapride in the treatment of reflux oesophagitis: a double-blind comparison with ranitidine.

We conducted a double-blind study comparing two dosage regimens of a prokinetic drug, cisapride (10 mg q.d.s. and 20 mg b.d.), with a low dose of a H2-receptor antagonist (150 mg ranitidine b.d.) in the treatment of 155 patients with reflux oesophagitis as determined by endoscopy. The active treatment took 8 to 12 weeks depending on whether complete healing was found at endoscopy. Improvement in oesophagitis grades from baseline to endpoint was observed in 68% of patients in the 10 mg cisapride q.d.s. group, 83% in the cisapride 20 mg b.d. group and 81% in the ranitidine group (N.S.). At endpoint, the percentages of endoscopically cured patients with initial grades I or II were 52% for 10 mg cisapride q.d.s., 71% for 20 mg cisapride b.d. and 80% for ranitidine (N.S.). The proportional improvement of the overall reflux symptom score (60%) also showed no significant difference between the three groups. In the treatment of mild reflux oesophagitis (grades I and II) similar results can be expected from 20 mg cisapride b.d. and 150 mg ranitidine b.d. As the results of the two dosage regimens of cisapride were not different, the 20 mg twice daily regimen is preferred because it will improve patient compliance. It is concluded that in reflux oesophagitis grades I and II, the efficacy of 20 mg cisapride b.d. and 150 mg ranitidine b.d. are broadly similar.

Treatment of gastro-oesophageal reflux disease with rabeprazole in primary and secondary care: does Helicobacter pylori infection affect proton pump inhibitor effectiveness?

BACKGROUND: The presence of the gastric pathogen, Helicobacter pylori influences acid suppression by proton pump inhibitors and treatment outcome in patients with gastro-oesophageal reflux disease. AIM: To determine the influence of H. pylori infection on effectiveness of rabeprazole in primary and secondary care patients with gastro-oesophageal reflux disease. METHODS: Patients from primary and secondary care centres with uninvestigated gastro-oesophageal reflux disease (based on symptoms only) and investigated gastro-oesophageal reflux disease (endoscopically confirmed oesophagitis or endoscopy-negative reflux disease) were tested for H. pylori and treated with rabeprazole 20 mg once daily for 4-8 weeks in a non-randomized, multicentre, open-label study. Primary end-point for treatment effectiveness was complete resolution of both heartburn and acid regurgitation at 4-8 weeks; secondary end-point was quality of life as registered with the Psychological General Well-being Index. RESULTS: Data of 1787 patients could be analysed; mean duration of treatment was 36.3 days. At the evaluation visit 76.9% were heartburn-free, 77.7% regurgitation-free and 71% had complete symptom resolution. Overall Psychological General Well-being Index scores improved accordingly. Treatment was equally effective in patients with or without H. pylori infection, but more effective in patients with oesophagitis when compared with symptomatic gastro-oesophageal reflux disease. CONCLUSIONS: The effectiveness of rabeprazole in gastro-oesophageal reflux disease is not affected by the presence of H. pylori infection.

N-methyl,N-propargyl-2-aminotetralins:novel dopamine agonists with monoamine oxidase inhibiting properties.

A series of mono- (5 and 7) and dihydroxylated (5,6 and 6,7)N-methyl,N-propargyl-2-aminotetralins were studied with respect to their dopamine agonistic and monoamine oxidase inhibitory activities. MAO inhibition was found to be reduced by hydroxylation of the aromatic ring. Among the hydroxylated compounds the 7-OH analogue was the most potent inhibitor in in vitro and ex vivo experiments. Both catecholic structures were equipotent with apomorphine as displacers of the specific in vitro binding of [3H]NPA to rat striatal homogenates. Moreover, the catecholic analogues had a potency comparable to that of apomorphine in the gamma-butyrolactone model whereas the monohydroxy analogues were less active. On the basis of their effectiveness to induce stereotypy in rats and to reverse reserpine-induced hypomotility in mice (both used as indices of postsynaptic dopamine receptor stimulation) the catecholic compounds were more potent than the monohydroxy analogues but much less active than apomorphine. Dopamine agonistic activity was also reflected in decreased HVA levels in the striatum whilst effects on striatal 3-MT levels reflected the balance between dopamine agonistic (decrease in 3-MT) and MAO inhibitory (increase in 3-MT) activity of the various compounds. It was concluded that both the mono- and dihydroxylated compounds have MAO inhibiting and dopamine agonistic activities. The MAO inhibitory activity predominated within the monohydroxy structures whereas the dopamine agonistic effect was predominant for the catecholic compounds. It would thus appear that, at least for the 2-aminotetralins, it is difficult to prepare an analogue which combines a high degree of both MAO inhibitory and DA agonistic activity.

Neuropharmacological profile of a new series of dopamine agonists: N-n-propyl-hexahydronaphthoxazines.

It has been demonstrated that within the series of hydroxylated (7-OH, 9-OH) and non-hydroxylated (N-0498) hexahydronaphthoxazines the 9-OH (N-0500) analogue is a very potent centrally acting DA receptor agonist. In in vitro [3H]DP-5,6-ADTN binding experiments, reflecting D-2 dopaminergic activity, N-0500 was equipotent with apomorphine and RU-29717, whereas both the 7-OH (N-0499) and N-0498 were much less effective. In in vivo tests related to DA receptor stimulation N-0500 was found to be the most active compound. In the gamma-butyrolactone model, a test for DA autoreceptor activation, N-0500 was 10 times as potent as apomorphine, but 3 times less active than RU-29717. The locomotor activity of mice was inhibited more strongly by N-0500 than by N-0499. Striatal concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid were rapidly reduced by N-0500 both after intraperitoneal and oral administration, indicating that this compound is well absorbed from the gastrointestinal tract and passes the blood-brain barrier to activate DA autoreceptors. In models for postsynaptic DA receptor stimulation (induction of stereotypy in rats, reversal of reserpine-induced immobility of mice) N-0500 was found to be as effective as RU-29717 in inducing stereotyped behaviors in rats, but was much less effective than RU-29717 in restoring the mobility of reserpinized mice, suggesting a selectivity for D-2 DA receptors by N-0500 in contrast to the mixed D-1/D-2 receptor activity of RU-29717. In in vitro binding experiments for evaluating the affinity towards other receptor types, N-0500 exhibited only a weak affinity towards 5-HT1 and alpha 2 binding sites and possessed a very weak affinity for 5-HT2 and alpha 1 receptor sites. It was concluded from these in vitro binding experiments that N-0500, has not only a very high affinity for D-2 DA receptors, but is more selective than RU-29717 and much more selective than the ergot bromocriptine. On the basis of its very potent in vivo central D-2 dopamine receptor activities and its in vitro selectivity, N-0500, being the most potent compound within the series, is a much more specifically acting drug than many of the dopaminergic ergolines and might therefore be a good candidate for the treatment of Parkinson's disease.

The neuropharmacological profile of N-methyl-N-propargyl-2-aminotetralin: a potent monoamine oxidase inhibitor.

N-methyl-N-propargyl-2-aminotetralin (N-0425), a semi rigid analogue of deprenyl was found to be a potent inhibitor of monoamine oxidase type-A and -B. The MAO inhibitory potency was determined in in-vitro, ex-vivo and in-vivo experiments for racemic N-0425 and for both enantiomers, and compared with deprenyl. Racemic N-0425 and (-)N-0425 were found to inactivate both MAO-A and -B to about the same extent in rat brain homogenates, whereas (+)N-0425 was 10 times more potent in inhibiting MAO-B than MAO-A under in-vitro conditions. The latter compound was almost 3 times less active than (-)deprenyl with respect to inactivation of MAO-B. In ex-vivo experiments it was shown that (+/-)- and (+)N-0425 inhibited rat striatal MAO-B activity almost completely 2 h after a dose of 0.01 mmol/kg ip, whereas both compounds produced a much less rapid inactivation of type-A MAO, which was about 65% after 23 h. No potentiation of the tyramine induced increase in systolic blood pressure was found in normotensive rats following doses up to 0.01 mmol/kg ip of racemic N-0425, but a potentiation was observed after a higher dose of 0.04 mmol/kg. Levels of dopamine and noradrenaline were both increased in rat frontal cortex after the administration of N-0425, which can be interpreted as a reflection of MAO inactivation.(ABSTRACT TRUNCATED AT 250 WORDS)

The hydroxy-hexanydronaphthoxazines: a new group of very potent and selective dopamine agonists.

Replacement of the pyrrole ring system in the dopaminergic oxaergolines (e.g. RU 29717) by a phenolic OH group leads to the hydroxy-hexahydronaphthoxazines, a new group of potent dopamine agonists which exhibit increased selectivity due to their lower affinity for adrenergic and 5-HT receptors.

Factors affecting short- and long-term outcome of a short therapeutic trial with cisapride in dyspeptic patients.

In a Dutch general practice trial conducted in 599 patients with symptoms of dyspepsia, the response to 5 mg cisapride three times daily was rated excellent or good in 61% of patients at week 2. On increasing the dose to 10 mg three times daily in 132 patients with poor to moderate response, the result at the end of treatment was rated as good or excellent in 45% of these patients, and the mean symptom score further decreased significantly (p < 0.05). The longer the pretreatment duration of dyspeptic symptoms, the lower was the overall response rate to cisapride short-term therapy (80% in patients with complaints < 3 months versus 50% in those with complaints > 4 years). Cisapride also proved effective in patients previously treated with prokinetic agents (72% response rate), antacids (66%) and H2-receptor antagonists (48%). On long-term follow-up, dyspepsia relapse rates among the total patient population (n = 357) and the patient sample fully 'cured' after 4 weeks of cisapride (n = 226) were respectively 30% and 27% after 6 months. Factors affecting recurrence of dyspeptic symptoms included age, duration of symptoms prior to trial entry and mean symptom score at end of the treatment study, but not the symptom severity prior to treatment. Relapsing patients presented mainly with the same symptom profile as at the first study, and the majority (88%) responded well to repeated treatment with cisapride. In conclusion, most patients responded well to a short therapeutic trial with cisapride and remained free from relapse in the subsequent 6 months. Repeated treatment in patients with recurrent symptoms appeared to be successful.

Separation of valtrate and isovaltrate by means of preparative liquid chromatography.

In this study valtrate and isovaltrate, two isomeric valepotriates present in various Valeriana species, were separated on a preparative scale with a Waters preparative Liquid Chromatography/500 A system. A rapid separation was achieved with the solvent methylene chloride-n-propanol-acetone (99 + 0.5 + 0.5). Extensive use of the recycle mode of the instrument resulted in a considerable reduction of the amount of solvent used, without affecting the purity and the recovery (greater than 90%) of the separated components. With the method presented in this communication 1 gram of a mixture of valtrate and isovaltrate was separated in 20 minutes using 2.1 liters of solvent.

Antispasmodic effects of valeriana compounds: an in-vivo and in-vitro study on the guinea-pig ileum.

The valepotriates isovaltrate and valtrate, and the essential oil compound valeranone caused a suppression of rhythmic contractions in a closed part of the guinea-pig ileum in-vivo. The same compounds and didrovaltrate relaxed potassium stimulated contractures and inhibited BaCl2 contractions in guinea-pig ileum preparations in-vitro. Guinea-pig stomach fundic strips stimulated by carbachol were also relaxed by these substances. Potassium stimulated smooth muscle cells were also relaxed by the valeriana compounds (10(-5)-10(-4) M) even, when autonomic receptors were blocked by appropriate antagonists. In lower concentrations (10(-6)-10(-5) M), the compounds did not affect the dose-response curves of carbachol and isoprenaline. In some experiments valeranone at 4.10(-6) M produced an increased isoprenaline relaxation of the guinea-pig ileum. Valeranone and didrovaltrate were about equipotent to papaverine in inhibiting BaCl2 contractions. It is concluded that the valeriana compounds probably relax stimulated smooth muscle cells by acting as musculotropic agents and not by interacting with receptors of the autonomic nervous system.

Synthesis and some pharmacological properties of a conformationally restricted imipramine analogue.

The synthesis of the semi-rigid imipramine analogue 2-(N,N-dimethylaminomethylene)-2,3,7,8-tetrahydro-1H-quino[1,8-ab] [I]-benzazepine is described. The compound was pharmacologically evaluated in a number of general in vivo screening tests for antidepressive activity. From these preliminary tests the compound appeared to show an imipramine-like activity. However, it did not have an effect on the noradrenaline depletion by 4, alpha-dimethyl-m-tyramine. These results are discussed on the basis of the conformational requirements determining the pharmacological profile of antidepressants.