Central pharmacological control of corticosterone secretion in the intact rat. Demonstration of cholinergic and serotoninergic facilitatory and alpha-adrenergic inhibitory mechanisms.

A method is described for demonstrating the hypothalamic control of corticosterone in the intact rat. Oxotremorine 0.01--0.05 mg/kg IP and 5-hydroxy-L-tryptophan 1--50 mg/kg IP raise plasma corticosterone levels in dose-related fashion. The oxotremorine response is blocked by atropine 1 mg/kg SC and the 5-hydroxy-L-tryptophan response by mianserin 10 mg/kg IP. alpha-Methylparatyrosine methyl ester 400 mg/kg IP raises plasma corticosterone levels 14--16 h later. This rise can be suppressed by clonidine 0.01--0.05 mg/kg IP and this suppression is antagonized by piperoxane 5--50 mg/kg IP. Apomorphine 5 mg/kg IP does not lower plasma corticosterone levels in rats pre-tested with alpha-methylparatyrosine. The response to oxotremorine cannot be blocked by atropine methylbromide or by mianserin. The response to 5-hydroxy-L-tryptophan is unaffected by benserazide or atropine sulphate. These data suggest separate cholinergic and serotoninergic facilitation of corticosterone release in the intact rat. The stimulating drugs used appear to be acting centrally. The data also support the presence of a noradrenergic inhibitory system mediated by alpha-adrenoceptors. Dopaminergic receptors appear to play no part in the central control of corticosterone secretion after pre-treatment with alpha-methylparatyrosine.

Efficacy of clonidine in treatment of alcohol withdrawal state.

Clonidine hydrochloride 5 micrograms/kg and placebo were given orally to 11 patients experiencing well-developed alcohol withdrawal states. Active drug and placebo were given in a randomised, cross-over double blind fashion 2 h apart. Clonidine significantly suppressed heart rate (P = 0.002), arterial blood pressure (P = 0.006), and an accumulated score of withdrawal symptoms and signs (P = 0.004). These data suggest that clonidine may be useful in the management of alcohol withdrawal states, and that the underlying pathophysiology of at least some of these manifestations may be sympathetic nervous system hyperactivity.

The effect of repeated electroconvulsive shocks on growth hormone secretion and growth hormone responses to clonidine in the intact rat.

The effect of repeated electroconvulsive shocks (ECS) on growth hormone (GH) secretion was studied in rats. Male Sprague-Dawley animals were given one ECS daily for 10 days under halothane anaesthesia. Control animals were anaesthetised only. GH secretion was studied 24 h after the last ECS or sham procedure. Background GH secretion was significantly greater in ECS-treated than in sham-treated animals (P less than 0.001). The GH response to IV clonidine (0.01--0.1 mg/kg) did not differ between the two groups. The size of the GH response was not directly related to the basal GH secretion and could not be explained in terms of it.

A deadly spread: cellular mechanisms of α-synuclein transfer.

Classically, Parkinson's disease (PD) is linked to dopamine neuron death in the substantia nigra pars compacta. Intracytoplasmic protein inclusions named Lewy bodies, and corresponding Lewy neurites found in neuronal processes, are also key features of the degenerative process in the substantia nigra. The molecular mechanisms by which substantia nigra dopamine neurons die and whether the Lewy pathology is directly involved in the cell death pathway are open questions. More recently, it has become apparent that Lewy pathology gradually involves greater parts of the PD brain and is widespread in late stages. In this review, we first discuss the role of misfolded α-synuclein protein, which is the main constituent of Lewy bodies, in the pathogenesis of PD. We then describe recent evidence that α-synuclein might transfer between cells in PD brains. We discuss in detail the possible molecular mechanisms underlying the proposed propagation and the likely consequences for cells that take up α-synuclein. Finally, we focus on aspects of the pathogenic process that could be targeted with new pharmaceutical therapies or used to develop biomarkers for early PD detection.

Misoprostol clinical pharmacology. Establishment of activity in man.

Misoprostol has been evaluated in healthy subjects for both antisecretory and pharmacological activity. Doses used were determined initially from acute and chronic tolerance testing in healthy subjects. In the single dosage range of 50-200 micrograms, misoprostol inhibits gastric acid secretion in a dose-related manner both in the basal state and after stimuli such as histamine and standard test meals. The 200 micrograms dose differs significantly from placebo as an antisecretory agent. A preliminary study in six subjects suggested that the 400 micrograms dose does not produce a substantial increase in activity over the 200 micrograms dose. Furthermore, side-effects such as diarrhea and abdominal cramps appear to be dose related. The antisecretory action of misoprostol is maximal one hour after drug administration and is negligible after 4-5 hours. These factors have until now dictated a 50-200 micrograms q.i.d. dosing regimen for misoprostol in clinical trials against peptic ulcer. Misoprostol does not significantly affect platelet function in terms of ADP-, collagen- and thrombin-induced platelet aggregation. Measurements of FEV1, vital capacity, and peak expiratory flow rate have revealed that misoprostol has no significant bronchodilating or bronchoconstricting effect. Studies of endocrine function revealed only a slight rise within the normal range in serum cortisol in women.

A comparison of propranolol and compound RO3-4787 in the treatment of arterial hypertension in man.

1. The effects of propranolol and RO3-4787, a new beta-adrenoceptor antagonist with a partial agonist activity, have been studied in a blind, cross-over comparison with placebo. 2. In ten patients who completed the study, the two drugs produced a similar reduction in blood pressure; the reduction in heart rate with propranolol was significantly (P less than 0.001) greater than that produced by RO3-4787. 3. Plasma renin activity averaged 4.13 +/- 1.37 ng h-1 ml-1 on placebo, fell to 3.64 +/- 1.47 ng h-1 ml-1 on propranolol and to 2.50 +/- 1.39 ng h-1 ml-1 on RO3-4787. 4. No correlation was demonstrable between the log plasma concentration of either propranolol or RO3-4787 and change in blood pressure.

Plasma levels of nitroglycerin generated by three nitroglycerin patch preparations, Nitradisc, Transiderm-Nitro and Nitro-Dur and one ointment formulation, Nitrobid.

Twenty-four healthy male subjects participated in a study comparing plasma concentrations of nitroglycerin generated by single applications of Nitradisc 32 mg, Transiderm-Nitro 50 mg and Nitro-Dur 104 mg patches and from one inch of Nitrobid 2% ointment. The three patch preparations are designed to release 10 mg nitroglycerin systemically over a 24 h period. Nitrobid ointment is intended to deliver 15 mg nitroglycerin per inch of ointment, and to be reapplied at least every 8 h. Blood was taken for nitroglycerin assay up to and including 24 h after each application. Assay for nitroglycerin was performed using a gas chromatography-mass spectrometry technique. Plasma concentrations of nitroglycerin were sustained up to the 24 h mark with all three patch preparations, but not with application of Nitrobid ointment. Nitrobid was associated with a rapid rise in nitroglycerin plasma concentrations maximal 1 h after application. Plasma concentrations of nitroglycerin absorbed from Nitrobid ointment fell below those absorbed from all three patch preparations after 8 h. Clinically, all four formulations were similar with respect to side effects, with headache and dizziness being the most common.

Pharmacokinetics of lidocaine and its deethylated metabolite: dose and time dependency studies in man.

The concentrations of lidocaine and of its deethylated metabolite, MEGX, were measured in blood following the intravenous administration of 50 and 100 mg lidocaine hydrochloride, the oral administration of 100, 300, and 500 mg lidocaine hydrochloride monohydrate, and the oral administration of 300 mg lidocaine hydrochloride monohydrate every 8 h for seven doses, to three healthy volunteers. The range of values for the parameters defining the disposition kinetics of lidocaine were: terminal half-life, 50-231 min; total clearance, 13-17 ml/min/kg; initial dilution space, 0.13-2.5 liters/kg; and volume of distribution at steady state, 0.6-4.5 liters/kg. Lidocaine absorption from solution was rapid, but due to presystemic hepatic metabolism, the availability was low, the range of average values lying between 0.19 and 0.38. No dose or time dependency in lidocaine and monoethylglycinexylidide pharmacokinetics following the single dose studies of lidocaine were noted. Effective hepatic blood flow, based on total clearance and availability measurements, was estimated to be 18-27 ml/min/kg. The concentrations of MEGX were approximately one-third of those of lidocaine following intravenous lidocaine and were comparable following oral lidocaine, but as predicted, the dose normalized area under the MEGX concentration-time curve was constant and independent of the route of administration of lidocaine. In two subjects, the blood concentrations of lidocaine and MEGX following multiple doses of oral lidocaine were those predicted from the single dose studies. In the third subject, the degree of accumulation of lidocaine was greater than predicted. The reasons and mechanism for this difference between subjects on multiple dosing remains unclear.

Comparison of prizidilol hydrochloride (SK & F 92657), a new antihypertensive agent with beta-adrenoceptor antagonist and vasodilator activity with propranolol and hydralazine in normal volunteers.

1 Some cardiovascular pharmacology of prizidilol hydrochloride, a new antihypertensive compound with precapillary vasodilator and beta-adrenoceptor antagonist activity, in man is described. 2 To investigate further the pharmacological profile of this drug the effects of a single oral dose of 400 mg prizidilol hydrochloride were compared with propranolol 40 mg in combination with either 25 mg or 50 mg of hydralazine for up to 6 h after dosing, in a placebo controlled in eight healthy subjects. 3 Prizidolol hydrochloride significantly reduced supine and standing diastolic blood pressure and was more effective than propranolol combined with either dose of hydralazine in this respect. 4 Supine heart rate was significantly increased after prizidilol hydrochloride, but was not significantly changed after propranolol combined with either dose of hydralazine. The reasons for the increase in supine heart rate after prizidolol are discussed. 5 beta-adrenoceptor antagonism was assessed in terms of inhibition of exercise induced increases in heart rate and systolic blood pressure. At the doses used, prizidolol hydrochloride was less effective than propranolol and hydralazine combined, particularly during the first 3 h after dosing.

Effect of beta-adrenoceptor antagonists on prevalence of peripheral vascular symptoms in hypertensive patients.

1 Eight hundred patients were approached by questionnaire to give details of side effects of their antihypertensive medications. The response rate was 72.8%. The percentage of those questioned who were taking beta-adrenoceptor antagonists at the time was 54.6%. 2 Raynaud's phenomenon (P less than 0.05) and complaints of cold extremities (P less than 0.001) were significantly more frequent in women than in men, 74.8% of women complained of cold extremities. 3 Exposure to beta-adrenoceptor antagonists did not increase the prevalence of Raynaud's phenomenon in either men or women in the study, but did increase the prevalence of cold extremities in men (P less than 0.001). Propranolol, labetalol, oxprenolol and possibly atenolol were likely to produce such side effects. Smoking and the addition of vasodilators did not alter the effect of beta-adrenoceptor blockers on peripheral vascular symptoms. Complaints of cold extremities were not associated with an excess of complaints of other side effects.

Disposition of bemitradine, a renal vasodilator and diuretic, in man.

1. 14C-Bemitradine (50 mg) was rapidly and efficiently absorbed (approximately 89%) in man following a single oral dose, as a solution in gelatine capsules. Peak 14C levels of 895 +/- 154 ng equiv./ml (mean +/- S.E.M.) were reached within 2 h, and declined with half-lives of 1.07 +/- 0.25 and 13.0 +/- 5.6h. 2. No bemitradine was detected in plasma, but peak concn. (124 +/- 29 ng/ml) of its desethyl metabolite were reached at 1.05 +/- 0.28 h, and declined with a half-life of 1.32 +/- 0.08 h. 3. Desethylbemitradine was rapidly metabolized to its ether glucuronide, a phenol and a dihydrodiol which were also present as glucuronide conjugates. The glucuronides were the major compounds in plasma from 2 h after drug administration. 4. Excretion in 5 days amounted to 88.8 +/- 2.3% and 10.4 +/- 2.1% dose in urine and faeces respectively. No bemitradine or desethylbemitradine were excreted unchanged. 8-(2-Hydroxyethyl)-7-(3,4- dihydroxycyclohexa-1,5-dienyl)-1,2,4-triazolo-1,5c-pyrimidin e-5-amine (E; 17% dose); 8-(2-hydroxyethyl)-7-(4-hydroxyphenyl)-1,2,4-triazolo-1,5c- pyrimidine-5-amine (F; 4% dose), their glucuronides (A, 19% dose and B, 6% dose respectively), desethylbemitradine glucuronide (D, 25% dose) and an unidentified metabolite (C, 12% dose) were excreted in urine. Compound F was the major faecal metabolite.

Disposition of 3H-enisoprost, a gastric antisecretory prostaglandin, in healthy humans.

1. After oral administration of 3H-enisoprost (450 micrograms) to five healthy men, as a solution in capsules, peak 3H levels of 5624 +/- 566 pg equiv./ml (mean +/- S.E.M.) were reached within one hour. No unchanged drug was detected in plasma. 2. Enisoprost was rapidly de-esterified to SC-36067 [(+/-)11 alpha, 16 zeta-dihydroxy-16-methyl-9-oxoprost-4Z, 13E-dien-1-oic acid], a pharmacologically active analogue, which reached peak concentrations of 651 +/- 200 pg/ml within 20 min of dosing. SC-36067 was eliminated metabolically, with a half-life of 1.61 h, by a combination of beta-oxidation, omega-oxidation and 9-keto-reduction. 3. After nine days 59.0 +/- 2.98% and 17.4 +/- 1.57% of the dose was excreted in urine and faeces respectively. The majority of this excretion was complete in two days. 4. Five urinary metabolites were identified by GC-MS. These were (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-3 alpha-hydroxy-5-oxo-1 alpha-cyclopentanyl]propanoic acid (SC-41411; 3.6% dose), (+/-)3-[3 alpha,5-dihydroxy-2 beta-(4-hydroxy-4-methyl-1E-octenyl)-1 alpha-cyclopentanyl]propanoic acid (SC-41411 PGF analogue; 4.8% dose), (+/-)3-[2 beta-(8-carboxy-4-hydroxy- 4-methyl-1E-octenyl)-3 alpha-hydroxy-5-oxo-1 alpha-cyclopentanyl] propanoic acid (SC-41411-16-carboxylic acid; 22% dose), (+/-)3-[2 beta-(8-carboxy-4- hydroxy-4-methyl-1E-octenyl)-3 alpha,5-dihydroxy-1 alpha-cyclopentanyl] propanoic acid (SC-41411 PGF analogue-16-carboxylic acid; 8.5% dose) and its gamma lactone (2.6% dose). 5. These metabolites were also identified chromatographically in plasma, as were SC-36067, (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-1 alpha- cyclopent-3-enyl]propanoic acid and (+/-)3-[2 beta-(4-hydroxy-4-methyl-1E-octenyl)-5-oxo-cyclopent-1- propanoic acid. 6. Some 5-10% of the dose was excreted in urine as tritiated water, indicating that oxidation of the 11 alpha-hydroxy group in SC-36067 or its metabolites also occurred.

Single- and multiple-dose pharmacokinetics of nufenoxole in healthy human subjects.

1. In 12 healthy subjects, after single doses of 20, 40 and 80 mg of nufenoxole, mean peak plasma drug concentrations of 400, 815 and 1463 ng/ml were reached at 2.2, 2.5 and 2.5 h respectively. 2. Nufenoxole was absorbed with an apparent half-life of less than one hour at all three doses. Nufenoxole concentrations declined biphasically after the peak, with an initial and terminal half-life of four to five hours and about 27 h respectively. These half-lives were independent of the administered dose. 3. AUC and Cmax increased with increasing dose, but AUC did not increase proportionately to dose, due to a lower value for 80 mg than expected, possibly reflecting reduced absorption. 4. Observed nufenoxole concentrations, in another 12 healthy subjects receiving single, daily 80 mg oral doses of nufenoxole for eight days, were in excellent agreement with those predicted from single-dose pharmacokinetics.