The effects of oxytocin on the pattern of electrical propagation in the isolated pregnant uterus of the rat.

In the isolated pregnant myometrium of the rat, the pattern of propagation was investigated by recording simultaneously from 240 different extracellular sites while the contraction of the tissue was recorded isometrically. Analysis of all recorded electrograms allowed the two-dimensional spread of activity in the myometrium to be reconstructed. From these activation maps, the conduction velocities were measured in the longitudinal, oblique and transversal directions. At low concentrations (10(-9 )and 5x10(-9) M), oxytocin significantly increased the frequency and duration of electrical bursts and the average spike intervals, without affecting the homogeneity of action potential propagation, concomitant with a significant increase in the amplitude of contractions. At high concentrations (10(-8) and 5x10(-8) M), oxytocin induced conduction blocks and the size of inexcitable areas was increased, concomitantly with an increase in muscle contractures. In contrast, the conduction velocities in the longitudinal, oblique and circular directions were not influenced by oxytocin at any concentrations.

Pharmacokinetics of enrofloxacin after intravenous, intramuscular and oral administration in houbara bustard (Chlamydotis undulata macqueenii).

The in-vitro activity of enrofloxacin against 117 strains of bacteria isolated from bustards was determined. Minimum inhibitory concentrations for 72% of the Proteus spp., E. coli, Salmonella spp. and Klebsiella spp. (n = 61) and for 48% of the Streptococci spp. and Staphylococci spp. (n = 31) were < or = 0.5 microg/mL. The minimum inhibitory concentration (MIC) of 76% of Pseudomonas spp. (n = 25) was < or = 2 microg/mL. Fourteen strains were resistant to concentrations > or = 128 microg/mL. The elimination half-lives (t1/2 elim beta) (mean +/- SEM) of 10 mg/kg enrofloxacin in eight houbara bustards (Chlamydotis undulata) were 6.80 +/- 0.79, 6.39 +/- 1.49 and 5.63 +/- 0.54 h after oral (p.o.), intramuscular (i.m.) and intravenous (i.v.) administration, respectively. Enrofloxacin was rapidly absorbed from the bustard gastro-intestinal tract and maximum plasma concentrations of 1.84 +/- 0.16 microg/mL were achieved after 0.66 +/- 0.05 h. Maximum plasma concentration after i.m. administration of 10 mg/kg was 2.75 +/- 0.11 microg/mL at 1.72 +/- 0.19 h. Maximum plasma concentration after i.m. administration of 15 mg/kg in two birds was 4.86 microg/mL. Bioavailability was 97.3 +/- 13.7% and 62.7 +/- 11.1% after i.m. and oral administration, respectively. Plasma concentrations of enrofloxacin > or = 0.5 microg/mL were maintained for at least 12 h for all routes at 10 mg/kg and for 24 h after i.m. administration at 15 mg/kg. Plasma enrofloxacin concentrations were monitored during the first 3 days of treatment in five houbara bustards and kori bustards (Ardeotis kori) with bacterial infections receiving a single daily i.m. injection of 10 mg/kg for 3 days. The mean plasma enrofloxacin concentrations in the clinical cases at 27 and 51 h (3.69 and 3.86 microg/mL) and at 48 h (0.70 microg/mL) were significantly higher compared with the 3 h and 24 h time intervals from clinically normal birds. The maximum plasma concentration (Cmax)/MIC ratio was ranked i.v. (10/mg/kg) > i.m. (15 mg/kg) > i.m. (10 mg/kg) > oral (10 mg/kg), but it was only higher than 8:1 for i.v. and i.m. administrations of enrofloxacin at 10 mg/kg and 15 mg/kg, respectively, against a low MIC (0.5 microg/mL). A dosage regimen of 10 mg/kg repeated every 12 h, or 15 mg/kg repeated every 24 h, would be expected to give blood concentrations above 0. 5 microg/mL and hence provide therapeutic response in the bustard against a wide range of bacterial infections.

A randomized, double-blind comparison of the antihypertensive efficacy and safety of once-daily losartan compared to twice-daily captopril in mild to moderate essential hypertension.

INTRODUCTION: The antihypertensive efficacy and safety of losartan, a specific and selective angiotensin II (AII) receptor antagonist, was compared to captopril in patients with mild or moderate essential hypertension. DESIGN: This multinational, randomized trial consisted of a 4-week single-blind, placebo baseline period followed by a 12-week double-blind, parallel comparison of once-daily administration of losartan 50 mg or twice-daily administration of captopril 25 mg. After 6 weeks of treatment, the daily dosage was doubled in patients whose sitting diastolic blood pressure (SiDBP) remained > or = 90 mm Hg. PATIENTS: Patients with essential hypertension having a mean trough SiDBP of 95-115 mm Hg after the placebo baseline period were randomized to losartan (N = 192) or captopril (N = 204) treatment. MAIN OUTCOME MEASURES: The primary efficacy variable was the mean change from baseline to Week 12 in trough SiDBP. Safety was assessed by recording spontaneously reported or observed adverse experiences and clinical laboratory measurements. RESULTS: After 12 weeks, both treatments produced clinically important reductions in trough SiDBP and sitting systolic blood pressure (SiSBP). These mean reductions (SiDBP, SiSBP) were significantly greater in the losartan group (-11.5 and -15.4 mm Hg, respectively) than in the captopril group (-9.3 and -12.2 mm Hg, respectively) (p = 0.010 for diastolic and p = 0.023 for systolic). The percentage of patients exhibiting an excellent (trough SiDBP < 90 mm Hg) or good (trough SiDBP > 90 mm Hg, with decrease of > or = 10 mm Hg) antihypertensive response to losartan and captopril therapy at Week 12 was comparable (60.0% and 54.7%, respectively). The percentage of patients reporting a clinical adverse experience considered drug-related by the investigator was 13% in the captopril group and 10% in the losartan group. The incidence of drug-related cough was 2.6% in the losartan group and 4.4% in the captopril group. CONCLUSION: Once daily administration of losartan 50 to 100 mg is an effective treatment for patients with essential mild to moderate hypertension. The antihypertensive efficacy of losartan 50/100 mg is significantly greater than that of twice daily captopril 25/50 mg. Both treatments were generally well-tolerated. The number of patients with the side effect of cough was higher following captopril.

Circadian variation of alpha 1-adrenoceptor-mediated pressor response to phenylephrine in man.

The variability in the pressor effects of the alpha 1-adrenoceptor agonist phenylephrine was observed under placebo conditions in ten healthy subjects in a double blind randomized study. Phenylephrine infusions were administered before administration of placebo (baseline) and 2, 4, 8, 12, 24 and 48 h later. The doses of phenylephrine required to increase systolic blood pressure by 20 mmHg after 8 and 12 h (5.30 and 9.30 pm, 81.4 +/- 15.3 and 71.1 +/- 16.0 micrograms min-1, respectively) were significantly (P < 0.01) less than the baseline values (8.30 am, 108.0 +/- 27.6 g min-1). These results might indicate a circadian variation in the phenylephrine-induced alpha-adrenoceptor-mediated vascular response in healthy subjects. These observations lend further insight into circadian variations of vascular tone that might contribute to circadian rhythms in cardiovascular disease.

Paracetamol prescribing--an epidemic?

BACKGROUND: Although we are uncertain of its therapeutic mechanism, paracetamol is seen as a safe drug, especially for children. However, adult fatalities from overdose and its association with hepatotoxicity have cast doubt on its safety. OBJECTIVE: We aimed to establish the prescribing patterns of paracetamol in the United Arab Emirates (UAE). METHOD: The prescribing patterns in the UAE for paracetamol were studied by obtaining information on national utilization and recording in detail the pattern of prescribing in one primary health care centre. RESULTS: Paracetamol was included in 35.5% of all prescriptions from the study practice. Of these, 58.5% were for children under 12 years of age and overall 13.5% were for those infants under one year of age. CONCLUSIONS: National prescribing utilization is in keeping with the prescribing patterns of the index practice. Paracetamol prescribing is reaching epidemic proportions and the potential dangers of hepatotoxicity and the inhibition of the immune response in children are discussed.

Doing randomized controlled trials in a developing country: some practical realities.

BACKGROUND: Formal randomized controlled trial results are often reported. The difficulties of doing such trial are not. Developing countries represent a new field in which trials can be undertaken. In this context even less is known about the practicalities involved. METHOD AND RESULTS: A randomized, double-blind, parallel study took significantly longer than expected to complete and subject recruitment and participation fell short of expectations. Different recruitment strategies were used and these performed differently in terms of enrolling trialists. Subjects most frequently left the trial in its early stages. CONCLUSIONS: Possible explanations for these findings include the demography of the country, cultural factors, and the existence of an established doctor-patient relationship.

Effects of rilmenidine and clonidine on the electroencephalogram, saccadic eye movements, and psychomotor function.

Rilmenidine is a novel oxazoline derivative that is effective in the treatment of hypertension. Studies in animals have indicated that rilmenidine may reduce blood pressure without the associated central alpha 2 side effects of clonidine. The aim of this double-blind, crossover, placebo-controlled study was to evaluate the hypotensive and central sedative effects of single oral doses of rilmenidine (1 or 2 mg), clonidine (150 or 300 micrograms), and lorazepam (2.5 mg) in 12 healthy male volunteers. Drug effects were assessed with a test battery composed of resting electroencephalogram, auditory evoked responses (AERs), saccadic eye movements, psychomotor performance, and subjective ratings as well as blood pressure and heart rate. Rilmenidine and clonidine produced similar dose-dependent reductions in blood pressure without an effect on heart rate. Saccadic eye movements were not significantly impaired after rilmenidine (1 mg) treatment in contrast to after clonidine (150 micrograms) treatment. Peak saccadic velocity was impaired by all drugs except rilmenidine (1 mg), which was indistinguishable from placebo. The electroencephalographic spectral analysis also demonstrated greater sedation with lorazepam than with the other drugs and greater vigilance with placebo and rilmenidine (1 mg) than with lorazepam. AERs showed a differentiation in sedative effects between lorazepam and clonidine (300 micrograms) relative to placebo, rilmenidine (1 mg), and clonidine (150 micrograms). These results are consistent with the hypothesis that at lower doses, rilmenidine may act preferentially through imidazoline receptors, whereas at higher doses, alpha 2-adrenoceptors may become activated.

Propranolol reduces mortality in patients with portal hypertension secondary to schistosomiasis.

Although beta-adrenoceptor antagonists improve morbidity and mortality in patients with portal hypertension associated with cirrhosis, this has not been demonstrated in non-cirrhotic patients. In the present, double-blind, 24-month, prospective study of patients with endoscopically-proven varices and ultrasonographically-confirmed hepatic fibrosis, the effects of propranolol 160 mg LA and placebo on the incidence of rebleeding and mortality were compared in 82 patients with portal hypertension secondary to schistosomiasis. The results, analysed on intention-to-treat basis, indicated a reduction in rebleeding (median time to rebleeding 589 days for propanol v. 252 days for placebo; P < 0.02) and increased survival in the propranolol-treated patients (three deaths v. seven deaths on placebo; P < 0.02). Fifteen patients withdrew from the propranolol group and 18 from the placebo group. A positive prognostic indicator was a large portal vein diameter whereas a small liver size indicated a negative outcome.

Pharmacokinetic interaction between praziquantel and albendazole in Sudanese men.

It has been suggested that praziquantel (40 mg/kg) and albendazole (400 mg) administered together may have a synergistic effect on intestinal parasites. In the present study, the pharmacokinetics of these agents, alone and in combination, were investigated in the presence and absence of food in two groups of Sudanese males. The results indicated that praziquantel pharmacokinetics were not effected by co-administration of albendazole although, in the presence of food, the area under the curve (AUC(0-infinity)) of praziquantel increased 2.6 fold. The AUC(0-infinity) of albendazole sulphoxide (the active metabolite of albendazole) increased 4.5-fold when administered with praziquantel, eight-fold when given with food and 12-fold when given with praziquantel and food. The balance between the therapeutic efficacy of this combination of drugs and its safety profile needs to be studied, especially with regard to albendazole.

Fast and reliable QRS alignment technique for high-frequency analysis of signal-averaged ECG.

The process of QRS alignment as required in signal-averaged ECG can impose serious limitations on the spectral range of the signal output. This effect depends basically on the particular alignment technique being used and on the level and type of noise present in the recorded ECG. In clinical studies where a wide-band (1000 Hz) ECG averager is required, the conventional QRS alignment technique, based on maximum coherence matching (MCM) with a template beat, may not perform consistently well. An alternative QRS alignment technique based on the accurate detection of a single fiducial point (SFP) in the bandpass filtered (3-30 Hz) QRS complex was developed. Using computer simulation methods, a comparative assessment of the frequency bandwidths (3 dB points) offered by both MCM and SFP techniques as a function of noise level (15-100 muRMS) and type (EMG and 50 Hz interference), was carried out. The results of the comparative assessment indicated a better performance by the SFP technique in all cases of noise. Hence, the SFP technique would perform more reliably for high-frequency analysis of a noisy ECG, especially when 50 Hz interference is high. Furthermore, SFP is considerably faster than MCM (about four times) when implemented digitally, and its analogue realisation is feasible. The SFP technique is suitable for late-potential analysis in the signal-averaged ECG.

Time and frequency domain assessment of heart rate variability: a theoretical and clinical appreciation.

Non-invasive techniques for assessing heart rate variability can be used either diagnostically, as in identification of autonomic neuropathy associated with diabetes mellitus or tissue rejection following cardiac transplantation, or as a prognostic indicator in coronary artery disease. The methodology is based upon calculation of successive R-R intervals from an electrocardiogram, which can then be plotted as a frequency histogram (time domain analysis), undergo power spectral analysis to yield information in the frequency domain or be applied to chaos theory. In this review, several parameters are discussed which can be derived to quantify heart rate variability in the time and frequency domains; the latter providing information on autonomic balance. In the frequency domain up to three peaks may be observed, with the peak below 0.15 Hz being mediated by sympathetic and parasympathetic activity and peaks above 0.15 Hz being of vagal origin. The effects of different physiological and pathophysiological conditions on various indices of heart rate variability, and the use of heart rate variability analysis as a pharmacological method to assess the impact of drug therapy on sympathovagal balance are discussed.

Pharmacodynamics and pharmacokinetics of the class III antiarrhythmic agent dofetilide (UK-68,798) in humans.

The pharmacodynamics, pharmacokinetics, safety, and tolerance of the class III antiarrhythmic dofetilide (UK-68,798) were evaluated in two groups of healthy volunteers; first, single oral escalating doses (1, 2, 5, 7.5, and 10 micrograms/kg with random insertion of placebo) were administered in a double-blind manner and, second, its intravenous (0.5 mg) and oral (0.5 mg) administration were compared in an open two-way crossover design. Oral dofetilide from 5 micrograms/kg produced significant dose-dependent prolongations of the QTc interval compared to placebo. Maximal mean QTc prolongations were 5 micrograms/kg, 29 ms (7%) at 2 h; 7.5 micrograms/kg, 35 ms (9%) at 6 h; and 10 micrograms/kg, 47 ms (12%). Following i.v. infusion of dofetilide (0.5 mg) (n = 9), the QTc interval significantly increased from 401 +/- 26 to 504 +/- 105 ms at the end of the infusion. One subject exhibited excessive prolongation of his QTc interval (451-808 ms) 5 min after the infusion, which was associated with an asymptomatic run (5 beats) of polymorphic ventricular tachycardia and several multifocal ventricular ectopic beats. Following oral administration of dofetilide (0.5 mg) (n = 9), the QTc interval increased significantly from 396 +/- 27 ms to a maximum of 445 +/- 27 ms at 2 +/- 0.9 h postdosing. No changes occurred in PR intervals and QRS width. Small changes occurred in the heart rate and blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of rilmenidine on tests of autonomic function in humans.

The effects of rilmenidine, a new centrally acting antihypertensive agent, on a number of tests of autonomic function were investigated in six healthy male volunteers. Baroreflex function (delta RR interval [in milliseconds] with each millimeter of mercury change in systolic blood pressure) was determined in response to changes in pressure after injections of phenylephrine and nitroglycerin. Reflex cardiovascular responses to handgrip and standing, as well as during deep breathing and the Valsalva maneuver, were also investigated. Rilmenidine produced a dose-dependent decrease in blood pressure that was not accompanied by an increase in heart rate. Under conditions of low basal sympathetic activity, rilmenidine enhanced parasympathetic tone during the early reflex heart rate changes that occur immediately after standing and during deep breathing, as well as baroreflex heart rate responses to phenylephrine. During a test of sympathetic function, standing blood pressure, and heart rate after 3 minutes, rilmenidine reduced sympathetic tone.

Cibenzoline. A review of its pharmacological properties and therapeutic potential in arrhythmias.

Cibenzoline is a class I antiarrhythmic drug with limited class III and IV activity which can be administered orally or intravenously. An elimination half-life of about 8 to 12 hours permits twice daily administration, although age and renal function must be considered when determining dosage. Cibenzoline has some activity in ventricular and supraventricular arrhythmias, including drug-refractory ventricular tachycardia or ventricular arrhythmias following recent acute myocardial infarction, although results in patients with sustained ventricular tachycardia are less promising. In comparative trials, cibenzoline has demonstrated efficacy similar to or better than that of a variety of other class I antiarrhythmic drugs and was at least as well tolerated, with a more convenient dosage schedule. However, further studies to clarify the proarrhythmic effects of cibenzoline and its use in patients with impaired left ventricular function are required, and the use of cibenzoline (and other class I antiarrhythmic agents) in patients with other than potentially lethal ventricular arrhythmias should be avoided following the results of the CAST studies. Thus, cibenzoline is an effective antiarrhythmic agent with a favourable pharmacokinetic profile that may be considered with other class I drugs in patients requiring therapy for high risk arrhythmias.

Distinctive features of rilmenidine possibly related to its selectivity for imidazoline receptors.

Rilmenidine is an oxazoline derivative with antihypertensive activity which was developed to enhance the dissociation between the hypotensive and adverse effect profile of centrally acting agents. Experimental studies have indicated that rilmenidine is selective for both alpha 2-adrenoceptors (v alpha 1) and newly discovered nonadrenergic imidazoline receptors in the brain and in the periphery. In experimental studies, rilmenidine differs from clonidine in that it is more selective for imidazoline receptors than for alpha 2-adrenoceptors; at equihypotensive doses, rilmenidine causes less bradycardia and reduction in cardiac output, less sedation, and little or no antinociceptive action compared to clonidine. The hypotensive effects of rilmenidine are antagonised by idazoxan and yohimbine, but idazoxan (imidazoline structure) is six times more potent than yohimbine (a selective alpha 2-antagonist). In isolated renal proximal tubule cells, where imidazoline binding has also been shown, rilmenidine inhibits reabsorption of sodium. Clinical studies comparing 1 mg rilmenidine with placebo demonstrated significant reductions in blood pressure (BP) (61% rilmenidine v 23% placebo normalized to 160/90 mm Hg). The reduction in BP was not associated with classical alpha 2 side effects such as dry mouth or daytime drowsiness. Compared with clonidine (0.15 to 0.3 mg), equihypotensive doses of rilmenidine (1 to 2 mg) induced two to three times less dry mouth, daytime drowsiness, and constipation; no orthostatic hypotension was reported. Methyldopa (0.5 to 1 mg) v rilmenidine (1 to 2 mg) indicated a comparable reduction of BP with significantly less weakness, drowsiness, orthostatic dizziness, and dry mouth on rilmenidine; there was no evidence of the "clonidine withdrawal syndrome" on drug withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Time-dependence of inducible ventricular tachycardia in a chronic canine model.

The natural history of inducible ventricular tachycardia in post-infarction dogs was followed with serial programmed electrical stimulation (PES: 1-3 extrastimuli, 4 msec duration, 2 x diastolic threshold). Arrhythmia inducibility was defined as a minimum of four unstimulated ventricular ectopic beats. Of 119 dogs prepared for chronic electrophysiological study, 87 (73.1%) were ambulant 24 hours after surgery. Mean infarct size was 11.1 +/- 1.5% of left ventricular (LV) mass for animals dying in the first week, before stimulation. 92.4% of 66 animals were inducible when stimulated at one week, 66.7% at two weeks and 64.3% and 55.6% at the third and fourth weeks respectively (p less than 0.01, Chi-square analysis). Infarct sizes fell from 7.0 +/- 0.5% LV mass at first stimulation to 4.6 +/- 0.8% at third stimulation and could not be visualized thereafter (p less than 0.01,ANOVA). There was no statistical difference between infarct sizes for inducible and non-inducible animals, but in both cases infarcts were smaller (p less than 0.01) than for those animals which died suddenly during the first week. This time-dependent decrease in arrhythmia inducibility, which may be related to infarct size, should be considered when similar models are employed for chronic electrophysiological studies.