Sensory signalling effects of tegaserod in patients with irritable bowel syndrome with constipation.

Tegaserod relieves overall and multiple individual constipation-predominant irritable bowel syndrome (IBS-C) symptoms. However, mechanisms for the relief of abdominal pain/discomfort are not well understood. The effects of tegaserod on rectal sensitivity to distension were measured by the nociceptive flexion RIII reflex, as evidenced by spinal hyperexcitability (i.e. increase or facilitation of the RIII reflex), in IBS-C patients. A randomized, double-blind, placebo-controlled, parallel study was performed in 30 women with IBS-C. The effects of slow ramp rectal distension on the RIII reflex, recorded from the lower limb, were measured before [first experimental day (D1)] and after 7 days [day 8 (D8)] of placebo (n=15) or 6 mg tegaserod bid (n=15). Pressure-volume and sensation-volume relationships were measured during distension, and patients reported their IBS symptoms daily. On D1, rectal distension facilitated the RIII reflex in both treatment groups. On D8 vs D1 these facilitatory effects were significantly lower (P<0.001, analysis of variance) after tegaserod (mean reduction: -30.3+/-11.9%) than placebo (mean reduction: -10.1+/-12.9%). No significant changes in the volume-sensation relationship or differences in compliance were observed with tegaserod or placebo. In conclusion, tegaserod reduces the facilitatory effects of rectal distension on the RIII reflex in women with IBS-C.

Guanfacine kinetics in patients with hypertension.

Guanfacine kinetics were studied in 19 patients with hypertension after single and repeated oral doses. The single-dose study was performed in two homogeneous groups who received 2 mg (n = 9) and 4 mg (n = 10). The plasma concentrations were fitted in a two-compartment open model with first-order absorption. After a lag time of 0.8 hr, the absorption occurred rapidly (t 1/2 congruent to 0.53 hr). The fast and slow elimination phases occurred with t 1/2s of 2 and 19 hr. At therapeutic levels the percent of drug in red blood cells (55%) was independent of total drug concentration. Peak plasma levels had small interindividual variations. Comparison of kinetic parameters and AUC at the two doses studied demonstrated that their bioavailability was equal and the kinetics were linear. In a multiple-dosing study, performed in the same subjects, the plasma levels at steady state were in good agreement with the predicted values (p less than 0.001) and proportional to daily dosage. A single method based on four blood samples collected after 24, 28, 32, and 36 hr allows a reasonable prediction of the effective steady-state plasma levels during chronic dosing with guanfacine.

Reliability of clinical criteria for the diagnosis of dementia. A longitudinal multicenter study.

The reliability of the clinical diagnosis of dementia was estimated by comparing the diagnosis made at 1-year intervals on 55 consecutive subjects with suspected cognitive impairment seen at three different centers by neurologists and gerontologists. The diagnosis was based on history and clinical examination, the criteria of the Diagnostic and Statistical Manual of Mental Disorders (revised ed 3), the Modified Ischemic Score, and a computed tomographic scan. Fifty-two of 55 subjects were given the same diagnosis a year later indicating a reliability of 95%. The study shows that a diagnosis of dementia established by simple clinical criteria comparable to the NINCDS/ADRDA criteria affords sufficient reliability to allow the comparability of groups at different centers for purposes of research, including research on the evaluation of the efficacy of pharmacologic treatment.

Does long-term aggravation of Parkinson's disease result from nondopaminergic lesions?

The motor score with and without levodopa was estimated in 193 parkinsonian patients with variable length of evolution. The effect of levodopa on akinesia, rigidity, and tremor remained quite stable during the course of the disease. In contrast, the aggravation of gait disorder, postural instability, and dysarthria was more severe, with decreased percentage of improvement on levodopa in patients with longer evolution. It is suggested that aggravation of Parkinson's disease mainly results from increasing severity of cerebral nondopaminergic lesions.

Antihypertensive effects and plasma levels of guanfacine in man.

The antihypertensive effect and the plasma levels of guanfacine were studied for two months in 25 patients with sustained essential hypertension. In three patients, blood pressure was unchanged. In ten patients, blood pressure returned to the normal range within 15 days, at a daily dose of 2 mg. In 12 patients, increasing doses were necessary to normalize the blood pressure within two months. In these cases, the decrease in systolic pressure was negatively correlated with the daily dose of guanfacine (r = -0.40) and the steady-state plasma level (r = -0.62; P less than 0.01); analysis of the curves showed that the normalization of blood pressure coincided with a plasma drug level of 8 ng/ml, i.e., a 4-mg daily dose. This study demonstrated the efficacy of guanfacine monotherapy in hypertension and suggests that the normalization rate of blood pressure levels does not further increase with daily doses higher than 4 mg.

Pharmacokinetics and hepatic extraction ratio of pindolol in hypertensive patients with normal and impaired renal function.

The intravenous and oral pharmacokinetics and the hepatic extraction ratio of pindolol were determined in 24 hypertensive patients with normal or impaired renal function. In patients with normal renal function, the total clearance was the sum of equal parts of the renal and nonrenal clearances. The nonrenal clearance was found to be equal to the hepatic clearance directly measured from the hepatic extraction ratio. Compared to patients with normal renal function, patients with chronic renal failure exhibited (i) unchanged K12 and K21 and nonrenal clearances, and (ii) significantly decreased values in half-life of the beta phase, Kel, and total renal clearance. The renal clearance was positively correlated (P less than 0.01) to the creatinine clearance. Bioavailability was significantly reduced (P less than 0.01) in the patients with renal failure. Assuming that the nonrenal clearance was equal to the hepatic clearance, the study provides evidence that, in patients with renal insufficiency, (i) no increased metabolism accompanies the decrease in renal function, and (ii) decreased availability is due to reduced absorption.

Comparison of nicardipine and sodium nitroprusside in the treatment of paroxysmal hypertension following aortocoronary bypass surgery.

In an open, randomized, multicenter trial, intravenous nicardipine was compared with sodium nitroprusside in 74 patients with hypertension (mean arterial pressure [MAP] greater than or equal to 100 mm Hg) following coronary artery bypass surgery. Nicardipine was administered as a 2.5- to 12.5-mg bolus followed by a 2 to 4 mg/h infusion, and nitroprusside as a 0.5 to 6.0 micrograms/kg/min infusion. The aim was to reduce MAP to less than 90 mm Hg within 50 minutes and maintain it stable at 85 +/- 5 mm Hg. Nicardipine was effective in 35 of 38 patients (92%), and nitroprusside in 29 of 36 (81%) (NS). The decrease in MAP was not statistically different, but time until reaching the therapeutic end-point was shorter with nicardipine (P less than 0.01). Significant differences follow: increase in heart rate and decreases in mean pulmonary artery, right atrial, and pulmonary capillary wedge pressures were more marked with nitroprusside (P less than 0.01 and P less than 0.05, respectively), whereas elevation of cardiac index and depression of systemic vascular resistance were more marked with nicardipine (P less than 0.01 and P less than 0.05, respectively). Postreduction MAP was more stable with nicardipine, 51% +/- 24% of readings falling within the range 85 +/- 5 mm Hg versus 41% +/- 18% on nitroprusside (P = 0.058). Dose adjustment during the following 24 hours was less frequent with nicardipine, 1.1 +/- 1.6 versus 2.7 +/- 2.6 (P less than 0.01). Transfused blood volume was lower with nicardipine (924 +/- 644 mL) than nitroprusside (1,306 +/- 901 mL) (P = 0.08), despite similar postoperative blood losses.(ABSTRACT TRUNCATED AT 250 WORDS)

First-step treatment of mild to moderate uncomplicated essential hypertension by a new calcium antagonist: nicardipine.

Nicardipine, a new calcium antagonist, was tested in a 14-week double-blind trial including 15 outpatients with uncomplicated essential hypertension. They were randomly assigned to nicardipine (20-30 mg three times daily) or placebo as first-step treatment. When necessary but always after a minimum of 4 weeks, pindolol (15 mg/day) was combined with nicardipine or placebo. At the end of step 1 (85 +/- 6 days with nicardipine vs. 58 +/- 6 days with placebo, p less than 0.01), nicardipine induced larger drops in supine systolic and diastolic blood pressure (SBP and DBP) than the placebo (21 +/- 2.5 vs 1.4 +/- 3 mm Hg, p less than 0.001, and 13 +/- 2 vs. 3.5 +/- 1.5 mm Hg, p less than 0.001, respectively). In the nicardipine group (n = 57), 53% of patients had controlled blood pressure (SBP less than 160 mm Hg and DBP less than 95 mm Hg) versus 17% in the placebo group (n = 47), p less than 0.001. There was no significant correlation between the decrease in blood pressure and the age of patients. The most common side effects in the nicardipine group were flushes (12%), headache (8%), ankle edema (5%), and asthenia (4%). When blood pressure was not brought under control and pindolol was prescribed as the second-step treatment, the nicardipine group (n = 52) displayed larger drops in SBP and DBP than the placebo group (n = 40) (27 +/- 5 vs. 15 +/- 3 mm Hg, p less than 0.01, and 18 +/- 1 vs. 9 +/- 2 mm Hg, p less than 0.001, respectively). These results show that a calcium antagonist is useful for first-step treatment of hypertension.

[Preventive treatment of asthma with ketotifen : an analysis of 1 791 cases treated in general practice]. / Le kétotifène dans le traitement préventif de l'asthme. Analyse synthétique de 1 791 observations de médecine praticienne.

Ketotifene is a new preventive treatment for asthma possessing the main advantage of being administered orally. Results were analyzed after treatment of 1 791 patients with allergic paroxysmal asthma, at a daily dose of 2 mg for a minimum duration of 3 months. Ketotifene was found to be effective both against asthma attacks (no further episodes in 30% of cases, and reduction in their frequency by at least a half in 35%), and by the fact that associated anti-asthma medication could be suppressed. Positive effects were noted after two weeks of treatment, with improvement increasing during the observation period (3 months). Tolerance was good, the principal side effect being somnolence (13% of cases), which occurred early in treatment but was reversible in more than one-third of these patients.

Isradipine for the treatment of hypertension following coronary artery bypass graft surgery: a randomized trial versus sodium nitroprusside.

In a randomized trial, a calcium antagonist, isradipine (ISR) and sodium nitroprusside (SNP) were compared in the management of hypertension in the early period following coronary artery bypass grafting (CABG). Patients with a mean arterial pressure (MAP) of greater than 100 mmHg were treated with a 6 h i.v. infusion of ISR (n = 98) or SNP (n = 100). Mean MAP at baseline was 113 (ISR) and 112 mmHg (SNP). Blood pressure control (MAP less than or equal to 90 mmHg within 25 min) was achieved in 92% (ISR) and 84% (SNP), within a mean of 12 and 15 min, respectively (P less than 0.01 between groups). At 25 min, mean percentage changes from baseline for ISR and SNP were: MAP -24.3% vs. -21.4% (P less than 0.05), heart rate +4.1% vs. +8.4% (P less than 0.01), rate-pressure-product -16.9% vs. -10.6% (P less than 0.001), cardiac index +19.2% vs. +4.6% (P less than 0.001), stroke volume index +16.1% vs. -1.9% (P less than 0.001), and peripheral vascular resistance -35.4% vs. -22.0%, (P less than 0.001). Treatment was discontinued before 6 h in 24 patients in each group because of low blood pressure. Hypotension (MAP less than 70 mmHg) and tachycardia were less frequent with ISR than with SNP. In conclusion, ISR is effective and well tolerated in the treatment of hypertension following CABG, and has a haemodynamic profile which may be more favourable than that seen after treatment with SNP.

Pityrosporum ovale (Malassezia furfur) as the causative agent of seborrhoeic dermatitis: new treatment options.

Several studies indicate that Pityrosporum ovale plays an important role in seborrhoeic dermatitis. Many of these are treatment studies which describe the effectiveness of antimycotics, paralleled by a reduction in the number of P. ovale colonies and then recolonization, leading to a recurrence of seborrhoeic dermatitis. In this study 20 patients with seborrhoeic dermatitis of the scalp were treated with terbinafine (Lamisil) 1% solution once daily for 4 weeks. Eleven of 18 patients (61%) were cured and they were still free of lesions 2 weeks after stopping treatment. No side-effects related to treatment were seen. There was also a significant reduction in the number of P. ovale colonies. This may explain both the good clinical effect and the observation that all patients who were cleared of P. ovale were still free of lesions 2 weeks after stopping treatment.

Electrophysiologic effects of intravenous nicardipine on sinus node function and conduction in humans.

We conducted an intracardiac study of the electrophysiologic effects and kinetics of intravenous nicardipine (N) in 16 patients with or without impaired cardiac conduction, using a randomized, double-blind, crossover design versus placebo (P). N or P were infused intravenously over 5 min: the dose of N was 9.46 +/- 3.85 mg. Standard electrophysiologic parameters of atrioventricular (AV) conduction and sinus function were measured under basal conditions, between 10 and 25 min, and at 65 min, after beginning the first infusion of N or P, and between 10 and 25 min after beginning the second infusion of N or P. Treatment with N significantly reduced systolic (S) and diastolic (D) blood pressure (BP) at 10 min (35 +/- 19 and 25 +/- 17 mm Hg, respectively). N significantly shortened sinus cycle length (SCL), corrected sinus recovery time (CSNRT), AH interval, AV node (AVN) Wenckebach cycle length, and anterograde and retrograde effective (ERPs) and functional refractory periods (FRPs) of the AVN. Infranodal parameters were unaffected. Mean plasma N concentrations at 10 min were 18.5 +/- 7.7 ng/ml/kg and 5.3 +/- 3 ng/ml/kg at 60 min. Two patients experienced slight adverse effects (anginal pain and nausea); another with sick sinus syndrome developed a sinus pause. We conclude that intravenous N affects nodal, but not His conduction, and that it should be administered with care in the presence of SSS.

[The relation between anti-hypertensive action and plasmatic concentration of pindolol. Preliminary study]. / Relation entre l'action anti-hypertensive et la concentration plasmatique du pindolol. Etude préliminaire

A correlation study between the antihypertensive effect and the plasma level of pindolol was performed in 10 patients with permanent essential hypertension. Pindolol was given orally (20 mg/day) during 9 days. The highly significant fall in blood pressure (delta SBP and delta DBP) is directly correlated negatively correlated, to the pretreatment pressure (p less than 0.02 for deltaSBP and p less than 0.05 deltaDBP) and negatively correlated to the pindolol plasma level (P less than 0.001 for delta SBP and p less than 0.05 for delta DBP). Multiple regression analysis shows, for delta SBP, a stronger influence of plasma level than of basal blood pressure. These results suggest that pindolol could have a specific effect in some hypertensive patients.

Follow-up of children born of bromocriptine-treated mothers.

A survey carried out in France at the beginning of 1984 concerning development of children born of mothers treated with bromocriptine (BC) during part or all of the pregnancy showed the absence of any adverse effects of BC in 64 children born from 53 mothers. In 60 cases, BC was prescribed (2.5-7.5 mg/day) for hyperprolactinemia; 23 mothers were treated with BC for 4 weeks or less, and 23 others for 30 weeks or more. After a follow-up of between 6 months and 9 years, all children are normal. Psychological development in the 23 children born to mothers treated with BC during more than 30 weeks of pregnancy actually appears more precocious, with excellent scholastic performance in the oldest.

Comparison of three regimens of Parlodel-SRO in levodopa-treated parkinsonians: a randomized double-blind crossover study.

Parlodel-SRO is a newly developed slow-release formulation of bromocriptine, which prevents initial plasma peak--a known source of adverse events--and extends the half-life of the compound, an interesting feature for the management of motor symptoms in Parkinsonians. This study was designed to determine the best daily administration schedule for 30 mg Parlodel-SRO in 18 parkinsonians previously treated with levodopa and standard Bromocriptine (Br). The 30 mg dose was replaced from one day to the next, in a randomized, double-blind latin square design trial. Three consecutive 7-day courses were implemented, during which a total daily dose of 30 mg P-SRO was administered in one dose, two intakes (b.i.d.) and three intakes, (t.i.d.) respectively. The b.i.d. schedule produced the best improvement in UPDRS scores, especially as to postural stability, walking, bradykinesia; it also provided greater pharmacological stability throughout the assessment day. Adverse event analysis was not in favor of a single daily dose. It appeared that P-SRO administered in two 15 mg intakes (morning and evening) produces the best benefit-risk ratio in Parkinsonians who were already being treated with levodopa.