Open Crossover Trial Research Articles

The effect of respiratory alkalosis on oxygen consumption in anesthetized patients

Study Objective: To investigate whether hyperventilation significantly altered oxygen consumption in anesthetized and paralyzed patients undergoing surgery. Design: Open crossover trial with 1 hour of hyperventilation preceded and followed by 1 hour of normoventilation. Setting: University medical center. Patients: Eight patients (five men and three women) undergoing lengthy orthopedic surgery with general anesthesia and muscle paralysis. Interventions: After baseline normoventilationfor 1 hour (Period 1), the anesthetized patients were hyperventilated to an arterial carbon dioxide tension (PaCO 2) of 20 to 25 mmHg for 1 hour (Period 2). Patients then experienced another hour of normoventilation (Period 5). Measurements and Main Results: Hemodynamic variables, electrocardiography, temperature, end-tidal partial pressure of CO 2 (P ETCO 2), oxygen consumption (VO 2), carbon dioxide production, and minute ventilation were continuously followed throughout the study, and arterial blood gases were drawn at the beginning and end of each study period. During the period of hyperventilation, pH was significantly higher and P. ETCO 2 and (PaCO 2) significantly lower compared with the periods of normoventilation. (VO 2), was significantly increased during hyperventilation compared with the periods of normoventilation. Hemodynamic variables and temperature were similar in the three study periods. Conclusions: In anesthetized paralyzed patients, there is an increase in whole-body (VO 2), with hypocapnic alkalosis.

Bioavailability of Omeprazole as Enteric Coated (EC) Granules in Conjunction with Food on the First and Seventh Days of Treatment

The influence of food intake on the bioavailability of omeprazole was studied after single and repeated administrations of enteric coated (EC) granules. 12 healthy males participated in an open crossover trial consisting of 3 study periods. Omeprazole 20mg was given as a single intravenous dose and orally as EC granules once daily for 7 days either immediately before or immediately after breakfast (periods 2 and 3). Plasma concentrations of omeprazole were followed after the intravenous dose and on days 1 and 7 in the other periods.

Pharmacokinetics of cefodizime during continuous ambulatory peritoneal dialysis

In a single-dose open cross-over trial we studied the pharmacokinetics of cefodizime 1 g in four uraemic patients treated by continuous ambulatory peritoneal dialysis (CAPD). Cefodizime was administered, successively with a wash out, (a) iv over 3 min and (b) by intraperitoneal (ip) administration together with the dialysate fluid (2 litres). Concentrations of cefodizime were measured by HPLC in blood and dialysate samples collected during an 8-h dwell period and in additional dialysate samples collected up to 48 h after drug administration. The mean (relative) total clearances following the iv and ip administration were 23 and 31 ml/min, respectively, and the terminal half-lives 5.5 and 6.7 h, respectively. Following iv administration, the peritoneal clearance was approximately 0.5 ml/min. After ip administration high concentrations of cefodizime were measured in the dialysate throughout the dwell period and systemic availability was good (80%) but variable.

Pharmacokinetics of midazolam and alpha-hydroxy-midazolam following rectal and intravenous administration.

1. In an open cross-over trial, plasma concentrations of midazolam were measured in eight healthy male volunteers following administration of 0.3 mg kg-1 body weight given by the rectal and intravenous routes. 2. Maximum plasma concentrations of 92-156 ng ml-1 (mean 118 ng ml-1) were recorded from 20 to 50 min (mean 31 min) after rectal application. The rectal bioavailability was 40-65% (mean 52%) and the terminal half-life was 114-305 min (mean 161 min). 3. A substantial first-pass hepatic effect was observed following rectal administration. 4. No systemic or local intolerance was noted. 5. In conclusion, the rectal route of administration provides a rapid and reliable absorption of midazolam.

Pharmacokinetics, converting enzyme inhibition and peripheral arterial hemodynamics of ramipril in healthy volunteers

The effects of a 10 mg dose of ramipril, a new angiotensin I converting enzyme (ACE) inhibitor, on systemic blood pressure, heart rate, brachial artery blood flow, brachial artery diameter, carotid artery blood flow, carotid artery diameter, forearm vascular resistance, plasma ACE and renin activities and plasma aldosterone were investigated. Ramipril's effects in 6 healthy volunteers on a normal sodium diet were compared with those of placebo over a 24-hour period after oral drug intake in an open cross-over trial. Ramipril inhibited plasma ACE activity, an effect that peaked at 3 to 4 hours and persisted up to at least 24 hours. Plasma renin activity increased from 4 to 12 hours after drug intake and plasma aldosterone was slightly decreased. Systemic blood pressure in the supine position was slightly decreased between 6 and 8 hours after drug intake but heart rate remained unaffected. Ramipril significantly increased brachial artery blood flow, brachial artery diameter and carotid artery blood flow and decreased forearm vascular resistance between 3 and 8 hours after drug administration. These peripheral arterial vasodilating effects were more marked in the muscular resistance vessels and affected both large arteries and arterioles in the brachial vascular territory. A correlation was found between the log of plasma concentrations of ramipril diacid metabolite and the drug-induced plasma ACE activity inhibition and increase in brachial artery blood flow. There was also a correlation between these 2 latter effects. A plasma ACE activity inhibition of 80% was required to induce significant increases in brachial artery blood flow and carotid artery blood flow.

24-hour antiarrhythmic effect of conventional and slow-release verapamil in chronic atrial fibrillation

Twenty-four-hour heart rate control by verapamil given as conventional tablets t.d.s., or as a new slow release formulation once daily, has been compared in an open cross-over trial. Eight patients with chronic atrial fibrillation and one with chronic atrial flutter were studied outside hospital. Trough serum concentration of verapamil did not differ during the two dosage regimens (59 ng/ml - conventional formulation and 49.3 ng/ml - slow release tablet). The average serum concentration of digoxin in the patients was not changed. Compared to the control phase, both dosage regimens significantly and equally reduced individual and average heart rates throughout the entire 24-h period. A positive correlation between the serum concentration of verapamil and the relative increase in average R-R interval was demonstrated. It is concluded that dosage t.d.s. with conventional tablets of verapamil or once daily with the slow release formulation gave the same antiarrhythmic efficacy over 24 h, and was associated with equal trough serum concentrations of verapamil.

Twice-daily verapamil for hypertension: A comparison with propranolol

Recent reports have confirmed that some slow calcium channel inhibitors have useful antihypertensive properties because they produce dilatation of the peripheral arterioles without reflex tachycardia. Verapamil is such a drug, but its clinical role in the management of hypertension is not clear. An open crossover trial was performed to compare the 24-hour profiles of blood pressure reduction after long-term therapy with a standard β-adrenoceptor blocker, propranolol, and verapamil. Nineteen patients were studied by continuous ambulatory intraarterial recording and the order of drug administration was determined by random allocation. The drugs were administered 2 times a day and titrated according to casual clinic pressures (propranolol, 40 to 240 mg 2 times a day; verapamil, 120 to 240 mg 2 times a day). Mean hourly blood pressure and heart rate values were obtained over a 24-hour cycle and the responses to isometric and dynamic exercise were also examined. The drugs produced a uniform and comparable reduction in blood pressure throughout the day, together with a reduction in heart rate, which was greater with propranolol. Comparable effects were also seen on the pressor responses to exercise. Both drugs were equally well tolerated and caused no patient withdrawals. Thus, oral verapamil given 2 times a day shows a degree of efficacy similar to that of propranolol and provides 24-hour blood pressure control. This slow calcium channel inhibitor was well tolerated and may be used as initial therapy for hypertension.

Urethral Sphincteric Insufficiency in Postmenopausal Females

A randomized open comparative cross-over trial was carried out in 20 postmenopausal women, mean age 69 years, suffering from urinary incontinence due to urethral sphincteric insufficiency. They were treated with phenylpropanolamine (PPA) 50 mg p.o. twice daily or estriol vaginal suppositories 1 mg daily separately and in combination for periods of 4 weeks. Urodynamic investigations were carried out before and after each period of treatment. Both PPA and estriol increased the maximal urethral closure pressure and the continence area significantly compared to the initial values, but combined treatment was substantially more effective. The functional urethral length increased significantly while on estriol. No significant change was registered in the bladder pressure or in the pressure transmission ratio. PPA was clinically more effective than estriol, but not sufficient to obtain complete continence. With combined treatment 8 patients became completely continent, 9 were considerably improved and only 1 patient remained unchanged. 2 patients dropped out of the study because of side effects. Combined treatment with PPA and estriol represents a recommendable treatment to postmenopausal women with urinary incontinence due to urethral sphincteric insufficiency.

The efficacy of drug delivery by a pear-shaped spacer and metered dose inhaler

The efficacy of terbutaline delivered via a 750 ml spacer device (Nebuhaler) compared with a metered dose inhaler alone was studied by means of an open cross-over trial in eight patients with stable asthma. The FEV1 and FVC response curves with cumulative doses up to 8 mg were shifted significantly to the left using the device, whilst side effects were not significantly increased. These results indicate that the spacer significantly improves aerosol drug delivery from a pressurized inhaler, even in patients whose inhalation technique was considered adequate.

Propranolol versus verapamil for the treatment of essential hypertension

Recent reports have confirmed that slow calcium channel inhibitors have useful antihypertensive properties because they produce dilatation of the peripheral arterioles without reflex tachycardia. Their clinical place in the management of hypertension has yet to be clearly defined, and thus we have performed an open crossover trial to compare the 24-hour profiles of blood pressure reduction after chronic therapy with propranolol and verapamil. Nineteen patients were studied by continuous ambulatory intraarterial recording and the order of drug administration was decided by random allocation. Drug dosage was twice daily and titrated according to casual clinic pressures (propranolol, 40 to 240 mg twice a day; verapamil, 120 to 240 mg twice a day). Mean hourly blood pressure and heart rate values were obtained over a 24-hour cycle, and the responses to isometric and dynamic exercise were also examined. Both drugs were shown to produce a uniform and comparable reduction in blood pressure throughout the whole day, together with a reduction in heart rate, which was greater with propranolol. Comparable effects were also seen on the pressor responses to exercise. Both drugs were equally well tolerated and caused no patient withdrawals. We conclude that oral verapamil given twice daily showed a similar degree of efficacy to propranolol and provided 24-hour blood pressure control. This slow calcium channel inhibitor may be useful as initial therapy for hypertension, particularly for those patients in whom beta-adrenoreceptor blockers are contraindicated.

Randomized open cross-over trial between Metoclopramide (MCP) and dexamethazone (DXM) for the prevention of cisplatin-induced nausea and vomiting

Thirty-five patients, receiving chemotherapeutic regimens including cisplatin (CDDP) were entered into a randomized open cross-over trial. Sixteen patients had previously received chemotherapy. Metoclopramide (MCP) was given i.v. in 4 doses of 1 mg/kg over a period of 4 1 2 hr , dexamethazone (DXM) was administered i.m. in 4 doses of 8 mg over 24 hr and another 10 mg i.v. just prior to CDDP administration. Sixteen patients who expressed a positive opinion on both previous antiemetics were given placebo (PLC). No significant differences were found between MCP and DXM, considering the mean score of both emesis intensity and patient's opinion. The mean duration of the symptoms was significantly longer with MCP than with DXM ( P < 0.02). Both antiemetic agents were more effective than PLC. No significant side-effects were observed. The results of this study indicate that both MCP and DXM provide a similar protection against CDDP-induced nausea and vomiting.

The efficacy of drug delivery by a pear-shaped spacer and metered dose inhaler

The efficacy of terbutaline delivered via a 750 ml spacer device (Nebuhaler) compared with a metered dose inhaler alone was studied by means of an open cross-over trial in eight patients with stable asthma. The FEV 1 and FVC response curves with cumulative doses up to 8 mg were shifted significantly to the left using the device, whilst side effects were not significantly increased. These results indicate that the spacer significantly improves aerosol drug delivery from a pressurized inhaler, even in patients whose inhalation technique was considered adequate.