Bioavailability and single-dose pharmacokinetics of intramuscular phenytoin.

Comparison of phenytoin plasma concentrations in an intravenous and intramuscular crossover study in 12 healthy ambulant, male subjects indicates that phenytoin administered intramuscularly is absorbed over a period of approximately five days. A model simulating precipitation and redissolution of the drug at the injection site has been shown to satisfactorily fit observed plasma concentration data following intramuscular administration. It is proposed that this model will be useful in the selection of an appropriate dosing regimen in situations in which intramuscular administration of phenytoin is indicated.

Bioavailability and pain study of cefamandole nafate.

The bioavailability of parental cefamandole, nafate, a new cephalosporin antibiotic, was evaluated with respect to the effects of a lidocaine diluent on its tolerability and absorption after intramuscular administration. Twelve adult male volunteers were injected with 1 Gm of cefamandole nafate in a three-way randomized, crossover study using the intravenous or the intramuscular route with cefamandole nafate in saline or in 1% lidocaine. The intramuscular injections were double blinded. Mean serum concentrations and cumulative urine outputs of cefamandole nafate were not significantly different (P > 0.05) following intramuscular administration using either the saline or lidocaine diluents. Furthermore, there was no significant difference in the areas under the serum concentration-time curve (AUC). The degree of pain experienced by subjects receiving intramuscular cefamandole nafate was evaluated during 1 hour after injection using a numerical scoring system. Lidocaine diluent significantly reduced the incidence and duration of pain after cefamandole nafate injection, and this form of administration was well accepted by the subjects in the study.

Nifedipine kinetics and bioavailability after single intravenous and oral doses in normal subjects.

Nifedipine kinetics have not been described in clinically relevant detail because of difficulties in formulating a stable preparation for intravenous use and lack of a specific and sensitive assay for plasma nifedipine. We recently developed a gas-chromatographic method and determined conditions in which nifedipine could be protected from photodegradation. Therefore, we evaluated the kinetics and bioavailability of nifedipine in 12 normal subjects after single intravenous (1 mg/5 min) and oral (10 mg) doses. After intravenous dosing, the drug was eliminated with a half-time of 1.77 +/- 0.25 hour, and total clearance was calculated at 0.62 +/- 0.09 liter/kg/hr. With oral drug administration, the elimination half-time was twice as long for the group; but within these subjects, marked variability in the rate of appearance of the drug in plasma was observed, giving profiles consistent with fast and slow absorption. In the latter group, peak plasma drug concentrations were only one third the level seen in those exhibiting a faster absorption profile, although the extent of drug absorption (as derived from areas under the plasma level-time curves) did not vary. Bioavailability was 0.45 +/- 0.08. Untoward effects resulting from the drug's pharmaco-subjects after intravenous administration (flushing).

The pharmacokinetics of oral isradipine in normal volunteers.

The pharmacokinetics and relative bioavailability of oral isradipine, a dihydropyridine calcium channel blocking agent, were determined in 42 normal male volunteers participating in two separate studies. Eighteen of the subjects received 2.5-, 5-, and 10-mg oral doses of isradipine solution (Study 1). The remaining 24 subjects received four 2.5-mg capsules, one 10-mg capsule, and 10 mg of isradipine as an oral solution (Study 2). Venous blood samples were obtained prior to and at frequent intervals after administration of each dose form. Plasma isradipine concentrations were measured by radioimmunoassay. No significant dose effect occurred with respect to any pharmacokinetic parameter except AUC and Cmax in Study 1. In Study 2, Cmax, tmax, and MRT were significantly different after the solution compared with the capsular formulations. The respective pharmacokinetic parameters (mean +/- SD) for the 10-mg solution and 10-mg capsule in Study 2 were time to maximum concentration, 0.40 +/- .28 and 1.57 +/- 0.44 hours; oral clearance, 284.9 +/- 105.3 and 317.0 +/- 138.4 L/hr; elimination half-life, 5.36 +/- 1.8 and 6.63 +/- 2.4 hrs, respectively. Headache, dizziness, and tachycardia were the most frequent adverse effects in both studies.

Multiple dose pharmacokinetics of four different doses of nisoldipine in hypertensive patients.

This randomized double-blind parallel group study characterized the pharmacokinetics of the calcium channel antagonist, nisoldipine (core-coat tablets), administered once daily for 7 days in doses of 5 mg (n = 12), 10 mg (n = 13), 20 mg (n = 12), and 30 mg (n = 11) to patients with mild to moderate hypertension. Serial blood samples were obtained from 0 to 24 hours and from 0 to 48 hours after nisoldipine administration on days 1 and 7, respectively. Nisoldipine plasma concentrations were determined by gas chromatography with electron capture detection. No statistically significant difference was found in dose-normalized area under the curve between the four groups. Area under the curve (standardized to body weight) correlated to dose (r = .74, P less than .05). No significant difference existed in oral clearance (L/h/kg) when analyzed for equivalence across the four doses: 8.21 +/- 3.47 (5 mg), 11.84 +/- 13.85 (10 mg), 11.48 +/- 7.49 (20 mg), and 10.36 +/- 5.49 (30 mg). The present investigation characterizes the pharmacokinetics of nisoldipine core-coat tablets in hypertensive patients and demonstrates the dose proportionality or linearity of nisoldipine plasma concentrations and area under the curve, measured over a dose range of 5 to 30 mg.

The acute effects of the enkephalin analogue BW 942C in humans.

BW 942C hydrochloride is an enkephalin analogue that has exhibited a wide separation between antidiarrheal dosages and dosages inducing adverse effects in animals. This has likewise been the case in humans when administered orally. In this study, the safety and tolerance of single 0.5-mg doses of intravenous BW 942C compared with placebo were assessed in humans. Four healthy male volunteers received BW 942C, and two received placebo. The effects of BW 942C on serum growth hormone (GH), luteinizing hormone (LH), prolactin (PR), and follicle-stimulating hormone (FSH) were assessed in three of these volunteers. No significant changes were apparent in vital signs, in clinical chemistry, hematologic and urine studies following BW 942C administration. BW 942C did not appear to alter mood as assessed by two psychologic mood scales. Prolactin levels tended to increase in volunteers receiving BW 942C two hours postinfusion. Luteinizing hormone concentrations decreased slightly at two and six hours. No trends in FSH or GH could be identified. Pulmonary function testing did not reveal any significant changes in oximetry, spirometry, or plethysmography in any of the subjects. A marked decrease in CO2 responsiveness in two subjects may indicate that BW 942C has mild ventilatory depressant effects. Untoward effects experienced in volunteers receiving BW 942C included heaviness in the limbs, nasal stuffiness, mouth dryness, facial flushing, skin rash, and prickling sensations. These effects bear a striking similarity to those experienced after parenteral administration of other enkephalin analogues. Intravenous administration of BW 942C up to 0.5 mg appears safe from a laboratory, physiologic, and clinical perspective with unusual untoward effects that may preclude rational use of the drug by the parenteral route.

Ceftazidime versus tobramycin/ticarcillin in treating hospital acquired pneumonia and bacteremia.

Thirty-five patients in a neurosurgical intensive care unit who had nosocomial pneumonia and bacteremia were randomly assigned to receive either ceftazidime (Cef) or the combination of ticarcillin and pharmacokinetically adjusted doses of tobramycin (T/T). Fifteen of 17 patients (88%) who received Cef were cured or improved compared to 15 of 18 (83%) who received T/T. The original pathogen was eradicated from the respiratory secretion in 10 of 15 patients receiving Cef compared to only 6 of 18 patients receiving T/T (p = 0.12). All patients in both treatment groups who had positive blood cultures cleared the organism from the bloodstream. No cases of drug toxicity, including renal toxicity, were seen in either group. Cef used as a single agent in nosocomial pneumonias and bacteremias performed at least as well as T/T.

Variation in postoperative analgesic requirements in the morbidly obese following gastric bypass surgery.

Patient-controlled analgesia is a relatively new method of administering intravenous narcotics for postoperative pain relief. The technique involves the self-administration of a given analgesic in a bolus dose with the aid of a timed infusion and sequencing device. Ten morbidity obese patients undergoing elective gastric bypass surgery were treated in a prospective, unblinded, pilot project to evaluate the efficacy of patient-controlled analgesia. Analgesic therapy was satisfactory in all patients. The mean total dose of morphine sulfate administered during the first 36 hours postoperatively was 66 mg, an average of 1.7 mg/hr. There was a tenfold variation (17.5-175 mg) in the 36 hr total dose. The total dose was not related to body surface area, age, sex, dose per injection, or anesthetic agent. The large variation in individual narcotic analgesic requirements could be a major factor in the suboptimal management of postoperative pain with conventional dosing. Patient-controlled analgesia may circumvent these problems.

Home monitoring of theophylline levels: a novel therapeutic approach.

This pilot clinical investigation was conducted to compare a home therapeutic drug-monitoring (TDM) method for theophylline blood levels and a traditional TDM method with respect to various patient outcome factors. Outpatients with chronic obstructive pulmonary diseases (COPD) or asthma who were receiving long-term theophylline therapy were randomized to one of two groups: home TDM or traditional TDM (controls). Patients in the former group monitored their serum theophylline levels at home over 6 months. Patients in both groups completed survey instruments, including questionnaires, visual analog scales, and other psychosocial measures, at designated times throughout the study period. Pulmonary function tests and dyspnea index scores were evaluated at each clinic visit. Results indicated a significantly lower (p less than 0.05) number of changes in concomitant drug therapy in the home TDM group compared with controls. Other indicators that showed a trend toward more favorable outcomes in the home TDM group included symptomology, percentage of levels within the therapeutic range, patient attitudes regarding participation in health care management, and pulmonary function test results. Home monitoring prevented unnecessary clinic visits in several instances when theophylline dosage adjustments were based on telephone reports from patients. The utility of a home TDM method for theophylline has not been reported previously despite potential for broad applications. Findings from this preliminary study may support the use and feasibility of state-of-the-art methodologies in carefully selected subpopulations outside the confines of the hospital or clinic setting.

The postoperative adverse effects of inhalational anesthetics.

Inhalational general anesthetics can contribute to postoperative morbidity (Table II). Postoperative effects of inhalational anesthetics on the central nervous system are speculative. The "toxic" effects of these agents during the postoperative period are most often an extension of their pharmacologic and physiochemical properties. Inhalational anesthetics may produce a number of varied changes in mental status after surgery such as headache, emergence excitement, and delirium. It is very important for health professionals to be aware of the risk of perioperative myocardial infarction in patients with preexisting heart disease if early detection and treatment are to occur. Relative to the common postoperative problems of atelectasis, pneumonia, and aspiration, inhalational agents may have a contributory role especially in patients with preexisting pulmonary disease. Postoperative nausea and vomiting are other common problems in which inhalational agents may have a role in their development. Although extensively investigated, suspected halothane hepatoxicity is a very rare complication if it exists at all. The renal effects of inhalational anesthetics are usually mild and transitory, although the use of methoxyflurane can produce direct nephrotoxicity. The evidence to support a clinically significant direct immunosuppressant effect of inhalational anesthetics after surgery is inconclusive. A concensus exists that any minor, short-lived effects are in all probability overshadowed by the nonspecific stress of surgery itself. By reducing this stress, anesthetics undoubtedly have a protective effect. There are probably no major mutagenic or carcinogenic effects of inhalational anesthetics under normal conditions. Inhalational anesthetics should be avoided during pregnancy because of their teratogenic potential and their effects on the uterus.(ABSTRACT TRUNCATED AT 250 WORDS)