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.

Fleroxacin pharmacokinetics in patients with liver cirrhosis.

In this open-label study, the disposition of fleroxacin in liver disease in 12 healthy male volunteers, 6 male cirrhotics without ascites (group A), and 6 male cirrhotics with ascites (group B) was evaluated. Fleroxacin (400 mg) was administered orally and intravenously to each subject in a random crossover fashion. Fleroxacin was completely absorbed and achieved similar peak concentrations in plasma in all three study groups (P greater than 0.05). The volume of distribution exceeded 1 liter/kg in healthy controls and was not affected by liver impairment (P greater than 0.05). Only group B demonstrated differences in the pharmacokinetic parameters evaluated: the systemic and renal clearances of fleroxacin and the renal clearances and clearances of the two major metabolites of fleroxacin formed, N-demethyl fleroxacin and fleroxacin N-oxide, were significantly lower and the half-lives of the parent drug and its metabolites were significantly longer in group B than in healthy controls and group A (P less than 0.05). The elimination of the two metabolites appeared to be formation rate limited in all three study groups. It was concluded from this study that a 50% reduction in the fleroxacin maintenance dose in patients with liver disease appears justified only in patients with ascites. However, no change in the fleroxacin loading dose is needed in patients with compromised liver function.

Rapid screening for polymorphisms in dextromethorphan and mephenytoin metabolism.

1. The phenotyping parameters for dextromethorphan and mephenytoin were assessed in 48 normal male volunteers following administration of each metabolic probe drug on separate occasions and together according to a randomized 3-way crossover design. 2. Neither the urinary S-/R-mephenytoin ratio nor the dextromethorphan metabolic ratio were altered significantly by coadministration of the probe drugs. 3. Five-hundred and nineteen subjects were screened for expression of mephenytoin 4-hydroxylase and dextromethorphan O-demethylase activity following the coadministration of mephenytoin and dextromethorphan. The activity was determined in each case by methods not requiring any quantitative measurements. 4. Nineteen (3.7%) of the subjects were identified as poor metabolizers (PMs) of mephenytoin and 35 subjects (6.7%) as PMs of dextromethorphan. 5. All PMs of dextromethorphan were confirmed by more rigorous evaluation of the metabolic ratio.

Negative inotropic effect of intravenous nifedipine in coronary artery disease: relation to plasma levels.

The relative extent of the vasodilator versus direct negative inotropic effects of nifedipine was studied in 15 male patients with documented coronary artery disease and normal left ventricular function. At the time of diagnostic cardiac catheterization, three groups of five patients received dose of 1, 2, and 3 mg intravenous nifedipine at a rate of 0.33 mg/min. Hemodynamic measurements and blood collections were made before, during, and every 5 minutes for 30 minutes after infusion of nifedipine. Heart rate increased and mean arterial pressure decreased significantly after the 2 and 3 mg doses of nifedipine. Systemic vascular resistance was significantly decreased and cardiac index increased after all doses of nifedipine. Maximal left ventricular dp/dt (dp/dtmax) was significantly decreased after the 3 mg infusion. The reduction in dp/dtmax was most consistent with a reduction in left ventricular contractility as opposed to changes in loading conditions. Plasma concentrations of nifedipine were significantly correlated with bidirectional changes in dp/dtmax (r = 0.86). Nifedipine concentrations below 28.2 ng/ml were associated with a rise in dp/dtmax, whereas concentrations above that level were associated with a reduction in dp/dtmax. These data indicate that intravenous nifedipine produces dose- and concentration-dependent depression of myocardial contractility in patients with coronary artery disease. Nifedipine concentrations associated with negative inotropic effects are readily achievable with common oral and sublingual doses.

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.

Patient-controlled analgesia: a review of effectiveness of therapy and an evaluation of currently available devices.

Patient-controlled analgesia (PCA) is a major advance in the management of pain in postoperative and cancer patients. The success of PCA has resulted in a proliferation of marketed devices to administer small bolus doses of parenteral pain-control drugs at fixed intervals controlled by the patient with the push of a button. Because patients demonstrate marked individual variation in pain medication requirements, PCA devices should be able to accommodate rapidly changing requirements for drugs with a minimum amount of effort on behalf of health care personnel. Crude electronic devices were developed in the late 1960s and the early 1970s and usually consisted of a syringe pump connected to some sort of timing device. Most modern PCA devices marketed in the past five years are much more sophisticated devices that are microprocessor based and some newer devices even generate hard copy for a permanent record of drug administration. Although many such devices are available (including a totally disposable PCA device), few have undergone extensive clinical evaluation. A review of the literature shows many devices are available for use without a single publication to document the safety and utility of the device in the routine patient care situation. Use of the PCA method of pain control will grow, and all hospital-based health care personnel should become familiar with their use and limitations.

Biopharmaceutical comparison of two levothyroxine sodium products.

The relative bioavailability and therapeutic equivalence of two brands of levothyroxine sodium tablets, Levothroid and Synthroid, were compared in patients who had been receiving long-term levothyroxine replacement therapy. Eighteen patients with primary hypothyroidism were randomly assigned to receive therapeutic dosages of Levothroid or Synthroid for 43 days and then were switched to the opposite product for 43 more days. The pharmacokinetic profiles of the two drugs were evaluated on days 43 and 86 by analyzing blood samples drawn at various intervals after the final dose. Relative bioavailability was determined by comparing the absorption profiles and areas under the serum concentration-time curves (AUCs) of total and free serum thyroxine. In addition, the potency of the levothyroxine sodium tablets was determined by high-performance liquid chromatography. The time to reach maximum concentration and the maximum concentration of total thyroxine after treatment with Levothroid did not differ significantly from those after treatment with Synthroid. The mean +/- S.D. AUC of total thyroxine after Levothroid administration (2339 +/- 404 pg.hr/mL) was slightly but significantly higher (p = 0.047) than that following Synthroid (2169 +/- 422 pg.hr/mL). However, the main index of biological activity, thyrotropin concentration, did not differ significantly between the two products. All tablets tested were within the stated potency requirements of the USP. The AUC of total serum thyroxine and the serum thyrotropin concentration after long-term replacement therapy with Levothroid or Synthroid indicate that any differences in bioavailability between the two products are clinically unimportant and that the two products are therapeutically interchangeable.

Patient-controlled analgesia using butorphanol for postoperative pain relief: an open-label study.

Patient-controlled analgesia (PCA) has been studied extensively for the treatment of postoperative pain using narcotic analgesics. Butorphanol, a nonnarcotic injectable analgesic, has not previously been investigated using this drug delivery mechanism. Twenty-five patients undergoing general abdominal surgery and general anesthesia used a PCA device with butorphanol as the analgesic agent. Most patients (84%) were able to obtain excellent postoperative pain relief. The role of butorphanol in the management of postoperative pain should be expanded to include patient-controlled drug delivery.

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.

Drug delivery for intractable cancer pain. Use of a new disposable parenteral infusion device for continuous outpatient epidural narcotic infusion.

Administration of narcotic analgesics through the epidural route has proven useful for treating pain of acute and chronic nature. This route of narcotic administration is frequently chosen for cancer patients with intractable pain that may be refractory to treatment by conventional oral or parenteral therapy. Implantable constant infusion devices have been commonly described as an alternative drug delivery system for this type of patient. This case report describes the use of the Travenol Infusor (Travenol Laboratories Inc., Deerfield, Illinois) an external, lightweight, disposable, drug delivery device for delivering continuous epidural morphine infusion to a patient with severe cancer pain. The patient has achieved stable pain relief for greater than 8 months without hospital admission for pain control, or management of complications due to the drug delivery system. The Travenol Infusor may prove to be an alternative drug delivery system for patients requiring continuous epidural narcotic infusion.

Patient-controlled analgesia in gynecologic oncology.

Patient-controlled analgesia (PCA) is currently being evaluated as an alternative to prn intramuscular injections for the relief of postoperative pain in patients with gynecologic malignancies. From June 1985 to May 1986, twenty patients undergoing abdominal hysterectomy received PCA rather than traditional intramuscular injections for relief of postoperative pain. PCA was administered by a lightweight, wearable, disposable system, the Travenol Infuser with Patient Control Module. The PCA device delivered a 1-mg intermittent intravenous injection of morphine upon patient demand with a delay of 6 min between allowable administrations. The mean amount of morphine utilized postoperatively by the PCA patients (66 mg over 48 hr) was not significantly different from the amount used by a control group receiving prn im morphine injections. No cases of respiratory or cardiac depression were observed, and patients were generally alert throughout the period of analgesia. These data suggest that PCA is a safe and effective mode of analgesia administration. In addition, the unique characteristics of this new compact device were well accepted.

Influence of tablet dissolution on furosemide bioavailability: a bioequivalence study.

In order to evaluate the in vitro dissolution and in vivo bioavailability relationship for furosemide, a bioequivalence study was carried out. Furosemide (40 mg) was administered orally to 12 normal volunteers in a 6 x 6 crossover design using six products (five tablets and one solution) obtained from three pharmaceutical companies. Plasma and urine concentrations of furosemide were quantitated by high-performance liquid chromatography (HPLC). Plasma furosemide profiles were analyzed by non-compartmental methods. Compared to the oral solution, all of the formulations exhibited lower peak furosemide concentrations, longer mean residence times, and, in some cases, diminished bioavailability (range, 66-96%). Similar results were obtained when the reference product (a rapidly dissolving tablet) was used as the standard. All of the products failed the 75/75 rule when compared to either reference standard, apparently because of large intersubject variability. The total amount of furosemide excreted in urine could be associated with the percentage drug dissolved (in vitro) at 30 min. The pH 5.6 dissolution medium (compared to pH 4.6) appears to be an appropriate test medium for assuring batch uniformity and bioequivalence of furosemide products.

Evaluation of a disposable, nonelectronic, patient-controlled-analgesia device for postoperative pain.

The safety and efficacy of a disposable, nonelectronic, patient-controlled-analgesia (PCA) device for alleviating postoperative pain were evaluated. Patients who were to undergo abdominal surgical procedures under general anesthesia were instructed in the use of the Travenol Infusor with Patient Control Module. Patients used the PCA device upon emerging from anesthesia in the recovery room. The PCA device delivered a 1-mg i.v. injection of morphine sulfate upon patient demand, with a relative delay of six minutes between allowable administrations. Nursing staff evaluated pain and sedation every four hours using a five-point scale. In the 50 patients evaluated, the highest analgesic use occurred during the first four to eight postoperative hours. After the immediate postoperative period, patients experienced either mild or no pain during approximately 90% of the evaluation periods. No patient suffered respiratory depression during self-dosing. Results of a poststudy self-assessment questionnaire showed that 90% of the patients reported experiencing mild to moderate pain overall, and 78% reported only mild discomfort throughout the postoperative period. Ninety-two percent of the patients strongly preferred PCA therapy over intramuscular injections. The Travenol Infusor with Patient Control Module represents a safe and effective device for PCA therapy of postoperative pain.

Clinical outcome of nosocomial pneumonia following imipenem/cilastatin therapy.

Eighteen patients in a neurosurgery intensive care unit who had nosocomial pneumonia and/or bacteremia were treated with imipenem/cilastatin. The 16 patients who were evaluable had pneumonia; 4 of these had concurrent bacteremia. Eleven patients had a satisfactory clinical response (69 percent) and all patients with positive blood cultures had the organism eradicated. There were 44 organisms isolated from the initial culture of bronchial secretion and 32 of these organisms were gram-negative bacilli (72.5 percent). One patient with pneumonia who initially had Pseudomonas aeruginosa sensitive to imipenem developed resistance during therapy. Adverse effects were minimal; one case of nausea occurred, which was thought to be related to a short infusion time. The most prominent laboratory abnormality was an increase in platelet count, seen in 50 percent of treated patients.

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.