A comparison of the anti-hypertensive effectiveness of two triameterene/hydrochlorothiazide combinations: Maxzide versus Dyazide.

The hydrochlorothiazide component of Maxzide (Lederle Laboratories, Pearl River, NY) has been shown to be more bioavailable than the hydrochlorothiazide component of Dyazide (Smith, Kline and French Laboratories, Philadelphia, PA). The authors compared the antihypertensive effectiveness of a half-tablet of Maxzide (25 mg of hydrochlorothiazide and 37.5 mg of triamterene) to one capsule of Dyazide (25 mg of hydrochlorothiazide and 50 mg of triamterene) to determine if the difference in bioavailability would be reflected in differences in blood pressure control and metabolic changes. Thirty patients were studied in a randomized open-label crossover design study. There was a significant reduction in systolic blood pressure for both treatments although there was no difference in blood pressures at any time during the study between the two agents. There were no statistically significant differences between Maxzide and Dyazide in terms of metabolic changes for potassium, magnesium, glucose, cholesterol, triglycerides, uric acid, or calcium. Although the hydrochlorothiazide component of Maxzide is more bioavailable than that of Dyazide this did not translate into enhanced hypotensive efficacy.

Comparative bioavailability characteristics of commercial quinidine polygalacturonate and sulfate tablets.

This study compared the relative bioavailability characteristics of quinidine polygalacturonate (QP) and quinidine sulfate (QS) after oral administration of commercial tablets and a liquid form prepared from crushed tablets in 13 healthy adult male volunteers. Each subject received the following four single-dose treatments in a randomized, crossover manner with a one-week washout period between treatments: 400 mg QS liquid, two 200-mg QS tablets, 550 mg QP liquid, and two 275-mg QP tablets. All four treatments were equivalent in terms of the dose of quinidine base. Multiple serum samples and two 24-hour urine specimens were collected over 24 and 48 hours, respectively, and assayed for quinidine with a specific HPLC assay method. For the absorption and disposition parameters measured (maximum serum concentration, time to reach maximum concentration, area under the concentration-time curve [0-48 hours], absorption and elimination rate constants, absorption and elimination half-lives, apparent total body clearance, apparent volume of distribution, and dose fraction excreted in the urine) no significant differences were observed for any of the parameters among the four treatments (p greater than 0.05). The results of the present investigation demonstrated that QP and QS produced identical serum quinidine concentration-time curves when given in the form of a tablet or liquid. The clinical implications of these observations with respect to the dosing of QP are discussed.

Disposition and toxicity of amphotericin-B in the hyperlipidemic Zucker rat model.

The pharmacokinetics and toxicity of the lipophilic antifungal agent, amphotericin-B (AmpB), were studied in the hyperlipidemic obese rat model and compared with lean litter-mates. Serial blood samples were obtained for 36 h following a single intravenous infusion of AmpB (1.2 mg/kg) with pre- and post-drug measurements of renal function. Although triglyceride, cholesterol, HDL-cholesterol and LDL + VLDL-cholesterol levels were elevated in the obese compared with lean rats, protein: lipoprotein ratios were similar. There was a 2-fold increase in the area under the serum concentration-time curve of AmpB in obese rats compared to lean litter-mates (15,600 +/- 6900 v. 7800 +/- 2900 ng. h/ml; P less than 0.05); no differences in elimination rate constants were found between groups. Weight-corrected volume of distribution and total body clearance were significantly lower in obese compared with lean rats; no differences were found in absolute clearance or volume. Kidney levels of AmpB were markedly increased in obese versus lean rats. Similarly, kidney to serum ratios of AmpB were greater in obese compared with lean rats (152 +/- 113 v. 41 +/- 23; P less than 0.001). There was a significant decline in the creatinine clearance from baseline in the obese rats coupled with a rise in serum creatinine; no differences were found in lean rats. Similarities in absolute pharmacokinetic variables and protein: lipoprotein ratios suggest differences in AmpB disposition and toxicity are a result of differences in lipoprotein-mediated transport mechanisms between obese and lean rats.

Phonophoresis: an in vivo evaluation using three topical anaesthetic preparations.

An electrical sensory perception threshold technique has been developed for use with human volunteers. This technique has been used to reproducibly quantify the effects of three different commercially available topical anaesthetic preparations on superficial sensory cells (nociceptors) in the skin. Low intensities (0.25 W cm-2 SATA) of 1.1 MHz ultrasound had no detectable effects upon the rate of penetration of either one of the three anaesthetic preparations through human skin under conditions where temperature increases had been minimized.

[Study of the in vivo penetration of cotrimoxazole in alveolar macrophages]. / Etude de la pénétration in vivo du cotrimoxazole dans les macrophages alvéolaires.

Kinetic of cotrimoxazole was studied in serum, alveolar macrophages and BAL fluid from guinea pigs receiving sulfamethoxazole (SMX, 100 mg/kg) and trimethoprim (TMP, 20 mg/kg). Guinea pigs were killed by cervical dislocation 30 min, 1 h, 3 h, 6 h and 24 h after intraperitoneal injection. Lung lavage was performed to obtain alveolar macrophages and BAL fluid. TMP and SMX levels were assayed using high-performance-liquid chromatography. Highest SMX levels were obtained in serum at 30 min, in BAL fluid at 1 h and in alveolar macrophages at 3 h. Mean SMX/TMP ratios (30 min, 1 h, 3 h) was 26.5 +/- 0.8 in serum, 3.76 +/- 1.8 in BAL fluid and 1.15 +/- 0.02 in alveolar macrophages.

Pharmacokinetics of imipenem/cilastatin in neutropenic patients with haematological malignancies.

The pharmacokinetics of imipenem/cilastatin were studied in febrile neutropenic patients with haematological malignancies. The peak plasma concentrations (36.4 +/- 4.96 mg/l), plasma half-life (60 min), volume of distribution (0.28 +/- 0.02 l/kg) and plasma clearance (3.23 +/- 0.38 ml/min/kg) were comparable with those in normal healthy volunteers suggesting that the drug handling is not appreciably altered in this group of patients. The administration of 12.5 mg/kg (max 1 g), 6-hourly achieved levels that were up to 3.5 times MICs of most relevant bacteria. The drug therefore has a potential use as empirical monotherapy in febrile neutropenic patients.

EMLA: a new topical anesthetic.

Eutectic Mixture of Local Anesthetics (EMLA) containing 5% lidocaine and prilocaine in a cream was found to give effective topical analgesia in normal and diseased skin, making it useful for superficial surgery and various other clinical procedures. To be effective, an adequate amount must be applied under occlusion and at the right time before the intervention.

Steady plasma levodopa concentrations required for good clinical response to CR-4 in patients with 'on-off'.

Ten patients with Parkinson's disease and severe motor fluctuations were given Sinemet (25/100) for 4 weeks followed by 4 weeks of Sinemet (CR-4). After each drug preparation was optimized, patients were rated by neurological examination and plasma levodopa (LD) measured at hourly intervals (9 a.m.-4 p.m.). For the group as a whole, variations throughout the day of plasma LD and clinical state were no different on the 2 formulations. Three patients whose fluctuations responded well to CR-4 had either much less variable plasma LD levels on CR-4 or were able to maintain plasma LD above a minimum threshold. In severe fluctuators, a major benefit from CR-4 can be expected only in those patients who can maintain steady plasma LD levels above the threshold for achieving the 'on' state.

Pharmacokinetics of single-dose oral and intramuscular ketorolac tromethamine in the young and elderly.

The elderly are likely candidates to receive analgesics for pain from a variety of etiologies. Ketorolac tromethamine is a nonsteroidal, analgesic, anti-inflammatory, antipyretic investigational drug with anti-prostaglandin synthetase activity. Sixteen healthy, young men (mean age 30 years and mean weight 75 kg) and 13 healthy, elderly subjects (11 men and two women; mean age 72 years and mean weight 75 kg) participated in an open-label, parallel single-dose study. On each day of ketorolac tromethamine administration the subjects fasted overnight and for 2 hours post-dose. A single intramuscular (IM) dose of 30 mg of ketorolac tromethamine was administered followed by an oral dose (PO) of 10 mg after a 1 week washout period for the elderly subjects. Plasma samples were taken from 0 through 48 hours post-dose and analyzed for ketorolac by HPLC. The elimination of ketorolac was decreased slightly in the elderly following both doses, as evidenced by a prolongation in half-life (4.7 to 6.1 hours for PO and 4.5 to 7.0 hours for IM) and a reduced total plasma clearance compared to the young adult subjects. These differences were statistically significant (P less than .001). Considerable overlap frequently was observed when comparing the range of values obtained for the young and elderly for plasma half-life, clearance, AUC, Tmax and Cmax. The absorption of ketorolac tromethamine was not altered substantially in the elderly following either dose route. Ketorolac plasma protein binding was not altered substantially in the elderly. The present results show that the elderly may need slightly less frequent dosing of ketorolac than young adults to maintain similar plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamic modeling of concentration-effect relationships after controlled-release carbidopa/levodopa (Sinemet CR4) in Parkinson's disease.

Eight parkinsonian patients participated in a pharmacokinetic pharmacodynamic study of sequential doses of controlled-release carbidopa (CD)/levodopa (LD) at 4-hour intervals, with serial blood samples obtained before and after each dose. Effect measurements obtained with each blood sample included tapping and walking speed as well as a global assessment of motor function. Analysis of the data by extended least squares regression for linear, Emax, and sigmoid Emax pharmacodynamic models revealed that linear relationships do not provide the best fit between LD plasma concentrations and clinical effects after controlled-release CD/LD. The data are fit best to models that are curvilinear in nature. LD plasma concentrations greater than 2.0 micrograms/ml resulted in sustained effects on walking and global scores while the greatest rate of change in walking and global scores occurred at 0.9 micrograms/ml. LD plasma concentrations fluctuating around 0.9 micrograms/ml may result in the "on/off" effects seen in Parkinson's disease.

Factors affecting penetration of retrograde coronary venous injections into normal and ischemic canine myocardium: assessment by contrast echocardiography and digital angiography.

Ths experimental study described myocardial echo contrast enhancement through coronary venous injections. Retrograde administration of renografin was performed in 15 closed-chest dogs. Two-dimensional echocardiography was used to study myocardial echo contrast enhancement before and after coronary artery occlusion. Digital subtraction venography was used to assess delivery, drainage and shunting of the retrograde injectate. Systolic/diastolic blood pressure in the great cardiac vein measured 7 +/- 3/1 +/- 0.6 mm Hg and increased to 29 +/- 11/5 +/- 3 after coronary sinus occlusion and to 55 +/- 2.3/15 +/- 12 mm Hg during coronary sinus contrast injection. Myocardial contrast echo appearance in a midpapillary left ventricular short axis cross-section was limited to the anteroseptal region, extending to 28.4 +/- 11.3% of the section circumference after great cardiac vein injections and 35.3 +/- 17% after coronary sinus injections (difference NS). After occlusion of the left anterior descending coronary artery, great cardiac vein contrast injections resulted in opacification of 36.6 +/- 9.7% of the section circumference (N.S. vs preocclusion control) and opacified most, but not all asynergic segments. After occlusion of the circumflex coronary artery, myocardial echo contrast uptake was restricted to the septum and the anterior wall. The ischemic and asynergic posterolateral myocardial segments were not opacified. Digital subtraction coronary venography revealed rapid drainage of retrogradely injected contrast to the right atrium, in spite of coronary sinus balloon occlusion via venovenous anastomoses. Retrograde coronary venous contrast injections may help define myocardial regions which are accessible with retrograde coronary venous interventions.

The effect of perfluorochemical fluosol-DA (20%) on myocardial infarct healing in the rabbit.

Although the perfluorochemical Fluosol-DA 20% has been shown to reduce myocardial infarct size, its effect on the evolution of infarct healing has not been determined. Rabbits (n = 91) were randomized to ether-oxygenated Fluosol-DA (20 ml/kg) administered intravenously at the time of reperfusion after 30 min of coronary occlusion or no intervention. Animals were sacrificed at 1, 3, 7, and 14 days after infarction. Infarct size was significantly reduced in Fluosol-DA treated animals when compared with controls at one and three days. Infarct thinning was observed at one and three days in both groups. Left ventricular wall thickness in the infarcted area was greater with Fluosol-DA than control at 7 and 14 days. Increasing amounts of foamy macrophages containing perfluorochemical particles were noted in treated animals at 7 and 14 days. No differences were noted in hydroxyproline content between groups. These studies suggest that Fluosol-DA results in persistence of foamy macrophages without significantly altering infarct topography in the temporary occlusion rabbit model.

Effect of time of dosing relative to a meal on the raft formation of an anti-reflux agent.

Gamma scintigraphy was used in twelve healthy volunteers to establish whether the time of dosing of Liquid Gaviscon relative to a meal influenced its therapeutic action. Indium-113m labelled Liquid Gaviscon was administered to fasted subjects, 30 min after a technetium-99m labelled meal or immediately before ingestion of the meal. The time for 50% of the Gaviscon to empty from the stomach was 0.36 +/- 0.13 h, 3.10 +/- 0.31 h and 0.68 +/- 0.04 h (s.e.m.), respectively. The preparation was found to empty rapidly from the fasted stomach and could not be floated on a meal consumed subsequently. For raft formation to occur, Liquid Gaviscon should be taken 30 min after a meal.

EMLA cream in the treatment of post-herpetic neuralgia. Efficacy and pharmacokinetic profile.

The analgesic efficacy of 5% of EMLA cream (5 or 10 g) when applied for 24 h periods was evaluated in 5 female and 7 male patients (mean age 69 years, range 50-85 years) with refractory post-herpetic neuralgia (PHN). Mean visual analogue pain intensity scores for all patients were significantly improved 6 h after application (P less than 0.05). In a subgroup of patients with facial PHN receiving EMLA cream, 5 g (n = 4), there were significant improvements in pain intensity scores at 6 h (P less than 0.05). 8 h (P less than 0.01) and 10 h (P less than 0.01) after application. Plasma lignocaine and plasma prilocaine concentrations were well below potentially toxic levels in all patients after application.

Pharmaceutical design and development of a Sinemet controlled-release formulation.

Many different formulation techniques are available for designing controlled-release dosage forms. Five different erosion-controlled or diffusion-controlled delivery systems were evaluated to select the 1 most suitable for Sinemet CR. The system ultimately selected, containing carbidopa-levodopa 50-200 mg, is a monolithic matrix tablet designed to have both of its active components released by surface dissolution and erosion. This system was found to be the most effective following extensive in vitro testing, pharmacokinetic studies, and clinical trials. Sinemet CR releases both carbidopa and levodopa by a 1st-order release rate. Controlled-release dosage forms of levodopa with slower in vitro release rates have lower plasma levels.

Pharmacokinetics and bioavailability of Sinemet CR: a summary of human studies.

The pharmacokinetics of Sinemet CR, a controlled-release formulation containing carbidopa and levodopa, were investigated in healthy young and elderly volunteers and in patients with Parkinson's disease. Sinemet CR produced more sustained plasma levels of levodopa, carbidopa, and 3-O methyldopa than did conventional Sinemet. In elderly subjects, the corresponding steady-state plasma levels fluctuated in narrower ranges with Sinemet CR than those following the administration of Sinemet. Results indicate a levodopa bioavailability of 71% for Sinemet CR, in contrast to a bioavailability of 99% for Sinemet for these subjects. The carbidopa bioavailability of Sinemet CR was 58% relative to that of Sinemet. Systemic decarboxylase inhibition was comparable between the 2 regimens as indicated by the renal clearance of levodopa. The absorption of levodopa was slower and more protracted with Sinemet CR than with Sinemet. Food increased the levodopa bioavailability of Sinemet CR. This increase was attributed to an increased gastric retention time. No dose-dumping occurred with Sinemet CR in either the nonfasting or the fasting state. Levodopa bioavailability was lower in young volunteers than in elderly volunteers. This was attributed to an age-related decrease in gastric emptying and in 1st-pass metabolic decarboxylation in the gastrointestinal (GI) tract. In parkinsonian patients, as in healthy subjects, the Sinemet CR formulation produced more sustained levodopa plasma levels. These patients required a higher total daily dosage of Sinemet CR than of Sinemet for control of parkinsonian symptoms, but less frequent dosing was required during chronic therapy. Peak plasma levodopa levels increased proportionately with increasing Sinemet CR dosage. These observations were consistent with the pharmacokinetic characteristics of the formulation.

Controlled-release carbidopa/levodopa (Sinemet 50/200 CR4): clinical and pharmacokinetic studies.

Several controlled-release carbidopa/levodopa preparations have been formulated to achieve a more stable and extended antiparkinsonian action. The most effective is Sinemet CR (Sinemet CR4), with an erodible polymer matrix that retards release of levodopa. In 19 parkinsonians with prominent dose-by-dose fluctuations, double-blind crossover trials comparing 8-week regimens of standard carbidopa/levodopa (25/100) to Sinemet CR (50/200) showed comparable clinical outcomes, with mean daily dosing for optimal control reduced from 10.2 to 5.4 (although mean daily levodopa dosage increased from 1,340 to 1,781 mg/day). Most patients improved on the Sinemet CR regimen in hours "on" and in ratings of clinical state and disability. With pharmacokinetic studies correlated to clinical ratings, plasma levodopa was less variable during Sinemet CR treatment, and clinical responses showed greater uniformity. Compared to standard Sinemet 25/100, time to peak levodopa concentration (2.3 versus 1.1 hrs), onset of maximal clinical improvement (2.2 versus 1.1 hrs), and other indices were significantly delayed with Sinemet CR. Levodopa bioavailability and clearance were similar between formulations. Although onset of clinical response is slower, the Sinemet CR formulation lessens peak-dose and "wearing-off" responses occurring with conventional carbidopa/levodopa and offers substantial improvement for some parkinsonians.

Gastrointestinal transit of Sinemet CR in healthy volunteers.

The gastrointestinal transit and systemic absorption of Sinemet CR (50/200) and standard Sinemet (25/100) have been studied in fasting and "fed" healthy human subjects. Both formulations were labeled with a gamma-emitting radionuclide, and their gastric emptying, colon arrival, and in vivo dissolution profiles were monitored using gamma scintigraphy. The standard dosage forms were found to disperse soon after administration and to empty rapidly from both the fasting and the "fed" stomach. The erosion of the controlled-release (CR) system was independent of food. Dosing after a light breakfast altered the gastric emptying profile of the CR formulation and led to significant differences in the plasma levels of levodopa.