bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Altering Small Bowel Transit Time on Sustained Release Theophylline Absorption
Authors: Bryson Judy C. , Dukes George E. , Kirby M. Gray , Heizer William D. , Powell J. Robert
Published: March 2013

The relationship between variations in small bowel transit time (SBTT) and the absorption of theophylline from a sustained‐release product was evaluated in a three‐way, randomized, crossover study in 12 healthy male nonsmokers. Subjects received sustained‐release theophylline (600 mg) with loperamide (8 mg every 6 hour × 8 doses), metoclopramide (15 mg every 6 hour × 8 doses) or placebo (every 6 hour × 8 doses). Theophylline solution (400 mg) was used as a reference standard. Serum samples were collected periodically for 72 hours for theophylline concentration determinations. SBTT was measured by the lactulose hydrogen breath test. Compared with placebo (98 ± 53 min), SBTT was increased with loperamide (211 ± 87 min; P < 0.001) and decreased with metoclopramide (55 ± 18 min; P < 0.001). Loperamide decreased the rate, but not the extent of theophylline absorption from this product. This was evident from the reduced Cmax, the prolonged Tmax, and the decreased fraction of the dose absorbed at 24 hours, while the area under the curves remained the same. In contrast, metoclopramide had no effect either on rate or extent of absorption. The data suggest that the effect of loperamide on these absorption parameters was due to an increase in the dissolution time of this sustained‐release product.
Impaired Absorption of Tetracycline by Colestipol Is Not Reversed by Orange Juice
Authors: Friedman H. , Greenblatt D. J. , LeDuc B. W.
Published: March 2013

Nine volunteers received a 500 mg oral dose of tetracycline hydrochloride in three trials: A: With 180 ml water; B: With 30 gm colestipol in 180 ml water; C: With 30 gm colestipol in 180 ml orange juice. Tetracycline concentrations in multiple urine samples collected during 48 hours after each dose were determined by high pressure liquid chromatography. The three trials did not differ significantly in 48 hour cumulative urine volume (3086 vs 3207 vs 3194 ml for Trials A, B, and C). However, the three trials differed significantly in 48 hour excretion of tetracycline (F = 28.2; P < .001). During Trial A, mean excretion was 237 mg; this was significantly (P < .05) reduced to 109 mg in Trial B and 104 mg in Trial C. However, Trials B and C were not different. Thus, coadministration of tetracycline with colestipol significantly impairs tetracycline absorption by more than 50%. Mixing colestipol with orange juice does not alter colestipol‐induced impairment of tetracycline absorption.
Multicenter Evaluation of the Hemodynamic Effects of Bisoprolol in Patients with Mild to Moderate Hypertension
Authors: Prisant L. Michael , Carr Albert A. , Desnoyers Mark , Westcott R. Jeffrey , Zinny Miguel A. , O'Donnell Denis M. , Bryzinski Brian , McKee Bonnie , Nelson Bennie R.
Published: March 2013

Twenty‐six patients with mild‐to‐moderate essential hypertension participated in a 6‐week outpatient, multicenter, randomized, double‐blind, placebo‐controlled two‐way crossover study to assess the hemodynamic effects of bisoprolol (20 mg QD) at steady state. Hemodynamic assessments included sitting blood pressure, heart rate, and left‐ventricular ejection fraction by radionuclide ventriculography after 7 days of bisoprolol or placebo at trough (24 h post‐dose) and peak (3 h post‐dose) values. The group adjusted mean ejection fraction was not significantly different in patients receiving bisoprolol compared with the placebo group at either peak or trough measurements; in fact, means in patients taking bisoprolol were slightly higher than in the placebo group. No symptomatic hypotension was documented. Blood pressure, measured 24 hours after dosing, was significantly lower in those receiving bisoprolol when compared with the placebo group, by 7.7 mm Hg and 9 mm Hg for diastolic and systolic blood pressure, respectively. Similarly, mean values of heart rate were 10 beats/min lower in the bisoprolol patients than in the placebo group. Only headache and insomnia occurred as adverse events. Bisoprolol (20 mg QD) effectively lowered blood pressure over a 24‐hour period without significantly reducing ejection fraction or causing adverse clinical or biochemical events.
Effect of Phenytoin on the Clinical Pharmacokinetics of Amiodarone
Authors: Nolan Paul E. , Marcus Frank I. , Karol Michael D. , Hoyer Gifford L. , Gear Kathleen
Published: March 2013

Five healthy male volunteers were given oral amiodarone hydrochloride, 200 mg per day for 6½ weeks, to determine its effects on the pharmacokinetics of both intravenous and oral phenytoin. Predose amiodarone and N‐desethylamiodarone serum concentrations were obtained weekly during weeks 2–6. Amiodarone serum concentrations (ASC) increased during weeks 2–4 and then decreased sharply during weeks 5–6 when oral phenytoin, 2–4 mg/kg/day, was co‐administered. In addition, N‐desethylamiodarone serum concentrations (DEASC) exceeded corresponding ASC during weeks 5–6 whereas during weeks 2–4, DEASC were less than ASC. Because of the long elimination half‐life for amiodarone previously reported in healthy volunteers after single doses of amiodarone and the frequent administration of amiodarone associated with this half‐life, a modified equation for a continuous infusion was used to describe each subject's ASC versus time data. Pre‐phenytoin ASC were fitted to an appropriate function to predict ASC during weeks 5–6 assuming no interaction. Observed versus predicted ASC were compared for weeks 5 and 6. Observed ASC during weeks 5 and 6 were (mean ± SD) 0.25 ± 0.09 μg/mL and 0.19 ± 0.07 μg/mL, respectively. Corresponding predicted ASC were 0.36 ± 0.12 μg/mL (P = .011) and 0.38 ± 0.13 μg/mL (P = .004). These represented percent differences of 32.2 ± 12.5% and 49.3 ± 5.6% for weeks 5 and 6, respectively. Assuming there were no changes in the bioavailability of amiodarone during continuous administration, these findings strongly suggest induction of amiodarone metabolism by phenytoin. The clinical significance of this interaction remains to be determined.
Thermal Injury Effects on Drug Disposition: A Prospective Study with Piperacillin
Authors: Shikuma Lois R. , Ackerman Bruce H. , Weaver Ross H. , Solem Lynn D. , Strate Richard G. , Cerra Frank B. , Zaske Darwin E.
Published: March 2013

The disposition of piperacillin was prospectively evaluated in nine severely burned patients who had normal renal and hepatic function. Wide interpatient variations were demonstrated in the drug's distribution volume, half‐life, and clearance, with mean (±SD) values of 55.0 (±44.2) liters, 3.6 (±5.2) hours, and 14.9 (±6.3) liters/hour, respectively. Piperacillin clearance was best explained by patient factors other than age, renal function, and the percentage of body surface area burns. Piperacillin disposition was related to the patients' serum albumin, total bilirubin, blood urea nitrogen, and the amount of urea nitrogen excreted daily in urine. Altered piperacillin disposition thus appeared to occur secondary to changes in the patients' physiologic and metabolic state caused by injury‐related stress and fluid therapy. The patient's physiologic and metabolic response to injury, along with age and renal function, should be considered when instituting treatment with piperacillin or other agents cleared from the body in a similar manner.
Effect of Food on the Pharmacokinetics of Cyclosporine in Healthy Subjects Following Oral and Intravenous Administration
Authors: Gupta Suneel K. , Manfro Roberto C. , Tomlanovich Stephen J. , Gambertoglio John G. , Garovoy Marvin R. , Benet Leslie Z.
Published: March 2013

The pharmacokinetics of cyclosporine were studied in healthy subjects following administration of cyclosporine both orally (10 mg kg−1) and intravenously (4 mg kg−1) without and with high fat meals. Both blood and plasma samples (separated at 37°C) were analyzed for cyclosporine concentration. Blood and plasma clearances of cyclosporine were calculated to be 0.36 and 0.47 L hr−1 Kg−1, respectively, and volume of distribution at steady state was calculated to be 1.21 L Kg−1, when cyclosporine was administered without a high fat meal. Using plasma analysis, the oral bioavailability of cyclosporine was estimated to be 21 and 79%, when administered without and with a high fat meal, respectively. When cyclosporine was administered intravenously together with a high fat meal, both clearance and volume of distribution increased significantly. Blood and plasma clearances of cyclosporine were 0.44 and 0.70 L hr−1 Kg−1, respectively, when cyclosporine was administered along with a high fat meal. We conclude that food not only enhances the absorption of cyclosporine but also enhances its clearance and volume of distribution. The observed variability in clearance, bioavailability, and volume of distribution values for cyclosporine across various pharmacokinetic studies can be partially accounted by the type of food administered and the sampling matrix used for analysis.
Diphenhydramine: Pharmacokinetics and Pharmacodynamics in Elderly Adults, Young Adults, and Children
Authors: Simons Keith J. , Watson Wade T. A. , Martin Tara J. , Chen Ms. Xue Yu , Simons F. Estelle R.
Published: March 2013

The pharmacokinetics and pharmacodynamics of the H1‐receptor antagonist diphenhydramine were studied in 21 fasting subjects divided into three age groups: elderly, (mean age 69.4 ± 4.3 years), young adults, (mean age 31.5 ± 10.4 years), and children, (mean age 8.9 ± 1.7 years). All subjects ingested a single dose of diphenhydramine syrup 1.25 mg/kg, in mean doses of 86.0 ± 7.3 mg, 87.9 ± 12.4 mg, and 39.5 ± 8.4 mg, respectively. Blood samples were collected hourly for 6 hours, every 2 hours until 12 hours, at 24 hours, and, in the adults, up to 72 hours after diphenhydramine administration. At these times, histamine skin tests were performed and wheal and flare areas were computed. The mean serum elimination half‐life values for diphenhydramine differed significantly in elderly adults, young adults, and children, with values of 13.5 ± 4.2 hours, 9.2 ± 2.5 hours, and 5.4 ±1.8 hours being found respectively in each age group. Clearance rates for diphenhydramine also differed significantly with age, being 11.7 ± 3.1 mL/min/kg in elderly adults, 23.3 ± 9.4 mL/min/kg in young adults and 49.2 ± 22.8 mL/min/kg in children. Diphenhydramine produced a maximum wheal suppression of 39.6 ± 22.5% and a maximum flare suppression of 46.5 ± 32.1% at 5 and 6 hours respectively in the elderly, a maximum wheal suppression of 45.5 ± 25.0% and a maximum flare suppression of 53.4 ± 16.9% at 6 and 4 hours respectively in young adults; and a maximum wheal suppression of 68.4 ± 10.2% and a maximum flare suppression of 87.2 ± 4.2% at 2 hours in children.
New Natural Products in Cancer Chemotherapy
Authors: Slichenmyer William J. , Von Hoff Daniel D.
Published: March 2013

Four new and clinically relevant antineoplastic natural products are reviewed. Taxol is derived from the bark of the western yew. It promotes the formation of microtubule bundles which deform the cytoskeleton and interfere with mitosis. Although phase II efficacy testing is incomplete, taxol is effective in the treatment of patients with ovarian carcinoma and has some activity in patients with non‐small cell lung cancer and melanoma. It remains untested against several other neoplasms. The chief toxicities of taxol are myelosuppression, mucositis, anaphylactoid reactions, and peripheral neuropathy. Homoharringtonine is the most active and abundant of the cephalotaxine esters derived from the genus Cephalotaxus. This agent appears to act at the ribosome to inhibit protein synthesis and has clinical activity in patients with acute myelogenous leukemia. The dose limiting toxicities of homoharringtonine are hypotension and myelosuppression. SKF 104864 and CPT‐11 are derivatives of camptothecin which are still in early clinical trials. They are cytotoxic in vitro, acting through an interaction with topoisomerase I to induce DNA fragmentation. The spectra of activity and toxicity of SKF 104864 and CPT‐11 are still undefined. All four of these new natural products offer possibilities for clinical activity for patients with a variety of malignancies.
Reduced Systemic Absorption of Intrabronchial Lidocaine by High‐Frequency Nebulization
Authors: Labedzki Lothar , Scavone Joseph M. , Ochs Hermann R. , Greenblatt David J.
Published: March 2013

Serum lidocaine concentrations were measured in a series of patients during and after topical administration of lidocaine used to anesthetize the nasal mucosa, pharynx, and larynx for diagnostic fiberoptic bronchoscopy. In one group of patients (N = 9) the trachea and bronchi were sprayed with a 2% lidocaine solution administered in 2 mL volumes. Another group (N = 14) received a 2% lidocaine solution which was administered by inhalation of lidocaine dispensed by a high‐frequency nebulizer. Multiple serum samples drawn over a 1‐hour period were analyzed by gas chromatography with nitrogen‐phosphorous detection. In the spray group versus the inhalation group, there were no differences in mean age (54 vs 55 years), total lidocaine dose (572 vs 525 mg), or time of peak serum lidocaine concentration (43 vs 41 minutes after dose). However, the peak serum lidocaine concentrations were significantly lower in the inhalation group vs the spray group (1.40 vs 3.63 μg/mL). Thus, administration of lidocaine via inhalation by ultrasonic nebulization results in lower peak serum concentrations, and a reduction in the likelihood of toxicity, than when administered by conventional topical spray.
Circadian Variation in Serum Amikacin Levels
Authors: Elting Linda , Bodey Gerald P. , Rosenbaum Beverly , Fainstein Victor
Published: March 2013

Variable serum amikacin levels have been reported in the same patient even after a steady state presumably has been reached. Therefore, the authors investigated the optimal schedule for monitoring serum levels of the drug in 50 neutropenic patients receiving continuous infusion amikacin therapy for infections. We found that levels obtained in the early morning hours were significantly higher than those obtained for the same patient in the evening. As these differences parallel those previously demonstrated for renal function, they may be explained by the pattern of drug clearance by the kidneys. We recommend that blood specimens for the detection of rising serum amikacin levels in a therapeutic setting be obtained in the early morning and at the same time each day so that meaningful comparisons of peak concentrations can be made. However, late evening samples should also be tested whenever dosage modifications are considered so that continuous therapeutic serum concentrations can be ensured.
Systemic Absorption of Clindamycin Following Intra vaginal Application of Clindamycin Phosphate 1% Cream
Authors: Borin Marie T.
Published: March 2013

The extent to which clindamycin is absorbed systemically following intravaginal application of clindamycin phosphate 1% cream was assessed in 12 healthy female volunteers. Each subject received a single intravenous dose of clindamycin phosphate sterile solution (48 mg). A week later, each subject received 50 mg (5 mL) doses of intravaginal cream according to one of two dosage regimens: once daily (qd) for seven consecutive doses or twice daily (q12hr) for 13 consecutive doses. Steady state was achieved on or before day 4 for both regimens. The absolute bioavailabilities of the two intravaginal treatments were 6% for qd dosing and 13% for q12hr dosing, indicating that only a small fraction of the intravaginal dose is absorbed systemically.
Inaccuracy of Hourly Sampled pH Measurements in Describing the Effect of Antisecretory Drugs on Circadian Gastric Acidity
Authors: Mela Giuseppe Sandro , Savarino Vincenzo
Published: March 2013

This study was carried out in order to verify whether gastric pH measurements obtained with continuous monitoring are more accurate in assessing the pharmacodynamic properties of antisecretory drugs than those obtained with the traditional hourly nasogastric aspiration method. Accordingly, we compared the most commonly used acidity indexes (median of pHs and mean of [H+]s) and the total circadian time spent above 4.0 pH units, all of which were calculated from both raw data sampled at rates of a few seconds with modern apparatus and data obtained from the same profiles scanned punctually at a 60 minute rate. The analysis referred to 231 continuous gastric pH‐metries which were performed over the circadian period to evaluate the acid inhibitory effects of different doses and dosage regimens of various H2‐antagonists. In the population as a whole, the numbers and percentages of subjects, whose 60‐minute sampled medians of pHs and means of [H+]s differed by less than ±10% from those obtained from raw fast‐acquired data, were 107 (46%) and 34 (15%), respectively. There was even less agreement in the case of the circadian time above 4.0 pH units (26 cases = 11%). No statistical difference (P = .7) between the concordance rates of each variable in the three groups was observed. Considered simultaneously, there was concordance of the above three indexes in only seven out of the 231 cases. These results show that the hourly sampling rate fails to represent adequately gastric acidity changes induced by antisecretory drugs, due to the scarcity of experimental points. The acidity indexes calculated from these slowly sampled data are inaccurate, especially when the means of [H+]s are considered, and the duration of action of the drug often is defined randomly.
Pharmacokinetics of Continuous Intravenous Infusion of Methadone in the Early Post‐Burn Period
Authors: Denson Donald D. , Concilus Robert R. , Warden Glenn , Raj P. Prithvi
Published: March 2013

The pharmacokinetics of methadone were studied in 14 patients with acute, severe burns and receiving an intravenous infusion of methadone to control their pain. Serum methadone concentrations were measured by gas chromatography on 5 mL arterial blood samples obtained at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0 and 24 hours after the start of infusion. Albumin and Alpha‐1‐Acid glycoprotein (AAG) were measured by radial immunodiffusion. Serum methadone concentration‐time data were fit with the appropriate sum of exponentials equation using iterative nonlinear regression analysis.

All serum methadone concentration‐time data were best described by a monoexponential equation. Estimates of Vd (180 ± 62 L) were not significantly different from those predicted for Vc from body weight using literature values (156 ± 41). Estimates of Vd were, however, significantly lower than those predicted for Vz using literature values (282 ± 74) (P < 0.001). in addition, CL values (53.0 ± 19.3 L/h) were significantly higher than those predicted from body weight using literature values (9.2 ± 2.3 L/h) (P < 0.001). These changes resulted in estimates of the elimination half‐life for methadone of 2.6 ± 1.1 h. Methadone protein binding was independent of both albumin and AAG concentration. Multiple regression demonstrated that the significant predictors of CL in the early post burn injury period were serum albumin, days post injury and age. The coefficient of determination (r2) for this model was 0.8190.

In summary, methadone CL is markedly elevated while the Vc is essentially unchanged during the early post burn injury period. These changes suggest that normal loading doses but increased maintenance doses of methadone should be used during this period to provide prolonged analgesia.
Rapid‐Acting Parenteral Antihypertensive Agents
Authors: Chun Grace , Frishman William H.
Published: March 2013

Parenteral antihypertensive agents are useful in those clinical situations where rapid reduction of blood pressure is necessary or where treatment with oral antihypertensive medications is not feasible. Given the diverse selection of parenteral antihypertensive drugs now available, therapy can be individualized. The presence of concurrent diseases will often influence the decision‐making process regarding choice of an agent. Complications of parenteral antihypertensive therapy can arise from the intrinsic properties of the various drugs or the development of severe hypotension. Gradual lowering of blood pressure, in conjunction with careful clinical evaluation, will minimize the risks of acute parenteral antihypertensive therapy. Given that parenteral antihypertensive therapy often needs to be replaced by oral therapy, those drugs that can be used both parenterally and orally may have an advantage.
Third Generation Cephalosporins: Safety Profiles After 10 Years of Clinical Use
Authors: Neu Harold C.
Published: March 2013

Compared with aminoglycosides, chloramphenicol, sulfonamides, tetracyclines, and even penicillins, the cephalosporins represent a remarkably safe class of antibiotics. Among the cephalosporins, the extended spectrum, third generation agents developed generally produce few side effects and appear to be less allergenic than the penicillins. Nephrotoxicity has not been a problem at recommended doses. Some third generation agents can cause hypoprothrombinemia if not administered with vitamin K, and disulfiram‐like reactions occur with some agents because of the presence of a thiomethyl tetruzole moiety affixed to the cephem nucleus. There is a greater incidence of diarrhea associated with the agents excreted through a primarily biliary route, and this may contribute to the selection of drug resistant bacteria. Some agents are less active against staphylococci and their use may result in an increased incidence of superinfection or overgrowth of enterococci. If attention is given to the potential for adverse effects, many of these problems can be avoided and the third generation cephalosporins can be used safely in hospitals, nursing homes, and home care settings.
Evaluation of the Clinical Pharmacology of Nilvadipine in Patients with Mild to Moderate Essential Hypertension
Authors: Weir Matthew R. , Vlachkis Nicholas D. , DeQuattro Vincent , Douglas Janice , Svetkey Laura P. , Singh S. , Wiedl Sheila C. , Chen C‐F. , Woodward David L. , Saunders Elijah
Published: March 2013

Eighty‐four patients with diastolic blood pressure ranging from 100–115 mm Hg were randomized into a multicenter, parallel, double‐blind, placebo‐controlled, dose response study with nilvadipine (6 mg, 8 mg, 10 mg tid for 28 days). The hypotensive response pattern to nilvadipine was similar with all three doses although duration of response was dose dependent. Maximal decreases in diastolic hlood pressure occurred at 1 hour when assessed on days 1 and 15 (16.0, 17.4, and 15.8 mm Hg, vs 17.2, 18.7, and 17.5 mm Hg, respectively). The hypotensive effect remained significant compared to placebo for at least 4 hours after dosing. The increase in heart rate associated with the maximal hypotensive response was minimal and not clinically significant (day 1: 7.6, 5.2, and 4.0 beats/min with 6, 8, and 10 mg; day 15: 4.0, 5.1, 2.6 beats/min with 6, 8, 9, and 10 mg, respectively). Finally, a correlation between plasma drug concentrations and nilvadipine‐induced hypotensive response was observed (r = 0.48). Black and white hypertensive patients had similar hypotensive responses. Plasma nilvadipine concentrations on day 15 were similar to those on day 1 suggesting no accumulation of drug with a tid regimen. The most common drug related side effect was headache; less frequently seen were dizziness, edema, palpitations, and abdominal pain. Nilvadipine was well tolerated (only three patients were discontinued due to side effects). The efficacy, lack of tachycardia, and side effect profile observed in this study suggest that nilvadipine may be an important addition to the treatment of hypertension.
The Neuropsychiatric Effects of Aspartame in Normal Volunteers
Authors: Lapierre Katherine A. , Greenblatt David J. , Goddard Jill E. , Harmatz Jerold S. , Shader Richard I.
Published: March 2013

Ten healthy volunteers with no history of aspartame intolerance (6 men and 4 women, aged 21–36 years) received a single dose of aspartame (15 mg/kg body weight in capsules) or matching placebo in a randomized, double‐blind crossover study. Eleven blood samples collected over 24 hours were analyzed for plasma glucose and amino acid concentrations. The following variables were evaluated at 1, 2, 4, 8, and 24 hours postdosage: changes in mood measured on visual analog scales, cognitive function determined by digit‐symbol substitution test (DSST) and arithmetic test scores, and reaction time measured with a brake‐pedal reaction timer. Memory was tested at 2 and 24 hours after dosage based on recall of standardized 16‐item word lists. No significant differences between aspartame and placebo were found in measures of sedation, hunger, headache, reaction‐time, cognition, or memory at any time during the study. Plasma phenylalanine levels were significantly higher following aspartame (P < .01) than with placebo between 1 and 6 hours postdosage, reaching a maximum difference of +3.36 μmol/dl at 2 hours. Plasma glucose concentrations were not significantly different between aspartame and placebo. The results of this study suggest that following a single 15 mg/kg dose of aspartame, no detectable effects are observed in a group of healthy volunteers with no history of aspartame intolerance, despite significant increases in plasma phenylalanine concentrations.
Acute Interstitial Nephritis with Glomerulopathy Due to Nonsteroidal Anti‐Inflammatory Agents: A Review of Its Clinical Spectrum and Effects of Steroid Therapy
Authors: Porile James L. , Bakris George L. , Garella Serafino
Published: March 2013

We reviewed case reports of patients who developed acute renal failure and/or nephrotic range proteinuria in the course of receiving treatment with nonsteroidal anti‐inflammatory agents (NSAIA). Those cases that contained information sufficient to confirm the diagnosis of acute interstitial nephritis with glomerulopathy (AING), including a suggestive clinical syndrome with appropriate renal biopsy findings, were further analyzed to achieve a more complete description of this clinical entity and its responsiveness to steroid treatment. Analysis of the cases that fulfilled the inclusion criteria confirmed that the disorder is twice as common in women and occurs mainly in elderly people, usually after long‐term use of NSAIAs for musculoskeletal problems. Fenoprofen was implicated in 47% of the cases. Evidence of systemic hypersensitivity was uncommon. Two thirds of the cases displayed clinical and/or histological evidence of both acute interstitial nephritis and increased glomerular permeability. These findings strongly suggest that this condition is distinct from other drug‐induced “allergic” acute interstitial nephritides. In the absence of complicating factors, all patients improved following discontinuation of the offending agents. No evidence was found to suggest that steroid therapy altered the clinical course of this process.
Pharmacokinetics of Rimexolone After Intra‐Articular Administration
Authors: Derendorf Hartmut , Möllmann Helmut , Voortman G. , van den Ouweland Frank A. , VAN, de Putte Levinus B. A. , Gevers Greet , Dequeker Jan , VAN Vliet‐Daskaiopoulou E.
Published: March 2013

The pharmacokinetics of rimexolone were investigated after intra‐articular injection into the knee joints of patients with rheumatoid arthritis. After a single dose of 40 mg rimexolone the drug could be detected in plasma over 3 months. The suspension dissolves in the synovia very slowly and provides a sustained release of the steroid in the joint. Pharmacokinetic analysis was performed on the assumption that the disposition of rimexolone after intra‐articular administration is absorption limited (“flip‐flop‐case”). Dose linearity was studied in a range from 40 to 200 mg. Total body clearance averaged 106 L/h and was independent of dose. The mean residence time of rimexolone in the knee joint is very long and averaged 25 days. It could be shown that the mean residence time of different glucocorticoids correlates well with the duration of their clinical effectiveness.
A Pharmacokinetic and Pharmacodynamic Comparison of Metoprolol CR/ZOK with a Conventional Slow Release Preparation
Authors: Oosterhuis Berend , Jonkman Jan , Zuiderwijk Peter , Sollie Frans
Published: March 2013

The plasma concentration‐time profile and hemodynamic effects of metoprolol after the administration of metoprolol CR/ZOK, a multiple‐unit controlled release formulation and a conventional slow release formulation, metoprolol Durules (Astra, AB Hassle, Mölndal, Sweden) once daily, were investigated in 12 healthy men. Data were collected over one 24‐hour dose interval at steady state after 5 days of treatment. The study was a randomized, three‐way, crossover double‐blind comparison of metoprolol CR/ZOK 200 mg, metoprolol Durules® 200 mg and placebo. The reduction in exercise heart rate compared with placebo treatment was used as a measure of β1‐blockade. The metoprolol plasma concentration‐time profile during treatment with metoprolol CR/ZOK was smooth and uniform, showing a more constant release profile than that obtained with metoprolol Durules®. This was demonstrated by the significantly longer time period during which the plasma concentration exceeded 75% of the maximum concentration (T75), for metoprolol CR/ZOK compared with metoprolol Durules® (P< .01). The Fluctuation Index of plasma metoprolol concentration was significantly smaller for metoprolol CR/ZOK than for metoprolol Durules® (P< .001). The pharmacokinetic differences between the formulations also produced differences in the time profiles of exercise heart rate. The percentage fluctuation in exercise heart rate over the dose interval tended to be smaller for metoprolol CR/ZOK. At the start and the end of the dosing interval, the CR/ZOK formulation was significantly more effective (P< .01). These results indicate that Metoprolol CR/ZOK has a more sustained time profile of β1‐blockade at steady state. In spite of considerable between‐subject pharmacokinetic variability, there was only modest between‐subject variation in overall pharmacodynamic response.
The Relationship Between Metoprolol Plasma Concentration and Beta1‐Blockade in Healthy Subjects: A Study on Conventional Metoprolol and Metoprolol CR/ZOK Formulations
Authors: Abrahamsson Bertil , Lücker Peter , Olofsson Bertil , Regårdh Carl‐Gunnar , Sandberg Anders , Wieselgren Ingrid , Bergstrand Robert
Published: March 2013

Four studies using different daily doses (100 mg, 200 mg, 300 mg and 400 mg) have examined the bioequivalence of the once daily formulation metoprolol CR/ZOK and conventional metoprolol tablets (CT). These studies showed metoprolol CR/ZOK to have a similar beta1‐blocking activity to metoprolol CT but that the bioavailability of the new formulation was lower. This paper presents the analysis of data from all four studies, looking at the relationship between plasma concentrations and beta1‐blockade measured as reduction of exercise induced tachycardia.

The log linear pharmacodynamic model was used for each of the four doses to compare the two formulations. Mean slopes and intercepts in the linear regression analysis of log plasma concentration of metoprolol versus beta1‐blockade did not differ significantly between CR/ZOK and CT in any of the four studies. After having shown lack of influence of the absorption rate on the plasma concentration—effect relationship, data for CR/ZOK and CT formulations from the 200 mg study were pooled for each individual subject and fitted to an Emaxmodel. The maximal β1‐blocking effect (Emax) was 28% (95% confidence interval: 25–31%) and the plasma concentration for obtaining 50% ofEmax(C50) was 105 nmol/L (95% confidence interval: 74–135 nmol/L). The plasma concentration‐effect data from the 100 mg, 300 mg and 400 mg studies were reasonably well within the 95% prediction interval based on the 200 mg study, which showed the validity of the obtained relationship. The hyperbolic concentration‐beta1‐blocking effect relationship, as described by the Emax‐model explains why a similar or even increased effect is obtained over a dosing interval for metoprolol CR/ZOK compared with metoprolol CT, in spite of the reduced bioavailability of the CR/ZOK formulation.
A Comparison of a Controlled Release (CR/ZOK) Formulation of Metoprolol, Once Daily, with Conventional Metoprolol Tablets, Twice Daily, in Mild to Moderate Hypertension
Authors: Carruthers George , Shearer Robin , Taylor Wayne , Moore Marianne
Published: March 2013

In a randomized double‐blind multicenter study in 100 hypertensive patients, the effect of once daily (od) dosing with a new controlled release (CR/ZOK) formulation of metoprolol was compared with that of twice daily (bid) dosing with metoprolol conventional tablets. Eligible patients had a resting seated diastolic blood pressure (DBP) ≥ 95 mm Hg and <110 mm Hg at the end of a 6‐week open placebo run‐in. The active treatment phase lasted 8 weeks. The starting dose was 100 mg od in the CR/ZOK group (N = 53) and 50 mg bid in the tablet group (N = 47). The dose was increased to 200 mg od and 100 mg bid, respectively, in nonresponders (DBP >95 mm Hg) at the end of the first 4‐week period. Approximately 40% of both groups received concomitant diuretic therapy throughout the study. The SBP, DBP and HR were reduced compared to baseline in both treatment groups after 4 and 8 weeks. After 4 weeks, 85% of the CR/ZOK group and 74% of the tablet group had DBP <95 mm Hg. After another 4 weeks, the corresponding figures were 93% and 93%. There was no statistically significant difference between the treatment groups in the decrease in either SBP, DBP or HR, nor was there any difference in the percentage of responders. Both treatments were equally well tolerated. In conclusion, the antihypertensive effect of once daily dosing (100–200 mg) with the new CR/ZOK formulation of metoprolol is as effective as that of twice daily dosing (50–100 mg) with conventional metoprolol tablets.
Tolerability and Well‐Being with Metoprolol in a Controlled Release (CR/ZOK) Formulation: A Review Article
Authors: Dimenäs Elof , Dahlöf Carl
Published: March 2013

Extensive research and clinical usage of metoprolol have shown the compound to be safe and well tolerated if the contraindications are taken into consideration. However, as with other beta‐blockers, unwanted effects may occur during treatment. Although usually mild, these side effects may be of considerable clinical importance, especially since once initiated, therapy is often life‐long.

Results of previous studies have indicated that some of these symptoms are associated with high plasma concentrations of the drug. Theoretically, side effects may thus be reduced by administration of metoprolol in a controlled‐release formulation (CR/ZOK) which yields relatively low plasma concentrations over approximately 24 hours.

Using clinically relevant doses, metoprolol CR/ZOK affects beta2‐adrenoceptor‐mediated functions (e.g., broncho‐dilatation in asthmatics) less than tablets do. In addition, less leg fatigue during exercise has been reported. The clinical studies published so far indicate that metoprolol CR/ZOK is as well tolerated as or better tolerated than, conventional metoprolol tablets. Furthermore, metoprolol CR/ZOK is tolerated equally or better than atenolol in terms of CNS‐related symptoms.
Reassessment of Benefit—Risk Ratio and Treatment Algorithms for Antiarrhythmic Drug Therapy After the Cardiac Arrhythmia Suppression Trial
Authors: Anderson Jeffrey L.
Published: March 2013

The Cardiac Arrhythmia Suppression Trial (CAST) has led to serious reconsideration of both the benefit—risk ratio of antiarrhythmic drug therapy and the appropriate therapeutic approach to various cardiac arrhythmias. Class IC drugs, such as encainide and flecainide, should not be used to treat asymptomatic postinfarction arrhythmias. Furthermore, because the CAST raises serious questions about the concept of treating asymptomatic but “potentially malignant” (prognostically important) arrhythmias guided by ambulatory monitoring, the prophylactic use of any of the antiarrhythmic agents (except beta blockers) must be considered inappropriate and potentially harmful until otherwise established by specific clinical trials.

For prophylaxis of malignant ventricular arrhythmias (sustained ventricular tachycardia or ventricular fibrillation), treatment may still begin with standard agents in classes IA, IB, or both, preferably guided by electrophysiologic testing alone or in combination with noninvasive testing. Class IC therapy may be most useful in those patients in this group who do not have such high‐risk characteristics for proarrhythmia as a history of multiple myocardial infarctions (MIs), congestive heart failure, or low ejection fraction. Amiodarone is moderately effective for treating these arrhythmias but is reserved as second‐ or third‐line therapy because of its potential organ toxicity. Sotalol, a beta blocker with class III activity, is often effective and relatively well tolerated in these patients and may become a preferred drug when approved.

For symptomatic but nonmalignant ventricular arrhythmias, a more conservative approach is more appropriate than in the past, with therapy reversed for those with debilitating symptoms. An initial trial of beta blockade is often appropriate before class I agents are considered. Class IC therapy should be avoided in patients with a history of MI (especially recent or multiple MIs), and probably in other patients with symptomatic coronary artery disease (e.g., angina, heart failure). The CAST emphasizes the need for further experimental and clinical trials and the development of new agents based on a better understanding of the overall benefit—risk ratio. As this occurs, treatment algorithms will continue to evolve.
Antihypertensive Effects of a New Sustained‐Release Formulation of Nifedipine
Authors: Zachariah Prince K. , Schwartz Gary L. , Sheps Sheldon G. , Schirger Alexander , Carlson Christopher A. , Moore Andrew G.
Published: March 2013

The blood pressure response to a new sustained‐release formulation of nifedipine was evaluated in an 8‐week, double‐blind, placebo‐controlled study. Twenty‐nine patients with mild essential hypertension were randomized to receive placebo (N = 9), 30 mg nifedipine (N = 10), or 60 mg nifedipine (N = 10). During treatment, 30‐mg and 60‐mg doses of nifedipine administered once daily decreased office blood pressures from 137/98 ± 8/2 mm Hg and 141/98 ± 15/2 mm Hg at baseline, respectively, to 126/89 ± 9/7 mm Hg and 126/86 ± 6/7 mm Hg (P < .005). Noninvasive automatic ambulatory blood pressure monitoring demonstrated a marginally significant (P < .10) reduction in the mean 24‐hour blood pressure of 2/6 ± 8/8 mm Hg and 5/6 ± 9/9 mm Hg for patients taking 30 mg and 60 mg nifedipine once daily, respectively. Diastolic blood pressure load (the percentage of ambulatory diastolic blood pressure readings greater than 90 mm Hg) during 24 hours was decreased by 41% and 35%, with 30 mg and 60 mg nifedipine administered once daily, respectively. No significant dose response to nifedipine at these dose levels was observed. Although the once‐daily formulation of nifedipine achieved effective control of office blood pressure, similar control was not observed in awake and 24‐hour periods in all patients.
Pulmonary Function in the Elderly: Response to Theophylline Bronchodilation
Authors: Chandler Mary H. H. , Clifton G. Dennis , Burki Nausherwan K. , Hunt Bernard A. , Blouin Robert A.
Published: March 2013

This clinical investigation was designed to characterize the pharmacologic response to theophylline in elderly individuals. Incremental theophylline plasma concentrations (0, 5, 10, 15, and 20 mcg/mL), achieved through dose escalation of intravenous aminophylline, were correlated with pulmonary airway responses in ten young and ten elderly male asthmatic volunteers. The older group had lower baseline pulmonary function values, suggestive of a greater degree of baseline airways obstruction. Despite wide intersubject variability, the elderly subjects demonstrated a lower absolute change in bronchodilator response to equal concentrations of theophylline than did their younger counterparts (P <.05). A progressive increase in heart rate was noted with increasing theophylline concentrations, but no significant difference in heart rate change between groups was detected (P > .05). Whether the difference in theophylline induced bronchodilator response observed in the young and elderly groups is due to a difference in age or in severity of airway obstruction is yet unknown.
A Double‐Blind Single Dose Comparison of Intramuscular Ketorolac Tromethamine and Pethidine in the Treatment of Renal Colic
Authors: Oosterlinck W. , Philp N. H. , Charig C. , Gillies G. , Hetherington J. W. , Lloyd J.
Published: March 2013

The efficacy of a single dose of intramuscular ketorolac 10 mg or 90 mg was compared with pethidine 100 mg in a randomized double‐blind study in 121 patients reporting at least moderate pain due to renal colic. Pain was assessed before drug administration, and then at 1 hour and 12 hours after the dose. Sedation was also assessed at these times, and additionally at the 12 hour assessment the time of the next analgesic dose was recorded. At 1 hour after dosing, pain scores had decreased in all groups; the largest decrease was seen in the ketorolac 90 mg group. The difference in the decrease was significant between the two ketorolac groups, but the differences between ketorolac and pethidine were not significant. Fewer patients in the ketorolac 90 mg group (17%) required a further dose of analgesic within 10 hours than in either the ketorolac 10 mg group (39%) or the pethidine 100 mg group (47%). The difference between ketorolac 90 mg and pethidine 100 mg was statistically significant. At both assessment times the proportion of patients with no sedation was higher in the two ketorolac groups than in the pethidine group. The overall incidence of adverse events was low with all drugs, notably so for the occurrence of vomiting after ketorolac. The results of the study show that intramuscular ketorolac is efficacious in the treatment of renal colic.
Acute and Intermediate Cardiovascular Responses to Zero Gravity and to Fractional Gravity Levels Induced by Head‐Down or Head‐Up Tilt
Authors: Lathers Claire M. , Diamandis Peter H. , Riddle Jeanne M. , Mukai Chiaki , Elton Kay F. , Bungo Michael W. , Charles John B.
Published: March 2013

Determination of early cardiovascular responses to simulated gravity levels between 0 and 1 G will add knowledge of cardiovascular responses to space flight. Cardiovascular responses to 6 hours in a −5° head‐down bedrest model of weightlessness (0 G) were compared to those in head‐up tilts of +10°, +20°, and +42° (1/6, 1/3, and 2/3 G, respectively). Six healthy young adult males experienced the four angles on separate days. Impedance cardiography was used to measure thoracic fluid index, cardiac output, stroke volume, and peak flow. Although much intersubject variation occurred, the mean thoracic fluid content at −5° decreased during the first hour and remained decreased; 6‐hour values were similar to + 10° and +20°. Heart rate decreased the first 2 hours for all angles, then increased, converging at 3–4 hours, and reached control by hour 6. Stroke volume decreased for the first 3 hours at −5°, +10°, +20°; values at all four angles converged at hour 3 and increased in unison thereafter. Cardiac output and peak aortic flow reflected the angle at start of tilt; values at all angles converged by the second hour, decreased through the third hour, and increased thereafter. Pulse pressure decreased for the first 3 hours for angles −5°, +10°, and +20°, converged at the fourth hour, and returned to control. Peak flow at +42° was constant for the first 3 hours and increased thereafter. Blood pressure decreased for the first 2 hours, although the greatest decrease occurred at −5° and +42°; thereafter, values at all angles increased in unison and converged at the fourth hour. Total peripheral resistance increased during the first hour at −5° and +20° and decreased from hour 3 to hours 5–6 at the +42° angle. Cardiovascular values were related to tilt angle for the first 2 hours of tilt, but after hour 3 values at all four angles began to converge, suggesting that cardiovascular homeostatic mechanisms seek a common adapted state regardless of effective gravity level (tilt angle) up to 2/3 G.
Effects of Single‐Dose and Short‐Term Oral Nifedipine on Indocyanine Green Clearance as Assessed by Spectrophotometry and High Performance Liquid Chromatography
Authors: Soons P. A. , Kroon J. M. , Breimer D. D.
Published: March 2013

The effects of single‐dose (10 mg) and short‐term (10 mg tid) nifedipine treatment on apparent hepatic blood flow, as assessed by indocyanine green (ICG) clearance, were studied in ten healthy male subjects. ICG was measured by both spectrophotometric and high performance liquid chromatography (HPLC) assay methods. Blood clearance of ICG and apparent hepatic blood flow were increased by 30 and 50%, respectively, after single‐dose nifedipine, whereas after 4 days' treatment these values were 12 and 30%. The spectrophotometric assay significantly overestimated ICG plasma concentrations from 7 minutes onwards. Although the spectrophotometric and HPLC assay showed marked differences in calculated half‐lives and volume of distribution of ICG, the ICG clearance values were similar for the two assay methods.
Effect of Food and Antacid on Absorption of Orally Administered Ticlopidine Hydrochloride
Authors: Shah J. , Fratis A. , Ellis D. , Murakami S. , Teitelbaum P.
Published: March 2013

Ticlopidine is a potent inhibitor of platelet aggregation. Absorption of ticlopidine after oral dosing is rapid and complete. Ticlopidine is extensively metabolized with a relative minor component of unchanged ticlopidine in plasma. The randomized crossover study described here was undertaken to examine the effect of food and antacid on the oral bioavailability of a single dose of ticlopidine (250 mg) in normal volunteers. After postprandial treatment the rate and extent of absorption of ticlopidine was earlier and greater relative to fasting treatment [tmax = 1.71 ± 0.33 hr (fed) vs 1.92 ± 0.56 hr (fasting) and AUC0–∝ = 2.164 ± 0.813 μg × hr/mL (fed) vs 1.808 ± 1.052 μg × hr/mL (fasting)]. The oral bioavailability of ticlopidine was increased by 20% when taken after a meal. In contrast, absorption of ticlopidine administered after antacid treatment was approximately 20% lower than under fasting conditions. Administration of ticlopidine with food is recommended to maximize gastrointestinal tolerance.
Plasma Codeine and Morphine Concentrations After a Single Oral Dose of Codeine Phosphate
Authors: Shah Jaymin C. , Mason William D.
Published: March 2013

Plasma concentrations of codeine and its O‐demethylated metabolite morphine were determined, by a sensitive and specific high performance liquid chromatography (HPLC) method, following a single oral dose of 60 mg codeine phosphate. Ten healthy volunteers received a single dose of 60 mg codeine phosphate. The plasma concentrations were analyzed for codeine and morphine at the 0.5, 1, 3, and 6 hours postdosing. The mean peak codeine plasma concentrations and tmax(time to reach maximum plasma codeine concentrations) were 88.1 ng/mL and 1.2 hours. Mean maximum concentrations of metabolically produced morphine was 2.7 ± 0.6 ng/mL. The mean ratio of areas under the plasma concentration‐time curves for morphine and codeine was 0.027. Thus, free morphine represented only about 2.7 ± 1.8% of the free codeine area in each case.