bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of Methylprednisolone Hemisuccinate and Methylprednisolone in Chronic Liver Disease
Authors: Ludwig Elizabeth A. , Kong Ah‐Ng , Camara Daniel S. , Jusko William J.
Published: March 2013

The disposition of methylprednisolone (MP) and its prodrug hemisuccinate (MPHS) was assessed in six middle‐aged patients with chronic liver disease (CLD) and compared with six younger, healthy subjects after a single IV dose of 25.4 mg of MPHS. Blood and urine samples were collected over 12 hours. Plasma and urine concentrations of MPHS and MP and plasma cortisol were measured by HPLC. MPHS clearance (CL) was significantly reduced in the CLD group (495 vs. 1389 mL/hr/kg) whereas volume of distribution (Vss) of MPHS (about 0.35 1/kg) did not differ. The elimination half‐life, t1/2β, was significantly longer in CLD (0.61 vs. 0.32 hr). The percent recovery of unchanged MPHS in urine was similar (about 9%) in both groups. The kinetic parameters of MP did not differ between the two groups for: clearance (about 370 L/hr/kg IBW), Vss (about 1.3 L/kg), and t1/2β (about 3.0 hr). The suppression t1/2 of cortisol after MPHS was longer (3.9 vs. 1.9 hr) indicating metabolic pathways for cortisol and MP are affected differently in CLD. Reduction in MPHS CL may reflect altered hepatic blood flow due to both cirrhosis and age effects. However, good availability of MP from MPHS and lack of perturbation of MP pharmacokinetics in CLD patients may provide therapeutic advantages in selection of this glucocorticoid. This is the first study that characterizes the disposition of the prodrug MPHS and the formation of MP simultaneously in CLD patients.
Oral Methylprednisolone Acetate (Medrol Tablets) for Seasonal Rhinitis: Examination of Dose and Symptom Response
Authors: Brooks C. D. , Karl K. J. , Francom S. F.
Published: March 2013

The authors compared the effect of several doses an oral corticosteroid on symptom profile and severity in ragweed hay fever. Thirty‐one patients were randomized to receive 0, 6, 12, or 24 mg methylprednisolone (Medrol Tablets [MP], Upjohn, Kalamazoo, MI). A baseline week in which no treatment was given preceded the treatment comparison. At the end of this week, symptom diaries showed that most of the subjects were experiencing moderate or severe symptoms. The corticoid produced dose‐related reduction in all symptoms. The difference between placebo and 24 mg MP was significant for all the symptoms monitored, except itching, which benefited marginally. With 6 mg MP, congestion, drainage, and eye symptoms showed significant drug‐placebo differences but itching, running/blowing, and sneezing did not. Not all rhinitis symptoms responded equally to corticoid treatment. Those that responded least could reflect histamine effect, which was not effectively suppressed by low‐dose, short‐term corticoid treatment.
In Vivo Determinations of Carbamazepine and Carbamazepine‐10, 11‐epoxide Binding Parameters to Serum Proteins in Monotherapy Patients
Authors: Kodama Yasuo , Kuranari Masae , Kodama Hirofumi , Fujii Isao , Takeyama Masaharu
Published: March 2013

The in vivo serum protein binding parameters of carbamazepine (CBZ) and carbamazepine‐10, 11‐epoxide (CBZ‐E), which was the main metabolite of CBZ in plasma, were determined in sera from 27 patients on CBZ monotherapy. Based on the results by recent studies, the authors assumed that CBZ and CBZ‐E binding to serum proteins were composed of specific binding sites on α1‐acid glycoprotein (AAG) and albumin. Therefore, the authors determined the binding parameters of each compound by specific binding equation for two proteins. Association constants for drug‐AAG binding were .071 L/μmol for CBZ and .016L/μmol for CBZ‐E. Conversely, those for drug‐albumin binding were .00052 L/μmol for CBZ and .00072 L/μmol for CBZ‐E. Within the investigated total concentration ranges in each compound, the AAG binding contributes largely to the drug‐serum protein interactions. Furthermore, our results indicate that the albumin binding contributes to the nonsaturable serum protein binding of these compounds in the therapeutic range.
Treatment of Stable Chronic Bronchitis with Iodinated Glycerol: A Double‐Blind, Placebo‐Controlled Trial
Authors: Repsher Lawrence H.
Published: March 2013

In a double‐blind trial, 29 patients were treated for stable, chronic bronchitis with iodinated glycerol (Organidin®, 60 mg four times daily; n = 16) or placebo (n = 13). The study consisted of a 2‐week single‐blind lead‐in period, followed by a 6‐week double‐blind treatment period, and assessed a total of 50 response variables. In this set of patients, treatment with iodinated glycerol was associated with statistically significant (P < 0.05) and/or positive trend (P < 0.1) toward improvement in cough frequency, cough severity, difficulty in raising sputum, sputum thickness, sputum stickiness, forced expiratory flow at FVC25%–75%, cell concentration in sputum, and several measures of physician assessment of patient condition. Iodinated glycerol was well tolerated during the 6‐week treatment period; no adverse effects were reported and no patient receiving iodinated glycerol withdrew from the study prematurely. In conclusion, this study demonstrates that iodinated glycerol, 60‐mg tablets given in a total daily dose of 240 mg, is safe and effective therapy for reducing symptoms in patients with stable, chronic bronchitis.
Antihypertensive Therapy in the Geriatric Patient: II. A Review of the Alpha1‐Adrenergic Blocking Agents
Authors: Studer Julie A. , Piepho Robert W.
Published: March 2013

The prevalence of hypertension increases with age. Multiple physiologic factors are involved in the development of hypertension in the elderly. Alpha1‐adrenergic blocking agents lower blood pressure through a reduction in total peripheral resistance. Prazosin, terazosin, and doxazosin have been shown to be equally effective in reducing blood pressure in older persons. The bioavailability, terminal elimination half‐life, and volume of distribution of prazosin is increased in the elderly. Hybrid drugs, such as ketanserin, urapidil, and indoramin are also effective in lowering blood pressure. Ketanserin seems to have a greater effect on blood pressure reduction in persons older than 60 years of age. Alpha1‐adrenergic blockers may be used safely in patients with diabetes, asthma, and hyperlipidemia.
The Drug Regulatory and Review Process in Guyana
Authors: Woo‐Ming Rex B.
Published: March 2013

After the old “Sale of Food and Drugs” Ordinance, Cap. 144 was repealed, the new Food and Drugs Act was enacted in 1971. This new Act has considerable flexibility and gives the Minister extensive authority to make Regulations (for carrying out the purposes and provisions of the Act). The Act controls the manufacture, importation, sale, advertising, labeling, packaging, and distribution of drug samples, and the testing of drugs. The Act also controls raw materials and finished products of drugs at the point of entry into the country, with a single agency coordinating both the inspection and analytical services. Developing countries could ensure the procurement of safe, good quality, and effective drugs and devices with the enactment of a similar Food and Drugs Act only. Rapid assessment of Drug Safety, Quality and Efficacy is done through Guyana's participation in the WHO Certification Scheme on the Quality of Pharmaceutical Products moving in International Commerce. This certification scheme is highly commendable especially to third‐world countries. The Food and Drug Regulations (1977) have several unique features for drug, cosmetic and device control and they allow for a system of centralized control with limited staff to enforce the legislation. In summary, enforcement of legislative control of imported pharmaceuticals and product evaluation can be considered strong points in the drug regulatory and review process in Guyana. A cautious attitude is observed so as to ensure efficacy, safety, and quality of drugs entering the market. This Drug Regulatory and Review Process is recommended for implementation by third‐world countries with outdated drug legislation.
The Pharmacokinetics of Isoproterenol in Critically Ill Pediatric Patients
Authors: Reyes Gerardo , Schwartz Philip H. , Newth Christopher J. L. , Eldadah Maher K.
Published: March 2013

The pharmacokinetics of isoproterenol (ISO) in infants and children have never been reported. The authors studied ISO pharmacokinetics in two disparate groups of pediatric intensive care unit patients: postoperative cardiac patients (POC, n = 10), and reactive airway disease patients (RAD, n = 9). In all, 44 blood samples were taken at steady‐state from the 19 patients, whereas from 15 patients samples were also taken just before and after discontinuation of ISO infusion. There were 12 male and 7 female patients in the study, and their ages ranged from 2 days to 14 years. The average ISO dosing rate was 0.30 μg/kg/minute for the whole study population, ranging from 0.01 to 5.5 μg/kg/minute. The POC patients received a significantly lower dosing rate than the RAD patients (0.029 ± 0.002 vs 0.50 ± 0.21 μg/kg/minute, P < .0001); the average steady‐state plasma concentrations of ISO were also lower in the POC patients (1.3 ± 0.3 versus 13.9 ± 4.9 ng/mL, P < .0001). The steady‐state plasma concentration, normalized to a dosing rate of .05 ng/kg/minute, was 1.9 ± 0.3 ng/mL for all patients, and the clearance was 42.5 ± 5.0 mg/kg/minute. Postoperative cardiac patients had a significant higher normalized steady‐state plasma concentration and moderately significant lower clearance than did RAD patients (2.1 ± 0.3 versus 1.7 ± 0.4 ng/mL, P < .05 and 33.2 ± 4.9 versus 48.4 ± 7.3, P < .06, respectively). The average plasma half‐life of ISO was 4.2 ± 1.5 minutes, and the volume of distribution was 216 ± 57 mg/kg. This study suggests that the pharmacokinetics of ISO in children is highly variable and may vary with serum concentration. The apparent higher clearance of ISO in the RAD patients may be related to an improved perfusion status relative to the POC patients or to a possible influence of nonlinear pharmacokinetics.
Effect of Gemfibrozil on Fatty Acids in Lipid Fractions of Plasma From Patients with Hypertriglyceridemia
Authors: Tavella Marcelo , Corder Clinton N. , McConathy Walter
Published: March 2013

The fatty acid composition of plasma triglycerides, phospholipids, and cholesterol esters have been studied during gemfibrozil (G)‐induced lipid‐lowering treatment in six patients with hypertriglyceridemia. Gemfibrozil caused significant plasma triglyceride reductions from 776 ± 573 to 226 ± 82 mg/dL (P < .001). Gemfibrozil therapy also caused significant changes in the plasma lipid fatty acid composition, mainly by increasing palmitoleic acid (16:1) in triglycerides (2.1–5.6%) and cholesterol esters (2.2–3.7%), concomitant with the significant decrease in the content of the linoleic acid (18:2) in phospholipids (20.1–16.0%) and triglycerides (18.0–15.2%). The ratio of unsaturated fatty acids (20:3 + 20:4/18:2) was increased in the phospholipid fraction. These findings support a G effect on the desaturation of fatty acids in patients with hypertriglyceridemia. Because fatty acid composition was significantly altered by G, those biologic systems dependent on the pattern of fatty acids may be modified in clinical important ways.
Nisoldipine: A New Dihydropyridine Calcium‐Channel Blocker
Authors: Mitchell Judith , Frishman William , Heiman Mark
Published: March 2013

Nisoldipine is a new calcium‐channel blocker of the dihydropyridine subclass, with a chemical structure similar to nifedipine. It has been used in clinical trials to assess its efficacy and safety in patients with hypertension, angina pectoris, and congestive heart failure. Similar to other dihydropyridines, nisoldipine is a potent peripheral and coronary dilator. The most optimal dosage regimen has not been established in clinical trials. The drug appears to have a favorable side‐effect profile.
Antipyrine Kinetics in Patients with Primary Biliary Cirrhosis
Authors: von Moltke Lisa L. , Abernethy Darrell R. , Kaplan Marshall M. , Greenblatt David J.
Published: March 2013

Fourteen antimitochrodrial antibody‐positive patients (13 women, 1 man) with biopsy‐proven primary biliary cirrhosis, aged 40 to 71 years (mean, 57 years) weighing 43 to 102 kg (mean, 63 kg), along with 14 age‐ and sex‐matched healthy controls, received a single 1.0‐ to 1.2‐g dose of intravenous antipyrine. Plasma antipyrine levels were determined during a 12‐ to 24‐hour period. Patients' mean serum chemistry values were: albumin, 3.9 g/dL (range, 3.1–4.4) and total bilirubin, 1.9 mg/dL (range, 0.3–10.9). Seven of the fourteen patients had cirrhosis. Mean kinetic variables for antipyrine in controls and primary biliary cirrhosis patients were: Vd, .54 versus .49 L/kg; half‐life, 12.0 versus 15.1 hours (P < .07); clearance, .55 versus .41 mL/min/kg (P < .04). Within the primary biliary cirrhosis group, there was no correlation between total bilirubin and clearance (r = .09), nor did clearance vary significantly among histologic categories. Clearance of antipyrine in primary biliary cirrhosis patients is reduced by an average of 25%, but the clinical prognosticators of serum bilirubin levels and histologic grade do not correlate with or predict the degree of clearance impairment.
Recent Developments in Drug Design: Computational Chemistry and Models of the Interaction of Ligands with Receptors
Authors: Bransome Edwin D.
Published: March 2013

Recent articles and advertisements suggest that drug design is within the reach of any chemically oriented scientist who obtains the latest three‐dimensional computer graphics programs for his personal computer. This sort of “rational” drug design has however had limited success. When it has been successful, it has required the rigorous application of computational chemistry. Bowen et al. in their accompanying paper provide a summary of a number of approaches and the assumptions involved. The papers by McDonnell et al. and Hendry describe two different approaches: utilizing molecular genetics to test the effective interaction in vitro of ligands with their receptors and utilizing the model structure of DNA as a blueprint for the structure of the intracellular targets of drugs.
The Mechanism of Action of Steroid Hormones: A New Twist to an Old Tale
Authors: McDonnell Donald P. , Clevenger Bill , Dana Sharon , Santiso‐Mere Dolores , Tzukerman Maty T. , Gleeson Martin A. G.
Published: March 2013

Steroid hormones, vitamins, and thyroid hormone are potent chemical messengers that exert dramatic effects on cell differentiation, homeostasis, and morphogenesis. These molecules, though diverse in structure, share a mechanistically similar mode of action. The effector molecules diffuse across cellular membranes and bind to specific high affinity receptors in the target cell nuclei. This interaction results in the conversion of an inactive receptor to one that can interact with the regulatory regions of target genes and modulate the rate of transcription of specific gene sets. The recent cloning and characterization of the functional receptors for these hormones has been enlightening as to the individual steps involved in steroid signal transduction. In addition, emerging evidence suggests that receptor function can be influenced by cell and promoter context indicating that it may be possible to develop tissue specific or tissue‐restricted drugs. The concept that a single receptor can modulate gene transcription in a cell‐specific manner is of great medical and pharmaceutical importance. The focus of this review is to highlight the recent developments in the steroid receptor field and to illustrate the novel approaches been undertaken to identify novel pharmaceuticals.
Absorption of Danazol After Administration to Different Sites of the Gastrointestinal Tract and the Relationship to Single‐ and Double‐Peak Phenomena in the Plasma Profiles
Authors: Charman William N. , Rogge Mark C. , Boddy Alexander W. , Barr William H. , Berger Bruce M.
Published: March 2013

The absorption of danazol (100 mg) after oral or intraintestinal administration to the proximal jejunum or proximal ileum has been studied in healthy female subjects. The extent of danazol absorption after administration as a solubilized glycerol mono‐oleate emulsion formulation was approximately twofold and fourfold greater after oral dosing when compared with jejunal or ileal administration, respectively. Although not statistically significant in this study, the extent of absorption after jejunal administration was generally greater than after ileal administration. After oral dosing, qualitative assessment identified the presence of double peaks or major shouldering characteristics in 14 of the 16 individual danazol plasma concentration‐time profiles, whereas only single peaks were present after intraintestinal administration. These data are consistent with the double peaking phenomena after oral administration of the emulsion formulation being stomach‐related. The double peaking effect may be explained in terms of a probable combination of gastric emptying regulated absorption (due to the presence of the lipid in the emulsion formulation) and the dependence of danazol solubility on bile salt solubilization within the upper small intestine.
Drug Development and Registration in Japan: Threshold of Transition
Authors: Currie W. J. C.
Published: March 2013

The responsibility for the regulation of pharmaceuticals is situated within the Pharmaceutical Affairs Bureau (PAB) of the Japanese Ministry of Health and Welfare. The scientific evaluation of the application is undertaken by a series of committees consisting of independent senior members of the medical and scientific community whereas all communication between them and the pharmaceutical company is conducted through PAB offices (Koseisho). As in the U.S., the Japanese drug application covers product quality, safety, and efficacy, but the actual data requirements differ between the two countries. Some of these differences have a basis in Japanese regulations whereas others emulate from demands set by senior members of the medical fraternity who carry great sway in Japan. These cause concern to international pharmaceutical companies since they may require studies to be duplicated with consequent delays. Moves toward the achievement of global harmonization of regulatory requirements with the associated benefits of reducing the numbers of animals sacrificed in the total development program and of important new medications reaching patients earlier are discussed.
Comparative Study on Benzodiazepine Use in Canada and Chile
Authors: Ruiz I. , Offermanns J. , Lanctôt K. L. , Busto U.
Published: March 2013

Benzodiazepines are the most prescribed psychotropic drugs in the world. Comparative international data on benzodiazepine use, specifically among developed and developing countries, are unavailable. To determine the different patterns of benzodiazepine use in two representative countries, use of benzodiazepines in Chile (a developing country) and Canada (a developed country) was undertaken. Wholesale data as provided by the intercontinental Medical statistics and drug import data were used as databases. Data on trends of benzodiazepine use was determined for 5 years using the methodology recommended by the WHO for drug use research, the defined daily dose/1000 inhabitants/day. Total benzodiazepine use was similar in both countries, but Canadian use had increased slowly. Patterns of use, however, differ widely among the two countries. A linear increase of rapidly eliminated benzodiazepines was observed in Canada, whereas the reverse occurs in Chile: the slowly eliminated benzodiazepines are the ones that have increased use. Hypnotic benzodiazepines are used twice as frequently in Canada than in Chile. Striking differences in the use of individual benzodiazepines are observed. Differences in healthcare systems determine wide differences in the way these drugs are prescribed. Demographic characteristics of the two countries also may account for the differences in benzodiazepine use. The authors conclude that, although total benzodiazepine consumption is similar in the two countries, patterns of benzodiazepine use vary widely. The different patterns of use may determine differences in the morbidity rates associated with the use of these drugs.
Digoxin Pharmacokinetics and Perindopril in Heart Failure Patients
Authors: Vandenburg M. J. , Stephens J. D. , Resplandy G. , Dews I. M. , Robinson J. , Desche P.
Published: March 2013

The influence of chronic perindopril treatment on digoxin pharmacokinetics was investigated in 10 patients with mild chronic heart failure under stable diuretic and digitalis treatment and normal renal function. Digoxin was administered at a dose of 0.125 mg/day (n = 2) or 0.250 mg/day (n = 8). The 24‐hour steady‐state digoxin profile was assessed before and after concomitant administration of perindopril for 1 month at doses of 2 mg once a day for the first 8 days and 4 mg once a day for the remaining 21 days. Chronic treatment with perindopril produced no significant effect on mean (± standard deviation) digoxin serum area under the curve for 24 hours (17.9 ± 7.4 versus 16.3 ± 4.4 ng/mL · h), peak digoxin concentration (1.3 ± 0.54 versus 1.2 ± 0.36 ng/mL), time to peak concentration (3 versus 4 hours), and apparent oral clearance of digoxin (237.7 ± 109.6 versus 237.4 ± 79.5 mL/min). Clinical and biologic tolerance of perindopril was good throughout the study. Chronic administration of perindopril did not alter steady‐state digoxin kinetics in patients with mild chronic heart failure and normal renal function, indicating that no adaptation of the digoxin dose is required during co‐prescription with perindopril in such patients.
Pharmacokinetics of Beta‐Methyldigoxin in Subjects with Normal and Impaired Renal Function
Authors: Tsutsumi Kimiko , Nakashima Hajime , Tateishi Tomonori , Imagawa Masaharu , Nakano Shigeyuki
Published: March 2013

Beta‐methyldigoxin (β‐MD) was administered orally (0.2 mg) to 24 patients with various degrees of renal function, to investigate its pharmacokinetic characteristics related to renal function. Serum and urine collected until 120 hours after dosing were assayed for β‐MD and digoxin by high‐performance liquid chromatography and fluorescence polarization immunoassay method. The steady‐state volume of distribution decreased proportionately as creatinine clearance (CLCR) decreased, although steady‐state volume of distribution of hemodialysis patients had large interindividual variability, and their mean value was not different from that of patients with normal renal function. Both renal clearance of β‐MD and digoxin were significantly correlated with CLCR (r = .820, P < .001 and r = .822, P < .01, respectively), and the slope of regression line for β‐MD was only 44% that for digoxin. Significantly reduced urinary excretion of total drug (β‐MD plus digoxin) was shown in patients with CLCR below 50 mL/minute/1.48 m2. This study suggests that the dosage modification is not necessary until CLCR decreases to below 50 mL/minute/ 1.48 m2, but careful attention should be given in the use of β‐MD in patients with CLCR below this value.
Evaluation of the Pharmacokinetics and Tolerability of Tirilazad Mesylate, a 21‐Aminosteroid Free Radical Scavenger: II. Multiple‐Dose Administration
Authors: Fleishaker J. C. , Peters G. R. , Cathcart K. S. , Steenwyk R. C.
Published: March 2013

The multiple dose tolerability and pharmacokinetics of tirilazad mesylate, a 21‐aminosteroid free radical scavenger, were assessed in 50 healthy male volunteers. Volunteers were randomized to receive intravenous normal saline placebo (n = 10), citrate vehicle placebo (n = 10), or 0.5 mg/kg/day (n = 6), 1.0 mg/kg/day (n = 6), 2.0 mg/kg/day (n = 6), 4.0 mg/kg/day (n = 6), or 6.0 mg/kg/day (n = 6) tirilazad mesylate in divided doses every 6 hours for 5 days, for a total of 21 doses. Drug was infused over 10 or 30 minutes. All tirilazad mesylate treatment groups and the citrate vehicle group had significantly more frequent and more intense pain at the injection site than did the saline group, but the pain intensity did not require interruption of dosing. Three episodes of clinical thrombophlebitis were observed. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, or renal function were apparent. Moderate and transient increases in serum alanine transaminase were observed in several subjects. In the 6.0 mg/kg/day group, 50% of the subjects exhibited increased alanine transaminase. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol, eosinophil, or lymphocyte levels). Tirilazad mesylate pharmacokinetics were linear over the dosage range studied. Steady state appeared to be achieved by the fifth day of dosing. After the last dose, a mean terminal half‐life of 35 hours was observed. This terminal phase is not observed after single dosing, but the portion of the area under the plasma tirilazad concentration‐time curve represented by this terminal phase is estimated to account for less than 5% of the total area after a single dose. Thus, single‐dose estimates of clearance may be predictive of clearance on multiple dosing, but volume of distribution estimates are not.
The Influence of Pretreatment Periods with Diltiazem on Nifedipine Kinetics
Authors: Ohashi Kyoichi , Sudo Toshiaki , Sakamoto Kouichi , Tateishi Tomonori , Fujimura Akio , Kumagai Yuji , Ebihara Akio
Published: March 2013

The effect of durations of diltiazem pretreatment on nifedipine kinetics was evaluated. Eighteen healthy male subjects were randomly allocated to three groups, 6 subjects each, for single doses of 60 mg diltiazem, and 3 days and 6 days with diltiazem 60 mg three times a day. All subjects received 20 mg nifedipine orally on two occasions using a double‐blind cross‐over, placebo‐controlled method. No significant difference on pharmacokinetic parameters of nifedipine without diltiazem were observed among three groups. The single dose with 60 mg diltiazem significantly increased the area under the plasma concentration‐time curve (AUC) for nifedipine compared with that in control an average of 35.1% (P < .05) and decreased the total body clearance (CL) an average of 24.0% (P < .05). Three days and 6 days pretreatment with diltiazem 60 mg three times a day significantly increased mean nifedipine AUC to 151.1% (P < .01), 188.0% (P < .05) of control values, and decreased CL to 58.2% (P < .01), 63.9% (P < .05) of control values, respectively. The elimination half‐life (t1/2) of nifedipine were significantly prolonged both after 3 days' and after 6 days' pretreatment of diltiazem. These results suggest that diltiazem affects the nifedipine kinetics rapidly and pretreatment duration dependently. A clinically important drug interaction may occur when both drugs are administered simultaneously.
Evidence of Plasma CoQ10‐Lowering Effect by HMG‐CoA Reductase Inhibitors: A Double‐Blind, Placebo‐Controlled Study
Authors: Ghirlanda G. , Oradei A. , Manto A. , Lippa S. , Uccioli L. , Caputo S. , Greco A. V. , Littarru G. P.
Published: March 2013

Inhibitors of HMG‐CoA reductase are new safe and effective cholesterol‐lowering agents. Elevation of alanine‐amino transferase (ALT) and aspartate‐amino transferase (AST) has been described in a few cases and a myopathy with elevation of creatinine kinase (CK) has been reported rarely. The inhibition of HMG‐CoA reductase affects also the biosynthesis of ubiquinone (CoQ10). We studied two groups of five healthy volunteers treated with 20 mg/day of pravastatin (Squibb, Italy) or simvastatin (MSD) for a month. Then we treated 30 hypercholesterolemic patients in a double‐blind controlled study with pravastatin, simvastatin (20 mg/day), or placebo for 3 months. At the beginning, and 3 months thereafter we measured plasma total cholesterol, CoQ10, ALT, AST, CK, and other parameters (urea, creatinine, uric acid, total bilirubin, gamma GT, total protein). Significant changes in the healthy volunteer group were detected for total cholesterol and CoQ10 levels, which underwent about a 40% reduction after the treatment. The same extent of reduction, compared with placebo was measured in hypercholesterolemic patients treated with pravastatin or simvastatin. Our data show that the treatment with HMG‐CoA reductase inhibitors lowers both total cholesterol and CoQ10 plasma levels in normal volunteers and in hypercholesterolemic patients. CoQ10 is essential for the production of energy and also has antioxidative properties. A diminution of CoQ10 availability may be the cause of membrane alteration with consequent cellular damage.
Clinical Use of Androgenic Steroids at a Major Medical Center: Who Prescribes Androgens and How Well Do They Do It?
Authors: Cavanah Stephen F. W. , Jacobson James M. , McIntyre Thomas
Published: March 2013

To assess prescribing practices for androgens at Wilford Hall USAF Medical Center, the authors analyzed prescriptions for all patients receiving therapy during a 12‐month period (n = 201) and reviewed the available outpatient records not maintained elsewhere (n = 105). The most commonly prescribed androgens were testosterone enanthate (144/201; 56.7%), and danazol (52/201; 25.9%). Review of the available outpatient medical records of 73 male patients using testosterone enanthate showed a mean age of 59.5 years, mean frequency of injection of 20 days, mean duration of therapy of 3.5 years, and mean dose of 226 mg. Therapy was initiated by a urologist (34/73; 46.6%), an endocrinologist (33/73; 45.2%), or an internist (6.73; 8.2%). Indications for therapy based on pretreatment laboratory and historical data included hypergonadotropic hypogonadism (24/73; 32.9%), hypogonadotropic hypogonadism (23/73; 31.5%), unspecified hypogonadism (7/73; 9.6%), and empiric treatment of elderly men with erectile dysfunction without evidence of hypogonadism (9/73; 26%). Pretreatment prostate examinations as well as measurement of serum testosterone (66/73; 90.4%) and serum gonadotropins (52/73; 71.2%) were often not performed. The authors conclude that records of patients treated with androgens show: 1) Doses are appropriate; 2) Empiric treatment of erectile dysfunction in elderly men is common despite the associated risks; 3) Laboratory and physical evaluation before treatment is often incomplete; 4) There was no evidence of androgenic substance abuse in patients studied.
Alpha Blockers: An Effective Extension to Your Patients' Risk Reduction Program
Authors: Houston Mark C.
Published: March 2013

This symposium discusses a rapidly changing philosophy in how to manage hypertension. Many committees in the United States and Canada over the years have tried to make the treatment of hypertension simple. And in their goal to do that, they have made it difficult and led many down a primrose path with somewhat narrow vision. One famous British physician in 1931 said, “the greatest danger to man with high blood pressure lies in its discovery since some fool is certain to try to reduce it.” There is a lot of credence to that rule.
High‐Calcium Diet in Spontaneously Hypertensive Rats: Intervention with Calcium Antagonist Verapamil
Authors: Saelens David A. , Zawada Edward T. , Peterson Jennifer , Lembke Jeanie M.
Published: March 2013

A number of studies have shown an antihypertensive effect for high‐calcium diets, but others have found no effect or, even a prohypertensive effect. Because of these disparate results, studies were conducted in spontaneously hypertensive rats (SHR) fed either a normal calcium diet (1.0% calcium) or a high‐calcium diet (4.0% calcium) with or without verapamil HCl (50 mg/kg body weight) from ages 5 to 12 weeks. Systolic blood pressure (SBP) and heart rate (HR) were measured by indirect tail cuff method. During the analysis of the electrolytes and vasoactive hormones monitored in this study, it was found that rats fed high‐calcium diet had significantly elevated serum ionized and total calcium and calcium excretion. Systolic blood pressure for the verapamil‐normal calcium diet (week 5, 148 ± 4 mm Hg; week 7, 162 ± 4 mm Hg) did not differ significantly from that of normal calcium diet (week 5, 152 ± 2 mm Hg; week 7, 160 ± 1 mm Hg). The high‐calcium diet potentiated the development of hypertension, i.e, SBP was (157 ± 2 mm Hg) on the 5th week and (174 ± 4 mm Hg) on the 7th week. Conversely, verapamil high‐calcium diet prevented the development of hypertension (week 5, SBP was 139 ± 4 mm Hg; week 7, SBP was 146 ± 3 mm Hg). The authors conclude: (1) dietary calcium supplementation is prohypertensive in SHR; (2) dietary calcium must influence blood pressure in SHR by action at the verapamil calcium channel; (3) the antihypertensive efficacy of verapamil in SHR is not blocked by high‐calcium diet; (4) there may be a synergism between elevation of ionized serum calcium and verapamil with regard to antihypertensive effect of verapamil.
Effect of Food and a Monoglyceride Emulsion Formulation on Danazol Bioavailability
Authors: Charman William N. , Rogge Mark C. , Boddy Alexander W. , Berger Bruce M.
Published: March 2013

The bioavailability of a single 100‐mg dose of danazol delivered from the commercial formulation (hard gelatin capsule) and from an experimental lipid emulsion formulation of danazol was studied in 11 healthy female volunteers in both fed and fasted states. The emulsion formulation (fasted) increased bioavailability fourfold compared with the capsule (P = .0001); the difference, however, was not significant in the fed state. Food increased the bioavailability of the capsule formulation more than threefold over fasted administration (P = .0001). In a separate study of 12 female volunteers, single doses of the emulsion formulation of danazol administered with food demonstrated essentially dose‐proportional pharmacokinetics over the dose range studied (50–200 mg). The authors conclude that factors that increase the extent of solubilization lead to significant enhancement in the bioavailability of danazol.
Pharmacokinetics of Vigabatrin Following Single and Multiple Oral Doses in Normal Volunteers
Authors: Hoke John F. , Yuh Lianng , Antony Kelly K. , Okerholm Richard A. , Elberfeld James M. , Sussman Neil M.
Published: March 2013

The pharmacokinetics of vigabatrin were investigated after single and multiple oral doses in two groups of 24 healthy male volunteers. Vigabatrin was well tolerated by the volunteers; headache was the most frequently reported adverse event. There were no clinically remarkable changes in serum chemistry, urinalysis, or hematology attributable to vigabatrin. For the single‐dose study, a stepwise linear contrast method was used to assess dose proportionality. The results showed that vigabatrin exhibited dose linear pharmacokinetics after single oral doses ranging from 0.5 to 4.0 g. Slight changes in the terminal phase half‐life and renal clearance were evident in the higher dosage groups. These changes with increasing dose of vigabatrin were relatively minor and not considered to be clinically important. Evaluation of the multiple‐dose pharmacokinetics indicated that vigabatrin exhibited dose linearity over the range of 0.5 to 2.0 g administered every 12 hours. The terminal phase half‐life and renal clearance of vigabatrin during multiple dosing were consistent with that after single doses. During multiple dosing, steady‐state concentrations of vigabatrin were reached on the second day of dosing, and drug accumulation was minimal.
Pharmacokinetics of Aztreonam in Healthy Elderly and Young Adult Volunteers
Authors: Meyers Burt R. , Wilkinson Patricia , Mendelson Meryl H. , Bournazos Cynthia , Tejero Carmelita , Hirschman Shalom Z.
Published: March 2013

Aztreonam is a monobactam exhibiting an antibacterial spectrum similar to that of the aminoglycosides, with activity against aerobic gram‐negative bacilli, and is the only related drug that may be given to patients hypersensitive to beta‐lactams. The pharmacokinetics of aztreonam were compared in two groups of healthy volunteers. The young group comprised 10 adults between the ages of 18 and 30 years, and the elderly group included 10 adults older than 65 years of age. The two groups each received two doses (1 and 2 g) aztreonam, separated by 1 week. Although the mean peak serum concentrations of aztreonam for the two groups were similar, there were differences in other pharmacokinetic parameters. For example, for the 2‐g dose the mean half‐life (1.8 ± .51 versus 3.1 ± .9 hour), and area under the curve (AUC) (294.42 ± 64.08 versus 469.01 ± 144.02 μg × hour/mL per 1.73 m2) were less for the younger group compared with the elderly group. The mean total body clearance of aztreonam was greater for the younger than the elderly group. The results were similar to the pharmacokinetic parameters derived from the 1‐g dose. These results mirror the lower creatinine clearances and higher serum creatinine levels found in the elderly group. The data suggest that lower doses of aztreonam given at less frequent intervals may be appropriate in the elderly population.
Effect of Moderate or Severe Hepatic Impairment on Clarithromycin Pharmacokinetics
Authors: Chu S.‐y. , Granneman G.R. , Pichotta P.J. , Decourt J. Ph. , Girault J. , Fourtillan J.B.
Published: March 2013

The pharmacokinetic and safety profiles of clarithromycin (C) and its 14‐hydroxy‐clarithromycin (HC) metabolite were determined after a multiple‐dose oral clarithromycin regimen (250 mg twice daily for five doses) in six healthy subjects and seven patients with moderate or severe hepatic impairment (Pugh grades B and C). Plasma and urine C and HC concentrations were determined using high‐performance liquid chromatography. Hepatic impairment resulted in increased harmonic mean C terminal disposition half‐life and mean ± SD C renal clearance (CLR) compared with normal volunteers (5.0 vs. 3.3 hr and 170 ± 69 vs. 111 ± 17 mL/min, respectively). Hepatic impairment also resulted in decreased metabolite peak plasma concentration and area under the plasma concentration‐versus‐time curve and decreased metabolite/parent concentration ratios compared with normal volunteers. These data suggest that 14‐hydroxylation of C was reduced by moderate to severe hepatic impairment. No adverse events were noted in either study group and there were no study‐related clinically significant changes in laboratory parameters. The decrease in C metabolic clearance appears to be partially offset by an increase in C CLR, resulting in comparable steady‐state concentrations of parent drug. In those indications in which the metabolite may be a necessary element of the antimicrobial activity of C, it would seem prudent to be cautious in using C in patients with moderate to severe hepatic impairment due to reduced production of HC. Otherwise, no dosage adjustment for C appears necessary for subjects with moderate or severe hepatic impairment provided that renal function is not impaired.
Pediatric Gastrointestinal Decontamination in Acute Toxin Ingestion
Authors: Phillips Scott , Gomez Hernan , Brent Jeffrey
Published: March 2013

The appropriate implementation of the various modalities of gastrointestinal (GI) decontamination is critical in the management of the pediatric patient who is examined in the emergency department or private office after an acute ingestion. Gastrointestinal decontamination includes gastric lavage, syrup of ipecac, activated charcoal, and whole bowel irrigation. Clinical studies have delineated the role and efficacy of these procedures. Trends in GI decontamination place less emphasis on ipecac and gastric lavage and more emphasis on activated charcoal alone in the patient with a mild overdose. Gastric lavage is indicated in serious ingestion and is most effective if done soon after the exposure. Whole bowel irrigation is the newest addition and has important clinical use in the treatment of serious iron ingestions as well as in older adolescent cocaine body stuffers and packers. Indications and contraindications of the various forms of GI decontamination are discussed and relevant clinical studies are reviewed.
Pharmacokinetics of Cyclosporine and Steady‐State Aspirin During Coadministration
Authors: Kovarik John M. , Mueller Edgar A. , Gaber Martin , Johnston Atholl , Jähnchen Eberhard
Published: March 2013

Anecdotal reports from clinical trials assessing the use of cyclosporine in the treatment of rheumatoid arthritis suggest an association between enhanced renal impairment and combined use of cyclosporine with nonsteroidal anti‐inflammatory drugs. To explore possible pharmacokinetic contributions to this phenomenon, a randomized, two‐period crossover investigation was performed in 24 healthy volunteers in which a single oral dose of 300 mg cyclosporine was administered alone and on day 10 of multiple oral dosing of aspirin 960 mg three times daily. Serial blood samples were obtained over 48 hours after each cyclosporine dose and over a steady‐state dosing interval for aspirin on day 9 (aspirin alone) and day 10 (coadministration of cyclosporine and aspirin). Cyclosporine whole blood concentrations were determined by a specific monoclonal radioimmunoassay and plasma concentrations of acetylsalicylic acid and metabolites by high‐performance liquid chromatography. Lack of a pharmacokinetic interaction was conclusively demonstrated for the rate and extent of cyclosporine and acetylsalicylic acid absorption and for the rate and extent of salicylic acid formation after a single dose of cyclosporine was coadministered during steady‐state aspirin dosing. If a clear association between enhanced renal impairment and the combined use of cyclosporine and aspirin is substantiated, the underlying mechanism appears to be pharmacodynamic rather than pharmacokinetic.
Pharmacokinetics of Azathioprine After Repeated Oral and Single Intravenous Administration
Authors: El‐Yazigi Adnan , Wahab Fida Abdel
Published: March 2013

The pharmacokinetics of azathioprine (AZN) were examined in 28 renal transplant patients treated orally with 25 to 150 mg AZN once daily in combination with cyclosporin A and prednisone, and after single intravenous (IV) injection of 5 mg/kg AZN using the rabbit as an in vivo model. The steady‐state concentrations of AZN observed in these patients ranged from 6 to 583 μg/L, and the interday coefficients of variation of the concentration in three randomly selected patients were 38%, 12%, and 4.6%. The frequency distribution pattern of the apparent oral clearance (TCLor) of AZN separates the patients almost equally into poor (TCLor = 0.126 to 4 L/hour · kg) and extensive metabolizers (TCLor = 5 to 12 L/hour · kg). The data obtained from the IV administration displayed the two‐compartment model characteristics with mean (standard error of the mean) of α, β, Vc, and total body clearance of 15.3 (2)/hour, 2.38 (.64)/hour, 1.05 (.3)L/kg, and 8.12 (1.26) L/hour · kg, respectively. The large variability in the pharmacokinetic parameters of AZN in patients and even in rabbits under carefully controlled conditions that may be ascribed to the complexity of its metabolism necessitates a careful approach to its dose selection.
Effect of Time of Food Administration on the Bioavailability of Didanosine From a Chewable Tablet Formulation
Authors: Knupp Catherine A. , Milbrath Rochelle , Barbhaiya Rashmi H.
Published: March 2013

The effect of the time of food administration on the bioavailability of didanosine, administered as a 300‐mg dose of a chewable tablet formulation, was evaluated in 10 men seropositive for the human immunodeficiency virus (HIV), but free of any symptoms of acquired immune deficiency syndrome (AIDS). Using an open, randomized, balanced, incomplete block crossover study design, each patient received the dose of didanosine under four of the five following conditions: (1) after an overnight fastt (2) 30 minutes before a meal, (3) 1 hour before a meal, (4) 1 hour after a meal or (5) 2 hours after a meal. The meal consisted of a standard high‐fat, high‐calorie breakfast, consumed over a 15‐minute period. Serial blood samples and the total urinary output were collected over a 12‐hour interval after each dose for analysis using validated high‐pressure liquid chromatography (HPLC)/ultraviolet (UV) methods. Concentration data were used to calculate pharmacokinetic parameters using noncompartmental methods. There were no significant differences among the fasting, 30‐minute before, and 1‐hour before the meal treatments with respect to maximum peak plasma concentration (Cmax), area under the curve (AUC(0‐∞)), or urinary recovery (%UR). Values for Cmax, AUC(0‐∞), and %UR observed for the 1 and 2 hours after the meal treatments were significantly less than those obtained under either fasting conditions or before the meal. There were no significant differences among any of the treatments with respect to time to reach peak concentration (tmax), half‐life (t 1/2), or renal clearance (CLR). Based on the data from this study, it is recommended that didanosine be administered 30 minutes to 1 hour before a meal, but not within 2 hours after a meal.
Effects of One Year of Treatment with Pravastatin, an HMG‐CoA Reductase Inhibitor, on Lipoprotein a
Authors: Hunninghake Donald B. , Stein Evan A. , Mellies Margot J.
Published: March 2013

Lipoprotein a [Lp(a)] has emerged as a critical factor in the assessment of cardiovascular risk. In the study reported here, Lp(a) concentrations were monitored in patients taking pravastatin, a new hydrophilic, HMG‐CoA reductase inhibitor. A cohort of patients with frozen plasma aliquots at baseline, week 12 of the double‐blind therapy, and week 48 of open‐label therapy (1 year's treatment) was selected from 306 participants in a phase 2 dose‐ranging study of pravastatin. The 125 men and women in the cohort had mean low‐density lipoprotein cholesterol (LDL‐C) concentrations of at least 150 mg/dL (3.88 mmol/L), and mean plasma triglyceride concentrations less than 250 mg/dL (2.82 mmol/L) during the baseline diet phase. During the double‐blind phase, 46 patients received placebo, and 79 received pravastatin 10, 20, or 40 mg daily. Only the 79 pravastatin‐treated patients in the cohort continued in the 48‐week open‐label study of pravastatin. During the double‐blind phase, Lp(a) decreased 4.6% in patients taking placebo, and 0.4% in patients taking pravastatin. Net change was not significant. At week 48, in the patients taking pravastatin, Lp(a) had increased 2.4%, a difference that again was not statistically significant. Low‐density lipoprotein cholesterol (‐33.6%), total cholesterol (‐25.6%), triglycerides (‐19.9%), high‐density lipoprotein cholesterol (HDL‐C) (+7.0%), apolipoprotein A‐I (+13.3%), and apolipoprotein B (‐33.0%) changed significantly (P < .01). Among 19 patients with baseline Lp(a) levels greater than 30 mg/dL, Lp(a) decreased insignificantly. Optimal pharmacologic therapy for patients with elevated total cholesterol and LDL‐C should lower total cholesterol and LDL‐C concentrations with beneficial or no adverse effects on other lipoprotein fractions. Pravastatin did not significantly affect Lp(a) concentrations, even in those patients with Lp(a) greater than 30 mg/dL at baseline and significantly elevated HDL‐C (P < 0.001).