bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic and Biopharmaceutic Aspects of Once Daily Treatment with Metoprolol CR/ZOK: A Review Article
Authors: Sandberg Anders , Abrahamsson Bertil , Regårdh Carl‐Gunnar , Wieselgren Ingrid , Bergstrand Robert
Published: March 2013

In the development of a new controlled release preparation and its subsequent assessment there are a number of factors that need to be considered both related to the drug itself and to the pharmaceutical preparation. This review describes the biopharmaceutical and pharmacokinetic properties of metoprolol CR/ZOK, a recently introduced formulation of a widely used beta1‐selective adrenoceptor antagonist intended for once daily usage.

The metoprolol CR/ZOK preparation provides reproducible dissolution and absorption properties resulting in stable plasma concentrations with minimum fluctuations over a 24‐hour dosage interval. This has been shown in extensive studies comprising over 200 healthy volunteers. Considerations for a new drug preparation such as bioavailability and variability in relation to a standard treatment and the clinical significance of taking the drug with food and in increasing doses, are potential concerns that do not seem to be a problem for the therapeutic use of metoprolol CR/ZOK. Furthermore, the pharmacokinetic data achieved in young healthy subjects appear to be relevant for the treatment of patients, as shown by the consistent plasma concentration profiles obtained in elderly and in hypertensive patients.
Pharmacokinetic and Pharmacodynamic Evaluation of Metoprolol Controlled Release (CR/ZOK) 50 mg in Young Subjects
Authors: Wieselgren Ingrid , Lundborg Per , Sandberg Anders , Olofsson Bertil , Bergstrand Robert
Published: March 2013

In this steady state, cross‐over study, the bioavailability and beta1‐blocking effects of metoprolol CR/ZOK 50 mg, conventional metoprolol 50 mg tablets and placebo were evaluated in 12 healthy male subjects (mean age 25 years) after once daily treatment in 5 days. The drugs were administered in a randomized order. The beta1‐blocking effect was defined as percent reduction from baseline in exercise heart rate.

The plasma concentration‐time profile following metoprolol CR/ZOK 50 mg administration was more even compared to conventional metoprolol tablets, with significantly lower Cmax (mean: 71 vs 221 nmol/L) and significantly higher Cmin (mean; 39 vs 6 nmol/L) for the CR/ZOK formulation. This difference in plasma concentrations was also well reflected by a significantly lower fluctuation index for metoprolol CR/ZOK 50 mg compared with the conventional 50 mg tablet (mean: 69 vs 529%). There was, however, no difference in systemic bioavailability between the two metoprolol formulations (90% confidence limits: 86–106%).

The beta1‐blockade was also more even after metoprolol CR/ZOK 50 mg compared to conventional tablets with a significantly lower Emax (mean: 14 vs 19%) and higher Emin (mean: 9 vs 0%) for CR/ZOK. The total effect over a dosage interval, defined as area under the effect curve, was significantly higher for metoprolol CR/ZOK compared to conventional tablets (90% confidence limits: 123–213%).

In conclusion, once daily administration of metoprolol CR/ZOK 50 mg to young healthy subjects resulted in smooth plasma concentration and produced a significant beta1‐blocking effect for 24 hours. Once daily treatment of metoprolol CR/ZOK 50 mg might therefore be a useful and clinically effective dose.
Pharmacokinetic and Pharmacodynamic Properties of Controlled Release (CR/ZOK) Metoprolol in Healthy Oriental Subjects: A Comparison with Conventional Formulations of Metoprolol and Atenolol
Authors: Darmansjah Iwan , Wong Ellick , Setiawati Arini , Moeloek Dangsina , Irawati Dewi , Siagian Minarma , Muchtar Armen
Published: March 2013

The steady state pharmacokinetics and pharmacodynamics of metoprolol controlled release tablets 100 mg CR/ZOK, was compared with those of metoprolol conventional tablets 100 mg (CT) and atenolol 50 mg (ATL) in ten healthy Oriental men. The study was of double‐blind, cross‐over placebo controlled design. The three study drugs and placebo were given in a random order once daily for 4 consecutive days with 1‐week wash‐out between each period. Treadmill exercise tests were performed and blood samples were obtained at fixed intervals after the fourth dose of each treatment.

There was less fluctuation in the plasma level—time profile after CR/ZOK than CT and ATL. Plasma concentrations were significantly higher on CR/ZOK than CT at 24 hours after dosing. The relative bioavailability of CR/ZOK to CT was 69.0%.

CR/ZOK achieved relatively more uniform beta‐blocking effect over the dose interval. Compared to CT and ATL, the peak effect after CR/ZOK was less pronounced and the beta‐blockade after 24 hours more effective.
A Double‐Blind Comparison of Metoprolol CR/ZOK 50 mg and Atenolol 50 mg Once Daily for Uncomplicated Hypertension
Authors: Klein Gernot , Berger Jürgen , Olsson Gunnar , Menzel Tomas
Published: March 2013

In a double‐blind study with parallel groups, the clinical bioequivalence of the antihypertensive effect of metoprolol CR/ZOK (controlled release formulation) 50 mg and atenolol 50 mg in ordinary tablets given once daily for uncomplicated hypertension was investigated. Clinical bioequivalence was defined as difference in blood pressure reduction less than 8 mmHg. The study involved 195 patients, 98 on metoprolol CR/ZOK and 97 on atenolol. All patients were taken off antihypertensive therapy during a 2‐week placebo run‐in period. Thereafter the patients were randomly allocated to metoprolol CR/ZOK 50 mg or atenolol 50 mg for 4 weeks. In patients with a diastolic blood pressure remaining above 90 mmHg, the dose was increased to 100 mg daily of the respective drug. After 4 weeks treatment with 50 mg of the two therapies, blood pressure and heart rate was significantly reduced in both treatment groups. At this dose, clinical bioequivalence was found regarding both blood pressure and heart rate reductions. After 8 weeks of therapy (100 mg doses given to 31 in the metoprolol group and 43 in the atenolol group), clinical bioequivalence according to stated definition was found for blood pressures and heart rate reductions, although the reductions of systolic and diastolic blood pressures at rest as well as diastolic blood pressure during exercise were significantly greater in the metoprolol group. In an evaluation of the responder rate after the 8 weeks of treatment, 89% of the patients in the metoprolol CR/ZOK group and 74% in the atenolol group (P < .05) had a diastolic blood pressure reduction to 90 mmHg or less.

In conclusion, metoprolol CR/ZOK 50 mg and atenolol 50 mg in a dosage once daily was shown to be clinically bioequivalent. After doubling the dose in those patients who did not respond with a reduction of diastolic blood pressure to 90 mmHg or less on the 50 mg doses, blood pressure reduction was greater in the metoprolol group, although within the limits of defined clinical bioequivalence. Antihypertensive response rate was higher with metoprolol CR/ZOK than atenolol treatment.
Long‐Term Cardiovascular Effects of Metoprolol Therapy: A Review Article
Authors: Olsson Gunnar , Åblad Bengt , Rydén Lars
Published: March 2013

Long‐term studies in primary and secondary prevention using metoprolol have showed improvement in prognosis. This review summarizes the clinical results of such studies, and puts these results into the perspective of findings in mechanistic and explanatory studies. Many possible factors may have contributed to explain the beneficial effects on prognosis. The antihypertensive action, cardiac anti‐ischemic action, antifibrillatory action, antiatherogenic and antithrombotic actions of metoprolol are discussed. The additive effects of these actions may explain the clinically observed beneficial effects. In the evaluation of a specific intervention, it is important to realize the multiple actions that may contribute, and not only discuss single factors.
The Effect of Ciprofloxacin on the Pharmacokinetic and ECG Parameters of Quinidine
Authors: Bleske Barry E. , Carver Peggy L. , Annesley Thomas M. , Bleske Jane R. M. , Morady Fred
Published: March 2013

Ciprofloxacin decreases the clearance of antipyrine and other drugs which, in part, undergo oxidative metabolism. Based on these findings, the authors hypothesized that ciprofloxacin may decrease the clearance of quinidine, a drug which also undergoes oxidative metabolism. The purpose of this study was to evaluate the effect of ciprofloxacin on the pharmacokinetic and ECG parameters of quinidine in seven healthy men. Oral quinidine sulfate 400 mg was administered alone (Phase A) and after oral ciprofloxacin pretreatment (Phase B) in a randomized crossover fashion with a 2‐week washout period between each phase. During Phase B, ciprofloxacin pretreatment (750 mg every 12 hours) was administered for 5 days before and 24 hours after quinidine administration. Quinidine serum samples were obtained over a 24‐hour period. QRS and QTc intervals were measured over a 12‐hour period. There were no significant differences in clearance (20.3 ± 3.3 L/hr vs 20.1 ± 2.3 L/hr, P = .836), half‐life (7.9 ± 1 hr vs 7.8 ± 0.8 hr, P = 0.8), maximum concentration (1.4 ± 0.6 mg/L vs 1.5 ± 0.6 mg/L, P = 0.613), or time to maximum concentration (1.5 ± 0.2 hr vs 1.5 ± 0.1 hr, P = 0.571) for quinidine between Phase A and Phase B, respectively. The largest decrease in clearance observed for Phase B compared to Phase A was 10%. There was also no significant difference in the degree of QRS and QTc prolongation between Phase A and Phase B. From these results, it appears that ciprofloxacin in the dose given does not alter the pharmacokinetic or ECG parameters of quinidine. Therefore, no adjustment in the dose of quinidine is needed when coadministered with ciprofloxacin.
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

Antiepileptic Drugs Third Edition. Editors: R. Levy, R. Mattson, B. Meldrum, I. Penry, and F. Dreifuss

Neuropeptide Y (Karolinska Institute Nobel Conference Series). Editors: Viktor Mutt, KjeiI Fuxe, Tom as Hokfelt, and Jan M. Lundberg.

Platelets and Vascular Occlusion Serono Symposia Publications from Raven Press, Vol. 54. Editors: Carlo Patrono and Garret A. FitzGerald.

Principles of Clinical Toxicology Thomas A. Gossel and J. Douglas Bricker.

New Therapeutic Strategies in Hypertension (Perspectives in Hypertension, Vol. 3) Editors: Norman M. Kaplan, Barry M. Brenner, and John H. Laragh.

Presentation of Clinical Data Bert Spilker and John Schoenfelder.

Hypertension: Pathophysiology, Diagnosis, and Management Editors: John H. Laragh and Barry M. Brenner.
Globalization of the Pharmaceutical Industry: The Physician's Role in Optimizing Drug Use
Authors: Young Michael D.
Published: March 2013

In this new era of globalization, the physician must consider cultural differences in choosing methods of disseminating information so that practitioners in diverse settings may optimize drug usage. In addition, increasing competition, stimulated by the imminent unification of the European market in 1992, demands that the industry physician be concerned with developing possible new indications and cost‐effective applications. These factors will enhance roles for the medical affairs physician in the pharmaceutical industry.
Changes in the Steady‐State Pharmacokinetics of Theophylline During Treatment with Dirithromycin
Authors: Bachmann Kenneth , Nunlee Michelle , Martin Mary , Sullivan Timothy , Jauregui Luis , DeSante Karl , Sides Gregory D.
Published: March 2013

The steady‐state plasma concentrations and pharmacokinetic characteristics of theophylline were studied during intermittent treatment with dirithromycin. The addition of dirithromycin (500 mg orally once daily at 7:00 am) to a sustained‐release theophylline dosing regimen (200 mg every 12 hours) elicited small changes in the steady‐state pharmacokinetics of theophylline. Mean steady‐state plasma theophylline trough concentrations (Cmin) were invariant before, during, and after dirithromycin treatment; however, mean average steady‐state plasma theophylline concentrations (Cav) declined by 18% during dirithromycin treatment (P < .05), and mean peak plasma concentrations (Css,max) declined by 26% (P < .01). Theophylline clearance (CL/F) exhibited an increase of comparable magnitude during dirithromycin treatment, although the increase in CL/F was not statistically significant (.05 < P < .1). Dirithromycin treatment alters the steady‐state pharmacokinetics of theophylline; however, the magnitude of the changes is small and is not likely to modify treatment outcomes.
Metabolic Effects of the Combination of Captopril and Hydrochlorothiazide in Hypertensive Subjects
Authors: Perani Guido , Martignoni Alessandra , Muggia Chiara , Ferrari Tommaso , Simonich Paolo , Pompei Raffaella , Marchesi Eugenia , Finardi Giorgio
Published: March 2013

The medium‐term (16 weeks) effects of the combination of captopril and hydrochlorothiazide (HCTZ) on some metabolic indexes, particularly on plasma lipoproteins, were evaluated in 20 mild to moderate hypertensive outpatients.

After a 4‐week wash‐out period, the subjects were given one tablet of a new commercially available fixed combination once/daily (i.e., captopril 50 mg + HCTZ 25 mg). The dose could be titrated to a maximum of one tablet twice daily according to individual blood pressure responses.

Both systolic and diastolic blood pressure significantly decreased at week 4 and showed a further decrease thereafter; the rate of responders (diastolic blood pressure at or below 90 mm Hg at the end of the study) was very high (90%).

The only metabolic change was a small though significant increase in HDL cholesterol (P < .05), almost entirely due to an increase in the denser HDL3 subfraction. The atherogenic fractions, namely total cholesterol, LDL cholesterol, and apoprotein B, showed no significant changes. Plasma triglycerides underwent a transient increase at week 8 (P < .05) but thereafter fell. Plasma glucose, creatinine, uric acid, and potassium were unchanged.

The fixed combination of captopril and HCTZ seems highly effective in lowering blood pressure and seems devoid of untoward metabolic effects. Its overall impact on the coronary risk profile in hypertensive subjects seems therefore to be favorable.
A Simple Method for the Estimation of Interaction Bias in Crossover Studies
Authors: Cleophas Ton J. M.
Published: March 2013

The crossover trial is considered the most powerful means of determining the efficacy of new drugs. However this study design is frequently invalidated by treatment‐by‐period interaction. If, for example, the effect of the first treatment period carries on into the next one, then it influences the response to the latter period (carryover effect). A second problem is that there are no reliable statistical methods to test for this potential bias. This article takes issue with these problems and gives an alternative method for the detection of interaction simply by looking at the data. In a crossover without interaction the second period should be a true reflection of the first. If, however, the data of a treatment are better in the second period than in the first, a carryover effect is probable. If worse, a rebound phenomenon or a negative carryover effect is likely. If both treatments are better or worse, a time effect or some other external influence might be present. The authors illustrate this simple method by a summary of a few selected trials that have been published recently. This method enables not only the detection of interaction but also the differentiation between different types of interactions. Therefore, investigators are advised to use it in order to make sure that there are no unexpected problems.
Use of Serum Theophylline Level as a Guide to Optimum Therapy in Patients with Chronic Obstructive Lung Disease
Authors: Ashutosh Kumar , Bajaj Randhir , Cho Chaidong , Sangani Geeta
Published: March 2013

Blood and urine samples were collected simultaneously with measurements of pulmonary function at 2‐hour intervals for 8 hours after oral administration of short‐acting (SAT) and long‐acting theophylline (LAT) preparations in 15 patients with stable chronic obstructive lung disease (COLD) on long‐term maintenance theophylline therapy. The relationship between pulmonary function tests, serum theophylline level, plasma and urinary adenosine 3′5′ cyclic monophosphate (cAMP) was examined.

The highest forced expiratory volume in one second FEV1 was obtained with STL of 12.8 μg/ml ± 5.21 SD and 9.14 μg/ml ± 6.15 (P <.05) after administration of SAT and LAT, respectively. A further increase in serum theophylline level (STL) offered no therapeutic benefit, and, in fact, was associated with a fall in FEV1 in many instances. Plasma or urinary cAMP measurements did not correlate with STL. STL at which the best pulmonary function is achieved is quite variable in patients with COLD on maintenance theophylline therapy, is frequently less than 10 μg/ml, and can be determined only by repeated measurements of pulmonary function at different STL. Therefore measurements of STL are of limited value in guiding treatment with theophylline.
Azathioprine Metabolism: Pharmacokinetics of 6‐Mercaptopurine, 6‐Thiouric Acid and 6‐Thioguanine Nucleotides in Renal Transplant Patients
Authors: Chan Gary L. C. , Erdmann Gary R. , Gruber Scott A. , Matas Arthur J. , Canafax Daniel M.
Published: March 2013

Despite extensive clinical experience with azathioprine (AZA), the disposition of various AZA metabolites remains obscure. We therefore evaluated the pharmacokinetics of three AZA metabolites: 6‐mercaptopurine (6‐MP), the immediate metabolite; 6‐thiouric acid (6‐TU), the final end product; and 6‐thioguanine nucleotides (TGN), the active moiety; in eight renal transplant patients after oral administration of AZA. The low peak plasma 6‐MP level of 73.7 ± 23.7 ng/mL (mean ± SD) and the short half‐life (t1/2) of 1.9 ± 0.6 hours suggest rapid conversion of 6‐MP to other metabolites. A peak plasma 6‐TU concentration of 1210 ± 785 ng/mL was observed at 3.5 ± 0.6 hours after the AZA dose. The strong correlation between 6‐TU t1/2 and serum creatinine (r = 0.98, P = .0008) supported our previous work showing that 6‐TU is primarily excreted by the kidneys. The total TGN levels in red blood cells (RBCs) in each patient remained largely unchanged over 24 hours with the intraindividual coefficient of variation ranging from 4.4% to 29.8%. In comparison, the mean TGN level varied considerably between patients, and ranged from undetectable to 413 pmol per 8 × 108 RBCs. However, there was no apparent correlation between white cell counts on day 0 (P > .5), day 7 (P > .5), or day 14 (P > .5) and RBC TGN level. The persistence of TGN in body tissues thus provides a pharmacokinetic rationale for the conventional once or twice daily AZA regimen. Unfortunately, the long elimination t1/2 may also predispose patients to excessive accumulation of the active metabolite and gradual development of TGN‐induced myelosuppression. Further studies including more patients are required to clarify the clinical significance of the interindividual variability in RBC TGN levels.
Influence of Captopril on Urinary Excretion of Furosemide in Hypertensive Subjects
Authors: Fujimura Akio , Shimokawa Yoji , Ebihara Akio
Published: March 2013

Influence of captopril on urinary excretion of furosemide was examined in a placebo‐controlled, crossover design. Furosemide (20 mg) was injected intravenously in eight hypertensive subjects with pretreatment with captopril (25 mg) or matching placebo. Urine samples for furosemide and sodium were collected during the following intervals: −60 ∼ 0, 0 ∼ 60, 60 ∼ 120, and 120 ∼ 180 minutes after furosemide. Blood samples for plasma renin activity (PRA) and angiotensin II (AII) were obtained, and blood pressure was measured at −60, 0, 60, 120, and 180 minutes after furosemide.

No significant difference was observed in urinary excretion of furosemide, volume or sodium between these trials. Although PRA increased following furosemide with captopril, as predicted plasma AII did not increase. Blood pressure significantly decreased following the combined therapy, but not furosemide alone.

These data indicate that the urinary excretion of furosemide and its subsequent diuretic effects are not influenced by captopril.
Pharmacokinetics and Pharmacodynamics of Oral and Intravenous Cimetidine in Seriously III Patients
Authors: Sandborn William J. , Forland Steven C. , Cutler Ralph E. , Strong Richard M.
Published: March 2013

This study was done to determine if the pharmacokinetics and gastric pH response of intravenous cimetidine are superior to oral dosing in seriously ill patients. A paired study of intravenous followed by oral liquid cimetidine was given to eight men and two women who were inpatients in a VA Hospital. Treatment was prescribed for either upper gastrointestinal (GI) bleeding or prophylaxis against GI bleeding. All patients received cimetidine 300 mg every 6 hours intravenously on day 1 and orally on day 2. After the fourth dose each day, venous blood samples and gastric pH measurements were taken serially for 6 hours. Peak serum cimetidine concentration was 2.0 ± 0.5 mg/L for the intravenous dose and 1.5 ± 0.3 mg/L for the oral dose (P = .001). Area under the curve (AUC) of cimetidine concentration was 3.81 ± 1.1 mg/hr/L for the intravenous dose and 4.19 ± 1.22 mg/hr/L for the oral dose (P > .30). Bioavailability (AUCpo/AUCiv) was 1.13 ± 0.25, demonstrating complete oral absorption. The time during a 6‐hour dosing interval that the gastric pH remained above 3.0 was 3.3 ± 2.1 hours for the intravenous dose and 2.5 ± 2.3 hours for the oral dose, P = .171). The time that the serum cimetidine concentration remained above 0.5 mg/L was 2.0 ± 0.9 hours for the intravenous dose and 2.7 ± 1.0 hours for the oral dose (P = .055).

We concluded that bioavailability, time that gastric pH is maintained >3.0, and time that the serum cimetidine concentration is >0.5 mg/L for intravenous cimetidine are not significantly different from oral cimetidine in seriously ill patients.
Absorption Characteristics of a New Valproate Formulation: Divalproex Sodium‐Coated Particles in Capsules (Depakote® Sprinkle)
Authors: Carrigan Philip J. , Brinker Dale R. , Cavanaugh John H. , Lamm Janet E. , Cloyd James C.
Published: March 2013

To determine the absorption characteristics of a new dosage form of divalproex sodium consisting of coated particles in a pull‐apart capsule (Depakote® Sprinkle, Abbott Laboratories, North Chicago, IL), two absorption studies were conducted in adult volunteers. Ten fasting men participated in a single‐dose, crossover study comparing absorption from Sprinkle capsules versus enteric‐coated tablets (study 1). Eleven men participated in a multidose study (study 2) in which Sprinkle capsules or enteric‐coated tablets were given once every 24 hours for three doses under fasting and nonfasting conditions. In study 1, the extent of absorption from Sprinkle capsules equalled that from enteric‐coated tablets. Compared to enteric‐coated tablets, Sprinkle capsules had earlier absorption onset, 1 versus 2.6 hours (P < .05), slightly slower absorption rate, time to reach peak (tmax) of 4.0 versus 3.4 hours (P > .1), and lower maximum peak plasma drug concentration (Cmax), 20.7 versus 25.9 mcg/mL (P < .05). In study 2, food intake did not affect onset or extent of absorption nor maximum concentration, but did slow rate of absorption. Time to reach peak concentration was 2.7 hours for tablet (fasting), 3.3 hours for capsule (fasting), and 4.8 hours for capsule (nonfasting) (P < .05). Intrasubject absorption performance from the three doses was highly consistent, regardless of food intake. These data indicate that Sprinkle capsules possess desirable absorption characteristics in a form that makes ingestion easier for patients who have difficulty taking other valproate dosage forms.
Chemical and Biological Studies of a Cigarette That Heats Rather Than Burns Tobacco
Authors: deBethizy J. Donald , Borgerding Michael F. , Doolittle David J. , Robinson John H. , McManus Kevin T. , Rahn Carolyn A. , Davis Riley A. , Burger Gary T. , Hayes Johnnie R. , Reynolds John H. , Hayes A. Wallace
Published: March 2013

Cigarettes can be developed that heat rather than burn tobacco. Such products would be expected to have less “tar” and other combustion products than cigarettes that burn tobacco. With one product of this type, benzo(a)pyrene, N‐nitrosamines, phenolic compounds, acetaldehyde, acrolein, hydrogen cyanide, and N‐heterocyclic compounds have been reduced 10‐ to 100‐fold compared to the Kentucky reference (1R4F) cigarette, a representative low‐tar cigarette. The yields of nicotine and carbon monoxide from this new cigarette are less than the yields of 95% and 75%, respectively, of the cigarettes sold in the United States during 1988. Nicotine absorption from smoking this new cigarette is not significantly different from that of tobacco‐burning cigarettes yielding equivalent levels of nicotine. The urine mutagenicity of smokers of new cigarettes is significantly less (P < .05) than that of smokers of tobacco‐burning cigarettes and is not significantly different (P > .10) from that of nonsmokers. We conclude that cigarettes which heat rather than burn tobacco can reduce the yield of tobacco combustion products. This simplification of smoke chemistry had no effect on nicotine absorption in smokers and resulted in a reduction of biological activity in smokers as measured by urine mutagenicity.
Effects of Gemfibrozil and Other Fibric Acid Derivatives on Blood Lipids and Lipoproteins
Authors: Zimetbaum Peter , Frishman William H. , Kahn Shoshonah
Published: March 2013

Fibric acid derivatives (FADs) are a class of drugs that have been shown to reduce the production of very low‐density lipoprotein (VLDL) while enhancing VLDL clearance due to the stimulation of lipoprotein lipase activity. The drugs can reduce plasma triglyceride levels while raising high‐density lipoprotein (HDL) cholesterol levels. Their effects on low‐density lipoprotein (LDL) cholesterol levels are less marked and more variable. There is evidence that oral gemfibrozil (Lopid®, Parke—Davis, Morris Plains, NJ) can reduce the risk of serious coronary events, specifically in those patients who had elevations of both LDL cholesterol levels and total plasma triglyceride levels with lower HDL cholesterol levels. Newer FADs (bezafibrate, ciprofibrate, fenofibrate) have been shown to have greater efficacy in reducing LDL cholesterol than gemfibrozil but, in general, these drugs are not as effective as the other primary drugs used to lower LDL levels. The FADs are also used to treat adult patients with very high levels of triglycerides who have pancreatitis and whose disease cannot be managed with dietary therapy. The FADs are well tolerated, with dyspepsia and abdominal pain the most common adverse effects. A small risk of cholelithiasis exists with these drugs, and caution should be used when combining these drugs with HMG‐CoAreductase inhibitors because the combination increases the incidence of hyperlipidemic myositis and rhabdomyolysis.
Drug Delivery Systems. 6. Transdermal Drug Delivery
Authors: Ranade Vasant V.
Published: March 2013

Transdermal drug delivery system has been in existence for a long time. In the past, the most commonly applied systems were topically applied creams and ointments for dermatological disorders. The occurrence of systemic side‐effects with some of these formulations is indicative of absorption through the skin. A number of drugs have been applied to the skin for systemic treatment. In a broad sense, the term transdermal delivery system includes all topically administered drug formulations intended to deliver the active ingredient into the general circulation. Transdermal therapeutic systems have been designed to provide controlled continuous delivery of drugs via the skin to the systemic circulation. The relative impermeability of skin is well known, and this is associated with its functions as a dual protective barrier against invasion by micro‐organisms and the prevention of the loss of physiologically essential substances such as water. Elucidation of factors that contribute to this impermeability has made the use of skin as a route for controlled systemic drug delivery possible. Basically, four systems are available that allow for effective absorption of drugs across the skin. The microsealed system is a partition‐controlled delivery system that contains a drug reservoir with a saturated suspension of drug in a water‐miscible solvent homogeneously dispersed in a silicone elastomer matrix. A second system is the matrix‐diffusion controlled system. The third and most widely used system for transdermal drug delivery is the membrane‐permeation controlled system. A fourth system, recently made available, is the gradient‐charged system. Additionally, advanced transdermal carriers include systems such as iontophoretic and sonophoretic systems, thermosetting gels, prodrugs, and liposomes. Many drugs have been formulated in transdermal systems, and others are being examined for the feasibility of their delivery in this manner (e.g., nicotine antihistamines, beta‐blockers, calcium channel blockers, non‐steroidal anti‐inflammatory drugs, contraceptives, anti‐arrhythmic drugs, insulin, antivirals, hormones, alpha‐interferon, and cancer chemotherapeutic agents). Research also continues on various chemical penetration enhancers that may allow delivery of therapeutic substances. For example, penetration enhancers such as Azone may allow delivery of larger‐sized molecules such as proteins and polypeptides.
Effect of Probenecid on the Pharmacokinetics and Pharmacodynamics of Procainamide
Authors: Lam Y. W. Francis , Boyd Rebecca A. , Chin Shu K. , Chang Donald , Giacomini Kathleen M.
Published: March 2013

Renal tubular transport of organic anions and cations is assumed to be mutually exclusive. However, results of a number of in vitro and in vivo studies suggest an interaction between the organic anion, probenecid, and various organic cations in the proximal renal tubule. To evaluate the clinical importance of such an interaction, the authors investigated the pharmacokinetics and pharmacodynamics of procainamide, an organic cation with a low therapeutic index that is excreted in part by active secretion in the proximal tubule, in the presence and absence of probenecid. In a randomized crossover study, six healthy subjects received a single 750‐mg N dose of procainamide, with and without prior probenecid administration (2 g orally). Blood and urine samples were obtained and pharmacokinetic parameters of procainamide were determined in each treatment period. QT intervals were measured from ECG recordings that were obtained at blood collection times for pharmacodynamic evaluation. Coadministration of probenecid did not result in any significant change in the overall disposition of procainamide. In particular, renal clearance was not significantly different (488 ± 95 mL/min without probenecid vs. 478 ± 69 mL/min in the presence of probenecid). Our data suggest an interaction between probenecid and procainamide in the proximal renal tubule does not exit. Reasons for this lack of interaction are discussed.
Pharmacokinetics and Oral Bioavailability of Hydrocortisone
Authors: Derendorf Hartmut , Möllmann Helmut , Barth Jürgen , Möllmann Carsten , Tunn Sabine , Krieg Michael
Published: March 2013

The pharmacokinetics of 20 mg hydrocortisone were studied after IV and oral administration. Endogenous hydrocortisone was suppressed by dexamethasone administration. Hydrocortisone concentrations were measured in plasma and saliva. After IV administration, hydrocortisone was eliminated with a total body clearance of 18 L/hr and a half‐life of 1.7 hr. The volume of distribution was 34 L. Oral bioavailability averaged 96%. Absorption was rapid, achieving maximum hydrocortisone levels of 300 ng/mL after 1 hour. Saliva levels were not proportional to plasma levels, but could be shown to reflect free, non‐protein bound hydrocortisone concentrations in plasma.
Orthostatic Function During a Stand Test Before and After Head‐Up or Head‐Down Bedrest
Authors: Lathers Claire M. , Diamandis Peter H. , Riddle Jeanne M. , Mukai Chiaki , Elton Kay F. , Bungo Michael W. , Charles John B.
Published: March 2013

Astronauts may exhibit orthostatic dysfunction upon returning to 1 g after space flight Understanding cardiovascular changes at 0 G will provide insights into the mechanisms of the loss of orthostatic tolerance, whether due to space flight or bedrest. Bedrest is one model used to produce cardiovascular changes that are associated with space flight. In the current study, young male adults were placed at −5°, +10, +20, or +42° bedrest (0, 1/6, 1/3, and 2/3g, respectively) for 6 hours on 4 different days. This was preceded and followed by a stand test: 5 minutes in the supine position, and then 5 minutes in the standing position, with the feet 9 inches apart and 6 inches from the wall. Cardiovascular values were measured at 1‐minute intervals. Systolic and diastolic pressures were measured using an automated blood pressure device; mean arterial pressure (MAP; mm Hg) was calculated. Heart rate (bpm) and cardiac parameters were measured with a thoracic impedance device. Minute 3, 4, and 5 values were used to determine whether there were time or angle effects. Of six subjects, one reported nausea upon 3 minutes of standing after 6 hours of bedrest at −5°. The same subject was lightheaded in the first minute of standing after 6 hours of bedrest at +10°. Mean heart rate pre‐bedrest in the supine position was 63 and increased by 24 bpm on standing. Heart rate post‐bedrest in the supine position was 65 and increased by 35 bpm on standing; standing heart rate increased 11 bpm after −5° bedrest. The increases after +10°, +20°, and +42° tilts were 4,3, and 4 bpm, respectively. Changes in the mean arterial blood pressure were minimal. Results from the stand test pre‐ and post‐ 6 hours of bedrest at −5° but not at +10°, +20°, or +42° are similar to those after space flight.
Metabolie Changes Observed in Astronauts
Authors: Leach Carolyn S. , Cintrón N. M. , Krauhs J. M.
Published: March 2013

Study of metabolic alterations that occur during space flight can provide insight into mechanisms of physiologic regulation. Results of medical experiments with astronauts reveal rapid loss of volume (2 L) from the legs and a transient early increase in left ventricular volume index. These findings indicate that, during space flight, fluid is redistributed from the legs toward the head. In about 2 days, total body water decreases 2 to 3%. Increased levels of plasma renin activity and antidiuretic hormone while blood sodium and plasma volume are reduced suggest that space flight‐associated factors are influencing the regulatory systems. In addition to fluid and electrolyte loss, Skylab astronauts lost an estimated 0.3 kg of protein. Endocrine factors, including increased cortisol and thyroxine and decreased insulin, are favorable for protein catabolism. The body appears to adapt to weightlessness at some physiologic cost. Readaptation to Earth's gravity at landing becomes another physiologic challenge.
Pharmacologic Considerations for Shuttle Astronauts
Authors: Santy Patricia A. , Bungo Michael W.
Published: March 2013

Medication usage by crewmembers in the preflight and inflight mission periods is common in the Shuttle Program. The most common medical reports for which medication is used are: space motion sickness (SMS), sleeplessness, headache, and backache. A number of medications are available in the Shuttle Medical Kit to treat these problems. Currently, astronauts test all frequently used medications before mission assignment to identify potential side‐effects, problems related to performance, personal likes/dislikes, and individual therapeutic effect. However, microgravity‐induced changes in drug pharmacokinetics, in combination with multiple operational factors, may significantly alter crew‐member responses inflight. This article discusses those factors that may impact pharmacologic efficacy during Shuttle missions.
Acute Hemodynamic Responses to Weightlessness During Parabolic Flight
Authors: Mukai Chiaki N. , Lathers Claire M. , Charles John B. , Bennett Barbara S. , Igarashi Makoto , Patel Saumil
Published: March 2013

Pilots and astronauts experience fluid shifts in variable gravity. Acute effects of fluid shifts on the cardiovascular system were monitored on NASA's KC‐135 aircraft during parabolic flight The variability of R‐R intervals in the electrocardiogram was measured as an indication of vagal cardiac neural activity. R‐R intervals were measured during the gravity transition from 2‐G to 0‐G produced by parabolic flight to assess the involvement of the autonomic nervous system in regulating the acute effects of fluid shifts. In seven subjects, a BoMed noninvasive continuous cardiac output monitor (NCCOM 3) monitored thoracic fluid index (TFI, ohms), heart rate (bpm), and cardiac output (1/min). Data were stored on a lap‐top computer with the subject in one of four postures: sitting, standing, supine, and semi‐supine, during one of four sets of eight to ten parabolas. Five seconds of data were averaged: before parabola onset (1.3‐G); parabola entry (1.9‐G); 0‐G; and parabola exit (1.7‐G). Three to eight parabolas were averaged for subjects in each posture; the mean for each posture was calculated. In each of five additional subjects, the coefficient of variation was calculated by dividing mean value by the standard deviation of 3 to 15 R‐R intervals. Eight to ten parabolas were averaged for each postural set. Compared with values collected before 0‐G, standing values during 0‐G showed that the thoracic fluid index decreased 2.5 ohms, heart rate decreased 22 bpm, and cardiac output increased 1 L/min. During sitting, thoracic fluid index decreased 1.25 ohms, heart rate decreased 10 bpm, whereas cardiac output increased 0.5 L/min. In the supine position, thoracic fluid index and heart rate were constant whereas cardiac output decreased 0.55 L/min. In the semi‐supine position, thoracic fluid index and heart rate were constant. Compared with values collected from 2‐G and 0‐G the coefficient of variation increased 66.4% in the standing position, 53.4% in the sitting position, and 43.3% in the semi‐supine position and decreased 11.6% in the supine position. The data indicated that cardiovascular changes are dependent on posture and gravity. During the four sets of parabolas in the four different postures, the greatest and smallest changes were observed in the standing and supine positions, respectively, during 0‐G. Fluid shifts from the legs to the thorax occurred during 0‐G in the supine and standing positions. The high values of the coefficient of variation at the onset of 0‐G suggest that vagal cardiac neural activity increases, but not significantly, in all positions except supine.
Pharmacology and Pharmacokinetics of Amiodarone
Authors: Freedman Michael D. , Somberg John C.
Published: March 2013

Amiodarone is a unique antiarrhythmic agent originally developed as a vasodilator. Classified electrophysiologically as a Type III antiarrhythmic, it also has both nonspecific antisympathetic and direct, fast channel‐membrane effects. Hemodynamic effects of orally administered amiodarone (a negative inotropic agent) are usually negligible, and are usually compensated for by induced vasodilation. Effects on thyroid and hepatic function may help to explain some of the unique pharmacologic as well as toxicologic effects of the drug. Amiodarone is poorly bioavailable (20–80%) and undergoes extensive enterohepatic circulation before entry into a central compartment. The principal metabolite, mono‐n‐desethyl amiodarone is also an antiarrhythmic. From this central compartment, it undergoes extensive tissue distribution (exceptionally high tissue/plasma partition coefficients). The distribution half‐life of amiodarone out of the central compartment to peripheral and deep tissue compartments (t1/2α) may be as short as 4 hours. The terminal half‐life (t1/2β) is both long and variable (9–77 days) secondary to the slow mobilization of the lipophilic medication out of (primarily) adipocytes. A pharmacokinetically based loading scheme is described, and data suggesting a role for routine amiodarone plasma levels are presented.
The New Drug Approvals of 1987, 1988, and 1989: Trends in Drug Development
Authors: Kaitin Kenneth I. , DiCerbo Patricia A. , Lasagna Louis
Published: March 2013

The new drug approvals of 1987, 1988, and 1989 were analyzed to determine whether there are any emerging trends in the US drug development and review processes. Sixty‐four new drugs were approved by the FDA during this period, of which 55 met the Center for the Study of Drug Development's definition of a new chemical entity (NEC). For the 55 NCEs, the mean length of the investigational new drug application (IND) phase (IND filing to NDA submission) was 5.2 years, the new drug application (NDA) phase (NDA submission to approval) was 2.9 years, and the total phase (IND filing to NDA approval) was 8.1 years. Nine of the 55 NCEs were classified by the FDA as 1A (important therapeutic gain), 15 were classified as 1B (modest gain), 29 were classified as 1C (little or no gain), and 2 were classified as 1AA (drugs to treat AIDS and AIDS‐related conditions); 10 drugs were granted orphan status. The mean NDA phase for 1A drugs was 2.4 years; 1B drugs, 2.9 years; 1C drugs, 3.1 years; 1AA drugs, 1.4 years; and orphan drugs, 2.5 years. Forty‐four of the 55 NCEs (80%) were available in foreign markets before US approval was given, with a mean of 6.5 years of prior marketing. These data are consistent with figures for previous years and suggest little change in the rate of new drug development and review in the United States.
Effects of Beta‐Adrenoreceptor Antagonists on Cerebral Blood Flow of Cirrhotic Patients with Portal Hypertension
Authors: Testa Roberto , Rodriguez Guido , Dagnino Franco , Grasso Alessandro , Gris Arturo , Marenco Stefano , Nobili Flavio , Risso Domenico , Rosadini Guido , Celle Guido
Published: March 2013

The current study evaluated the effect of two beta adrenergic—blocking agents, propranolol (PRP) and atenolol (ATN), versus placebo on cerebral blood flow (CBF) of three homogeneous groups of cirrhotic patients with portal hypertension. CBF was measured by the noninvasive 133‐Xenon inhalation method at rest and 1 hour after a single oral dose of PRP (40 mg), or ATN (100 mg), or placebo. Blood pressure and heart rate (HR) were measured at the beginning of each examination, and end‐tidal pCO2 (PeCO2) was monitored. The HR decreased significantly in both the PRP and ATN groups (P < .01), whereas no changes were recorded for both PeCO2 and mean arterial blood pressure (MABP). The comparisons of the CBF differences among groups (ANOVA with the significance levels adjusted by the Bonferroni's correction) showed a significant increase in CBF after ATN as compared with both placebo (P < .02) and PRP (P < .01), whereas no significant differences were seen after PRP as compared with placebo. Our results confirm that PRP does not significantly affect CBF, whereas ATN induces an increase in CBF, although the underlying mechanism is difficult to explain.
Amikacin Pharmacokinetics: Wide Interpatient Variation in 98 Patients
Authors: Zaske Darwin E. , Strate Richard G. , Kohls Philip R.
Published: March 2013

The disposition of amikacin was studied in 98 patients receiving treatment for severe gram‐negative sepsis. Several factors were identified which were significantly related to the drug's elimination rate. These included renal function (r = .67), age (r = –.55), distribution volume (r = .34), and weight (r = –.31). These variables explain 62% of the variance (R2) in elimination rate constant when combined in a multiple regression model. The drug's half‐life demonstrated considerable interpatient variation in patients with a normal serum creatinine (.68–14.4 hrs) or with a normal creatinine clearance (.68–7.2 hrs). The drug's distribution volume ranged from .08 to .48 L/Kg. The drug's clearance varied from 6.5 to 200 mL/hr/kg for patients with a normal serum creatinine and 17.8 to 200 mL/hr/kg for patients with a normal creatinine clearance. The interpatient variation in the drug's kinetic parameters is a concerning clinical problem. Measuring serum amikacin concentrations and adjusting dosage regimens are necessary to achieve desired peak and trough serum concentrations.
The Effects of an Antacid or Cimetidine on the Serum Concentrations of Azithromycin
Authors: Foulds George , Hilligoss Donald M. , Henry Eugenia B. , Gerber Nicholas
Published: March 2013

The effects of an antacid and of cimetidine on the serum concentrations of azithromycin were examined in volunteers. Ten subjects were given 500 mg azithromycin alone and immediately after being given 30 mL Maalox (Rorer, Fort Washington, PA) in a crossover design. There were no statistically significant differences in Tmax or AUC0–48 after administration of azithromycin alone or with antacid, but mean values of Cmax were reduced by 24% (P = .015). Thus, although Cmax was decreased, the extent of absorption of azithromycin was not affected by coadministration with an antacid. Two groups of six volunteers were given 500 mg azithromycin on day 1. On day 8, one group was given 800 mg cimetidine 2 hours before a dose of azithromycin; the remaining group received placebo before azithromycin. There were no differences in the pharmacokinetic parameters produced by administration with cimetidine or placebo, relative to those on day 1. Thus, cimetidine administered 2 hours before a dose of azithromycin had no apparent effect on the serum concentrations of azithromycin.
A Pharmacokinetic Analysis of Long‐Term Administration of Rubidium Chloride
Authors: Meltzer Herbert L.
Published: March 2013

When a substance with a long biologic half‐life is administered over an extended period with a varying dose schedule, many concerns about safety arise. In the case of rubidium chloride, which has been reported to have antidepressive activity, some of these concerns are related to the potential for unanticipated accumulation in the intracellular fluid, where replacement of more than 40% of the potassium ion is associated with toxicity in animals. A pharmacokinetic model of rubidium distribution, based on a three‐compartment system, is in accord with the empirical data from previous human trials. By comparison of predicted with observed plasma rubidium levels, a sudden change in the ratio of intra‐ to extracellular distribution of rubidium can be detected, and availability of this warning signal of potentially toxic intracellular accumulation can be useful during extended administration.