bluuebunny/crossref_metadata_2025 huggingface dataset:
Elucidating the Relationship Between Acetazolamide Plasma Protein Binding and Renal Clearance Using an Albumin Infusion
Authors: Gomolin Irving H. , Chapron Dennis J.
Published: March 2013

The effect of plasma protein binding changes on drug clearance is an important concept in clinical pharmacology. In a hypoalbuminemic patient receiving acetazolamide, albumin infusion (50 g) increased acetazolamide plasma protein binding towards normal as the serum albumin concentration rose (r = 0.91, P < .001). The ratio of acetazolamide renal plasma clearance to creatinine clearance decreased as serum albumin levels increased (r = 0.78, P <. 05) and the unbound drug fraction fell (r = 0.88, P <. 01), but clearance ratios based on unbound plasma acetazolamide levels did not change. Albumin infusion resulted in a nonparallel decline over time between plasma and unbound plasma acetazolamide concentrations. These data demonstrate that, over the range of observed serum albumin concentrations, acetazolamide renal plasma clearance is sensitive to changes in plasma protein binding. Furthermore, our findings emphasize the importance of measuring unbound drug levels when protein binding changes occur during the course of drug disposition studies. Finally, this methodology allows for the fascile assessment of the effects of plasma protein binding changes on renal drug clearance.
Comparison of Pentoxifylline Pharmacokinetics Between Smokers and Nonsmokers
Authors: Mauro Vincent F. , Mauro Laurie S. , Hageman John H.
Published: March 2013

Pentoxifylline is a synthetic xanthine derivative and is hepatically cleared. The natural dimethylxanthines theobromine and theophylline have been shown to have enhanced metabolism in smokers when compared with nonsmokers. Subsequently, the effect of smoking on pentoxifylline plasma concentrations was investigated. Twenty healthy volunteers (10 smokers and 10 nonsmokers) received pentoxifylline 400 mg as a controlled‐release tablet every 8 hours for 17 doses. Several blood samples were collected for 8 hours after the final dose. These samples were assayed for pentoxifylline and its metabolites. The mean values of the smokers were compared with those of the nonsmokers. With respect to pentoxifylline, no statistically significant differences in maximum concentration and time of maximum concentration were observed between the two groups. Although no statistical differences in plasma concentrations and area‐under‐the‐curve at steady state (AUCss) were observed, the oral clearance of pentoxifylline among the smokers (.22 ± .08 L/minute/kg) was significantly greater (P < .05) than that among the nonsmokers (0.15 ± 0.06 L/minute/kg) when corrected for body weight. With respect to the pentoxifylline metabolite 1‐(5‐hydroxy‐hexyl)‐3,7‐dimethylxanthine (MI), the maximum concentration and AUCss of the smokers were significantly decreased when compared with the nonsmokers. The AUCss of the smokers was 1438 ± 819 ng · hour/mL and of the nonsmokers was 2864 ± 1375 ng · hour/mL (P <. 02). The results of this trial suggest that smoking tends to reduce pentoxifylline plasma concentrations and significantly reduces Ml plasma concentrations.
Effect of Aging on the Pharmacokinetics of Acebutolol Enantiomers
Authors: Piquette‐Miller Micheline , Foster Robert T. , Kappagoda C. Tissa , Jamali Fakhreddin
Published: March 2013

Acebutolol (AC) is a chiral β‐blocker that is metabolized to an equipotent chiral metabolite, diacetolol (DC). A stereoselective disposition of AC and DC enantiomers has recently been reported in young healthy subjects. As many physiologic properties affecting drug disposition are progressively altered with increasing age, the effect of aging on the pharmacokinetics of AC and DC enantiomers were investigated in nine subjects ranging from 60 to 75 years after administration of an oral 200‐mg dose of racemic AC. Increasing age resulted in a significant prolongation of the elimination t1/2s of R‐ (r=0.913) and S‐DC (r=0.811). Also, the S:R ratios of AC urinary excretion (ΣXu) of enantiomers was significantly correlated with age (r=0.677). Contribution of declining renal junction to age‐associated pharmacokinetics changes was subsequently examined. Renal clearance and cumulative urinary excretion of both AC and DC enantiomers were positively correlated with creatinine clearance. In addition, declining creatinine clearance was associated with a subsequent decline in the enantiomer S:R ratio of AC in plasma (AUC S:R, r=0.807) and urine (ΣXu S;R r=0.807). Similarly, a progressive decline in the S:R ratio of DC collected in urine was evident (r=0.689). Age‐related changes in the enantiomers ratios may suggest that an active stereoselective pathway such as renal tubular secretion or nonrenal excretion may be affected in the elderly.
Investigation of Anti‐Motion Sickness Drugs in the Squirrel Monkey
Authors: Cheung B. S. K. , Money K. E. , Kohl R. L. , Kinter L. B.
Published: March 2013

Early attempts to develop an animal model for anti‐motion sickness drugs, using dogs and cats, were unsuccessful. Dogs did not show a beneficial effect of scopolamine (probably the best single anti‐motion sickness drug for humans thus far) and the findings in cats were not definitive. The authors have developed an animal model using the squirrel monkey (Saimiri sciureus) of the Bolivian phenotype. Unrestrained monkeys in a small lucite cage were tested in an apparatus that induces motion sickness by combining vertical oscillation and horizontal rotation in a visually unrestricted laboratory environment. Signs of motion sickness were scored using a rating scale. Ten susceptible monkeys (weighing 800–1000 g) were given a total of five tests each, to establish the baseline susceptibility level. Based on the anticholinergic activity of scopolamine, the sensitivity of squirrel monkey to scopolamine was investigated, and the appropriate dose of scopolamine for this species was determined. Then various anti‐motion sickness preparations were administered in subsequent tests: 100 ug scopolamine per monkey; 140 ug dexedrine; 50 ug scopolamine plus 70 ug dexedrine; 100 ug scopolamine plus 140 ug dexedrine; 3 mg promethazine; 3 mg promethazine plus 3 mg ephedrine. All these preparations were significantly effective in preventing motion sickness in the monkeys. Ephedrine, by itself, which is marginally effective in humans, was ineffective in the monkeys at the doses tried (0.3–6. 0 mg). The squirrel monkey appears to be a good animal model for antimotion sickness drugs. Peripherally acting antihistamines such as astemizole and terfenadine were found to be ineffective, whereas flunarizine, and an arginine vasopressin V1 antagonist, showed significant activity in preventing motion sickness.
Comparison of Verapamil, Diltiazem, and Labetalol on the Bioavailability and Metabolism of Imipramine
Authors: Hermann David J. , Krol Thomas F. , Dukes George E. , Hussey Elizabeth K. , Danis Marion , Han Yiang‐Hau , Powell J. Robert , Hak Lawrence J.
Published: March 2013

Twelve healthy male subjects completed this randomized, placebo controlled, four‐period crossover trial to determine the effect of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine. Subjects received a 7‐day course of one of four treatments; verapamil (120 mg every 8 hr), diltiazem (90 mg every 8 hr), labetalol (200 mg every 12 hr), or placebo (every 12 hr) during each study period. Imipramine (100 mg) was administered orally on the morning of day 4 of each study period. Plasma and urine samples were collected periodically over the ensuing 96 hours. Samples were assayed by HPLC for imipramine, desipramine, 2‐hydroxyimipramine, and 2‐hydroxydesipramine. Verapamil, diltiazem, and labetalol increased imipramine area under the plasma concentration time curve (relative bioavailability) as compared with placebo by 15%, 30%, and 53%, respectively. Verapamil and diltiazem did not demonstrate consistent changes in the formation of the measured metabolites. Labetalol caused a significant decrease in the amount of imipramine metabolized to 2‐hydroxyimipramine (mean decrease: 22%) and from desipramine to 2‐hydroxydesipramine (mean decrease: 8%). The molar ratios of plasma AUC of 2‐hydroxyimipramine and 2‐hydroxydesipramine to the parent compounds were significantly decreased. Since these metabolic processes are dependent on the cytochrome P450IID6 isozyme, these data suggest that labetalol decreases the oral clearance of imipramine by inhibiting this system. All three of these commonly used agents decreased the oral clearance of imipramine. These drug interactions could lead to elevated imipramine concentrations and have the potential for clinically important adverse events.
Diurnal Effect on Caffeine Clearance
Authors: Hashiguchi Masayuki , Fujimura Akio , Ohashi Kyo‐ichi , Ebihara Akio
Published: March 2013

Caffeine (300 mg) was given orally to nine healthy subjects at 10:00 am (day trial) or at 10:00 pm (night trial) using a crossover design. Saliva was obtained at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours after administration of caffeine. Urine was collected for 8 hours after caffeine dosing. Caffeine clearances in saliva during the day tried were not different from those in the night trial. No significant difference was observed in urinary molar ratios of metabolites (AFMU+ 1X + 1U / 17U) between the two trials. These data suggest that caffeine clearances in saliva do not vary with its administration time. Since caffeine clearances in plasma are reflected in the urinary ratios of caffeine metabolites, its clearance in plasma might also not be altered by the time of dosing.
Oral Anticoagulants: Pharmacodynamics, Clinical Indications and Adverse Effects
Authors: Freedman Michael D.
Published: March 2013

Discovered early in this century consequent to investigations of a bovine hemorrhagic disease, the oral anticoagulants inhibit a post translational modification required for various hepatically derived serine proteases to become active. These include Factors II, V, VII and X. Through their effect on Proteins S and C, the extrinsic pathway is also effected. While most of these agents exist as optically active enantiomers, with differing kinetics and pharmacologic profiles, they are generally administered in the clinic as racemic mixtures. Over the last 45 years, various studies have sought to better evaluate the role of the oral anticoagulation in both prevention and treatment of various types of thrombo‐occlusive and ‐embolic disease. Such exercises have allowed us to better understand the pathophysiology of those diseases as well as to better characterize the pre‐thrombotic state.
Comparison on Bioequivalence of Four Phenytoin Preparations in Patients with Multiple‐Dose Treatment
Authors: Tsai Jing‐Jane , Lai Ming‐Liang , Yang Yea‐Huei Kao , Huang Jin‐Ding
Published: March 2013

In previous pharmacokinetic studies on phenytoin, the authors found that a hybrid parameter, Vd/F, was much higher in Chinese subjects. It could be due to a lower bioavailability (F) of the tested phenytoin preparations and/or a higher volume of distribution (Vd) in Chinese. Therefore, the relative bioavailability of four phenytoin oral preparations, i.e. Dilantin (Taiwan), Dilantin (USA), Aleviatin (Taiwan), and Aleviatin (Japan), were compared in patients who regularly took Dilantin (Taiwan) with their phenytoin plasma level at steady state. Twenty‐four‐hour area under curve was measured by an HPLC method after substituting the daily dose with each 300‐mg dose of the test preparation. The plasma level resulted from Dilantin (USA) was found significantly higher than that from Dilantin (Taiwan). Similarly, Aleviatin (Japan) gave a significantly higher plasma level than Aleviatin (Taiwan). The study in part explained the unexpected high Vd/F of phenytoin in previous studies.
The Effects of Cardiac Transplantation and Cyclosporine Therapy on Digoxin Pharmacokinetics
Authors: Robieux Isabelle , Dorian Paul , Klein Julia , Chung Derrick , Zborowska‐Sluis Dana , Ogilvie Richard , Koren Gideon
Published: March 2013

Most patients needing cardiac transplantation are treated with digoxin for heart failure. Because of its narrow therapeutic range, even recommended doses of digoxin may cause severe toxicity. Several drugs, including quinidine, amiodarone, verapamil, and propafenone can interact with digoxin, leading to toxic accumulation of the glycoside. The authors have recently reported two cases of severe digitalis toxicity after the initiation of cyclosporine treatment in patients awaiting cardiac transplantation. A preliminary study on two additional patients suggested that cyclosporine reduced the plasma clearance and volume of distribution of digoxin. To assess the mechanism of this interaction, the authors studied digoxin pharmacokinetics in patients awaiting cardiac transplantation and again after the surgery, during chronic cyclosporine therapy. To separate the effects of transplantation and cyclosporine on digoxin pharmacokinetics, pharmacokinetic studies were subsequently performed in dogs to allow controlled experimental conditions for evaluation of the digoxin‐cyclosporine interaction.
Antihypertensive and Metabolic Effects of Concomitant Administration of Terazosin and Methyclothiazide for the Treatment of Essential Hypertension
Authors: Black Henry R. , Chrysant Steven G. , Curry Charles L. , Frishman William H. , Grimm Richard H. , Lasseter Kenneth C. , Okun Ronald , Pool James L. , Raizada Veena , Vlachakis Nicolas D. , Wombolt Duane G. , Hosmane Balakrishna S. , Jackson Linda A. , Juan David , Laddu Atul R.
Published: March 2013

The efficacy and safety of once‐daily 2.5‐ or 5.0‐mg methyclothiazide (MCTZ) added to once‐daily 5.0‐mg terazosin (TRZ) versus 5.0‐mg TRZ alone was evaluated in this double‐blind, multicenter study. All patients received TRZ during a 6‐week titration period. Hypertensive patients (222) (mean blood pressure of 159/104 mm Hg) were randomized to one of three treatment groups: TRZ alone (N = 76); TRZ + MCTZ‐2.5 mg (N = 74); and TRZ + MCTZ‐5.0 mg (N = 72) for the 8‐week double‐blind period. Changes in the supine and standing SBP/DBP from preTRZ period were: TRZ alone (−4.8/−8.1 and −2.0/−6.1 mm Hg); TRZ + MCTZ‐2.5 mg (−17.3/−12.4 and −16.0/−11.2 mm Hg); and TRZ + MCTZ‐5.0 mg (−20.6/−14.4 and −23.3/−14.6 mm Hg). Blood pressure changes in the combination groups were significantly greater than those in the TRZ alone group. However, there were no statistically significant differences between the TRZ + MCTZ‐2.5‐mg and TRZ + MCTZ‐5.0‐mg groups. The combination of TRZ and MCTZ tends to mitigate the adverse effects on serum glucose, uric, potassium and lipids usually associated with thiazide diuretics. Thus, combination treatment that begins with TRZ and adds MCTZ is effective in lowering blood pressure without any significant adverse metabolic effects.
Effects of Combined Bezafibrate‐Simvastatin Appraised in Healthy Subjects
Authors: Horsmans Y. , Desager J. P. , Harvengt C.
Published: March 2013

The occurrence of clinical and biochemical side effects of bezafibrate (400 mg daily) or simvastatin (20 mg daily) alone or combined was appraised in 13 healthy male normolipidemic subjects according to a single blind design. Each period of 2 weeks of treatment with bezafibrate or simvastatin or bezafibrate plus simvastatin was followed by a period of placebo (1 week). No subjects experienced myalgia or muscle weakness. Plasma creatine kinase (CK) elevations, particularly skeletal muscle CK (CK‐MM), were observed in 6 subjects: 11 times during different placebo periods, 5 times on bezafibrate, 4 times on simvastatin, and 4 times on combined bezafibrate‐simvastatin, but never reached 1,600 IU/L. Only a trend to an increase of CK mean values on combined bezafibrate‐simvastatin was shown. The hepatic transaminase and gamma‐glutamyltransferase activities remained unmodified throughout the trial, unlike alkaline phosphatase activity, which fell on bezafibrate and on bezafibrate plus simvastatin. The low‐density lipoprotein cholesterol level was more reduced with simvastatin than with bezafibrate. The addition of bezafibrate to simvastatin did not decrease it further. Lecithin: cholesterol acyltransferase activity expressed as fractional esterification rate was enhanced only on simvastatin and bezafibrate‐simvastatin.
Effect of Age and Dose on the Incidence of Adverse Events in the Treatment of Hypertension in Patients Receiving Terazosin
Authors: Hosmane B. S. , Maurath C. J. , Jordan D. C. , Laddu A.
Published: March 2013

Selected adverse events were evaluated from the combined randomized placebo‐controlled clinical trials (once‐a‐day or twice‐a‐day; monotherapy or combination therapy) of terazosin in hypertensive patients. The designs of these clinical trials were either titration to response or titration to a fixed dose. A grouped survival methodology using logistic regression, developed by Hosmane et al, was used to study the effects of age and dose on the incidence of adverse events. The analysis indicated that except for palpitations, nausea, headache, and dizziness the incidence of adverse events was not significantly related to either age or dose. Palpitations and headache decreased with increasing age and increasing dose and age, respectively. Dizziness and nausea increased at the maximum dose of 20 mg, but not at the 5‐ or 10‐mg doses.
Inhaled Corticosteroids in Asthma: A Dose‐Proportionality Study with Triamcinolone Acetonide Aerosol
Authors: Zaborny B. A. , Lukacsko P. , Barinov‐Colligon I. , Ziemniak J. A.
Published: March 2013

The systemic exposure to triamcinolone acetonide (TAA) after inhalation of aerosolized drug has not been examined previously. This study evaluates the plasma concentrations, pharmacokinetics and dose proportionality of TAA after single oral inhalations at doses of 400, 800, and 1600 mcg. Nine moderately asthmatic male patients received each of the doses in a randomized crossover manner using a 1‐week washout period between dosing. Serial blood samples were collected for 10 hours postdosing for the determination of plasma TAA concentrations by using a specific radioimmunoassay. The pharmacokinetic profiles that were obtained showed slow and limited absorption over the first 4 hours after dosing followed by rapid elimination with a half‐life of approximately 2 hours (range: 1.8–2.3 hr). Comparison of pharmacokinetic parameters from each dose group showed excellent proportionality and consistent absorption for all patients. Mean Cmax values ranged from 0.51 ng/mL after the 400 mcg dose to 1.01 ng/mL and 1.97 ng/mL after the 800 and 1600 mcg doses, respectively. Mean AUC0–10 values for these same doses were 2.6 ng × hr/mL, 5.3 ng × hr/mL and 10.5 ng × hr/mL, respectively. The results suggest that systemic exposure to TAA is minimal after oral inhalation, occurs in a dose proportional fashion, and produces circulating plasma concentrations which are unlikely to have significant adverse systemic effects.
What Preclinical Data Are Needed to Justify Once‐Daily Therapy?
Authors: Bergeron Michel G.
Published: March 2013

Before applying in clinical practice once‐daily dosing of antimicrobials, one must take into consideration several factors that may influence the pharmacodynamic interaction between antimicrobials and microbes at the site of infection. The ideal agent should demonstrate rapid concentration‐dependent killing activity and a postantibiotic effect that could allow for a clinically significant delay with levels below the minimal inhibitory concentration before regrowth of the microorganism. The pharmacokinetic properties of the antibiotic should allow for a good therapeutic ratio (concentration/MIC) at the site of infection. To evaluate the importance of dosage schedule on outcome, investigators have to use animal models where peak levels, half‐life, area under the curve, time above MIC in interstitial fluid or infected tissues, and other pharmacodynamic properties can be evaluated simultaneously. The pharmacodynamics of several antibiotics administered at different dosing interval is compared using an animal model of infected fibrin clots. In this model, once‐daily therapy resulted in better killing than other modes of administration. Aminoglycosides and quinolones may be better suited for once‐daily therapy than β‐lactams unless these latter agents have a long half‐life.
Plasma Bactericidal Activity of a New C‐5 Methyl Fluoroquinolone After Oral Doses of 400 and 800 mg
Authors: Gu Jian‐wei , Fang Wei , Neu Harold C.
Published: March 2013

The plasma bactericidal activity of a new C‐5 methyl fluoroquinolone, OPC‐17116, was determined after once‐daily oral ingestion of 400 mg and 800 mg in normal, healthy volunteers. OPC‐17116 at a 400‐mg dose produced plasma bactericidal titers greater than or equal to 1:16 at 12 hours against Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Haemophilus influenzae, and Moraxella catarrhalis. OPC‐17116 bactericidal titers against Pseudomonas aeruginosa were 1:2 or 1:4 at 6 and 12 hours. The plasma bactericidal titers against Streptococcus pyogenes and Streptococcus pneumoniae were 1:4 or greater, but bactericidal titers against Staphylococcus aureus were 1:2 at 12 hours and <1:2 at 24 hours. The 800‐mg dose of OPC‐17116 produced bactericidal titers of at least 1:32 at 12 hours for the Enterobacteriaceae, Haemophilus, and Moraxella, and 1:4 for S. pyogenes and S. pneumoniae, but bactericidal titers against S. aureaus were 1:2. These data would suggest that an 800‐mg dose of OPC‐17116 taken orally once daily would provide adequate concentrations to treat infections due to the pathogens examined in this study.
Impact of Food on the Bioavailability of Encainide
Authors: Hilleman Daniel E. , Mohiuddin Syed M. , Destache Christopher J. , Stoysich Anne M. , Nipper Henry C. , Malesker Mark A.
Published: March 2013

The bioavailability of drugs that undergo extensive presystemic hepatic metabolism may be increased by concomitant ingestion with food. The effect of food on the bioavailability of encainide, a class IC antiarrhythmic agent, was evaluated in 14 healthy subjects in this randomized crossover study. The subjects received encainide 35 mg every 8 hours for 7 days and were randomized to receive their test dose of encainide with food or after an overnight fast Encainide area‐under‐the‐concentration versus time curve (AUCs) were detectable in 3 of 14 subjects after fasting and in 7 of 14 after feeding. Although food increased the mean encainide AUC by more than threefold, this increase did not reach statistical significance because of the large number of subjects with indeterminate encainide AUCs. Food did significantly increase the AUC of O‐demethyl‐encainide (ODB), but not the AUC of methoxy‐O‐demethyl‐encainide (MODE). Despite the increase in ODE AUC, no significant effect on the surface electrocardiogram 2 hours after dose administration could be detected. Food may increase the bioavailability of encainide and one of its active metabolites (ODE). The clinical relevance of this pharmacodynamic effect warrants farther evaluation.
Hypothyroidism Complicated by Angina Pectoris: Therapeutic Approaches
Authors: Ellyin Fredrick M. , Kumar Yoginder , Somberg John C.
Published: March 2013

The association of hypothyroidism and coronary artery disease is not uncommon. The precipitation of angina pectoris, cardiac arrhythmia, and even myocardial infarction may occur in patients when initiating rapid replacement therapy for hypothyroidism. This is particularly true when replacement therapy is instituted in elderly persons or in patients with preexisting coronary artery disease. A starting daily dose of 12.5 to 25 μg and increments of 25 μg every 2 to 3 weeks is recommended. Close monitoring of cardiac symptoms is essential to avoid side effects. Medical management of angina pectoris includes administration of beta‐blockers, nitrates, or at times combination antianginal therapy may be most effective. Persistence of angina in these patients may require coronary angiography with subsequent angioplasty or coronary artery bypass surgery.
A Comparison of Regulatory Approval Times for New Chemical Entities in Australia, Canada, Sweden, the United Kingdom, and the United States
Authors: Pieterson Elizabeth A.
Published: March 2013

Regulatory approval times of new chemical entities (NCEs) in Australia, Canada, Sweden, the United Kingdom (UK), and the United States (US) were compared. The approval times of a set of common 25 NCEs and a larger set of unmatched NCEs were very similar in Australia, Canada, Sweden, and the US, with median approval times from 23 to 29 months. The median approval time in the UK was approximately 11 months. Analysis of the data showed that the approval times in Australia, Sweden, and the UK were not significantly affected by the therapeutic classification of the drug, the amount of additional data requested and received, or the submission date. In Canada, the date the drug submission was received and the frequency of additional data requests significantly affected the approval times. In the US, the date the drug submission was received and the frequency of additional data received significantly affected the approval times. The therapeutic classification of the drug did not significantly affect the approval time in Canada or the US.
Advances in the Diagnosis of Adverse Drug Reactions
Authors: Naranjo Claudio A. , Shear Neil H. , Lanctôt Krista L.
Published: March 2013

The clinician plays a key role in the detection and diagnosis of adverse drug reactions (ADRs). The diagnosis of ADRs, however, is a complex task. In the past, there were no systematically applied diagnostic criteria for ADRs, no formal methods of case analysis, no standardized epidemiologic approaches, and a limited knowledge of mechanisms. This resulted in the overdiagnosis of ADRs, which has negative consequences such as limiting treatment options. Recently, there have been various improvements in the diagnosis of ADRs, such as the development of standardized decision aids and of in vitro diagnostic tests. This article briefly reviews some of this knowledge, discusses the role of in vivo and in vitro rechallenge, and summarizes a probabilistic approach for collecting relevant information and diagnosing ADRs. The intention is to increase awareness of the different approaches for diagnosing ADRs as well as to stimulate researchers to continue to collect pharmacoepidemiologic information, study the pharmacologic, immunologic, and genetic factors involved in the pathogenesis of drug reactions, and develop and test new diagnostic instruments under various clinical conditions.
Mirror Images: The Analysis of Pharmaceutical Enantiomers
Authors: Pasutto Franco M.
Published: March 2013

Pharmaceutical enantiomers often exhibit different pharmacodynamic and pharmacokinetic properties. Stereospecific chromatographic assays are available to separate these stereoisomers. Therapeutic agents often contain chemical functional groups (e.g. amino, hydroxyl, carbonyl, and carboxylic acid). These can be reacted with enantiomerically pure reagents to give diastereoisomers suitable for analysis on achiral gas chromatographic (GC) and high performance liquid chromatrographic (HPLC) columns. Alternatively, derivatized or underivatized drugs may be resolved on chiral chromatographic phases. A wide variety of GC (e.g. amino acid, cyclodextrin, and metal‐complex) and HPLC (mobile phase additive, crown ether, π‐π interaction and related phases, protein, cyclodextrin, polysaccharide, methacrylate and amide polymer, and ligand exchange) columns are commercially available. This article reviews the chromatographic separation of enantiomers.
The Importance of Stereochemistry in Drug Action and Disposition
Authors: PhD John Caldwell
Published: March 2013

Many biologically active synthetic drugs contain chiral centers, although they are used as racemic mixtures. Enantiomers are hard to distinguish in the chemical laboratory but are readily discriminated in the body and differ in their biological activities and disposition. The pharmacokinetic profiles of enantiomers can be variable, especially for drugs with a first‐pass effect and enantioselective pharmacokinetic monitoring should be carried out. Ultimately, whether to exploit a racemate or a single enantiomer in therapy is a multi‐faceted decision to which drug disposition data have important contributions to make.
Pure Enantiomers of 2‐Arylpropionic Acids: Tools in Pain Research and Improved Drugs in Rheumatology
Authors: Brune Kay , Geisslinger Gerd , Menzel‐Soglowek S.
Published: March 2013

The mode of action of aspirinlike drugs in pain is widely referred to as inhibition of prostaglandin synthesis. Salicylic acid, however, at low doses, is an analgesic hut not a potent anti‐inflammatory agent. This “enigma” may be resolved by recent findings employing 2‐arylpropionic acids. Pure enantiomers of these chiral drugs show a different pharmacodynamic and pharmacokinetic profile. Using pure enantiomers of flurbiprofen, ibuprofen, and ketoprofen, we could show that (1) R‐enantiomers of these drugs are inverted to S‐enantiomers to a different degree in different species, including humans, (2) the pharmacokinetic parameters of both pure enantiomers differ in a drug‐ and a species‐specific manner, and (3) both enantiomers exert differential analgesic effects. It appears particularly interesting that R‐flurbiprofen, for instance, which is not or only to a small extent inverted in humans and rats, is practically devoid of prostaglandin synthesis inhibition in vitro. Consequently, in line with current thinking, R‐flurbiprofen is not toxic to the gastrointestinal tract and shows no anti‐inflammatory effects. In contrast to current concepts, however, this enantiomer does exert analgesic activity in different models of pain and nociception. It is concluded that R‐flurbiprofen and, possibly, other R‐enantiomers of 2‐arylpropionic acids may exert novel analgesic effects independently of peripheral prostaglandin synthesis inhibition in inflamed tissue.
Postmarketing Surveillance: Curriculum for the Clinical Pharmacologist. Part I: Postmarketing Surveillance Within the Continuum of the Drug Approval Process
Authors: Johnson Joyce , Tanner L. Ann
Published: March 2013

This series of two articles on postmarketing safety surveillance has been developed for use in training clinical pharmacologists. It provides a basic overview useful to clinical pharmacologists in a range of occupational functions. These reports can be used as the basis for a lecture or as background reading material for establishing a unit on postmarketing surveillance. For teaching rounds, multiple illustrations and summary tables have been included. These can readily be made into 35‐mm slides or transparencies. Table I outlines the curriculum on postmarketing surveillance for the clinical pharmacologist. The first article describes postmarketing surveillance within the continuum of the drug approval process. The relationship of clinical trials to safety surveillance after drug approval are reviewed. The importance of spontaneous adverse drug experience reporting also is discussed. The second article focuses on the regulatory aspects of postmarketing surveillance and discusses the FDA's (Food and Drug Administration) Spontaneous Reporting System. The two types of adverse experience reports in the Spontaneous Reporting System are described: reports voluntarily submitted by health care providers and others, and reports manufacturers are required by regulation to submit. The clinical pharmacologist's role in postmarketing surveillance is defined.
In Vitro Activity of Ro 23–9424, a Dual‐Acting Cephalosporin‐Quinolone Antimicrobial Agent
Authors: Qadri S. M. Hussain , Ueno Yoshio , Saldin Hishama , Cunha Burke A.
Published: March 2013

In vitro activity of new dual‐acting antibacterial Ro 23–9429 was tested against 1294 bacterial isolates from patients in a major tertiary care referral hospital in Saudi Arabia. Its activity was compared with that of ciprofloxacin, fleroxacin, ampicillin, cephalothin, cefoxitin, cefotaxime, ceftazidime, piperacillin, oxacillin, gentamicin, amikacin, imipenem, and vancomycin. Of the 621 members of Enterobacteriaceae tested, every single isolate was inhibited by Ro 23–9429 at minimum inhibitory concentration ranging between <.03 and 8 μg/mL. No other antimicrobial tested was as active as this dual‐acting cephalosporin‐fluoroqinolone. Similarly, all of the 255 isolates of Acinotobacter, Aeromonas hydrophila, Pseudomonas aeruginosa, and Xanthomonas maltophilia were susceptible to Ro 23–9429. It inhibited all the 120 isolates of methicillin‐resistant Staphylococcus aureus. Its in vitro activity against coagulase‐negative staphylococci and enterococci was superior or comparable to that of other drugs that are commonly used in clinical practice.
Concentration‐Dependent Protein Binding of a Novel Oral Thromboxane Synthase Inhibitor—FCE 22,178
Authors: Li Ronald C. , Rossi David T. , Narang Prem K.
Published: March 2013

The protein binding of FCE 22,178 in humans was determined ex vivo by equilibrium dialysis using plasma samples obtained from a dose‐ranging study in normal male volunteers. These data suggested that FCE 22,178 may exhibit concentration‐dependent protein binding over an in vivo concentration range of .8 to 64 μg/mL. Increase in free fraction at higher plasma drug concentrations corresponded directly to the dose‐dependent increase in renal drug clearance. Nonlinear parameter estimation showed that FCE 22,178 binds tightly to plasma proteins with an apparent equilibrium association constant of 1.44 × 105 mol/L. Predicted change in the free fraction is consistent with the observed changes in renal clearance.
Clinical Evaluation of H1‐Receptor and H2‐Receptor Antagonists for Acute Postoperative Pain
Authors: Berthold Charles W. , Dionne Raymond A.
Published: March 2013

The acute analgesic activity of an Histamine antagonist, terfenadine 60 mg, and an H2‐histamine antagonist, ranitidine 150 mg, were compared with ibuprofen 600 mg and placebo in a double‐Mind, placebo‐control Jed, parallel‐group study. Treatments were administered to a total of 127 patients 1 hour before oral surgery. Analgesia was assessed every 30 minutes for 240 minutes after surgery. Analgesic efficacy was compared using the following standard pain intensity scales: visual analog scale, category, graphic rating, and global evaluation. Ibuprofen was significantly better than all other treatments for all measures of analgesic activity. The effects of terfenadine and ranitidine were similar to placebo. These data indicate that pretreatments with a single dose of a histamine receptor antagonist specific for either the H1‐ or H2‐receptor does not produce analgesia in an oral surgery model of acute pain with overall assay sensitivity, suggesting that antihistamines that act primarily at peripheral sites are devoid of analgesic activity. These data contrast with other studies that have demonstrated analgesia using centrally acting antihistamines such as hydroxyzine, phenyltoloxamine, or orphenadrine.
Selectivity of Acebutolol, Atenolol, and Metoprolol in Healthy Volunteers Estimated by the Extent the Drugs Occupy β2‐Receptors in the Circulating Plasma
Authors: Kaila Timo , Iisalo Esko
Published: March 2013

The selectivity of acebutolol, atenolol, and metoprolol in healthy volunteers was estimated by determining the extent to which the drugs occupied β1‐receptors of rabbit lung and β2‐receptors of rat reticulocytes in the circulating plasma after drug intake. This ex vivo method had the advantage of including all drug components contributing to the drug‐receptor equilibrium in vivo and of excluding the factors regulating organ sensitivity to catecholamine stimulation. The oral doses of 400 mg acebutolol 100 mg atenolol, and 100 mg metoprolol were administered to six healthy male volunteers using a double‐blind, randomized, and cross‐over study design. The three drugs occupied β1‐receptors to a similar extent at 2 hours after drug intake. The receptor fraction occupied by metoprolol at 3 to 8 hours after drug intake was usually smaller, however (analysis of variance for repeated measures, P < .05) than that of the other drugs. Acebutolol occupied significantly larger fractions of β2‐receptors (analysis of variance for repeated measures, P < .05) than did atenolol and metoprolol. Therefore, at an identical β1‐receptor occupancy, the β2‐receptor occupancy of acebutolol was larger than that of the other agents. Apparently, active metabolites decreased markedly the selectivity of acebutolol, but not that of metoprolol. The receptor occupancy of the agents was well in agreement with the literature concerning the selectivity, intensity, and time‐course of drug actions after identical doses. Concluding, atenolol is slightly more selective than metoprolol and metoprolol is markedly more selective than acebutolol in the doses studied when estimated by the extent to which the drugs occupy β1‐ and β2‐receptors in the circulating plasma.
Finasteride, A Steroid 5α‐Reductase Inhibitor, Does Not Affect the Oxidative Metabolism of Antipyrine
Authors: Winchell G. A. , Gregoire S. , Taylor A. M. , Hegland J. , Hunninghake D. B.
Published: March 2013

A single‐blind study was conducted to investigate the effect of multiple doses of finasteride, a 5α‐reductase inhibitor for the treatment of benign prostatic hyperplasia, on the single‐dose pharmacokinetics of antipyrine. Twelve patients with benign prostatic hyperplasia received a total of four single oral doses of 18 mg/kg antipyrine before, during, and after treatment with 10 mg/day of finasteride for 28 days. Finasteride had no effect on antipyrine concentration profiles. There were also no changes in urinary excretion of three principal antipyrine metabolites. A slight increase in renal clearance of antipyrine was observed; however, this is not considered relevant because excretion of unchanged antipyrine represents a minor fraction of total elimination and is not directly related to oxidative metabolism. These results imply that significant interactions between finasteride and drugs metabolized by these cytochrome P‐450 enzymes are unlikely.
Assessment of Blood Pressure During Treatment with Naproxen or Ibuprofen in Hypertensive Patients Treated with Hydrochlorothiazide
Authors: Klassen David , Goodfriend Theodore L. , Schuna Arthur A. , Young Donald Y. , Peterson Craig A.
Published: March 2013

This study determined the effect of nonsteroidal anti‐inflammatory drug (NSAID) administration on blood pressure in hypertensive patients taking hydrochlorothiazide (HCTZ). Ninety‐seven patients with mild essential hypertension and a musculoskeletal indication for NSAID use were studied in a three‐phase, multi‐center, double‐blind, randomized, parallel study based in 15 academic and community clinics. Patients served as their own controls. Patients with stable hypertension, not taking antihypertensive or NSAID medications, were treated with HCTZ 50 mg/day. After 4 to 5 weeks of treatment and documented stable blood pressure, naproxen 375 mg twice a day or ibuprofen 800 mg three times a day was added. Blood pressure was measured at 2 and 4 weeks of NSAID therapy. The average diastolic blood pressure was 97.5 ± 2.4 mm Hg and the average of the mean arterial pressure (MAP) was 116.8 ± 6.04 before treatment with HCTZ. Hydrochlorothiazide treatment decreased diastolic blood pressure to 83.1 ± 5.6 mm Hg, and MAP to 101.1 ± 6.5 mm Hg. With naproxen or ibuprofen treatments, mean diastolic blood pressure increased less than 3 mm Hg. At 2 weeks, ibuprofen increased diastolic blood pressure by 2.6 mm Hg (P = .004) and naproxen increased diastolic blood pressure 0.7 mm Hg (P = .40). Both ibuprofen and naproxen significantly increased diastolic pressure at 4 weeks (2.1 mm Hg, P = .042; and 1.8 mm Hg, P = .043, respectively). There was no correlation between the pre‐NSAID blood pressure and the magnitude of change after 2 or 4 weeks of treatment. Changes in MAP reflected a pattern similar to diastolic pressure. Ibuprofen increased MAP 3.6 mm Hg (P < .001) and 2.7 mm Hg (P = .019) at 2 and 4 weeks, respectively. Naproxen increased MAP 1.1 mm Hg (P = .29) and 1.5 mm Hg (P = .16) at 2 and 4 weeks, respectively. Patient weight increased 1.0 kg (P < .001) and 0.9 kg (P < .001) with ibuprofen and 0.3 kg (P = .24) and .5 (P = .12) with naproxen at 2 and 4 weeks, respectively. Comparing naproxen and ibuprofen treatments, there were no significant differences in blood pressure or body weight changes. In patients with mild essential hypertension controlled with a thiazide diuretic, the concurrent use of either naproxen or ibuprofen resulted in small but statistically significant increases in blood pressure.
Ketoprofen Pharmacokinetics in the Elderly: Influence of Rheumatic Disease, Renal Function, and Dose
Authors: Skeith Kenneth J. , Russell Anthony S. , Jamali Fakhreddin
Published: March 2013

An age‐related accumulation of ketoprofen due to a reduced clearance has been reported in the elderly. Other studies have not observed these changes in the kinetics of unchanged ketoprofen, but have reported increased plasma levels and reduced urinary excretion of conjugated ketoprofen. The authors examined the effects of dose, renal function, and the presence of arthritis on the stereoselective kinetics of ketoprofen in five nonarthritic and six arthritic elderly subjects. There was a significant difference in renal function (CLCr, mL/min; arthritic, 71.8 ± 12.3, nonarthritic, 91.4 ± 11.1), but not in age or weight between the two groups. Subjects received 50 mg and then 150 mg enteric‐coated racemic ketoprofen, and plasma and urine samples were collected for 24 hours. No significant differences in CL/F, area under the curve (AUC), half‐life (t1/2), time to reach peak concentration (tmax), or maximum peak plasma concentration (Cmax) were found between groups or between doses, and values were similar to those previously reported in young adults. Urinary ketoprofen conjugate (S:R) ratio was 1.6 ± .25 and 1.65 ± .27 for arthritic and nonarthritic subjects. Greater amounts of conjugated ketoprofen enantiomers were present in the plasma of the arthritic compared with nonarthritic subjects. Renal clearance of ketoprofen conjugates exhibited stereoselectivity (R > S), and was decreased in the arthritic group. Significant changes in the kinetics of unchanged ketoprofen was not found to occur in elderly subjects in the presence or absence of rheumatic disease or moderate renal impairment. Dosage adjustments in the elderly based on age alone may not be necessary.
Selective Alpha‐1 Adrenoceptor Blockade and Renal Sodium Handling in Humans
Authors: Penner S. Brian , Stanko Carmen K. , Smyth Donald D.
Published: March 2013

In animal studies, acute interruption of the activity of renal alpha‐1 adrenoceptors by renal denervation results in an increase in sodium and water excretion. Chronic selective blockade of alpha‐1 adrenoceptors by prazosin in clinical practice has been associated with sodium retention, however. Previous studies in the authors' laboratory using chronic alpha‐1 blockade in the rat have demonstrated a decreased ability to excrete a saline load. Therefore, the authors determined the effect of chronic selective alpha‐1 adrenoceptor blockade with prazosin in eight healthy volunteers. Volunteers underwent a water load to establish a water diuresis, followed by a modest saline load using intravenous saline (0.9% NaCl). This experimental protocol was repeated after four weeks of prazosin therapy (5 mg twice daily). Prazosin failed to alter body weight (73.6 ± 4.2 versus 74.5 ± 4.1 kg, expressed as mean ± standard error), mean blood pressure (86.7 ± 2.7 versus 84.7 ± 2.3 mm Hg), creatinine clearance (127.0 ± 8.5 versus 133.4 ± 12.0 mL/min), renal blood flow as measured by para‐aminohippurate clearance (1202 ± 88 versus 1175 ± 69 mL/min) and the 24‐hour sodium excretion (115 ± 11 versus 128 ± 19 mmol). In the presence of the experimentally induced saline load, chronic prazosin treatment was associated with a decreased free water clearance (e.g., hour 3, 7.8 ± .7 versus 6.3 ± 2.0 mL/min; P ≤ .05) and fractional excretion of sodium (e.g., hour 3, 1.48 ± .10 versus 1.15 ± .13; P ≤ .05). The cumulative sodium excretion of the four 1‐hour urine collection periods during and after the saline infusion was decreased after the prazosin treatment (79.4 ± 7.8 versus 64.1 ± 6.1 mmol/4 hours; P ≤ .05). These results demonstrate that in normal volunteers, selective alpha‐1 adrenoceptor blockade with prazosin decreases the ability to excrete a modest saline load. These observations may explain, in part, the sodium retention observed clinically with chronic prazosin treatment.
Bioequivalence of a 17β‐Estradiol Hydroxypropyl‐β‐Cyclodextrin Complex in Postmenopausal Women
Authors: Hoon Timothy J. , Dawood M. Yusoff , Khan‐Dawood Firyal S. , Ramos Josefina , Batenhorst Randal L.
Published: March 2013

Five postmenopausal women received single doses of a 0.675 mg estradiol hydroxypropyl‐β‐cyclodextrin (estradiol‐HPβCD) sublingual tablet by the sublingual and oral route. A single dose of a 1 mg micronized estradiol tablet was given orally for comparison. Blood samples were obtained over 48 hours for measurement of estradiol, estrone, luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) concentrations. Sublingual administration produced faster and significantly higher peak estradiol concentrations than after oral administration of either estradiol‐HPβCD or micronized estradiol. The concentration‐time area under the curve of estradiol after sublingual estradiol‐HPβCD was also significantly larger than after oral administration of either estradiol‐HPβCD or micronized estradiol, reflecting a larger estradiol bioavailability. The estradiol/estrone concentration ratio after sublingual estradiol‐HPβCD revealed a predominance of estradiol for the first 2 hours after the dose, followed by an estrone predominance. Both oral doses produced a predominant delivery of estrone to the systemic circulation. There was no difference in time‐averaged LH suppression between the three phases. However, estradiol‐HPβCD sublingually produced greater FSH suppression than oral micronized estradiol.
Carryover Bias in Clinical Investigations
Authors: Cleophas Ton J. M.
Published: March 2013

If the effect of a treatment continues after the treatment is withdrawn then the response to a second treatment may well be due in part to the previous treatment. This, so called, carryover effect may bias any type of study in which subjects are tested more than once. Crossover studies can be routinely checked for this bias. In other study designs, however, common sense and alertness for unusual patterns in the data are the only defenses against it. The amount of carryover bias can be somewhat minimized by the following measures. Dose‐response studies, dose‐titration studies, and open‐evaluation studies should require a sufficient washout period between the administrations of drugs. The use of duplicate standard deviations for the estimation of intraindividual reproducibility of a test should always be combined with a statistical test for differences between the duplicate data. Subjective variables, which are frequently influenced by psychologic carryover effects, should be validated together with objective variables whenever possible. In spite of these measures, many cases of carryover effect remain unpreventable. We shall simply have to accept them.