bluuebunny/crossref_metadata_2025 huggingface dataset:
Adverse Dermatologic Reactions from Antiarrhythmic Drug Therapy
Authors: Sun Diana K. , Reiner David , Frishman William , Grossman Marc , Luftschein Stanley
Published: March 2013

Undesirable cutaneous reactions to drugs may occur early or late in the course of treatment. The ingestion of drugs may also aggravate existing dermatologic conditions. The adverse dermatologic reactions from antiarrhythmic drug therapy are reviewed. The exact incidence of dermatologic side effects from cardiovascular drugs has been difficult to estimate because of sporadic reporting. In this review, the cutaneous side effects are discussed according to drug class and the type of dermatologic reaction.
Disposition of Lorazepam in Gilbert's Syndrome: Effects of Fasting, Feeding, and Enterohepatic Circulation
Authors: Herman Robert J. , Chaudhary Archana , Szakacs Cameron B.
Published: March 2013

The effects of fasting and feeding of a high‐carbohydrate, low‐fat diet on the glucuronidation and enterohepatic circulation (EHC) of lorazepam were examined in seven healthy men (age 18–30 years) and seven matched patients with Gilbert's syndrome. A simultaneous intravenous/oral dosing regimen was used, with half of each group receiving treatment with neomycin and cholestyramine (neo/chol) to block the EHC of the drug. Feeding increased the clearance of free lorazepam from 10.96 ± 0.56 (mean ± SD) to 14.11 ± 1.21 mL/min/kg (P = 0.05) in patients with Gilbert's syndrome when examined in the presence of neo/chol. Clearances, on the other hand, decreased with feeding in control Gilbert's patients (7.61 ± 0.54 versus 8.82 ± 0.48 mL/min/kg), although the differences were not significant (P = 0.09). In contrast to both of these groups, feeding decreased lorazepam clearances (13.33 ± 0.32 to 12.45 ± 0.52 mL/min/kg, P = 0.17) in neo/chol‐treated normals and increased clearances (9.95 ± 1.84 to 12.38 ± 2.05 mL/min/kg, P = 0.04) in control normals. Lorazepam clearances were also 20–40% lower in patients with Gilbert's syndrome compared with normals when studied fasting and with neo/chol, or fed and in the control state (P < 0.05 for both). Thus, the glucuronidation and EHC of lorazepam is sensitive both to diet and to the presence or absence of the Gilbert's trait.
Phase I Study of E1077, a Novel Parenteral Cephem Antibiotic
Authors: Nakashima Mitsuyoshi , Uematsu Toshihiko , Nagashima Satoru , Inaba Hiroshi , Hirasawa Takihiro , Tomono Yoshiro , Ohno Toshiro , Okano Keiko , Morishita Nobumichi
Published: March 2013

The safety and pharmacokinetics of E1077, a new injectable cephem antibiotic, were evaluated in healthy male adult volunteers. In the single‐dose studies, 100, 250, 500, 1,000, and 2,000 mg of E1077 were administered by intravenous infusion at a constant rate for 60 minutes, then 1,000 mg of the drug by intravenous infusion at a constant rate for 5 minutes. The Cmax were 6.4, 15.7 ± 12.0, 34.7 ± 4.6, 63.2 ± 4.6, 142.7 ± 5.6, and 131.6 ± 36.0 (means ± SD) μg/mL, respectively, and the Cmax and AUC increased linearly with the dose. Plasma concentration‐time curves were well described by a two‐compartment open model. The plasma elimination half life of the drug was 1.88 ± 0.15 hours. The mean urinary recovery within the first 24 hours was 94.1 ± 5.1% of the dose. In the multiple‐dose study, 2,000 mg of E1077 was intravenously administered at a constant rate over 60 minutes every 12 hours for 4.5 days (a total of nine times). The Cmax after the first and ninth doses were 134.0 ± 17.4 and 135.5 ± 15.5 μg/mL, respectively, and trough levels in day 1 and day 5 (at 12 hours after the first and ninth administration, respectively) were 2.2 ± 0.8 and 1.9 ± 0.4 μg/mL, respectively. No accumulation of the drug in plasma was observed. There were no significant differences in plasma levels or in urinary recoveries between the single‐ and multiple‐dose regimens. The ratio of the concentrations of the diastereomers of A and B forms measured in the plasma or urine at each point of measurement was equal to that of the standard sample, and no difference was observed in the pharmacokinetics of E1077 between the two diastereomers. The fraction of the drug bound to plasma protein was independent of the total plasma concentration and was calculated as 14.5 ± 2.9%. There were no subjective or objective abnormal findings definitely related to the drug, except that two subjects reported mild feelings of sickness during the infusion.
Pharmacokinetics of Intravaginal Metronidazole Gel
Authors: Cunningham Francesca E. , Kraus Donna M. , Brubaker Linda , Fischer James H.
Published: March 2013

The pharmacokinetics of a single 500 mg oral dose of metronidazole and 5 g of 0.75% metronidazole intravaginal gel (37.5 mg metronidazole) were compared in 12 adult volunteers in a randomized crossover manner. Serial serum samples were collected over a 48‐hour period and analyzed for metronidazole and hydroxymetronidazole. Metronidazole serum concentrations after intravaginal administration were only 2% of concentrations seen with the standard 500‐mg oral dose. The dose‐adjusted maximum serum concentration (898 ± 121 ng/mL vs. 237 ± 69 ng/mL) and area under the serum concentration—time curve (9362 ± 2873 ng * hr/mL vs. 4977 ± 2671 ng * hr/mL) were significantly greater for the oral versus intravaginal dose of metronidazole. The time to reach maximum concentration (1.4 ± 0.6 hr vs. 8.4 ± 2.2 hr) was significantly shorter for the oral compared with the intravaginal dose. The mean bioavailability for the intravaginal gel was 56%. Our results show that the 0.75% gel formulation may offer the advantage of fewer systemic adverse effects compared with other formulations for the treatment of bacterial vaginosis.
Pharmacokinetics of Sparfloxacin in Humans After Single Oral Administration at Doses of 200, 400, 600, and 800 mg
Authors: Montay G. , Bruno R. , Vergniol J. C. , Ebmeier M. , Roux Y. Le , Guimart C. , Frydman A. , Chassard D. , Thebault J. J.
Published: March 2013

The pharmacokinetics of sparfloxacin at oral doses of 200, 400, 600, and 800 mg were studied in 12 healthy volunteers in a randomized double‐blind crossover study. Each dose administration was separated by a 1‐week washout period. Plasma and urine samples were collected up to 120 hours postdosing, for determination of free and total (free plus glucurono‐conjugated) sparfloxacin levels by high‐performance liquid chromatography assay and ultraviolet detection. Mean Cmax values ranged from 705 ± 158 to 1966 ± 620 ng/mL for the 200 to 800 mg doses, at median tmax ranging from 4 to 5 hours. A slight decrease of sparfloxacin bioavailability with increasing dose was observed because AUC was 87% to 88% of the expected area when the dose was doubled. The elimination half‐life values were constant over the dose range (with values ranging from 18 to 21 hours) as well as the renal clearance. The metabolic ratio conjugated/free drug was not modified by increasing dose.
Comparison of the Inhibition of Dietary Fat Absorption by Full Versus Divided Doses of Orlistat
Authors: Hussain Yasmin , Güzelhan Claudia , Odink Jacobus , van der Beek Eric J. , Hartmann Dieter
Published: March 2013

Orlistat is a potent and selective inhibitor of gastrointestinal lipases. The drug is designed for the treatment of obesity. The effect on dietary fat absorption of orlistat after administration of divided doses spread over 2 hours from mid‐meal, in comparison with that after administration of a full dose mid‐meal, was investigated in a randomized, single‐blind study including 16 hospitalized healthy males. After a 5‐day run‐in, to accustom the subjects to a diet of 2350 kcal and 76 g fat per day and to establish baseline fecal fat excretion, subjects received, in two parallel groups of eight over 8 days, three times a day 80 mg orlistat at mid‐meal, and placebo at mid‐meal and 0.5, 1, and 2 hr after mid‐meal (group A), or placebo at mid‐meal, and 20 mg orlistat at mid‐meal and 0.5, 1, and 2 hr after mid‐meal (group B). Feces were collected to measure total fat excretion. The mean (SD) of fecal fat in percent of dietary fat, after deduction of pretreatment fecal fat, was (%) 36.1 (4.2) and 37.0 (9.3) in groups A and B, respectively. Changing the mode of administration of orlistat, within the dose regimens investigated, does not affect its pharmacologic efficacy.
Diuretic Effects, Pharmacokinetics, and Safety of a New Centrally Acting Kappa‐Opioid Agonist (CI‐977) in Humans
Authors: Reece Phillip A. , Sedman Allen J. , Rose S. , Wright D. Scott , Dawkins Raymond , Rajagopalan Rukmini
Published: March 2013

The diuretic effects, pharmacokinetics, and safety of CI‐977, a new centrally acting selective kappa‐opioid agonist, were determined in 16 healthy subjects. Subjects received single intramuscular doses of CI‐977 (5, 15, or 25 μg) or placebo 1 week apart according to a randomized, double‐blind, placebo‐controlled, four‐period, crossover design. Serial blood and urine specimens were collected after each dose. Significant dose‐related decreases in negative free water clearance and urine osmolality and increases in urine volume were observed after administration of 15‐ and 25‐μg doses of CI‐977. CI‐977 had no effect on urine electrolyte excretion or serum antidiuretic hormone. Absorption of CI‐977 was rapid with individual tmax values ranging from 0.17 to 1.5 hours. Cmax and AUC(0‐∞) increased proportionally with dose. Individual elimination half‐life values ranged from 0.6 to 3.3 hours and were independent of dose. Changes in free water clearance were related to CI‐977 Cmax (r2 = 0.29, P = 0.0001) and AUC(0–4 hr) (r2 = 0.32, P = 0.0001) values. The most frequently reported adverse events after CI‐977 administration were dizziness, fatigue, paresthesia, headache, vasodilatation (facial flushing), emotional lability, high feeling, and abnormal thinking. The frequency and intensity of adverse events increased with increasing CI‐977 dose. In conclusion, CI‐977 Cmax and AUC(0‐∞) increased in proportion to dose over the range of 5 to 25 μg; decreases in negative free water clearance were related to CI‐977 dose and Cmax and AUC(0–4 hr) values; and the frequency and intensity of adverse events increased with increasing CI‐977 dose.
Disposition of Clozapine and Desmethylclozapine in Schizophrenic Patients
Authors: Lin Shih‐Ku , Chang Wen‐Ho , Chung Ming‐Cheng , Lam Y. W. Francis , Jann Michael W.
Published: March 2013

The disposition of the atypical clozapine and its desmethyl metabolite were evaluated in fourteen male chronic patients. A single 100 mg dose of clozapine was administered and blood sampling performed over the following 72 hours. The mean (SD) oral clearance and half‐life of clozapine were 55.4 (29.7) L/hr and 13.7 (9.9) hours, respectively. The mean (SD) AUC for clozapine and desmethylclozapine was 2389.9 (1406) and 751.1 (622.9) ng ·; hr/mL, respectively. The elimination of the metabolite is rate limited by its formation from cloza‐pine. A wide interpatient variability in clozapine and desmethylclozapine pharmacokinetics was observed.
Angiotensin‐Converting Enzyme Inhibition Increases Exercise Tolerance and Muscle Blood Flow in Rats with Peripheral Arterial Insufficiency
Authors: Yang H. T. , Terjung Ronald L.
Published: March 2013

To determine the effect of angiotensin‐converting enzyme (ACE) inhibition on exercise tolerance and muscle blood flow (BF) to ischemic limbs, both femoral arteries of male Sprague‐Dawley rats (≅325 g) were surgically stenosed. Rats were either active (treadmill run, 20 m/min @ 15% grade, 5 d/wk for 3 wk) or sedentary (limited to cage activity), and assigned to one of three doses of zabicipril at 0.0 (zero), 0.3 (low), and 3.0 (high) mg · kg−1 · d−1 administered via food intake (N=14–15/group). After 3 weeks, the left carotid and caudal arteries were catheterized under anesthesia for BF measurement later in the day. Muscle BF was determined during exercise at two treadmill speeds (20 and 30 m/min) with 85Sr and 141Ce labeled microspheres to ensure a peak BF. Plasma ACE was inhibited 31%, 65% in the low‐ and high‐dose sedentary rats and 75%, 74% in the low‐ and high‐dose active animals, respectively (P < 0.001). Angiotensin‐converting enzyme inhibition improved exercise tolerance by 3 weeks, at a low speed (20 m/min) in the sedentary groups (P < 0.025) and in a dose‐dependent manner at a higher speed (25 m/min) in the active groups (P < 0.001). Blood pressures and heart rates during running were not different among groups. However, total hindlimb BF, reduced to approximately 33% of normal by femoral stenosis, was increased by ACE inhibition and chronic activity in a dose‐dependent manner (P < 0.025). Blood flows to the plantar flexors were most improved (≅20–40%; to 124 mL · min−1 · 100 g−1) in the high‐dose groups (P < 0.01). The higher run speed did not increase BF above the low speed. Training adaptation, indicated by an enhanced muscle mitochondrial content (P < 0.001), was similar for low‐ and high‐dose active animals. Our results indicate that ACE inhibition improves BF to ischemic muscles and, together with chronic physical activity, improves exercise tolerance. The results from this study support those advocating ACE inhibition in managing appropriate patients with peripheral arterial insufficiency.
Telehygiene System for Preventive Chronopharmacology in Space
Authors: Halberg Franz , Cornélissen Germaine , Bingham Christopher , del Pozo Francisco , Arredondo Maria Teresa , Otsuka Kuniaki , Quadens Olga , Breus Tamara , Rapoport Semyon , Komarov Feodor
Published: March 2013

A remote computerized health care (telehygiene) system for space travel includes monitoring devices and pharmaceuticals aimed at the optimization of health and the environment. Early risk indicators are provided by dynamic characteristics of rhythms of several frequencies describing variation inside the physiologic range. These rhythm characteristics, assessed as one goes, can be updated and compacted as data accumulate by the use of chronobiologic software that resolves anticipated components of lower and lower frequency, thus providing summaries of data at intervals of differing length. At any time, harbingers of risk, including characteristics of circannual rhythms, can be retrieved in an instant. On their basis, early preventive action can be instituted for risk lowering and for delivery of timed treatment when needed. Preventive or curative health care in space and terrestrial spin‐offs are the more effective the more of the chronome (time‐structure) is resolved.
Comparing the Effects of Two In‐Flight Aerobic Exercise Protocols on Standing Heart Rates and VO2peak Before and After Space Flight
Authors: Siconolfi Steven F. , Charles John B. , Moore Alan D. , Barrows Linda H.
Published: March 2013

The effects of regular aerobic exercise on orthostatic tolerance have been the subject of a long‐standing controversy that will influence the use of exercise during space flight. To examine these effects, astronauts performed continuous (CE) aerobic exercise (n = 8), interval (IE) aerobic exercise (n = 4), or no (NE) exercise (n = 5) during flights of 7 to 11 days. Heart rate (HR) responses to an orthostatic challenge (stand test) were measured 10 days before flight and on landing day. V̇O2peak (graded treadmill exercise) was measured 7 to 21 days before and 2 days after flight. No significant differences across the groups were observed in standing HRs before or after flight. However, the within‐group mean HRs significantly increased in the NE (71–89 beats/min) and CE (60–85 beats/min) groups after space flight. The HRs for the IE group did not significantly increase (75–86 beats/min) after space flight. V̇O2peak decreased (P < .05) in the NE (‐9.5%) group, but did not change in the CE (‐2.4%) and IE (1%) groups. The relationship (r = 0.237) between the ΔHR and ΔV̇O2peak was not significant. These preliminary results indicate that: (1) continuous exercise does not affect the orthostatic HR response after space flight; (2) interval exercise may minimize an increase in the postflight orthostatic HR; and (3) both exercise protocols can maintain V̇O2peak.
Etiologic Significance of Arginine Vasopressin in Motion Sickness
Authors: Cheung Bob S. K. , Kohl Randall L. , Money Ken E. , Kinter Lewis B.
Published: March 2013

There is abundant evidence implicating the role of arginine vasopressin in motion sickness. The effects of AVP analogs on motion sickness were investigated in squirrel monkeys. Two specific V1 antagonists (SK&F 100273 and SK&F 103561) and three mixed V1/V2 antagonists (SK&F 101926, SK&F 105494, and SK&F 104146‐D) were tested on six highly susceptible monkeys. Intravenous injections of 200 ug of a V1 antagonist abolished emesis in all six monkeys, and few prodromal symptoms remained (latency to emesis > 120 minutes, P < .001). Mixed V1/V2 antagonists failed to abolish emesis in all monkeys. However, there was a slight increase in the latency to the first bout of emesis/retching with the mixed antagonists when compared with the baseline. The dose‐response relationship and rate of onset of action of the V1 antagonists (SK&F 100273) were explored. Latency to the first bout of emesis/retching increased to about twice that of the baseline when half of the effective antiemetic dose was used. The efficacy demonstrated by the specific V1 antagonists indicates that V1 receptors may modulate emesis.
Small Animal Model of Weightlessness for Pharmacokinetic Evaluation
Authors: Feldman Stuart , Brunner Lane J.
Published: March 2013

As the United States seeks a greater presence in space, physiologic changes associated with space flight become of greater concern. Exposure to a weightless environment has been shown to have numerous effects on body composition and organ function. Alterations include decreases in muscle and liver mass, changes in bone structure and integrity, and fluid shifts markedly affecting cardiovascular functioning. Furthermore, metabolic activity of the liver has been found to be altered in rats after extended periods of weightlessness. As the length of space travel increases, the probability for the need to administer pharmacologic agents to crew members during space flight for prophylaxis or treatment becomes greater. Thus, because of the observed physiologic and metabolic changes associated with weightlessness, it is reasonable to assume that the pharmacokinetics and pharmacodynamics of xenobiotics administered during space flight may be different that those found in 1g environment. To address these possible changes, the development of a model of weightlessness to investigate possible alterations in drug pharmacokinetics and pharmacodynamics before space flight is of importance. The tail‐suspended rat is a well‐described model of weightlessness. During the time of the suspension, the pharmacokinetics of marker compounds can be used to evaluate changes in hepatic and renal physiology. Rats suspended for different periods allow for the investigation of the length of weightlessness exposure and drug pharmacology. Results from the use of the suspended rat model provide valuable information regarding possible pharmacokinetic and pharmacodynamic changes associated with weightlessness, and therefore, provide space biomedical researchers with a method of investigating drug administration during space flight missions.
Application of Physiologically Based Pharmacokinetic Models for Assessing Drug Disposition in Space
Authors: Srinivasan R. Srini , Bourne David W. A. , Putcha Lakshmi
Published: March 2013

Exposure to weightlessness induces physiologic changes that may lead to pharmacokinetic and pharmacodynamic alterations of drugs administered to crew members in flight. Preliminary data from flight and ground‐based studies indicate that pharmacologically significant changes occur in the kinetics of medications given in weightlessness and in simulated microgravity (head‐down bed rest). Conducting flight studies on all available medications to identify the changes in their pharmacokinetic behavior in weightlessness is not feasible. An alternative approach for obtaining such information is to use computer simulations employing physiologically based pharmacokinetic (PBPK) models. Information thus obtained would be helpful in predicting the therapeutic effectiveness of medications in space, and also in developing plans for flight studies. This paper presents a brief review of relevant physiologic factors and pharmacokinetic implications of space flight, and includes a preliminary PBPK model for estimating plasma concentration‐time profiles of acetaminophen under different experimental conditions.
Ultra‐Long‐Duration Local Anesthesia Produced by Injection of Lecithin‐Coated Tetracaine Microcrystals
Authors: Boedeker Ben H. , Lojeski Edwin W. , Kline Mark D. , Haynes Duncan H.
Published: March 2013

This study was designed to determine if microencapsulated tetracaine would provide a longer duration of local anesthesia than nonmicroencapsulated (neat) tetracaine. Local anesthesia was determined by monitoring the response of the rat to tail clamping after the installation of a subcutaneous ring block. Ten percent microencapsulated tetracaine was found to provide local anesthesia of the tail for a 43‐hour duration. Ten percent tetracaine solution was toxic. One percent tetracaine solution provided a tail block lasting 8 hours. Lecithin membranes without drug provided no block. This study demonstrates that lecithin‐coated tetracaine microcrystals produce a local anesthetic effect that is ultra‐long in duration, reversible, and not systemically toxic.
Pharmacokinetics of Valproate After Multiple‐Dose Oral and Intravenous Infusion Administration: Gastrointestinal‐Related Diurnal Variation
Authors: Hussein Ziad , Mukherjee Debu , Lamm Janet , Cavanaugh John H. , Granneman G. Richard
Published: March 2013

A randomized, crossover study was conducted in healthy male volunteers to assess the diurnal variation in the steady‐state pharmacokinetics of valproate after multiple 250‐mg oral and intravenous infusion doses after an intravenous 750‐mg loading dose. Multiple blood samples were collected throughout each 168‐hour study period, and plasma valproate concentrations were quantitated using a gas chromatographic technique. Within‐regimen comparisons indicated statistically significant differences for mean steady‐state peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration‐versus‐time curve (AUC) between the second and third doses on day 4 after oral dosing, indicating a diurnal variation in the rate of valproate absorption from the delayed‐release tablet preparation. Between‐regimen steady‐state comparisons of pharmacokinetic parameters revealed some significant differences in mean time to Cmax (Tmax), Cmax, Cmin, AUC, and total body clearance for respective day‐4 dosing intervals, but not for the entire day 4, except for Cmin and Tmax. Mean elimination rate constant and half‐life did not significantly differ between the regimens. The regimens were bio‐equivalent at steady state, as assessed by 90% confidence intervals (two one‐sided test procedures) for Cmax, Cmin, and AUC, with similarity in degrees of fluctuation {(Cmax‐Cmin)/Caverage}. Despite the presence of diurnal variation in valproate absorption after oral dose administration, the steady‐state plasma concentration‐versus‐time profile was well maintained by both regimens within the accepted therapeutic range of 50 to 100 μg/mL.
Topical Ophthalmic β‐Adrenergic Blockade for the Treatment of Glaucoma and Ocular Hypertension
Authors: Frishman William H. , Fuksbrumer Moshe S. , Tannenbaum Mark
Published: March 2013

Since the late 1970s, topical β‐adrenergic blockers have been the drugs of choice in treating ocular hypertension and associated glaucoma. The currently available drugs are timolol, betaxolol, levobunolol, metipranolol, and carteolol. All reduce intraocular pressure by decreasing the production of aqueous humor. Although these drugs are applied locally in the eye, they may enter the general circulation and reach concentrations high enough to cause systemic effects, including alterations in heart rate and rhythm, bronchoconstriction, dyslipidemia, and central nervous system abnormalities. Interactions with other drugs may also occur. Ocular β‐ blockers differ in β1‐selectivity (betaxolol is β1‐selective, whereas the other drugs are nonselective) and in intrinsic sympathomimetic activity (ISA) or partial agonist properties (only carteolol possesses ISA). These differences give betaxolol and carteolol potential advantages in minimizing certain side effects. The advantage of betaxolol vis‐à‐vis systemic side effects is more clearly established than that of carteolol. Further systematic study is needed to determine what advantages, if any, are conferred by the presence of ISA.
Sources of Prediction Error When Using a Bayesian Method to Evaluate Nortriptyline Serum Concentrations
Authors: Kehoe William A. , Harralson Arthur F. , Jacisin John J. , Duong Tanya T.
Published: March 2013

A Bayesian method was used to evaluate nortriptyline (NTP) serum concentrations (Cps) and predict future Cps in two populations: five simulated groups (n = 20 each) with known clearance (CL) and volume of distribution (Vd), and an actual inpatient group (n = 20). The effects of weight, CL, Vd, and magnitude of Cps on absolute prediction error (APE) were evaluated. In simulated groups, Cps after two doses of NTP and for steady‐state were calculated for normal, increased, and decreased Vd and CL. In the actual patient group, Cps were measured in the first few days after starting NTP administration and again during maintenance therapy. The first Cps were used in the Bayesian program to estimate CL and Vd to predict the second Cps. In the simulated group, PE and APE differed significantly between normal and decreased values of CL. A large Vd resulted in less of a change in PE or APE in these subjects, but when combined with low CL led to the largest errors. In the actual patient group, PE was −5.9 ± 19.2 ng/mL and APE was 15.4 ± 12.6 ng/mL. In these patients, only body weight was correlated with the percent APE (r = 0.607, P = 0.005). The Bayesian method performs well clinically, but increased Vd and decreased CL can lead to higher PE. Clinically, the only factor that predicted higher APE was obesity. This may reflect an effect on Vd, and in these patients, a high APE may occur.
Pharmacokinetics of FK506 After Intravenous and Oral Administration in Patients Awaiting Renal Transplantation
Authors: Gruber Scott A. , Hewitt Jeanne M. , Sorenson Amy L. , Barber Donald L. , Bowers Larry , Rynders Greg , Arrazola Luis , Matas Arthur J. , Rosenberg Mark E. , Canafax Daniel M.
Published: March 2013

The authors examined the safety and pharmacokinetics of FK506, a new hepatically metabolized immunosuppressant, after single‐dose intravenous (IV) infusion (20 μg · kg−1 · 4 hours−1) and oral (80 μg/kg) administration in six nondialysis patients, aged 27 to 53 years, with chronic renal failure awaiting transplantation. A two‐period, randomized, crossover study protocol was used with blood samples drawn for 72 hours after each dose and a washout period of 4 days. Whole‐blood FK506 levels were determined using a standard, two‐step, nonspecific enzyme immunoassay. There were no significant changes in vital signs, EKG, or complete laboratory test battery for any patient during the entire study period. No side effects were noted after IV or oral FK506 dosing. Mean ± SD distribution half life was 0.9 ± 0.2 hours, elimination half life (t1/2β) 33 ± 8 hours, total body clearance (CL) 2.4 ± 1.1 L/hour, and bioavailability 14 ± 12%. There was no significant correlation between serum creatinine (Cr) and CL (r = 0.36) or between Cr and t1/2β (r = −0.30). It was found that FK506 is incompletely and erratically absorbed after oral administration and is rapidly distributed outside the blood compartment after IV dosing. An extended sampling period seems necessary to accurately characterize the slow elimination phase of FK506.
Verapamil and Nifedipine in Combination for the Treatment of Hypertension
Authors: Kaesemeyer W. H. , Carr A. A. , Bottini P. B. , Prisant L. M.
Published: March 2013

The authors examined the efficacy and safety of the combination of verapamil and nifedipine in the control of hypertension. Retrospective analysis of blood pressures was obtained on 50 patients who had historically documented essential hypertension and were receiving verapamil and nifedipine. The patients had moderate to severe hypertension; 27 of 50 (54%) were uncontrolled on prescribed regimens of two or more separate classes of drugs. Control was defined by the ability to maintain a blood pressure of ≤ 160/90 by providing doses of verapamil (max: 480 mg/day) and nifedipine (max: 180 mg/day). Twenty‐nine (50%) were black and 21 (42%) were white. Ages ranged from 16 to 84 years. Mean duration of therapy was 1–2 years. Only 3 of 50 (6%) were control failures after providing verapamil and nifedipine. Three of 50 (6%) were discontinued because of side effects — reversible hepatitis (2) and rash (1). There were no serious adverse events, i.e., CHF or arrhythmias. Manageable ankle edema was seen in 14 of 50 (28%) patients. Verapamil and nifedipine, a combination of a dihydropyridine and a non‐dihydropyridine calcium antagonist, was effective and safe in this group of patients with difficult‐to‐manage hypertension.
Investigation of the Influence of Acetylsalicylic Acid on the Steady State of Long‐Term Therapy With Theophylline in Elderly Male Patients With Normal Renal Function
Authors: Daigneault Ernest A. , Hamdy Ronald C. , Ferslew Kenneth E. , Rice Peter J. , Singh Jasvinder , PhD Leo M. Harvill , Kalbfleisch John H.
Published: March 2013

The risk inherent in the clinical control of patients with theophylline is widely recognized. Elderly patients may present an additional risk because of altered pharmacokinetics and the use of concomitant medication. Acetylsalicylic acid has been proposed for primary and secondary prevention of myocardial infarction and possible strokes. This investigation was undertaken to determine if concomitant administration of acetylsalicylic acid in elderly patients would alter steady‐state levels of theophylline. A population of smoking male patients older than 60 years of age under long‐term control of chronic obstructive pulmonary disease (COPD) with theophylline were evaluated for a baseline period of 3 days. Serum levels were measured at 6:00 am and 6:00 pm. An enteric‐coated acetylsalicylic acid preparation, 650 mg by mouth, was added to the daily slow‐release theophylline, 6:00 am hour dose regimen for 4 weeks. The serum levels of theophylline and salicylates were measured at 6:00 pm after dosing and at 6:00 am the following day, at weekly intervals for 4 weeks. Urine specimens collected before administration of medication at 6:00 am were analyzed for salicylates to further confirm dosage compliance. All volunteers continued to be clinically controlled throughout the treatment period, and no symptoms of either overdose or underdose of either medication occurred. Plateau or trough theophylline serum levels did not change significantly during the salicylate treatment period. Salicylate serum levels did show during treatment self‐induced metabolism. It is concluded that in elderly male patients, a daily concomitant therapeutic salicylate regimen does not alter steady‐state serum theophylline levels and therefore does not per se necessitate the assay of theophylline blood levels in elderly patients.
Dopamine‐Induced Antihypertensive Effects and Plasma Insulin Rise Are Blocked by Metoclopramide in Labetalol‐Treated Patients
Authors: Martin Gladys , Forte Pablo , Luchsinger Augusta , Mendoza Freddy , Urbina‐Quintana Adalberto , Pieretti Otto Hernandez , Romero Eduardo , Velasco Manuel
Published: March 2013

Eleven patients with moderate to severe hypertension were studied at the Vargas Hospital of Caracas. The patients were pretreated with labetalol, 800 to 1200 mg/day, orally, over a period of 1 week, after which an intravenous infusion of dopamine, .5 to 3 μg/kg/minute, was given. Two intravenous dopamine infusions (30 minutes each) were performed before and after the injection of metoclopramide (30 mg, intravenous bolus). Two washout periods were also included before and after metoclopramide administration. Dopamine induced a decrease of blood pressure from 171.9 + 6.35/103.6 ± 3.12 to 152.7 ± 7.55/93.8 ± 2.97 mm Hg (P < .001) without altering heart rate, and it increased plasma insulin levels from 8.29 ± .70 μU/mL to 12.09 ± 1.83 μU/mL (P < .01). Metoclopramide caused no changes of blood pressure or plasma insulin levels. Hypotensive responses and plasma insulin increases due to dopamine were blocked by metoclopramide, however. The authors conclude that a dopaminergic receptor may be involved in some cardiovascular responses and in modulating insulin secretion in humans.
Clinical Pharmacology of Pancreatic Enzymes in Patients with Cystic Fibrosis and In Vitro Performance of Microencapsulated Formulations
Authors: Kraisinger Marijo , Hochhaus Guenther , Stecenko Arlene , Bowser Ellen , Hendeles Leslie
Published: March 2013

Improving protein and fat absorption in patients with cystic fibrosis relates to the amount of biologically active enzyme reaching the duodenum. Microencapsulated formulations are more effective than conventional products but differ in content, ability to retard acid inactivation and the pH at which they release enzymes. Contaminants in these products contribute to hyperuricosuria.
Enzyme Induction by Moricizine: Time Course and Extent in Healthy Subjects
Authors: Benedek Irma H. , Davidson Anna F. , Pieniaszek Henry J.
Published: March 2013

Moricizine · HCl, a novel phenothiazine derivative with oral antiarrhythmic activity, was examined for its potential to induce its own hepatic metabolism and to alter the pharmacokinetics of the test substrate, antipyrine, in 12 healthy male subjects. Antipyrine oral clearance increased from a starting value of .74 mL/minute/kg to .98 (+32%, P < .01) after 7 days of moricizine administration (250 mg every 8 hours) and to 1.15 mL/minute/kg after 14 days (+47%, P < .05); t1/2 was correspondingly reduced. Moricizine oral clearance increased from a baseline of 3.01 L/hour/kg to 3.62 (+20%, P < .05) after 6 days of oral moricizine and 4.66 (+51%, not significant) after 13 days. Moricizine t1/2 was marginally, but consistently, increased (+23%, P < .05) instead of decreased as one would expect because of enzyme induction, presumably due to a decrease in systemic bioavailability and its influence on the oral volume of distribution. In half of the subjects who discontinued moricizine after 7 days, antipyrine pharmacokinetic values returned to near baseline 7 days later. Although moricizine was able to induce its own hepatic metabolism and that of antipyrine after 6 or 7 days of continuous administration, the electrocardiographic properties of moricizine did not appear to be altered by continuous dosing.
The Effects of Programmed Ventricular Stimulation on Plasma Procainamide Levels: An Experimental Model
Authors: Brautigam Robert T. , Porter R. Stephen , Kutalek Steven P.
Published: March 2013

To evaluate the effects of programmed ventricular stimulation on resultant plasma concentrations of intravenously administered procainamide, drug dosing was performed with and without ventricular stimulation on two separate days (48 hours apart) in 12 dogs (13 dosing trials) at ≥14 days after myocardial infarction (mean: 62 days). During infarct surgery, three bipolar electrodes were plunged into left ventricular epicardium, externalized, and later used for ventricular stimulation. On the first study day, procainamide was dosed to achieve two sequential plateau plasma levels (I and II), with a 20‐minute equilibrium period at each plateau before ventricular stimulation. Plasma procainamide concentrations were measured before initiation of ventricular stimulation and at the completion of ventricular stimulation for each sequential plateau level. Stimulation involved delivery of one, two, and three extrastimuli at three paced cycle lengths at three left ventricular sites before procainamide dosing and at each of the two procainamide plateau levels. Three dogs were excluded from analysis due to induction of lethal ventricular arrhythmias. No ventricular arrhythmias were induced in the remaining nine animals. On the second study day, procainamide was dosed identically, but no ventricular stimulation was performed. Intravenous drug administration and collection of plasma concentration samples were performed with ± 1 minute on both study days. Mean plasma procainamide concentrations at the end of ventricular stimulation at dosage Levels I & II were 10% and 12% greater (P < 0.02 and P < 0.005, respectively) than plasma concentrations measured at comparable times on the study day when no ventricular stimulation was performed. These data demonstrate that plasma concentrations of intravenously administered procainamide in dogs remain significantly greater after a full protocol of programmed ventricular stimulation than when no ventricular stimulation is performed. This may be related to hypotension during ventricular stimulation with a concomitant decrease in hepatic and renal clearance of procainamide. These findings have implications for dosing of intravenous procainamide in humans who undergo electrophysiologic testing.
Genetic Differences in Drug Disposition
Authors: May D. Gail
Published: March 2013

Genetic polymorphisms of drug metabolizing enzymes are well recognized. This review presents molecular mechanisms, ontogeny and clinical implications of genetically determined intersubject variation in some of these enzymes. Included are the polymorphic enzymes N‐acetyl transferase, cytochromes P4502D6 and 2C, which have been well described in humans. Information regarding other Phase I and Phase II polymorphic pathways, such as glutathione and methyl conjugation and alcohol and acetaldehyde oxidation continues to increase and are also discussed. Genetic factors effecting enzyme activity are frequently important determinants of the disposition of drugs and their efficacy and toxicity. In addition, associations between genetic differences in these enzymes and susceptibility to carcinogens and teratogens have been reported. Ultimately, the application of knowledge regarding these genetic factors of enzyme activity may guide medical therapy and minimize xenobiotic‐induced disease.
Cocaine‐Related Sudden Cardiac Death: A Hypothesis Correlating Basic Science and Clinical Observations
Authors: Bauman Jerry L. , Grawe Jeffrey J. , Winecoff Allison P. , Hariman Robert J.
Published: March 2013

Sudden, unexpected death due to cocaine in young otherwise healthy individuals occurs in an idiosyncratic manner and is commonly felt to be arrhythmogenic in nature, although the exact cause of death is rarely documented. In addition to indirect sympathomimetic actions, cocaine is a potent sodium channel blocking drug and, in this regard, most closely resembles agents such as flecainide. We suggest that sudden death due to cocaine is proarrhythmic in nature, occurring under similar circumstances as that due to specific antiarrhythmic drugs.
Controlled Study with a New Sustained‐Release Formulation of Nifedipine in Essential Hypertensive Patients
Authors: Galletti Ferruccio , Barba Gianvincenzo , Nardecchia Adele , Strazzullo Pasquale , Scagliusi Pasquale , Pirrelli Anna , Mancini Mario
Published: March 2013

The authors studied the antihypertensive effect and tolerability of a new sustained‐release formulation of nifedipine 50 mg once a day, in comparison with nifedipine retard 20 mg twice a day in patients with mild or moderate primary arterial hypertension. Both treatments significantly lowered blood pressure with no difference in daily blood pressure profile. At steady state, the two drugs determined comparable plasma levels of nifedipine as measured immediately before the morning dose. After a 12‐month treatment, the new formulation of nifedipine still displayed satisfactory blood pressure control in both supine and standing positions, with no change in tolerability throughout the study. In conclusion, this new sustained‐release formulation of nifedipine has similar efficacy and tolerability to conventional treatment with nifedipine retard 20 mg twice a day.
Pharmacokinetics and Safety of NM441, a New Quinolone, in Healthy Male Volunteers
Authors: Nakashima M. , Uematsu T. , Kosuge K. , Okuyama Y. , Morino A. , Ozaki M. , Takebe Y.
Published: March 2013

The safety and pharmacokinetics of NM441, a prodrug of a new thiazeto‐quinoline carboxylic acid derivative, NM394, were evaluated in healthy male volunteers given the drug orally in single doses of 20, 50, 100, 200, and 400 mg, and multiple doses of 300 mg twice daily for 6.5 days. No remarkable abnormalities were observed in symptoms, physical tests, laboratory tests, electrocardiogram (ECG), electroencephalogram (EEG), or equilibrium test. The mean plasma concentrations of active metabolite NM394 peaked between 0.5 and 1.0 hours, and the maximum concentrations were 0.68, 1.09, and 1.88 μg/mL at doses of 100, 200, and 400 mg, respectively. The mean half‐lives were 7.7 to 8.9 hours and were not affected by dose. The mean urinary excretion rates of NM394 were 46.0, 38.3, and 30.6% of the doses within 48 hours, respectively, and other metabolites were excreted in urine by 7% of the doses. The mean salivary concentrations of NM394 were approximately 20% of the plasma concentrations. The mean fecal excretion rates of NM394 and NM441 were 52.9 and 4.2%, respectively within 72 hours after dosing of 400 mg. The Cmax, AUC, and urinary excretion rates were not altered by food intake, whereas the Tmax was prolonged slightly. In the multiple‐dose study, the steady state of plasma concentration of NM394 was achieved on day 3 or 4, and further accumulation did not occur thereafter. The mean urinary excretion rate of NM394 was 49.0% during and 48 hours after the multiple administration. The acceptable safety and tolerance and defined pharmacokinetic characteristics of NM441 support further testing.
Human Pharmacokinetic Study of Immediate‐Release (Codeine Phosphate) and Sustained‐Release (Codeine Contin) Codeine
Authors: Band Christian J. , Band Pierre R. , Deschamps Michèle , Besner Jean‐Guy , Coldman Andrew J.
Published: March 2013

The authors compared, in a double‐blind, randomized, crossover study in 13 healthy adult volunteers, the single‐ and multiple‐dose pharmacokinetics, relative bioavailability, and side effects of a new oral sustained‐release formulation of codeine (SRC) containing 150 mg codeine base, with oral immediate‐release codeine phosphate (IRC). Sustained‐release codeine was given at a dose of 150 mg every 12 hours for 5 doses; IRC was given at a dose of 60 mg (2 × 30 mg) every 4 hours for the first 3 doses, and 30 mg every 4 hours thereafter for 12 doses. Plasma codeine levels were determined using a sensitive and specific high‐performance liquid chromatography method and corrected for dose administered and codeine base equivalent. Mean values for single‐dose pharmacokinetic parameters for SRC and IRC, respectively, were: Cmax of 217.8 and 138.8 ng/mL; Tmax of 2.3 and 1.1 hours; AUC0‐inf of 1202.3 and 1262.4 ng • mL−1 • hour−1; and t1/2el of 2.6 hours for both formulations. Their respective mean steady‐state pharmacokinetic parameters were: Cmax of 263.8 and 222.9 ng/mL; Tmax of 3.2 and 1.1 hours; AUC0–12h of 1576.4 and 1379.1 ng • mL−1 • hour−1; and t1/2el of 2.8 and 2.3 hours. These results indicate comparable bioavailability between both formulations with SRC providing delayed peak plasma levels. The sustained‐release character of SRC can be explained by a delayed absorption, which is not limiting to drug elimination. Sustained‐release codeine provides higher plasma codeine levels over a broader time interval and is expected to improve pain management.
Calcium‐Channel Entry Blocker Therapy for Hypertensive Patients with Concomitant Renal Impairment: A Focus on Isradipine
Authors: Frishman William H.
Published: March 2013

In the treatment of hypertension in renally impaired patients, normalization of blood pressure alone may not be sufficient to prevent significant morbidity to the kidneys. Treatment must reduce pressure in the renal vasculature, otherwise glomerular filtration rate and renal plasma flow will continue to deteriorate. Isradipine, a dihydropyridine calcium‐channel blocker, has been investigated as a suitable treatment in this setting. Isradipine maintains glomerular filtration rate, preserves or enhances renal plasma flow, decreases renal vascular resistance, maintains or reduces filtration fraction, and exerts a sustained natriuretic effect, all of which may enable isradipine to slow the rate of progression of renal deterioration. In addition, isradipine may decrease proteinuria and may decrease glomerular capillary pressure by dilating both the efferent and afferent arterioles. Unlike older calcium‐channel blockers, isradipine exhibits minimal cardiodepressant activity and is not associated with any negative inotropic effects. It is metabolized in the liver and dosage adjustments may not be necessary when administered to patients with renal insufficiency. Isradipine has a favorable renal effect profile and also has several properties that meet the requirements of other patient populations where an extra measure of antihypertensive safety is required, such as diabetics, dialysis patients, and transplant recipients. Side effects with isradipine are usually mild and transient, occurring in a dose‐dependent manner.
Pharmacodynamics of Bolus Famotidine Versus Infused Cimetidine, Ranitidine, and Famotidine
Authors: Amsden Guy W. , Goss Thomas F. , Harrison Nedra J. , D'Andrea David T. , Schentag Jerome J.
Published: March 2013

A four‐way crossover pilot study was conducted to compare the pharmacodynamic response of intermittent famotidine (20 mg every 12 hr) to continuous infusions of cimetidine (1200 mg/24 hr), ranitidine (150 mg/24 hr), and famotidine (40 mg/24 hr) in six normal male volunteers. Intragastric pH was monitored continuously for 24 hours. Comparisons included percent time during the 24‐hour period that gastric pH was greater than pH 4.0, and pH 5.0, and also for the steady‐state period of each regimen (12–24 hr). Although no statistically significant difference was observed for any of these comparisons, a clinically relevant trend was observed. In crossover experiments, famotidine intermittent infusions provided gastric pH readings above 4.0 and 5.0 for a longer duration than any of the continuous infusion regimens. Famotidine intermittent infusion regimens (20 mg every 12 hr) are at least equivalent to continuous infusions of cimetidine, ranitidine, and famotidine. Based on these findings, comparative studies in an appropriate critical care population would be beneficial, but any such studies must use a crossover design because of the even higher degree of intersubject variance in pH control. For this reason, the normal volunteer crossover model used here may provide important comparative information for the various regimens used in suppression of gastric acidity.