bluuebunny/crossref_metadata_2025 huggingface dataset:
Sucralfate on Serum Lipids and Lipoproteins in Normal Volunteers
Authors: Schwenk Michael H. , Berk Steven I. , Morgan Doreen V. , Maesaka John K. , Lehrer Michael
Published: March 2013

Sucralfate is used in the treatment and prophylaxis of peptic ulcer disease. One possible mechanism of action is the binding of bile acids. Because the absorption of dietary fat and cholesterol is dependent on the presence of bile acids in the small intestines, sucralfate therapy may produce changes in serum lipoprotein composition qualitatively similar to bile acid sequestrants, such as cholestyramine, which reduce serum cholesterol levels. Although changes in total serum cholesterol have not been reported in sucralfate efficacy studies, the effect of sucralfate on serum lipoprotein composition has not been specifically addressed. The purpose of this study was to prospectively examine the effect of sucralfate on serum lipids and lipoproteins in normal volunteers. Eight healthy volunteers (six men, two women) were recruited for this 10‐week study. Drugs known to affect cholesterol levels were not permitted before or during the study. Diet composition during the study period was unaltered from before the study. Subjects took 1 g sucralfate orally 1 hour before meals and at bedtime (four times a day) for 8 weeks, followed by a 2‐week washout period. Fasting blood samples were obtained at baseline and weekly, and were analyzed for serum total and HDL cholesterol and for triglycerides. Levels of LDL cholesterol were estimated. After eight weeks of sucralfate, HDL cholesterol increased from baseline by 2.5 mg/dL (6.6%, from 37.6 ± 9.5 to 40.1 ± 8.69 mg/dL), and LDL cholesterol decreased by 7.6 mg/dL (6.4%, from 134 ± 28.1 to 125.4 ± 34.1). Total cholesterol decreased by 3.5 mg/dL (1.8%, from 192.9 ± 34.3 to 189.4 ± 37.2 mg/dL). All cholesterol levels were higher at week 10 than at baseline. These changes were not statistically significant, possibly because of the small sample size and high dietary fat intake in this study. However, the changes in total, HDL, and LDL cholesterol would be clinically significant. Based on these findings, sucralfate should be studied in a larger cohort of hypercholesterolemic patients.
Bioavailability of Total and Unbound Disopyramide: Implications for Clinical Use of the Immediate and Controlled‐Release Dosage Forms
Authors: Piscitelli Deborah A. , Fischer James H. , Schoen Marieke Dekker , Hoon Timothy J. , Bauman Jerry L.
Published: March 2013

This study further characterized the impact of concentration‐dependent protein binding on the bioavailability and clinical use of the immediate‐release (IR) and controlled‐release (CR) dosage forms of disopyramide after single doses and during steady‐state conditions in ten healthy volunteers. Consistent with the clinical use of these products, steady state has incorporated an IR to CR conversion step. Side effects and electrocardiographic actions were quantitated using a visual analog scale and serial Holter monitor recordings, respectively. Significant decreases resulted in area under the curve for total disopyramide between single dose and steady state: IR, 47.8 ± 13.6 versus 33.0 ± 6.4 mg/Lxh (P < .05); and CR, 46.9 ± 9.5 versus 31.7 ± 5.9 mg/Lxh (P < .05). In contrast, there were no differences in area under the curve for unbound disopyramide between phases or products. During conversion, the mean IR peak significantly decreased (P < .05) to the nadir before the first CR dose for total (37%) and unbound (60%) concentrations. There were no major differences in change in QT interval or side effects detected between products or phases. These findings indicate that, because of concentration‐dependent protein binding, unbound, not total, concentrations should be used to estimate the bioavailability of disopyramide. Also, although the previously recommended conversion method (first CR dose 6 hours after the last IR dose) should provide an adequate transition in most, an alternative method (combined first CR with last IR dose) is indicated in select patients.
Lack of a Pharmacokinetic/Pharmacodynamic Interaction Between Nimodipine and Tirilazad Mesylate in Healthy Volunteers
Authors: Fleishaker Joseph C. , Hulst Laura K. , Peters Gary R.
Published: March 2013

The potential interaction between tirilazad mesylate, a membrane lipid peroxidation inhibitor, and nimodipine, a calcium‐channel antagonist, was assessed in 12 healthy male volunteers. Subjects received 60 mg nimodipine orally, 2.0 mg/kg tirilazad mesylate as a 10‐minute intravenous infusion, and a combination of the two treatments according to a balanced 3‐way crossover design. No significant effects of nimodipine on tirilazad mesylate pharmacokinetic parameters were observed (P > .05). Values for tirilazad mesylate clearance (34.9 ± 8.96 L/hr) and half‐life (29 ± 7.63 hr) were consistent with previous studies. Nimodipine pharmacokinetic parameters exhibited substantial variability, and mean AUC was approximately 25% below the range of previously published values. However, no significant differences in nimodipine pharmacokinetics were observed between treatments. Nimodipine administration increased heart rate slightly without a change in blood pressure, which was not observed after tirilazad administration and was not altered when tirilazad and nimodipine were coadministered. Thus, no significant interaction between tirilazad mesylate and nimodipine is detectable after single‐dose administration.
Evaluation of the Antipyretic Effect of Ketorolac, Acetaminophen, and Placebo in Endotoxin‐Induced Fever
Authors: Vargas Ramon , Maneatis Thomas , Bynum Lincoln , Peterson Craig , McMahon F. Gilbert
Published: March 2013

The authors studied the antipyretic effect of three intramuscular doses of ketorolac (15, 30, and 60 mg), acetaminophen 650 mg PO, and placebo in healthy male volunteers using an endotoxin‐induced fever model. In this double‐blind, double‐dummy, parallel study, subjects were assigned randomly with equal probability to one of the above treatment groups. Thirty minutes after study medication administration, a 20 unit per kilogram dose of reference standard endotoxin (RSE) was administered intravenously, and temperature was determined every 15 minutes for an 8‐hour period. Compared with placebo, all active treatment groups demonstrated a statistically significant reduction in both adjusted area under the temperature‐by‐time curve (AAUC) and the maximum increase over baseline temperature (dTmax). Furthermore, the 30 mg intramuscular dose of ketorolac demonstrated approximately the same antipyretic activity as the 650 mg oral dose of acetaminophen, and there was a statistically significant dose response across the three ketorolac doses studied (P < .0001). The majority of side effects reported during this study were symptoms associated with fever, including chills, headache, myalgia, and dizziness, all of which are effects of RSE. The frequency of side effects tended to be less in the treatment groups with the greatest antipyretic activity.
Nasal Mucosal Inflammation Has No Effect on the Absorption of Intranasal Triamcinolone Acetonide
Authors: Argenti Domenick , Colligon Irina , Heald Donald , Ziemniak John
Published: March 2013

The potential for enhanced systemic absorption of intranasal triamcinolone acetonide was explored in patients with inflamed nasal mucosa. Twelve allergic rhinitis patients with documented nasal inflammation, and 12 healthy volunteers, each received a single, therapeutic, 400‐μg dose of triamcinolone acetonide in each nostril. Blood was obtained at fixed time points after the dose, and plasma concentrations of triamcinolone acetonide were determined by radioimmunoassay. There were no statistically significant differences in any of the derived pharmacokinetic parameters (maximum plasma triamcinolone acetonide concentrations [Cmax], time to maximum plasma triamcinolone concentrations [Tmax], elimination half‐life [t1/2], and area under the plasma concentration‐time curve [AUC0–12] from 0 to 12 hours) between treatment groups. A once‐a‐day, chronic regimen (6 weeks) of triamcinolone acetonide was also administered to five patients with allergic rhinitis. Pharmacokinetic parameters were similar to the parameters derived from healthy volunteers after acute administration. There was no evidence of drug accumulation. The results of this study indicate that acute and chronic intranasal administration of therapeutic doses of triamcinolone acetonide to patients with inflamed nasal mucosa does not result in enhanced systemic drug absorption or accumulation.
Plasma and Leukemic Cell Pharmacokinetics of High‐Dose N4‐Behenoyl‐1‐β‐D‐arabinofuranosylcytosine in Acute Leukemia Patients
Authors: Yoshida Takashi , Kobayashi Kazumi , Okabe Yoko , Okumura Hirokazu , Matano Sadaya , Kanno Masatoshi , Takeda Yasushi , Ohtake Shigeki , Nakamura Shinobu , Matuda Tamotu
Published: March 2013

The pharmacokinetics of N4‐behenoyl‐1‐β‐D‐arabinofuranosylcytosine (BHAC), a lipophilic antitumor analog of 1‐β‐D‐arabinofuranosylcytosine (ara‐C), was investigated, by assay of plasma and leukemic cells of ten acute leukemic patients receiving 60‐minute intravenous (IV) infusion of 700 mg/m2 BHAC, for BHAC and 1‐β‐D‐arabinofuranosylcytosine 5′‐triphosphate (ara‐CTP) by high‐performance liquid chromatography, ara‐C by radioimmunoassay, and 1‐β‐D‐arabinofuranosyluracil (ara‐U) by gas chromatography‐mass fragmentography. The plasma concentration of BHAC reached a maximum (173.4 ± 75.3 μg/mL) at the end of the infusion and then declined in a biphasic pattern with an initial‐phase half‐life (t1/2α) of 1.00 ± .36 hours and a second‐phase half‐life (t1/2β) of 4.28 ± 2.35 hours. That of ara‐C similarly reached a maximum (102.2 ± 39.9 mg/mL) at the end of the infusion and then declined with t1/2α of 1.37 ± 1.11 hours and t1/2β of 11.2 ± 4.31 hours. Intracellular ara‐CTP concentration increased in a linear‐accumulation manner for the first 4 hours after the infusion, reached a maximum of .081 ± .112 μg/107 cells at approximately 7 hours, and then declined very slowly in accordance with a one‐compartment model with t1/2 of 13.56 ± 9.62 hours.
Drug Dosing in Renal Insufficiency
Authors: Talbert Robert L.
Published: March 2013

Drug dosing in renal insufficiency needs to be individualized whenever possible to optimize therapeutic outcomes and to minimize toxicity. Although a number of published tables that provide dosing guidelines and nomograms exist to assist in dose modification, individualization of therapy should be based on pharmacokinetic principles whenever possible. The basis equations to estimate the pharmacokinetic parameters of clearance, volume of distribution, and half‐life for intravenous drug administration of drugs with first‐order kinetics are not difficult to understand and apply. Their use should be encouraged in patient care.
The New Drug Approvals of 1990, 1991, and 1992: Trends in Drug Development
Authors: Kaitin Kenneth I. , Manocchia Michael , Seibring Mark , Lasagna Louis
Published: March 2013

Efforts to speed the development and review of new drugs have increased sharply in recent years. This report, which is the third in a series on trends in drug development, examines the new drug approvals of 1990, 1991, and 1992. During the 3‐year study period, the Food and Drug Administration (FDA) approved 79 new drugs, 74 of which met the Center for the Study of Drug Development's definition of a new chemical entity (NCE). Of the 74 NCEs, 36 (49%) were considered by the FDA to represent notable therapeutic gains and were selected for “priority” review (i.e., drugs rated 1P, 1A, 1AA, and 1B), and 38 (51%) were considered to represent little or no gain and received “standard” reviews (i.e., drugs rated 1S and 1C). Investigational new drug application (IND) filing and new drug application (NDA) submission dates on all 74 drugs were obtained from responses to our manufacturer surveys as well as from FDA and public sources. The mean length of the clinical phase (IND filing to NDA submission) was 6.1 years and that of the review phase (NDA submission to approval) was 2.6 years. Of the 74 NCEs, 43 (58%) were available in foreign markets at least 1 year before U.S. approval, with a mean of 5.6 years of foreign marketing. In general, 1990 to 1992 figures are similar to those in the last half of the 1980s.
Analysis of Adverse Events in a Dose Titration Study
Authors: Hsu Ping‐Hwa , Laddu Atul R.
Published: March 2013

The authors have examined the analysis of adverse event data from an efficacy dose escalation trial. Unlike the analysis of efficacy data, the assumption that when a patient experiences an adverse event at a given dose, he or she will experience the same at a greater dosage level was not applicable in the analysis of adverse event data. Because the time effect is confounded with the dose effect in a dose escalation design, any assessment of a dose‐effect relationship from such a scheme is found to be preliminary and suspect. For drugs that need to be dosed with a titration schedule, a time‐dose‐specific incidence of an adverse event provides more useful information than a dose‐specific incidence. The pace of dose titration, which was found to be important in the manifestation of an adverse event, also needs to be specified. These aspects are illustrated with data from a specially designed trial. The entire study contained a placebo arm and three arms of an active drug randomized in a parallel comparative fashion. Within each of the three active drug arms, a forced titration scheme was used to raise the dose to different levels, which distinguished the three arms. With an efficacy dose titration design, the dose‐response relationship for adverse events cannot be determined without incorporating a placebo arm and other arms with different maximum allowable doses. For drugs that need to be administered with a titration scheme, incidence of adverse events needs to be presented with the dosage, the time, and the pace of titration.
Computer‐Assisted Evaluation of Adverse Events Using a Bayesian Approach
Authors: Lanctôt Krista L. , Naranjo Claudio A.
Published: March 2013

The differential diagnosis of idiosyncratic adverse drug reactions (ADRs) is complex because for each adverse event there are many possible drug and nondrug causes. Recently efforts have been made to computerize causality assessment methods. A new computerized, user‐friendly diagnostic aid for Bayesian assessment of adverse drug events (MacBARDI‐Q&A) is described. This computer program performs a differential diagnosis on cutaneous reactions suspected of being drug‐induced. The authors' results indicate that development of a valid, simple and user‐friendly computerized procedure for evaluating adverse drug events is possible. The ongoing development and application of MacBARDI‐Q&A and other similar programs should improve the evaluation of putative adverse drug reactions.
Bolus Infusion of Famotidine: Effects on Gastric pH by Repeated 12‐Hour Doses of 20 mg in Postoperative Patients
Authors: Savarino Vincenzo , Mela Giuseppe Sandro , Zentilin Patrizia , Larghero Giancarlo , Cutela Patrizia , Mele Maria Raffaella , Vassallo Ambrogio , Mansi Carlo , Dallorto Enza , Celle Guido
Published: March 2013

This study was carried out to assess the efficacy of intravenous (IV) famotidine in suppressing gastric secretion over a 48‐hour period. Twenty postoperative patients requiring a nasogastric tube received famotidine 20 mg IV every 12 hours and gastric pH was measured continuously by means of an indwelling probe. A baseline recording was performed over the first 4 hours and then the drug was infused every 12 hours (q12h) over a 15‐minute period for the subsequent 48 hours. The mean pH value achieved during each time segment under active treatment was significantly higher (P < .001) than the mean basal value. Also the density distributions of minutes spent at the various pH units confirm that famotidine is highly effective (P < .001) in raising and maintaining gastric pH above 4.0 units during most of the drug‐related period (44 hours). It can be concluded that repeated intravenous boli of famotidine 20 mg every 12 hours allow us to obtain an effective control of intragastric acidity. The antisecretory action is consistent over the total 48‐hour period examined and therefore the use of intermittent infusion of famotidine seems to be advisable, as opposed to the recommended continuous IV administration of Cimetidine and ranitidine. There is, however, a considerable intersubject variability in the antisecretory response to the drug.
Effects of Inhibition of Serotonin Synthesis on 5‐Hydroxyindoleacetic Acid Excretion, in Healthy Subjects
Authors: Alfieri Anna B. , Cubeddu Luigi X.
Published: March 2013

The urinary excretion of 5‐hydroxyindoleacetic acid (5‐HIAA), the main metabolite of serotonin, reflects the content and turnover of gastrointestinal (GI) serotonin. Employing longitudinal measurements of 5‐HIAA, the authors investigated in healthy subjects (n = 43) how manipulations of serotonin synthesis affect GI serotonin. Under conditions of serotonin‐free diets, the intersubject and intrasubject variability (coefficient of variation) for 5‐HIAA excretion averaged 33% and 14%, respectively. Dietary tryptophan restrictions to 50% of minimal daily requirements (which is equivalent to a 10‐fold reduction in baseline tryptophan intake) decreased by half the urinary excretion of 5‐HIAA, irrespective of the caloric content of diet Restoration to the regular tryptophan intake produced a rapid normalization of the 5‐HIAA excretion. Neutral amino acids are known to compete with the intestinal transport absorption mechanisms of tryptophan. Administration of neutral aminoacids (1.8 g, by mouth, three times a day, before each meal) or of carbidopa (50 mg, by mouth, three times a day for 3 days) to a normal tryptophan diet failed to alter significantly the 5‐HIAA excretion. Further, neutral aminoacids failed to enhance the reduction in 5‐HIAA produced by the low‐tryptophan diet. The failure of these treatments to reduce 5‐HIAA excretion could be due to large capacity transport and decarboxylation systems for tryptophan. Other possibilities are discussed. In summary, dietary tryptophan is essential for the maintenance of GI serotonin. Reductions or increases in dietary tryptophan are the easiest and most effective method to alter GI serotonin. Finally, interpretation of the urinary levels of 5‐HIAA should take into account not only the amount of serotonin in the diet, but also that of tryptophan.
Pharmacokinetics and Pharmacodynamics of Intravenous OPC‐18790 in Humans: A Novel Nonglycosidic Inotropic Agent
Authors: Ohnishi Akihiro , Toyoki Takaaki , Ohno Toshiyuki , Takeshige Yoshiko , Fujita Tsuyoshi , Kodama Kazuhisa , Mishima Masayoshi , Hirayama Atsushi , Kitani Mami , Miyamoto Gohhachiro , Odomi Masatoshi , Tanaka Teruji
Published: March 2013

OPC‐18790, a nonglycosidic intropic agent, is now under clinical development for treatment of congestive heart failure. Two separate studies (one placebo‐controlled) were conducted to evaluate its pharmacokinetics and pharmacodynamics after intravenous administration to a total of 36 healthy male subjects. The drug was administered both rapidly as a .05‐, .1‐, .2‐, or .4‐mg/kg intravenous dose, and as a 1‐hour infusion of .5, 1.0, 2.5, 5.0,10.0, or 15.0 μg/kg/minute. Echocardiograms (ECHO) were evaluated before and immediately and 4 hours after the rapid administrations. Blood pressure (BP), heart rate (HR), and QTc in the electrocardiogram also were monitored in the rapid administration study. OPC‐18790 was generally well tolerated by all subjects. Maximum peak plasma concentration and area under the curve increased linearly with dose in both studies. The t1/2, total body clearance of drug from plasma (CL), and the dose fraction excreted unchanged in the urine (fe) were comparable and dose‐independent at the doses tested in both studies. The overall mean values of t1/2α, t1/2β, CL, and fe were .08 ± .01 hours, 3.64 ± .22 hours, .46 ± .01 L/kg, and 43.5 ± 1.0%, respectively. Echocardiograms showed that, immediately after rapid administration of up to .4 mg/kg, OPC‐18790 increased left cardiac function dose‐proportionally (P < .05 to .01): the ejection fraction by 21.1% and fractional shortening by 26.5% compared with the predose values, blood pressure, heart rate, and QTc did not differ between subjects given OPC‐18790 and these receiving placebo. Intravenous OPC‐18790 at the dose ranges used is considered to be safe and tolerable and exerts positive inotropic effects in a dose‐proportional manner. This drug is potentially useful in the treatment of severe congestive heart failure.
A Placebo‐Controlled Comparative Evaluation of Diclofenac Dispersible Versus Ibuprofen in Postoperative Pain After Third Molar Surgery
Authors: Bakshi R. , Frenkel G. , Dietlein G. , Meurer‐Witt B. , Schneider B. , Sinterhauf U.
Published: March 2013

The analgesic efficacy of single oral doses of drinkable diclofenac dispersible 50 mg was compared with that of Ibuprofen 400 mg and placebo in a randomized, double‐blind, parallel‐group trial in 257 adult patients (245 valid for efficacy) with severe postoperative pain after extraction of an impacted lower third molar. In this study, pain intensity (on a 100‐mm visual analog scale) and pain relief from baseline (using a jive‐point verbal rating scale) were assessed serially during an observation period of 6 hours. Intake of rescue analgesic was permitted in case of insufficient therapeutic effect; however at least 1 hour should have elapsed after test drug consumption. On the main efficacy variable, namely, reduction in the pain intensity score, both diclofenac dispersible (n = 83) and ibuprofen (n = 80) were statistically significantly (P < .01) superior to placebo (n = 82) starting at 20 and 40 minutes, respectively, after drug intake. The active medications were also significantly (P < .01) better than placebo for the secondary efficacy parameters viz. summed pain relief scores over 6 hours (TOTPAR‐6); frequency of remedication with a rescue analgesic in the three treatment groups (diclofenac, 24%; ibuprofen, 28%; placebo, 65%); mean time to remedication; and global evaluation. All the treatments were well tolerated. Thus assay sensitivity of this trial (ibuprofen significantly better than placebo) has been demonstrated; in addition, diclofenac as a dispersible formulation has been shown to be an effective analgesic for the treatment of post‐surgical dental pain.
The Use of Confidence Intervals to Describe the Precision of Trough/Peak Ratios for Diltiazem CD in the Treatment of Hypertension
Authors: Meeves Suzanne G. , Park Glen D.
Published: March 2013

Once‐daily diltiazem hydrochloride, CARDIZEM® CD (diltiazem CD) 300 mg, was evaluated for safety, efficacy, and the relationship between peak and trough antihypertensive ejects in a multicenter, placebo‐controlled, parallel design trial. After a 4‐ to 6‐week placebo baseline period, 111 patients with essential hypertension were randomized to receive placebo or diltiazem CD for a 4‐week treatment period. Diltiazem CD 300 mg lowered supine diastolic and systolic blood pressure at trough significantly more than placebo (‐7.5 mm Hg vs. −1.3 mm Hg, P = 0.0001 and −6.4 mm Hg vs. 0.5 mm Hg, P = 0.0051, respectively). Supine blood pressure was also measured hourly from 6 to 10 hours after the dose to assess peak effect and trough/peak ratios. Using the largest residual drug effect of−6.3 mm Hg at 6 hours as peak and the 24−hour residual drug effect of−5.9 mm Hg as trough, the trough/peak ratio was estimated to be 71%, with a lower one‐sided 95% confidence limit of 50%. The precision of the trough/peak ratio is estimated by the lower confidence limit of 50%, which establishes the trough/peak ratio as statistically ≥ 50%. No statistically significant differences in supine DBP were noted between the peak effect hours, indicating a plateau of the peak antihypertensive effect from 6 to 10 hours post‐dose. Diltiazem CD therapy was well tolerated, with no serious treatment‐related adverse events reported during the trial and no patients discontinuing the trial due to a treatment‐related adverse event. This trial demonstrates diltiazem CD 300 mg is a safe and effective therapy when administered once daily for the treatment of essential hypertension.
Alternatives to Least Squares Linear Regression Analysis for Computation of Standard Curves for Quantitation by High Performance Liquid Chromatography: Applications to Clinical Pharmacology
Authors: Szabo George K. , Browne Hilary K. , Ajami Alfred , Josephs Ephraim G.
Published: March 2013

Standard curves and validation points for high‐performance liquid chromatography (HPLC) determination of four drugs (carbamazepine and phenytoin at therapeutic drug monitoring concentrations and deuterium labeled carbamazepine and phenytoin at tracer dose concentrations) were computed using standard least squares linear regressions analysis and six alternative regression techniques (weighted 1/x, 1/y, 1/x2, 1/y2least squares linear, log/log least squares linear, and robust). The coefficient of determination (R2) and the coefficient of prediction (R2pred) values for standard curves and the computed values for validation points did not differ significantly among the seven methods. The lower limit of quantitation (LLQ) values obtained with all six of the alternative regression methods were significantly (P < .01) lower than the LLQ values obtained with least squares linear regression analysis. The lowest LLQ values were obtained with 1/x2and 1/y2weighting and were threefold to tenfold less than the values obtained with unweighted least squares linear regression analysis (P < .001). The authors conclude that alternative regression analysis techniques (especially 1/x2and 1/y2weighting) offer significant advantages for clinical pharmacology studies when concentration values being measured by HPLC are near the LLQ of the method determined by unweighted least squares linear regression analysis. In other situations, alternative forms of regression analysis had no significant advantages in our study.
Effect of Zatosetron on Ipecac‐Induced Emesis in Dogs and Healthy Men
Authors: Schwartz Steven M. , Goldberg Mark J. , Gidda Jaswant S. , Cerimele Benito J.
Published: March 2013

Serotonin receptor (5‐HT3) antagonists provide effective antiemetic therapy in cancer patients receiving emetogenic chemotherapy, such as cisplatin. Animal studies have shown that 5‐HT3 receptor antagonists also have antiemetic activity in ipecac‐induced emesis. The authors investigated the antiemetic activity of zatosetron maleate, a 5‐HT3 receptor antagonist, on ipecac‐induced emesis in dogs and healthy men. They also evaluated the effect of ipecac administration on serotonin release and metabolism by measuring urinary 5‐hydroxyindoleacetic acid (5‐HIAA) excretion in healthy men. In separate randomized, placebo‐controlled trials, 20 dogs received zatosetron intravenously and eight healthy men received zatosetron (50 mg) orally, followed by ipecac syrup. In both trials, emetic response to ipecac was recorded, including the number and time of vomits and retches. Zatosetron treatment inhibited and delayed ipecac‐induced emesis in both groups. In dogs, zatosetron inhibited ipecac‐induced emesis in a dose‐dependent manner with a 100‐μg/kg dose producing complete inhibition. In men, zatosetron administration resulted in fewer emetic episodes after ipecac than had occurred with placebo administration (P = .03); vomiting was completely inhibited by zatosetron. In men, ipecac administration did not affect the urinary 5‐HIAA/creatinine ratio (mg/g) or 5‐HIAA excretion rate (μg/hour). Our study demonstrates that zatosetron has similar efficacy on ipecac‐induced emesis in healthy men, as has been shown previously with other 5‐HT3 receptor antagonists in chemotherapy‐induced emesis in cancer patients. We did not observe the increase of urinary 5‐HIAA in our study with ipecac‐induced emesis, however, as has been described previously in cisplatin‐induced emesis. Our study indicates that ipecac‐induced emesis may be a useful model for testing 5‐HT3 receptor antagonists for antiemetic activity in dogs and healthy men.
Comparison of the Pharmacokinetics, Pharmacodynamics, and Safety of Oral (Catapres) and Transdermal (M‐5041T) Clonidine in Healthy Subjects
Authors: Fujimura Akio , Ebihara Akio , Ohashi Kyo‐ichi , Shiga Tsuyoshi , Kumagai Yuji , Nakashima Hajime , Kotegawa Tsutomu
Published: March 2013

The pharmacokinetic as well as pharmacodynamic properties of a transdermal clonidine, M‐5041T (M) and its safety were compared with those of oral clonidine, Catapres (Nippon Boehringer Ingelheim, Hyogo, Japan). One patch of M containing 6 mg of clonidine was applied on the right chest for 3 days or one tablet of Catapres (.075 mg) was given orally every 12 hours for 3 days in eight healthy subjects. The study was conducted by a crossover design with 14 to 16 days' interval between the cross‐over. Blood and urine samples for clonidine concentration were obtained, and blood pressure (BP) was measured for a 168‐hour period after application of M and for a 96‐hour period after initiation of Catapres therapy. Plasma concentration of clonidine increased gradually after application of M and decreased gradually after removal, whereas this parameter increased rapidly during the absorption phase and decreased rapidly in the elimination phase after each dosage of Catapres. Elimination half‐life of clonidine after removal of M was significantly greater than that after the final dosage of Catapres. No significant difference was observed in maximum plasma concentration or area under the plasma concentration ‐time curve between the two trials. The BP lowering effects of M and Catapres did not differ significantly. Adverse symptoms occurred more frequently during Catapres therapy than during treatment with M. Most of these symptoms were observed when plasma clonidine concentration was relatively higher in each trial. These results suggest that M is effective for the treatment of hypertension with a lower incidence of adverse symptoms. Because the current study was nonblind and involved small number of subjects, however, a large controlled study is needed to evaluate its safety further.
Ischemic Hepatitis in a Patient with Congestive Cardiomyopathy: An Innovative Approach to Therapy Using Intravenous Dobutamine
Authors: Levy Daniel K. , Schwartz Jonathan M. , Frishman William H. , Schwarz Michael L. , LeJemtel Thierry H.
Published: March 2013

Patients who sustain a transient period of hypotension or low cardiac output can develop massive elevations of the serum transaminases without serum markers of acute hepatitis, a recent myocardial infarction or exposure to toxins and chemicals. This condition is often termed “ischemic hepatitis” (IH), with its pathological correlate being centrilobular necrosis. Recognition of IH can help in the appropriate management of these patients, and avoid unnecessary diagnostic testing. The authors describe a patient with congestive cardiomyopathy in whom IH developed as part of a complicated hospital course. The condition appeared to reverse with the administration of dobutamine, suggesting inotropic therapy as an appropriate treatment modality.
Drugs and Endogenous Ligands Compete for Receptor Occupancy
Authors: Colburn Wayne A.
Published: March 2013

Dietary and endogenous ligands compete with drugs for receptor occupancy and therefore should be considered during therapeutic interventions and during pharmacokinetic/pharmacodynamic modeling. When disease is the result of an overabundance of these natural ligands, antibodies and/or their Fab fragments may be useful as therapeutic agents to reverse the effects of the natural ligands.
Pyrazinoylguanidine Downregulates the Glucose Fatty‐Acid Cycle in Hypertensive, Hyperinsulinemic Diabetic Patients
Authors: Vesell Elliot S. , Chambers Charles E. , Seaton Theresa DeAngelo , Passananti G. Thomas , Demers Laurence M. , Beyer Karl H.
Published: March 2013

Eight hypertensive patients with noninsulin dependent diabetes mellitus (NIDDM) were administered the experimental drug pyrazinoylguanidine (PZG) either alone or in combination with calcium‐channel or β‐blockers. This treatment appeared to “downregulate” the glucose fatty acid cycle and reduced both systolic and diastolic blood pressures and mean body weight. Patients served as their own controls in this dose‐escalation study, which included placebo treatment (baseline) 3 weeks, 300 mg PZG for 3 weeks and 600 mg for 3 weeks. PZG reduced increased serum concentrations of free fatty acids (FFA), glucose, and triglycerides (TG). TG concentrations correlated inversely with serum HDL‐cholesterol concentrations. The beta‐blockers used by several patients increased their FFA, glucose, insulin and TG concentrations, as well as blunting their response to PZG. The calcium‐channel blockers exerted these effects to a much lesser extent. PZG reduced or abolished glycosuria, related to PZG's capacity to decrease hyperglycemia. Withdrawal of PZG restored glycosuria, as blood sugar increased. PZG was well tolerated. No patient reported any adverse effect or missed a weekly clinic visit (12 weeks). PZG deserves further study as supplementary and/or replacement therapy in NIDDM patients who are hypertensive and hyperlipidemic.
A Comprehensive Guyton Model Analysis of Physiologic Responses to Preadapting the Blood Volume as a Countermeasure to Fluid Shifts
Authors: Simanonok Karl E. , Srinivasan R. Srini , Myrick Emily E. , Blomkalns Andra L. , Charles John B.
Published: March 2013

The Guyton model of fluid, electrolyte, and circulatory regulation is an extensive mathematical model capable of simulating a variety of experimental conditions. It has been modified for use at NASA to simulate head‐down tilt, a frequently used analog of weightlessness. Weightlessness causes a headword shift of body fluids that is believed to expand central blood volume, triggering a series of physiologic responses resulting in large losses of body fluids. We used the modified Guyton model to test the hypothesis that preadaptation of the blood volume before weightless exposure could counteract the central volume expansion caused by fluid shifts, and thereby attenuate the circulatory and renal responses that result in body fluid losses. Simulation results show that circulatory preadaptation, by a procedure resembling blood donation immediately before head‐down bedrest, is effective in damping the physiologic responses to fluid shifts and reducing body fluid losses. After 10 hours of head‐down tilt, preadaptation also produces higher blood volume, extracellular volume, and total body water for 20 to 30 days of bedrest, compared with non‐preadapted control. These results indicate that circulatory preadaptation before current Space Shuttle missions may be beneficial for the maintenance of reentry and postflight orthostatic tolerance in astronauts. This paper presents a comprehensive examination of the simulation results pertaining to changes in relevant physiologic variables produced by blood volume reduction before a prolonged head‐down tilt. The objectives were to study and develop the countermeasure theoretically, to aid in planning experimental studies of the countermeasure, and to identify potentially disadvantageous physiologic responses that may be caused by the countermeasure.
The Spectrum of Syncope
Authors: Schraeder Paul L. , Lathers Claire M. , Charles John B.
Published: March 2013

Syncope is a loss of consciousness and postural tone. Although arising suddenly from prolonged recumbency or returning from weightlessness to Earth's gravity can result in syncope from orthostatic or vasovagal effects, there are many other possible causes. These causes can he divided into several groups. Causes listed in the cardiovascular category, especially cardiac causes, are more likely to occur in the elderly; noncardiac causes are more common in the younger population. The cases described herein illustrate the often unexpected mechanisms of syncope in otherwise healthy individuals. Two of the cases emphasize the usefulness of prolonged combined EEG/EKG monitoring. The categories of loss of consciousness experienced by air crew members are reviewed. The most important screening tool in identifying the mechanism(s) of syncope is a detailed history emphasizing a search for underlying disease, the specific associated circumstances, and pre‐ and post‐event symptoms. The type of diagnostic studies, i.e., cardiac or neurologic, undertaken should be based on the historical data. Seizures must be considered as a possible mechanism of otherwise unexplained loss of consciousness in nonelderly persons, including air crew members.
Mechanisms of Vasovagal Syncope: Relevance to Postflight Orthostatic Intolerance
Authors: Smith Michael L.
Published: March 2013

Orthostatic intolerance can present a very serious limitation to astronauts attempting any junctions requiring the upright position. Vasovagal syncope is a common cause of fainting characterized by paradoxic bradycardia and vasodilation in the presence of decreasing arterial pressure. Several mechanisms have been proposed to mediate vasovagal syncope and it seems likely that redundant mechanisms exist both centrally and peripherally which can mediate these responses. Spaceflight alters reflex control of cardiovascular function in several ways which may influence susceptibility to vasovagal syncope provoked by the Bezold‐Jarisch reflex.
Preinflation Before Acceleration on Tolerance to Simulated Space Shuttle Reentry G Profiles in Dehydrated Subjects
Authors: Krutz R. W. , Sawin C. F. , Stegmann B. J. , Burton R. R.
Published: March 2013

This study was conducted to determine if preinflation of a standard five‐bladder anti‐g suit 10 minutes before exposure to a centrifuge simulation of a Space Shuttle reentry would provide significantly better protection against orthostasis than the standard symptomatic inflation regimen. This study differed significantly from prior studies: The rate of g onset was slower, peak g was lower, duration of exposure was longer, and the subjects were dehydrated to mimic conditions observed in astronauts immediately postflight. Preinflation demonstrated physiological advantages as determined by arterial blood pressure and heart rate changes in seven healthy male, experienced centrifuge subjects.
Comparison of Cardiovascular Function During the Early Hours of Bed Rest and Space Flight
Authors: Lathers Claire M. , Charles John B.
Published: March 2013

This paper reviews the cardiovascular responses of six healthy male subjects to 6 hours in a 5° head‐down bed rest model of weightlessness, and compares these responses to those obtained when subjects were positioned in head‐up tilts of 10°, 20°, and 42°, simulating 1/6, 1/3, and 2/3 G, respectively. Thoracic fluid index, cardiac output, stroke volume, and peak flow were measured using impedance cardiography. Cardiac dimensions and volumes were determined from two‐dimensional guided M‐mode echocardiograms in the left lateral decubitus position at 0, 2, 4, and 6 hours. Cardiovascular responses to a stand test were compared before and after bed rest. The impedance values were related to tilt angle for the first 2 hours of tilt; however, after 3 hours, at all four angles, values began to converge, indicating that cardiovascular homeostatic mechanisms seek a common adapted state, regardless of effective gravity level (tilt angle) up to 2/3 G. Echocardiography revealed that left ventricular end‐diastolic and end‐systolic volume, stroke volume, ejection fraction, heart rate, and cardiac output had returned to control values by hour 6 for all tilt angles. The lack of a significant immediate change in left ventricular end‐diastolic volume, despite decrements in stroke volume (P < .05) and heart rate (not significant), indicates that multiple factors may play a role in the adaptation to simulated hypogravity. The echocardiography data indicated that no angle of tilt, whether head‐down or head‐up for 4 to 6 hours, mimicked exactly the changes in cardiovascular function recorded after 4 to 6 hours of space flight. Changes in left ventricular end‐diastolic volume during space flight and tilt may be similar, but follow a different time course. Nevertheless, head‐down tilt at 5° for 6 hours mimics some (stroke volume, systolic and diastolic blood pressure, mean arterial blood pressure, and total resistance), but not all, of the changes occurring in an equivalent time of space flight. The magnitude of the change in the mean heart rate response to standing was greater after six hours of tilt at −5° or 10°. Thus, results from the stand test after 6 hours of bed rest at −5° and 10°, but not at 20° or 42°, are similar to those obtained after space flight.
Short‐Term Space Flight on Nitrogenous Compounds, Lipoproteins, and Serum Proteins
Authors: Leach Carolyn S. , Lane Helen W. , Krauhs Jane M.
Published: March 2013

Biochemical variables in blood were measured in venous blood samples from 38 to 72 Space Shuttle astronauts before and immediately after flights of 2 to 11 days. Mean pre‐ and postflight values were compared using the paired t‐test or the Wilcoxon signed‐rank test. The largest change in serum enzymes was a 21% increase (P = .0014) in γ‐glutamyltranspeptidase, which may have been related to stress. The median value of apolipoprotein (apo) A‐I decreased from 152 to 127 mg/dL (P > .0001), but the change in apo B (77 to 73 mg/dL) was not statistically significant, and the mean apo A‐I/apo B ratio remained well above 1.5. A decrease in dietary fat and cholesterol intake during shuttle missions may have been a cause of the change in apo A‐I. Twelve of the 16 nonenzyme serum proteins measured were significantly elevated (P > .05), possibly because of hemoconcentration and increased protein catabolism. The 56% increase in haptoglobin may be related to release of suppressed erythropoiesis at landing.
Surgical Problems in Space: An Overview
Authors: McCuaig Katherine
Published: March 2013

Terrestrial experience indicates that surgical emergencies may cause significant morbidity in space, and may present unique problems. Microgravity physiologic changes that may increase susceptibility to, and complications from, injury include fluid redistribution and diuresis, bone demineralization, and immune system alterations. Conventional diagnostic tests may be unavailable or unreliable—e.g. the radiologic finding of “air under the diaphragm”, which conventionally indicates perforation of an air‐containing hollow viscus, such as the stomach, with a gravity‐dependent rising of gas in the abdominal cavity to collect under the diaphragm. Microgravity surgical experience is limited, but studies conducted in the U.S.S.R. and on KC‐135 aircraft indicate that, although surgical procedures are possible, weight and volume constraints, lack of gravity, altered fluid mechanics, and risk of environmental contamination mandate considerable modifications of conventional equipment and technique.
Comparison of Equations for Predicting Bound Serum Concentrations of Carbamazepine and Carbamazepine‐10, 11‐epoxide After Polytherapy in Patients with Epilepsy
Authors: Kodama Yasuo , Kuranari Masae , Kodama Hirofumi , Tsutsumi Kimiko , Fujii Isao , Takeyama Masaharu
Published: March 2013

In a previous study, an equation with in vivo population binding parameters of carbamazepine and carbamazepine‐10, 11‐epoxide (CBZ‐E) to serum proteins for the relation between unbound and bound serum concentrations was defined. A review by Pynnönen indicates that the average bound/unbound plasma fraction ratio is 3.0 for carbamazepine and 1.0 for CBZ‐E. In this study, the ability of equations with in vivo population binding parameters of the previous study (method 1) or with the average bound/unbound plasma fraction ratio of 3.0 of Pynnönen (method 2) to predict the bound serum carbamazepine concentration was retrospectively evaluated using 85 serum samples from 46 patients with epilepsy taking carbamazepine polytherapy. In 21 serum samples from 16 patients, the ability of these equations to predict bound serum CBZ‐E concentration was also determined with in vivo population binding parameters from the previous study (method A) or with the average bound/unbound plasma fraction ratio of 1.0 of Pynnönen (method B). Mean prediction error, mean absolute prediction error (MAE), and root mean squared error (RMSE) were calculated for each method, and these values served as a measure of prediction bias and precision. Method 1 showed a bias to overpredict bound serum carbamazepine. The MAE and RMSE were significantly smaller with method 2 (MAE = 2.4 μmol/L; RMSE = 3.2 μmol/L) than with method 1 (MAE = 4.1 μmol/L; RMSE = 4.8 μmol/L). Method 2 was superior to method 1 in terms of accuracy and precision. For bound CBZ‐E prediction, method B had a bias to underprediction. The MAE and RMSE were smaller with method A (MAE = 0.581 μmol/L; RMSE = 0.796 μmol/L) than with method B (MAE = 0.724 μmol/L; RMSE = 0.905 μmol/L). Method A was superior to method B in terms of accuracy and precision.
Comparison of Amlodipine and Benazepril Monotherapy to Amlodipine Plus Benazepril In Patients with Systemic Hypertension: A Randomized, Double‐Blind, Placebo‐Controlled, Parallel‐Group Study
Authors: Frishman William H. , Ram C. Venkata S. , McMahon F. Gilbert , Chrysant Steven G. , Graff Alan , Kupiec James W. , Hsu Huang
Published: March 2013

A single‐blind, run‐in, randomized, double‐blind, parallel‐group, placebo‐controlled comparison trial was conducted to assess the safety and efficacy of low‐dose amlodipine 2.5 mg daily, low‐dose benazepril 10 mg daily, and the combination of the two drugs at the same doses used once daily in patients (n = 401) with mild to moderate (stages I and II) systemic hypertension. Both monotherapy regimens were shown to significantly reduce both systolic and diastolic blood pressure compared with baseline placebo values, and the combination regimen was shown to be superior in lowering systolic and diastolic blood pressure when compared with either of the monotherapy regimens. The combination therapy also resulted in a greater percentage of patients having successful clinical response in mean sitting diastolic blood pressure. The amlodipine and benazepril regimen was also shown to be associated with a similar incidence of adverse experiences as the active monotherapy or placebo regimens, although the group given combination therapy appeared to have a lower incidence of edema than the group given amlodipine alone. Low‐dose amlodipine (2.5 mg) plus benazepril (10 mg) provides greater blood‐pressure‐lowering efficacy than either monotherapy, and has an excellent safety profile.
Review of Limited Systemic Absorption of Orlistat, a Lipase Inhibitor, in Healthy Human Volunteers
Authors: Zhi Jianguo , Melia Angela T. , Eggers Herwig , Joly Raymond , Patel Indravadan H.
Published: March 2013

Orlistat, a lipase inhibitor, acts locally in the gastrointestinal tract. Systemic absorption is not required for its efficacy, but knowledge of the extent of its systemic absorption is important for its safe use in obese patients, the intended target population. Pharmacokinetic screening was carried out by monitoring plasma concentrations of unchanged orlistat in 25 phase 1 studies (including two mass balance studies) in normal and obese healthy volunteers. The results of these studies indicate an extremely low degree of systemic absorption for orlistat when administered with a hypocaloric, well‐balanced diet with 20% to 30% of calories derived from fat (50–80 gm). To further characterize the pharmacokinetics and excretion pathways of orlistat, two mass balance studies using 14C‐labeled orlistat were conducted. After oral dosing of radiolabeled orlistat with a fatty meal (28–30 gm fat), almost the entire dose was recovered from fecal samples; little was found in plasma and urine. It is concluded that systemic absorption of orlistat is negligible; at a clinically efficacious dose level, orlistat is unlikely to produce systemic lipase inhibition.