Investigation of (d, 3n) reaction cross section using theoretical nuclear codes calculations on some nuclear materials.

It is important to examine the effects of the nuclear reaction, which is used as a building material in nuclear reactors. Nuclear reactions occur as a result of the interaction between incident particles with the target nuclei. The charged particle-induced reactions have prime importance in understanding the reaction mechanism which can be applicable to understand the particles resulting from the reaction. It is useful to develop shielding the particle accelerators and fusion reactors. The present study contributes to providing the theoretical prediction of excitation functions for 112Cd (d, 3n)111In, 141Pr (d, 3n)140Nd, 167Er (d, 3n)166Tm, 197Au (d, 3n)196Hg and 209Bi (d, 3n)208Po reactions using theoretical model codes such as TALYS-1.95, EMPIRE-3.2.3, and ALICE-2014 within the incident deuteron energy range of threshold energy to 50 MeV. Also, newly developed (d, 3n) cross-section formula (Kavun, 2020) calculations have been performed for these reactions at 20 MeV of deuteron energy. Lastly, all calculated results have been compared with one another and with the previously published experimental data of the EXFOR database.

A first-in-human study of DS-1040, an inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor, in healthy subjects.

Essentials DS-1040 inhibits the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa). Infusion of DS-1040 was safe and well tolerated in healthy young and elderly subjects. DS-1040 substantially decreased TAFIa activity but had no impact on bleeding time. DS-1040 may provide an option of safer thrombolytic therapy. SUMMARY: Background Current treatments for acute ischemic stroke and venous thromboembolism, such as recombinant tissue-type plasminogen activator and thrombectomy, are limited by a narrow time window and the risk of bleeding. DS-1040 is a novel low molecular weight compound that inhibits the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa), and was developed as a fibrinolysis enhancer for the treatment of thromboembolic diseases. Objectives This first-in-human, randomized, placebo-controlled, three-part, phase 1 study was conducted to evaluate the safety, pharmacokinetics and pharmacodynamics of DS-1040 in healthy subjects. Subjects/Methods Young (18-45 years) or elderly (65-75 years) subjects (N = 103) were randomized to receive single ascending doses of DS-1040 ranging from 0.1 mg to 40 mg, or placebo, administered either as a 0.5-h intravenous infusion or as a 24-h continuous infusion. Results All doses of DS-1040 were tolerated, and no serious adverse events (AEs) or discontinuations resulting from AEs occurred during the study. Bleeding time remained within the normal range for all doses tested in all subjects. Plasma exposure of DS-1040 increased proportionally with increase in dose. Elderly subjects had higher exposures to DS-1040 and prolonged elimination times, probably because of decreased renal clearance. DS-1040 caused a substantial dose-dependent and time-dependent decrease in TAFIa activity and in 50% clot lysis time. The levels of D-dimer, indicative of endogenous fibrinolysis, increased in some individuals following DS-1040 treatment. No effects of DS-1040 on coagulation parameters or platelet aggregation were observed. Conclusions The novel fibrinolysis-enhancing agent DS-1040 has favorable pharmacokinetic/pharmacodynamic properties and a favorable safety profile, warranting further clinical development.

The effects of hepatic impairment on the pharmacokinetics of doxazosin.

The pharmacokinetics of doxazosin was determined in an open-label study of 12 male volunteers with hepatic impairment (stable alcoholic cirrhosis) and 12 healthy male volunteers. Participants (fasting) received a single 2 mg doxazosin tablet, and blood samples were collected over a 120-hour period. Safety assessments included laboratory and vital sign (blood pressure, pulse rate, and ECGs) measurements and recording of all reported adverse events. The mean peak plasma concentrations were 10.8 ng/mL and 12.3 ng/mL for the subjects with hepatic impairment and healthy subjects, respectively. The corresponding mean area under the plasma concentration-time curve values were 246 and 172 ng.h/mL, a 43% increase in exposure in the subjects with hepatic impairment (p = 0.02). Although the apparent oral clearance was reduced by 30% in men with hepatic impairment compared with healthy subjects (p = 0.02), the elimination halflife was not significantly changed (24 vs. 22 hours, respectively). Laboratory test results, vital signs, and the incidence of adverse events were similar for the two treatment groups. These findings indicate that the recommended dosing regimen for doxazosin is appropriate for patients with clinically mild to moderate hepatic impairment.

Clinical pharmacokinetics of doxazosin in a controlled-release gastrointestinal therapeutic system (GITS) formulation.

AIMS: A controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin mesylate, a long-acting selective alpha1-adrenoceptor antagonist, was developed to enhance the pharmacokinetic profile and simplify the titration schedule by precisely controlling drug delivery rate, permitting an initial dose of 4 mg once daily, compared with standard doxazosin, which is initiated at 1 mg day-1 and titrated to a higher therapeutically effective dose. The aim of the present work was to evaluate the pharmacokinetics and bioavailability of doxazosin GITS with respect to the effect of food, age and gender, and multiple dosing. In addition, in vitro performance was assessed in conditions simulating the gastrointestinal environment. METHODS: A three-way crossover study in 24 subjects assessed the comparative bioavailability of doxazosin GITS under fed and fasting conditions and doxazosin standard under fasting condition. A multiple-dose, two-way crossover study in 35 subjects assessed the comparative pharmacokinetics and bioavailability of doxazosin GITS and doxazosin standard 4 and 8 mg upon multiple dosing. A multiple-dose, four-parallel-group study was conducted to determine the steady-state pharmacokinetics and bioavailability of doxazosin GITS 4 mg in 41 young and elderly male and female subjects. The release-rate profiles of doxazosin GITS were determined in artificial gastric fluid (pH=1.2), intestinal fluid (pH=7.5), and water. The effect of agitation on the dissolution characteristics of doxazosin GITS in artificial gastric fluid was studied at stirring rates of 50, 75, and 100 rev min-1. RESULTS: In vitro studies demonstrated that release rates for the GITS tablet are independent of pH in the range of 1.2 (gastric) to 7. 5 (intestinal), and of stirring rates simulating gastrointestinal motility. Clinical pharmacology studies showed that doxazosin GITS had a lower maximum plasma concentration, prolonged time to reach maximum plasma concentration, and a higher minimum plasma concentration compared with doxazosin standard. Thus, the GITS formulation results in a more gradual absorption of doxazosin, and a reduced plasma doxazosin concentration peak-to-trough fluctuation ratio. The relative bioavailability of doxazosin GITS is approximately 60%. With a high-fat meal, the maximum plasma concentration and area under the concentration-time curve were 31% and 18% higher, respectively (P<0.05). Bioequivalence was established between the dose strengths of two 4 mg doxazosin GITS tablets and one 8 mg doxazosin GITS tablet. For both young adult and elderly subjects, and males and females, the pharmacokinetics of doxazosin GITS once daily for 7 days were comparable. Doxazosin GITS was well tolerated in the subjects studied, including young and elderly males and females. CONCLUSIONS: The GITS formulation of doxazosin enhances the pharmacokinetic profile compared with doxazosin standard, allowing more gradual absorption of doxazosin, and a reduced plasma doxazosin peak-to-trough concentration ratio. Thus, doxazosin GITS therapy can be initiated at a therapeutic dose of 4 mg with reduced haemodynamic side-effects.

Pharmacokinetics of ampicillin and sulbactam in pediatric patients.

Intravenous ampicillin-sulbactam is effective in the treatment of various infections in adults, but little is known about the pharmacokinetics (PK) of ampicillin-sulbactam in children. The objective of this study was to determine the PK of ampicillin and sulbactam in pediatric patients with intra-abdominal infection, skin and/or skin structure infection, or periorbital-preseptal and facial cellulitis. Intravenous ampicillin and sulbactam (2:1), 40 to 80 mg/kg of body weight, were given every 6 h for 2 to 6 days to 28 pediatric patients. The ages ranged from 1 to 6 years for 10 patients, 6.1 to 10 years for 9 patients, and 10.1 to 12 years for 9 patients. Multiple blood samples were obtained and analyzed for ampicillin and sulbactam in plasma and serum by high-performance liquid chromatography. The mean maximum concentration of drug in serum ranged from 177 to 200 micrograms/ml for ampicillin and 82 to 102 micrograms/ml for sulbactam in the three age groups. The mean total clearance, steady-state distribution volume, and half-life were 4.76 ml/min/kg, 0.32 liter/kg, and 0.77 h, respectively, for ampicillin and 4.95 ml/min/kg, 0.34 liter/kg, and 0.81 h, respectively, for sulbactam. Dose or gender did not affect the PK of ampicillin or sulbactam. The PK of ampicillin and sulbactam in these patients were comparable to those reported in adults. The combination was well tolerated in pediatric patients.

Clinical correlation of maximal urinary flow rate and plasma doxazosin concentrations in the treatment of benign prostatic hyperplasia. Multicenter Study Group.

OBJECTIVES: To investigate the relationship among doxazosin dose, plasma concentration, and clinical response in 248 hypertensive men with benign prostatic hyperplasia (BPH) in a 16-week, placebo-controlled, double-blind study. METHODS: After a 2-week placebo run-in period, patients were randomized to treatment with either doxazosin (titrated to doses of 2, 4, 8, or 12 mg once daily) or placebo. After 6, 10, and 14 weeks, plasma concentrations of doxazosin were measured at 2 to 6 hours (peak) and approximately 24 hours (trough) after dosing. Changes in maximal urinary flow rate (Qmax) compared with baseline were measured at the same time points. Patients recorded their symptoms in a daily diary and completed a questionnaire at weeks 2, 8, and 16 to assess both obstructive and irritative BPH symptoms. In addition, BPH symptoms were assessed by the investigator at each study visit. RESULTS: Steady-state peak and trough plasma doxazosin concentrations were achieved by 6 weeks of therapy and were maintained between 6 and 14 weeks of active treatment. Peak and trough plasma concentrations increased linearly within the dose range of 2 to 12 mg and were positively correlated with a corresponding mean improvement in Qmax (P = 0.001 and P = 0.008, respectively), consistent with a 24-hour once-daily dosing of doxazosin. Clinical response to doxazosin plateaued at peak and trough plasma concentrations of between 60 and 80 ng/mL and 25 ng/mL, respectively, corresponding to a dose of 8 mg daily. Patient assessment of obstructive BPH symptoms showed significant improvement in the 4- and 8-mg doxazosin treatment groups compared with placebo. CONCLUSIONS: In patients with BPH, both doxazosin plasma concentration and Qmax increased linearly with increasing dose, in the range of 2 to 8 mg daily. The maximal therapeutic dosage of doxazosin would appear to be 8 mg in this group of BPH patients. Further studies are required to support these findings.

Pharmacokinetic interaction between finasteride and terazosin, but not finasteride and doxazosin.

The alpha 1-adrenoceptor antagonists doxazosin and terazosin and the 5 alpha-reductase inhibitor finasteride are used in the treatment of benign prostatic hyperplasia. The aim of this study was to assess the potential pharmacokinetic interaction of doxazosin or terazosin when coadministered with finasteride. This was a randomized, placebo-controlled, multi-center study. Ninety healthy men were assigned to one of six treatment groups: doxazosin; doxazosin plus finasteride; terazosin; terazosin plus finasteride; placebo; and placebo plus finasteride. Plasma concentrations, maximum plasma concentration (Cmax), time to maximum concentration (tmax), and area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) of doxazosin, terazosin, and finasteride were determined. Ratios of Cmax and AUC for doxazosin and terazosin were not significantly altered by coadministration with finasteride. The Cmax and AUC0-24 of finasteride were not significantly altered by coadministration with doxazosin. However, Cmax and AUC0-24 of finasteride were significantly higher after coadministration with terazosin. There is no statistically significant pharmacokinetic interaction between finasteride and doxazosin; however, there is a statistically significant interaction between finasteride and terazosin, which affects the pharmacokinetics of finasteride but not those of terazosin. The clinical significance of this interaction remains to be determined.

Effect of time of administration on the pharmacokinetics and tolerance of doxazosin in healthy male volunteers.

A randomized, open-label, two-way crossover study of 24 normotensive, healthy male volunteers with nocturia was conducted to compare morning and evening administration of doxazosin in terms of pharmacokinetics and tolerance. In both the morning and evening phases, participants received doxazosin 1 mg once daily for 10 days, followed by 2 mg once daily for 5 days. Pharmacokinetic data were evaluated from blood samples serially collected for 72 hours after drug administration on the last day of each phase. Vital signs and adverse events were recorded throughout the study. Mean peak plasma concentrations (C(max)) were 16.98 and 15.76 ng/mL after morning and evening administration, respectively. Corresponding mean values of area under the plasma concentration-time curve (AUC0-24) were 227.90 and 253.66 ng.hr/mL, respectively. Statistical analysis of the log-transformed values for C(max) and AUC0-24 indicated that morning and evening administration of doxazosin were bioequivalent. There were no statistically or clinically significant differences between phases for mean apparent half-life (t1/2) or total body clearance. There were no clinically relevant differences in blood pressure or in pulse rate between phases, and no occurrences of orthostatic hypotension. The incidence of adverse experiences during morning and evening administration was similar. Morning and evening administration of doxazosin are equivalent and have similar tolerance profiles.

The effect of gastric pH on the absorption of controlled-release theophylline dosage forms in humans.

The bioavailability of three marketed controlled-release dosage forms and a reference solution of theophylline was studied in eight subjects with normal gastric fluid acidity and seven subjects who were achlorhydric. Gastric pH was monitored with a Heidelberg capsule. One of the controlled-release dosage forms dissolved more rapidly in vitro when exposed to acid conditions, one dissolved more rapidly in pH 7.5 media, and the third dissolved at a rate independent of pH. Using a crossover design, each subject received each dosage form twice. Blood was sampled for up to 47 hr after each dose, and serum was assayed for theophylline by HPLC. The product which dissolved more rapidly under acid conditions in vitro exhibited a 3 hr longer Tmax in the achlorhydrics compared to the normal subjects. The product which dissolved more rapidly in the pH 7.5 media exhibited a relatively higher AUC(0-infinity) in the achlorhydric subjects than in normal subjects after the AUC data were normalized for clearance differences between the two subject groups. The in vivo bioavailability of these dosage forms could be related to the in vitro dissolution characteristics for some parameters. However, with the exception of the mean Tmax values, the mean bioavailability parameters differed by less than 20% between the two subjects groups.

The effect of raising gastric pH with ranitidine on the absorption and elimination of theophylline from a sustained-release theophylline tablet.

Prior to evaluating the effect of ranitidine on theophylline absorption from a sustained-release theophylline tablet, the effect of ranitidine on the time course of gastric pH in 12 healthy subjects was evaluated with an encapsulated radio-telemetry device (Heidelberg capsule). Gastric pH was measured hourly from 7 AM to 1 PM prior to beginning ranitidine treatment at 2 PM (150 mg every 4 hr for eight doses). The next day, pH was again measured hourly from 7 AM to 7 PM. Subjects fasted overnight and remained fasted until lunch at 11 AM. Prior to ranitidine treatment, the mean morning gastric pH remained between 1.5 and 2.2. After lunch, the pH increased to 2.2-2.3. During ranitidine treatment the mean morning gastric pH measurements were 5.5 to 5.8, decreasing after lunch to 3.1 by 4 PM and increasing to 3.9 at 7 PM. One week later the subjects participated in a three-way crossover theophylline bioavailability study receiving at weekly intervals, single doses at 7 AM of (a) 5 x 100-mg immediate-release tablets, (b) 2 x 300-mg sustained-release theophylline tablets, and (c) 2 x 300-mg sustained-release theophylline tablets after ranitidine pretreatment of 150 mg every 4 hr beginning at 2 PM the previous day. The increase in gastric pH with ranitidine had no effect (P greater than 0.05) on the rate and extent of absorption or on the elimination rate of theophylline.

Effect of pH on the in vitro dissolution and in vivo absorption of controlled-release theophylline in dogs.

Dogs were used to examine the effect of elevated gastric pH on the absorption of controlled-released theophylline dosage forms with pH-dependent dissolution. In vitro studies showed that a controlled-release theophylline tablet dissolved more rapidly if it was initially exposed to an acidic media. In contrast, a controlled-release theophylline beaded capsule was slightly more rapidly dissolved in the absence of an initial exposure to an acidic media. Gastric pH was increased from 0.5-2.5 to 4.5-7.0 in four dogs by using 150-mg ranitidine HCl tablets, administered every 3 h, to induce an achlorhydric condition. Gastric pH was monitored using a Heidelberg capsule. Ranitidine was shown to have no apparent effect on the absorption or clearance of theophylline administered to the dogs as an oral liquid. The mean area under the concentration-time curve to infinity (AUCinf) for the controlled-release theophylline tablet was 21% greater (p less than 0.05) when administered to the four dogs without ranitidine treatment, compared with that following dosing with ranitidine. In contrast, the controlled-release beaded capsule exhibited a 10% greater AUCinf when ranitidine was given concomitantly. In general, ranitidine-induced changes in the in vivo absorption rate parameters for both dosage forms were opposite to those predicted from the in vitro dissolution rates. The results of this study demonstrated that the extent of theophylline absorption from controlled-release dosage forms, in control dogs and dogs with ranitidine-induced achlorhydria, corresponds to the pH-dependent in vitro dissolution properties of the products.