bluuebunny/crossref_metadata_2025 huggingface dataset:
The Pharmacokinetics and Pharmacodynamics of Irbesartan in Heart Failure
Authors: Kostis John B. , Vachharajani Nimish N. , Hadjilambris Ophelia W. , Kollia Georgia D. , Palmisano Maria , Marino Maria R.
Published: September 2022

Alterations m the pharmacokinetic parameters of a number of medications have been observed in patients with heart failure. Because the angiotensin II receptor antagonist irbesartan has beneficial effects in patients with heart failure, the pharmacokinetics and pharmacodynamics of irbesartan in 10 patients with New York Heart Association (NYHA) class II or III heart failure compared with 10 control subjects matched with respect to race, age, weight, and sex were studied. In a crossover study, participants were randomized to receive open‐label irbesartan 75 mg as either an oral capsule or an intravenous (IV) infusion in the first treatment period. After a 7‐ to 10‐day washout period, participants were crossed over to the other treatment arm. Single‐dose noncompartmental pharmacokinetic parameters, angiotensin II levels, and plasma renin activity (PRA) of irbesartan were determined for each participant. Following oral and IV administration, the pharmacokinetics of irbesartan in patients with heart failure was not significantly different from those of matched controls, indicating that there is little influence of potential changes in organ/tissue perfusion and gut edema on the absorption, distribution, and elimination of irbesartan. After dosing with irbesartan, mean increases in angiotensin II and PRA concentrations were higher in patients with heart failure than in the matched controls, but there was more interpatient variability in the patients with heart failure. Given the variability of the data, no definitive conclusions can be made with regard to these pharmacodynamic parameters. The results of this study indicate that the pharmacokinetics of irbesartan following oral and IV administration is not altered in patients with heart failure. Therefore, this indicates that no dosage adjustment is needed when prescribing irbesartan in heart failure patients.
Pharmacokinetics, Excretion, and Mass Balance of 14C after Administration of 14C‐Cholesterol‐Labeled AmBisome to Healthy Volunteers
Authors: Bekersky Ihor , Fielding Robert M. , Dressler Dawna E. , Kline Sandra , Buell Donald N. , Walsh Thomas J.
Published: September 2022

Amphotericin B (AmB) in small unilamellar liposomes (AmBisome) provides higher plasma concentrations and greater safety than the conventional deoxycholate formulation. The authors compared the disposition of the liposome's drug and cholesterol components by measuring AmB and radioactivity in plasma, urine, and feces for 1 week after a single 2‐hour infusion of 14C‐cholesterol‐labeled AmBisome (2 mg/kg, 1 μCi/kg) in healthy adults (4 males, 1 female). The plasma profile of 14C‐cholesterol differed from that of AmB, lacking an initial rapid disappearance phase, having a lower total clearance, and having a volume of distribution (0.13 L/kg) close to that of the plasma compartment. The biphasic disappearance and long plasma half‐life (147 h) of 14C‐cholesterol were similar to those of other low‐clearance liposomes. This and the low clearance of 14C‐cholesterol from the plasma compartment suggest that it served as a liposome marker. The plasma drug‐lipid ratio fell during the study, showing that AmB was cleared from plasma more rapidly than cholesterol or liposomes and suggesting that the composition of the liposomes changed over time. 14C‐radioactivity was recovered mainly in the feces (9.5% of dose), consistent with the catabolism of cholesterol to bile salts. Combined fecal and renal clearances were < 18% of total clearance, suggesting that most of the liposomal drug and lipid remained in the body 1 week after dosing. Thus, AmBisome remains in the circulation for an extended period of time while releasing AmB, resulting in its markedly altered pharmacokinetic and safety profiles.
Effects of Celecoxib and Diclofenac on Blood Pressure, Renal Function, and Vasoactive Prostanoids in Young and Elderly Subjects
Authors: Dilger Karin , Herrlinger Charlotte , Peters Jörg , Seyberth Hannsjörg W. , Schweer Horst , Klotz Ulrich
Published: September 2022

Cyclooxygenase (COX) inhibitors are among the most widely used drugs, especially in the elderly. It has been claimed that the new COX‐2 inhibitors offer advantages in terms of drug safety. To test this hypothesis, the authors compared in a double‐blind, randomized trial the effects of celecoxib (200 mg bid) and diclofenac (75 mg bid) on blood pressure and renal function in two groups (each n =12) of young (mean age = 32 years) and elderly (mean age = 68 years) normotensive subjects. Changes from baseline in the 24‐hour blood pressure profiles, parameters of the renin‐angiotensin‐aldosterone system, inulin clearance, urinary marker proteins, and eicosanoid excretion were monitored during the treatment period of 2 weeks. Comparison between celecoxib and diclofenac showed no significant difference in minor alterations of blood pressure. During daytime, there was a trend to elevation of mean arterial blood pressure (mmHg) by celecoxib in the elderly of 2.8 (95% confidence interval [Cl] = −2.5 to 8.2) in comparison with the young subjects of −1.3 (95% Cl = −3.7 to 1.0); there was also a trend to elevation of mean arterial blood pressure by diclofenac in the elderly of 4.1 (95% Cl = −1.2 to 9.4) in comparison with the young subjects of 0.4 (95% Cl =−2.4 to 3.2). In both populations, the authors found no significant drug effects on the parameters of the renin‐angiotensin‐aldosterone system, inulin clearance, and urinaiy marker proteins. As expected, diclofenac reduced excretion of all prostanoids, whereas celecoxib did not affect production of TxB2 and its metabolites. Neither in young nor in elderly normotensive subjects were blood pressure and renal function significantly affected by a short‐terrn treatment with standard doses of celecoxib and diclofenac. Therefore, normal aging appears not to represent a special risk factor in therapy with these two agents.
Pharmacokinetic Evaluation of the Possible Interaction between Selected Concomitant Medications and Orlistat at Steady State in Healthy Subjects
Authors: Zhi Jianguo , Moore Rema , Kanitra Linda , Mulligan Thomas E.
Published: September 2022

To investigate the influence of orlistat on the pharmacokinetics of selected concomitant medications (amitriptyline, atorvastatin, cyclosporine, losartan, metformin, phentermine, and sihutramine) at or within two‐fold of therapeutic doses, open‐label, multiple‐dose (for 6 or 7 days), randomized, two‐period (except for cyclosporine, for which a three‐way crossover design was used) crossover studies were performed in healthy volunteers ages 18 to 65 years, with a body mass index between 18 and 30 kg/m2. At steady state, blood samples were taken for measuring plasma concentrations of interacting drugs and/or active metabolites. Subjects were also evaluated for adverse events, vital signs, and clinical and laboratoryr safety. Treatments were compared for AUC0–24′ Cmax' tmax' and t1/2 of selected concomitant medications (parent drugs and/or active metabolites). ANOVA was performed to assess the significance of the carry‐over effect and provide the variance estimate for the 90% confidence intervals (CIs). With the exception of cyclosporine, whose absorption was reduced by approximately one‐third, the results of the statistical analysis demonstrated equivalence for the two primary parameters for all drugs studied: ratios of the log‐transformed means for both AUC and Cmax were close to 1.00, with 90% CIs contained entirely within the bioequivalence region of 0.80 to 1.25; there were no clinically significant differences in t1/2 and tmax'. There was a higher incidence of adverse events under treatment B (selective concomitant medications and orlistat) than under treatment A (selective concomitant medications alone); most of this difference was due to expected gastrointestinal adverse events known to occur with orlistat. Other adverse events were sporadic and unremarkable. All adverse events were either mild or moderate in intensity There were no clinically relevant changes in vital signs or laboratory values. In conclusion, except for cyclosporine, there was no effect of orlistat on the pharmacokinetics of selective concomitant medications when these drugs were taken concomitantly with orlistat.
Zolpidem Pharmacokinetic Properties in Young Females: Influence of Smoking and Oral Contraceptive Use
Authors: Olubodun Joel O. , Ochs Hermann R. , Trüten Volker , Klein Arno , von Moltke Lisa L. , Harmatz Jerold S. , Shader Richard I. , Greenblatt David J.
Published: September 2022

Sixteen normal healthy female volunteers, ages 22 to 42 years, participated in this study to determine the pharmacokinetic characteristics of zolpidem and the influence of oral contraceptives and smoking. Five of the volunteers were cigarette smokers, and 8 were on oral contraceptive preparations (OCP). All subjects received a 5 mg oral dose of zolpidem tartrate, followed by multiple blood samples that were assayed by HPLC with fluorescence detection. Among all subjects, mean apparent oral clearance was 376 ml/min (5.8 ml/min/kg), elimination half‐life was 2.4 hours, and maximum serum zolpidem concentration was 60 ng/ml. Clearance was higher (445 vs. 345 ml/min) and half‐life was shorter (1.8 vs. 2.7 h) in smokers than nonsmokers, although the differences were not statistically significant. Likewise, zolpidem clearance was higher and half‐life shorter in women using OCP, but differences were not significant. Differences in zolpidem kinetics associated with smoking may be explained by the small contribution of cytochrome P450‐1A2 to net clearance of zolpidem. In any case, the differences were quantitatively small and not likely to be ofclinical importance.
A Double‐Blind, Placebo‐Controlled Study of the Efficacy and Safety of Ebastine 20 mg Once Daily Given with and without Food in the Treatment of Seasonal Allergic Rhinitis
Authors: Hampel Frank ,   The Ebastine Study Group, Gillen Michael , Rohatagi Shashank S. , Lim Janet , Georges George
Published: September 2022

The efficacy and safety of ebastine 20 mg once daily given with and without food were compared in patients ages 12 to 70 years with seasonal allergic rhinitis (SAR) caused by mountain cedar allergen. This double‐blind, placebo‐controlled study was conducted at six centers in Texas. Efficacy and safety analyses were performed on the intent‐to‐treat population, which comprised 652 patients; 540 patients completed the study. Following 2 weeks' treatment, no significant differences (p ≥ 0.91) were found between the ebastine with and without food groups in the percentage change from baseline of daily “reflective” total rhinitis symptom scores (i.e., patients' assessment of severity over the previous 12 h), but both ebastine groups exhibited significantly greater reductions versus patients receiving placebo (p < 0.0001). There were also no significant differences in the percentages ofpatients experiencing adverse events between the ebastine with and without food groups. Mean steady‐state plasma concentrations of ebastine and its active metabolite carebastine were, respectively, 5.5% (ns) and 15.1% (p < 0.05) higher when ebastine was given with food versus its administration without food. Overall, these results indicate that in clinical practice, ebastine does not need to be administered with reference to food.
Effect of Seville Orange Juice and Grapefruit Juice on Indinavir Pharmacokinetics
Authors: Penzak Scott R. , Acosta Edward P. , Turner Michele , Edwards David J. , Hon Yuen Yi , Desai Hiral D. , Jann Michael W
Published: September 2022

Considerable interpatient variability in indinavir pharmacokinetics, possibly due in part to variable metabolism of the drug through intestinal cytochrome P450 (CYP) 3A4, may contribute to poor virologic response in certain individuals with HIV infection. The purpose of this study was to characterize the influence of intestinal CYP3A4 modulation with grapefruit juice and Seville orange juice on indinavir pharmacokinetics. In an open‐label, three‐period crossover study, 13 healthy volunteers received indinavir 800 mg every 8 hours for 1 day and a single 800 mg dose the next morning. The last two indinavir doses were taken with 8 ounces of Seville orange juice, single‐strength grapefruit juice, or water (control). Plasma samples were collected at time 0 (predose) and at 0.5, 1, 2, 3, 4, and 5 hours after the last indinavir dose. Concentration‐time data were analyzed using noncompartmental methods. Coadministration of Seville orange juice and indinavir resulted in a statistically significant increase in indinavir tmax (1.87 [1.65‐2.22] vs. 1.25 [1.03‐1.60] h; p < 0.05) without altering other pharmacokinetic parameter values. Grapefruit juice administration did not result in any changes in indinavir pharmacokinetics. Modulation of intestinal CYP3A4 by grapefruit juice and Seville orange juice did not alter the systemic availability of indinavir. The contribution of presystemic metabolism to indinavir interpatient variability appears to be small.
Effects of Meals and Meal Composition on the Bioavailability of Fenretinide
Authors: Doose Dennis R. , Minn Fredrick L. , Stellar Susan , Nayak Ramchandra K.
Published: September 2022

The effects of meals and meal composition on the bioavailability of fenretinide, N‐(4‐hydroxyphenyl) retinamide, a synthetic retinoid undergoing clinical trials, were examined in two separate studies using an open, randomized, crossover design. In the first study, 13 healthy male volunteers received 300‐mg doses of fenretinide (1) while fasting and (2) after a high‐fat breakfast. In a subsequent study, 15 subjects received 300 mg fenretinide after each of three different test meals (high‐fat, high‐protein, and high‐carbohydrate) separated by a 1‐week washout period. Plasma specimens obtained over a 72‐hour period after each treatment were assayed by high‐pressure liquid chromatography to characterize the effects of a meal and meal composition on the bioavailability of fenretinide. Results from the initial study demonstrated a significant increase in the bioavailability of fenretinide after a high‐fat meal. In the follow‐up study, the bioavailability of fenretinide, as assessed by total area under the plasma concentration curve, was three times greater after the high‐fat meal than after the high‐carbohydrate meal. This supported the findings of the first study. Although to a lesser extent, the high‐protein meal also produced a greater area under the curve than the high‐carbohydrate meal. These combined findings demonstrate that the bioavailability of fenretinide is markedly influenced not only by administration with meals but also by the specific composition of such meals.
The Effect of Antacid and Ranitidine on Droxicam Pharmacokinetics
Authors: Bartlett A. , Costa A. , Martínez L. , Roser R. , Sagarra R. , Sánchez J.
Published: September 2022

Droxicam is a nonsteroidal anti‐inflammatory drug that is a pro‐drug of piroxicam. The influence of concomitant administration of antacid or ranitidine on droxicam pharmacokinetics has been investigated. On three separate phases, 15 healthy volunteers received a single oral 20‐mg dose of droxicam either alone, with antacid (400 mg aluminum hydroxide + 400 mg magnesium hydroxide, three times/day), or with ranitidine (300 mg, two times/day) for 6 days. Piroxicam, the active substance from droxicam, was quantified by high‐performance liquid chromatography. The pharmacokinetic parameters for droxicam given alone were: maximum peak plasma concentration (Cmax) = 1.53 ± .21 μg/mL (mean ± SD), time to peak concentration (Tmax) = 7.5 ± 2.1 hr, t 1/2a = 1.38 ± .82 hour, t1/2el = 53.3 ± 11.9 hr, Cl/F = 2.98 ± .71 mL/min, volume of distribution (Vd/F) = 13.2 ± 1.8 L and area under the curve (AUC) = 117.6 ± 26.8 μg/hour/mL. The subject effect was significant for all the pharmacokinetic parameters except for the absorption half‐life (P > .05). Concomitant antacid or ranitidine administration had no significant effect on any of the droxicam pharmacokinetic parameters. The results of this study suggest that antacid or ranitidine do not significantly alter the oral absorption or pharmacokinetic disposition of single‐dose droxicam.
Comparative Effects of Verapamil and Volume Overload on Atrial Natriuretic Factors and the Renin‐Angiotensin Aldosterone‐Vasopressin System
Authors: Buckley Jill Wikman , Hedner Thomas , Masotto Claudio , Posvar Edward , Negro‐Villar Andres , Cubeddu Luigi X.
Published: September 2022

The authors compared the effects of verapamil (120 mg three times daily for 3 days) with those of acute volume expansion with normal saline on the plasma levels of atrial natriuretic factors (ANF), renin (PRA), angiotensin 11 (AII), aldosterone (ALD), and arginine‐vasopressin (AVP) in healthy subjects. A randomized, double‐blind, placebo‐controlled study of crossover design was employed, where each individual received two acute volume overloads 1 week apart, one during placebo and the other during treatment with verapamil. Verapamil reduced blood pressure (BP) and increased the plasma levels of ANF, PRA, All, ALD, and AVP. Strong positive correlations were observed between PRA, All, ALD, and AVP, but not with ANF. Acute volume expansion (1500 mL saline in 15 minutes, in supine legs‐up position) similarly to verapamil increased ANF levels; however, opposite to verapamil, it reduced PRA‐All‐ALD, did not modify AVP levels, and increased BP. The mechanisms of these changes are discussed. In verapamil‐treated subjects, volume expansion produced an additional increase in ANF and inhibited the PRA‐All‐ALD axis, suggesting that in young healthy individuals, verapamil does not interfere with the reflex compensatory hormonal mechanisms activated under circumstances of acute volume‐salt overload, with rapid expansion of the central vascular compartment. Our study indicates that verapamil and volume expansion represent two different stimuli for ANF secretion associated with opposite changes in the PRA‐All‐ALD axis. In addition, verapamil can be used as a tool to study and understand the simultaneous increases in ANF and in PRA, All, ALD, and AVP, characteristics of congestive heart failure.
Matrix Metalloproteinases and Abdominal Aortic Aneurysms: A Potential Therapeutic Target
Authors: Sinha Sanjai , Frishman William H.
Published: September 2022

Abdominal aortic aneurysm (AAA) is a leading cause of death in the United States, and there is no effective treatment in the early course of disease. Therapy to retard or reverse aneurysmal growth requires an understanding of the underlying vascular pathology. Recent research has indicated that enzymatic degradation of structural matrix proteins plays a large role in the formation of AAAs. Specifically, many studies have implicated a family of matrix degrading enzymes, known as matrix metalloproteinases (MMPs), as vital factors in the disease. Although AAA was once thought to be purely secondary to atherosclerosis, investigators have demonstrated various differences between the diseases in both levels and distribution of MMPs, suggesting independent mechanisms. Experimental models have shown that inhibition of these proteinases may slow aortic wall matrix breakdown. The purpose of this article is to review the current literature regarding the role of individual MMPs in AAA, including their complex regulatory mechanisms and possible cellular sources, the importance of MMPs as a potential therapeutic target in the prevention and treatment of AAA, and their inhibition using novel pharmacologic interventions in animal models.
Pharmacokinetic and Pharmacodynamic Characteristics and Safety of Inhaled Albuterol Enantiomers in Healthy Volunteers
Authors: Gumbhir‐Shah Kavita , Kellerman Donald J. , DeGraw Sidney , Koch Patrick , Jusko William J.
Published: September 2022

The pharmacokinetics and pharmacodynamics of inhaled albuterol given as single or multiple doses of racemate (RS‐) or single enantiomers (R‐, S‐) were determined. In an open‐label, three‐way crossover, parallel‐dose study, 1.25 and 5 mg of (R)‐ and (S)‐albuterol and 2.5 and 10 mg of (RS)‐albuterol were given via nebulization to 15 healthy volunteers. The pharmacokinetic parameters of each enantiomer were determined by noncompartmental and model‐fitting analyses. Both (R)‐ and (S)‐albuterol showed rapid absorption and biexponential decline, with half‐lives (t1/2) averaging 4 and 6 hours, respectively. There were no differences in pharmacokinetics of (R)‐albuterol when administered as (R)‐ or (RS)‐albuterol at the 5‐mg dose with equivalent relative bioavailability as seen from maximum concentration (Cmax) and area under the concentration‐time curve (AUC). The same was true for (S)‐albuterol at the 1.25‐mg and 5‐mg doses. The data from 5‐mg doses were considered to be more reliable due to assay sensitivity limitations, and indicated equivalent absorption and disposition of the individual enantiomers. There was no evidence of in vivo racemization, and (R)‐albuterol did not interconvert to (S)‐albuterol. Plasma potassium, plasma glucose, heart rate, and QTc interval were used in linear and Emax models to assess responses relating to (R)‐albuterol concentrations. The Emax for potassium change was 1.32 meq/L, with an EC50 of 0.59 and 0.94 ng/mL after administration of (R)‐ and (RS)‐albuterol, respectively. The slopes and intercepts for glucose and heart rate changes were similar after administration of (R)‐ and (RS)‐albuterol. No concentration‐effect relationships were evident for QTc interval or for (S)‐albuterol. The extrapulmonary responses of (R)‐albuterol and adverse effects were similar for single R‐enantiomer or the racemic mixture.
Pharmacodynamics and Pharmacokinetics of a Single Oral Dose of Nitrazepam in Healthy Volunteers: An Interethnic Comparative Study between Japanese and European Volunteers
Authors: van Gerven J. M. A. , Uchida E. , Uchida N. , Pieters M. S. M. , Meinders A. J. , Schoemaker R. C. , Nanhekhan L. V. , Kroon J. M. , de Visser S. J. , Altorf B. , Yasuda K. , Yasuhara H. , Cohen A. F.
Published: September 2022

Potential interethnic differences in drug disposition and effects between Japanese and white subjects hamper the registration in Japan of medications already used in Western countries. This double‐blind, placebo‐controlled, crossover study was conducted to compare the pharmacodynamics and pharmacokinetics of a single oral dose of nitrazepam (5 mg) in age‐ and sex‐matched Japanese (n = 8) and white (n = 8) healthy volunteers. The study was performed in centers in Japan and the Netherlands using the same methods and study design. Subjects were individually matched for gender, age, and body stature. Drug effects were measured by means of saccadic and smooth pursuit eye movements and visual analog lines obtained from the scales of Bond and Lader. There were no pharmacokinetic differences between the Japanese and white subjects. Clearance of nitrazepam was 0.91 ± 0.165 mL/min/kg and 1.17 ± 0.492 mL/min/kg, and half‐life (t1/2) was 22.1 ± 4.96 hours and 21.5 ± 7.51 hours for the Japanese and European groups, respectively. Pharmacokinetic parameters showed no significant correlation with age, height, or weight. The average time‐effect curves for the different parameters were comparable between groups. Compared with placebo, both groups showed similar significant reductions in average peak velocity and increases in saccadic inaccuracy and reaction time. Visual analog scores showed clear sedation in the white subjects, but insignificant effects in the Japanese subjects. Smooth pursuit did not change significantly in either group. Slope and intercept of the concentration‐effect relationships for saccadic peak velocity showed considerable intersubject variability, but no clear differences between groups. The pharmacokinetics and pharmacodynamics of nitrazepam were similar in matched healthy Japanese and white subjects. Interethnic comparative studies are feasible, and provide meaningful information about potential racial differences in disposition and action of drugs. Such studies can form a rational basis for comparative clinical trials.
Pharmacologic Therapy for Asthma: Overview and Historical Perspective
Authors: Cockcroft D. W.
Published: September 2022

For the 30 years between 1967 and 1997, pharmacologic therapy of asthma has consisted primarily of five classes of drugs, β2‐agonists, anticholinergics, theophyllines, cromones, and corticosteroids. The first four of these classes of drugs have origins in herbal treatments going back 5000 or 6000 years. This article briefly reviews the history of asthma pharmacotherapy up to the late 1990s and outlines a current approach to the pharmacotherapy of asthma, which is but one component of an integrated overall approach to asthma treatment involving patient education and environmental control as well.
Pharmacokinetics and Safety of Z‐321, a Novel Specific Orally Active Prolyl Endopeptidase Inhibitor, in Healthy Male Volunteers
Authors: Umemura Kazuo , Kondo Kazunao , Ikeda Yasuhiko , Nishimoto Masahiko , Hiraga Yoshihiro , Yoshida Yasuhisa , Nakashima Mitsuyoshi
Published: September 2022

This study investigates the pharmacokinetics and safety profile of Z‐321, (4R)‐3‐(indan‐2‐ylacetyl)‐4‐(1‐pyrrolidinylcarbonyl)‐1,3‐thiazolidine, a novel specific orally active prolyl endopeptidase (PEP) inhibitor. Following a preliminary safety evaluation wherein 2 subjects received 3.75 and 15 mg doses and 2 other subjects received 7.5 and 30 mg doses, 16 subjects were assigned to two groups of 8 subjects each. In each group, 6 subjects were to receive active treatment, and 1 or 2 subjects were to receive placebo treatment. One group received 60 mg under fasted and fed conditions. A separate group of 8 subjects received 60 mg of Z‐321 or a placebo in a bid regimen for 6 days and the morning dose on day 7. The concentrations of Z‐321 and its main metabolites—R‐ and S‐sulfoxide; RR‐, SS‐, and RS‐indanol; and indanolsulfoxides in plasma and urine—were determined by the HPLC method. In the multiple‐dose study, the cholinesterase activity was gradually increased and reached above the normal range on day 8 in 3 of 6 subjects given Z‐321 and gradually returned to the normal range after completion of dosing. The elevation of plasma cholinesterase activity was considered to be an action of Z‐321, but this remains to be verified. In a single‐dose study at a dose of 30 mg, headache and vomiting were observed in 1 of 6 subjects. In the multiple‐dose study, slight skin itching and eczema in 3 and 2 of 6 subjects, respectively, and headache in 2 of 6 subjects were observed, but all symptoms were not severe. There were no other abnormal findings in objective signs and laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, and urinalysis. The Cmax of Z‐321 at 30, 60, and 120 mg in the fasting state were 63.7 ± 23.9, 102.0 ± 43.1, and 543.3 ± 437.0 ng/ml (mean ± SD), respectively, at 0.9 hours after administration, and the t1/2 was about 1.8 hours. There were no dramatic changes in the pharmacokinetics of Z‐321 in the presence of food. In the multiple‐dose study, there was no drug accumulation trend in plasma. These results indicate that Z‐321 has acceptable pharmacodynamic and pharmacokinetics profiles for clinical use without any serious adverse events, as verified in healthy young male volunteers.
Pharmacokinetics of Calcium Absorption from Two Commercial Calcium Supplements
Authors: Heller Howard J. , Stewart Alan , Haynes Sharon , Pak Charles Y. C.
Published: September 2022

This study was conducted to compare pharmacokinetic indices of calcium absorption after a single oral (500 mg calcium) load of Citracal (calcium citrate) and Os‐Cal (calcium carbonate). In 18 postmenopausal normal women, venous blood samples were obtained for the measurement of calcium before and hourly for 6 hours after an oral ingestion of Citracal, Os‐Cal, or placebo with a breakfast meal. The change in area under the curve (ΔAUC) in serum calcium from preload was 2.5‐fold greater for Citracal than Os‐Cal, and the peak‐basal variation in serum calcium was 76% higher for Citracal than Os‐Cal. The increment in serum calcium from preload after Citracal administration was significantly higher than that obtained after placebo load during most time periods and significantly higher than that of Os‐Cal at 1, 4, and 5 hours after load. In contrast, ΔAUC and peak basal variation of Os‐Cal did not differ significantly from placebo, and increment in serum calcium was significantly increased from placebo only at 6 hours. In conclusion, Citracal is much more bioavailable than Os‐Cal.
Single‐Dose Oral Pharmacokinetics of Three Formulations of Thalidomide in Healthy Male Volunteers
Authors: Teo Steve K. , Colburn Wayne A. , Thomas Steve D.
Published: September 2022

Thalidomide was recently approved in the United States for the treatment of erythema nodosum leprosum, a complication of leprosy. The present study determined the bioequivalence and pharmacokinetics of Celgene's commercial and clinical trial thalidomide formulations and the Brazilian Tortuga formulation in an open‐label, single‐dose, three‐way crossover design. Seventeen healthy subjects were given 200 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using compartmental methods for the two Celgene formulations and using noncompartmental methods for all three formulations. All subjects reported adverse events, none of which was serious or unexpected. Celgene formulations were bioequivalent when comparing Cmax, tmax, and AUC. There was significant variability in plasma levels from the Tortuga formulation, giving a mean profile that was distinctly different from the two Celgene formulations with a lower Cmax value and a longer terminal phase. The lower Cmax was probably due to slower absorption. The terminal rate constant for the Tortuga formulation was significantly less, giving rise to a terminal half‐life of 15 hours compared to about 5 to 6 hours for the Celgene formulations. Confidence intervals for Cmax between the Tortuga and the Celgene formulations were outside the 80% to 125% range, indicating a lack of bioequivalence. Extent of absorption, as measured by AUC0‐∞;, was approximately equal for all three formulations. Terminal half‐life for Tortuga was two to three times longer compared to the Celgene formulations and is clear evidence for absorption rate limitations. The two Celgene formulations showed similar pharmacokinetic parameters with profiles that were best described by a one‐compartment model with first‐order absorption and elimination. The authors conclude that Celgene's clinical trial and commercial thalidomide formulations are similar to each other and distinctly different from the Tortuga formulation and that all three formulations exhibited absorption rate—limited elimination.
Rosiglitazone Has No Clinically Significant Effect on Nifedipine Pharmacokinetics
Authors: Harris Robert Z. , Inglis Anne Marie L. , Miller Ann K. , Thompson Kathleen A. , Finnerty Dana , Patterson Scott , Jorkasky Diane K. , Freed Martin I.
Published: September 2022

To examine the effects of repeat oral dosing of rosiglitazone on the pharmacokinetics of nifedipine, a prototype CYP3A4 substrate, a randomized, open‐label, crossover study was performed with two treatment phases separated by a washout period of at least 14 days. Twenty‐eight healthy male volunteers received either a single 20 mg oral nifedipine dose or rosiglitazone 8 mg orally once daily for 14 days with a single 20 mg oral nifedipine dose administered on day 14. Plasma nifedipine concentrations were determined over the 24‐hour period following administration of the nifedipine doses. Lack of effect was defined as the demonstration that the 90% CI was contained entirely within a symmetrical 30% range either side of unity on the loge‐scale. Following rosiglitazone + nifedipine administration, the area under the nifedipine concentration‐time curve from time zero to infinity (AUC0‐∞;) was 13% lower than that after administration of nifedipine alone. This difference in nifedipine AUC0‐∞; was not deemed to be clinically significant since the 90% CI was contained within the protocol‐defined 30% range (point estimate for ratio of geometric means 0.87; 90% CI: 0.79, 0.96). Rosiglitazone had no marked effect on nifedipine peak plasma concentration (point estimate: 0.99; 90% CI: 0.73, 1.34) or time to peak concentration compared with nifedipine alone. Rosiglitazone coadministration produced a small decrease in the mean nifedipine half‐life (point estimate: −0.77; 90% CI: mean difference −1.29 h, −0.25 h). Both treatment regimens were well tolerated and associated with a favorable safety profile. Rosiglitazone, at the highest dose used in clinical studies, produced a small, clinically insignificant decrease in nifedipine exposure. The very small effect on nifedipine pharmacokinetics suggests that rosiglitazone is an extremely weak inducer of CYP3A4, a characteristic that distinguishes rosiglitazone from troglitazone.
Parental Perspectives About What It Means to Bully
Authors: Stives Kristen L. , May David C. , Bethel Cindy L.
Published: September 2022

While most bullying researchers argue that any definition of bullying must include three core elements (power imbalance, intent to cause harm, and repetitive negative actions), relatively few researchers have examined whether parents define bullying along these three elements. Among those that have, most find that parents focus on the intent to cause harm and ignore or discount the power imbalance and repetition elements. Using qualitative data from 50 parents in a southeastern state, we explore parental definitions of bullying and trace how their definitions match those three elements. We find that most parents include intent to cause harm in their definition but far fewer mention the power imbalance or repetition commonly found in scholarly definitions. Additionally, we uncover a fourth component that was important for several parents: the fact that bullies engage in that activity to build their own self-esteem. Implications for policy and research are discussed.
Proceedings of the 2022 National Toxicology Program Satellite Symposium
Authors: Quist Erin M. , Choudhary Shambhunath , Lang Richard , Tokarz Debra A. , Hoenerhoff Mark , Nagel Jonathan , Everitt Jeffrey I.
Published: September 2022

The 2022 annual National Toxicology Program Satellite Symposium, entitled “Pathology Potpourri,” was held in Austin, Texas at the Society of Toxicologic Pathology’s 40th annual meeting during a half-day session on Sunday, June 19. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers’ talks along with select images that were used by the audience for voting and discussion. Various lesions and topics covered during the symposium included induced and spontaneous neoplastic and nonneoplastic lesions in the mouse lung, spontaneous lesions in the reproductive tract of a female cynomolgus macaque, induced vascular lesions in a mouse asthma model and interesting case studies in a rhesus macaque, dog and genetically engineered mouse model.
The rhythms of “acostumbrarse”: Noticing quiet hydro-politics in Colombia’s Caribbean coast
Authors: Berman-Arévalo Eloisa , Valdivia Gabriela
Published: September 2022

In Colombia’s Caribbean region, where Black Diaspora agrarian spaces have been overtaken by oil palm plantations, access to safe drinking water has become increasingly difficult. Leticia is a water spring located in this historical afro descendant territory. Leticia’s near exhaustion in 2015 as a consequence of oil palm encroachment caused little public outrage even though nearby communities have depended on its waters for decades. Some residents explained their response to Leticia’s fate as acostumbrarse or “getting used to” these forms of harm. While such responses are often discounted as expressions of “giving up,” we argue that acostumbrarse to Leticia’s precarity expresses self-affirmation that overflows liberal notions of resistance. In conversation with Black and Caribbean Studies intellect and poetics, we first problematize how dominant ways of writing about black harm not only reproduce anti-black violence but also neglect the desires of quiet sovereignty in the experience of harm. Second, we re-story Leticia’s sociality as immanent and acostumbrarse as a collective politics of perseverance that ebbs and flows in this hydro-sociality. Our goal is to open space for noticing and storying quiet responses such as acostumbrarse as an opaque politics of perseverance, forming and reforming through recurring and punctuated experiences of both life and death, harm and collective self-affirmation.
Peripheral humanitarianism: Ephemerality, experimentation, and effects of refugee provisioning in Paris
Authors: Ramakrishnan Kavita , Thieme Tatiana A
Published: September 2022

This article examines the place-based assemblages of humanitarian care, which emerge at neighbourhood scales in response to a wider politics of exclusion. We ground our discussion in the variegated humanitarian efforts and solidarities that took place in a working-class neighbourhood on the periphery of Paris, which brought into sharp relief the combination of precarity and provisioning in the wake of the 2015 ‘refugee crisis’. Drawing on ethnographic encounters, we recount the combination of reactive, emergency humanitarian logics (between 2016 and 2017) and experimental humanitarian strategies contesting wider exclusionary and deterrence-based asylum practices (2018 to the present). We show how modes of ephemeral and experimental humanitarianism operated across local spatiotemporal nodes – inside a welcome centre (the ‘Bubble’), and on the surrounding streets. We argue that attention to the effects of the ephemeral and experimental solidarities and encounters that formed outside the formal infrastructure of humanitarian care in Paris were in part palliative, but profound in their re-imagining of a progressive politics of solidarity amidst protracted and overlapping precarities. We propose peripheral humanitarianism to describe these effects, a spatially and temporally contingent humanitarian assemblage engaging with both traditional and DIY humanitarian responses that challenges structural exclusions of racialized ‘others’.
Systematic review of exercise therapy in the management of post-thrombotic syndrome
Authors: Jasionowska Sara , Turner Benedict R H , Machin Matthew , Onida Sarah , Gwozdz Adam M , Shalhoub Joseph , Davies Alun H
Published: September 2022

Objectives

Exercise improves haemodynamic parameters in patients with chronic venous disease. There is a paucity of evidence on its effect in post-thrombotic syndrome (PTS). The aim of this systematic review is to assess the impact of exercise in PTS.

Methods

Adhering to PRISMA guidelines and following PROSPERO registration (CRD42021220924), MEDLINE, Cochrane Library, EMBASE database, and trial registries were searched on 19th May 2022.

Results

One article met the inclusion criteria and a narrative synthesis was carried out. The included randomised controlled trial reported a between-group mean difference of 4.6 points ( p = .027) in the VEINES-QOL score and −2.0 points ( p = .14) in the Villalta score, in favour of exercise therapy. The statistical significance threshold was not reached.

Conclusion

Data on exercise in PTS remains sparse but exercise appears to be a safe intervention. In the context of this literature, a potential future trial and outcome reporting measures are suggested.
The effect of AUT00206, a Kv3 potassium channel modulator, on dopamine synthesis capacity and the reliability of [18F]-FDOPA imaging in schizophrenia
Authors: Angelescu Ilinca , Kaar Stephen J , Marques Tiago Reis , Borgan Faith , Veronesse Mattia , Sharman Alice , Sajjala Anil , Deakin Bill , Hutchison John , Large Charles , Howes Oliver D
Published: September 2022

Background:

Current treatments for schizophrenia act directly on dopamine (DA) receptors but are ineffective for many patients, highlighting the need to develop new treatment approaches. Striatal DA dysfunction, indexed using [18F]-FDOPA imaging, is linked to the pathoetiology of schizophrenia. We evaluated the effect of a novel drug, AUT00206, a Kv3.1/3.2 potassium channel modulator, on dopaminergic function in schizophrenia and its relationship with symptom change. Additionally, we investigated the test–retest reliability of [18F]-FDOPA PET in schizophrenia to determine its potential as a biomarker for drug discovery.

Methods:

Twenty patients with schizophrenia received symptom measures and [18F]-FDOPA PET scans, before and after being randomised to AUT00206 or placebo groups for up to 28 days treatment.

Results:

AUT00206 had no significant effect on DA synthesis capacity. However, there was a correlation between reduction in striatal dopamine synthesis capacity (indexed as Kicer) and reduction in symptoms, in the AUT00206 group ( r = 0.58, p = 0.03). This was not observed in the placebo group ( r = −0.15, p = 0.75), although the placebo group may have been underpowered to detect an effect. The intraclass correlation coefficients of [18F]-FDOPA indices in the placebo group ranged from 0.83 to 0.93 across striatal regions.

Conclusions:

The relationship between reduction in DA synthesis capacity and improvement in symptoms in the AUT00206 group provides evidence for a pharmacodynamic effect of the Kv3 channel modulator. The lack of a significant overall reduction in DA synthesis capacity in the AUT00206 group could be due to variability and the low number of subjects in this study. These findings support further investigation of Kv3 channel modulators for schizophrenia treatment. [18F]-FDOPA PET imaging showed very good test–retest reliability in patients with schizophrenia.
Outcome of non-small-cell lung cancer with driven mutations treated with anti-PD-(L)1 agents: A systematic review
Authors: Luciani Andrea , Ghidini Antonio , Borgonovo Karen , Parati Maria Chiara , Petrelli Fausto
Published: September 2022

Patients whose tumours harbour epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK) driver mutations can benefit most from treatment with tyrosine kinase inhibitors (TKIs). Most trials with immune checkpoint inhibitors (ICIs) included few patients whose tumour had oncogenic driver alterations. We therefore performed a meta-analysis of studies reporting the activity of ICIs in oncogene addicted NSCLC. A comprehensive search of MEDLINE, The Cochrane Library and EMBASE was conducted to identify relevant studies published up to 31 January 2021. The primary outcomes were median overall survival (OS); the secondary endpoints were progression-free survival and overall response rate (PFS and ORR). Overall, 46 studies were screened and selected for final analysis. The pooled ORR was 14.5% (95% CI 9.6-21.2%). The median pooled PFS in EGFR/ALK mutated cases was 3.9 months (95% CI 3-5.2 months). Median pooled OS was 10.7 months (95% CI 9.2-12.5 months). All registration trials in second line did not show any benefit of immunotherapy for the subgroup of patients with EGFR-mutated or ALK-rearranged tumours. The unsatisfied benefit of immunotherapy in oncogene-addicted tumours has been debated and is mainly due to the lower mutation burden of these neoplasms. Our data do not support the use of immunotherapy in the setting of oncogene actionable tumours. More data are needed to confirm or reject the benefit of the combination of TKIs with ICIs.
Drought and water management in ancient Maya society
Authors: Bhattacharya Tripti , Krause Samantha , Penny Dan , Wahl David
Published: September 2022

Paleoclimate research in the Maya region of Mesoamerica provides compelling evidence of drought during key periods of cultural transition in Maya society. These include the transition from the Preclassic to the Classic, and from Classic to the Postclassic. Previous research emphasized a causal relationship between drought and cultural change, or so-called “collapse” in the Maya region. Recent advances in the range and precision of climate-sensitive proxies and the development of new archives have enabled quantitative reconstructions of past hydroclimate, as well as providing evidence of high impact, short-duration events, such as tropical cyclones. Simultaneously, archaeological research has unearthed widespread evidence of technologies used by the Maya to exert control over water resources in urban, rural, and agricultural settings. Evidence suggests that many of these water features were in use for multiple generations, possibly centuries, and many were constructed during the Terminal Preclassic and Terminal Classic periods. We suggest that, given the availability of new archaeological and paleoclimate records, these data can be combined to identify the full complexity of Maya adaptation to hydroclimate variability to emphasize adaptation and resilience to both water scarcity and over-abundance (e.g., flooding). Such syntheses, which can offer lessons for present-day efforts to grapple with regional climate change, will benefit from additional studies in data-poor zones of the Maya region, as well as public archiving of paleoclimate and archaeological data.
Investigating Safety in Numbers in Cycling After the Entry of Dock-Based Bikeshare Programs in Three U.S. Cities
Authors: Dong Xiaoxia , Hamidi Shima , Dumbaugh Eric
Published: September 2022

This paper investigates the safety in numbers effect in cycling by comparing monthly bicycle crash trends before and after public bikeshare’s launch in Philadelphia and Pittsburgh, PA, from 2010 to 2019, and in Portland, OR, from 2014 to 2019. To estimate the bicycle crash trend in each city, the authors conduct time series analysis with a regression discontinuity design using generalized linear quasi-Poisson models. The entries of dock-based public bikeshare programs signal an increase in biking activity on the road and serve as the point of discontinuity in the analysis. For each city, the analysis models pre- and post-bikeshare bicycle crash trends inside and outside bikeshare program’s service area separately to compare crash trends at different biking activity levels within the same local context. Results show that before bikeshare, crash trends inside and outside service areas had similar patterns in Philadelphia and Portland while moving in opposite directions in Pittsburgh. The post-bikeshare crash trends differed across cities for both inside and outside of the service areas. The finding that bicycle crash trends changed in different patterns across the three cities indicates that there may be no single safety in numbers effect on bicycle crashes. The inconsistent patterns of bicycle crash trends within and across cities suggest confounding factors underlying the change in bicycle crashes.