Double dosing ulipristal acetate emergency contraception for individuals with obesity: a randomised crossover trial.

Objective: To determine whether increasing the dose of ulipristal acetate (UPA)-containing emergency contraception (EC) improves pharmacodynamic outcomes in individuals with obesity.

Study Design: We enrolled healthy, regularly-cycling, confirmed ovulatory, reproductive-age individuals with body mass index (BMI) >30 kg/m and weight >80 kg in a randomised crossover study. We monitored participants with transvaginal ultrasound and blood sampling for progesterone, luteinising hormone (LH), and estradiol every other day until a dominant follicle measuring >15 mm was visualised.

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies.

Double Dosing Levonorgestrel-Based Emergency Contraception for Individuals With Obesity: A Randomized Controlled Trial.

Objective: To assess whether dose escalation (ie, doubling the dose) of emergency contraception that contains levonorgestrel (LNG) improves pharmacodynamic outcomes in individuals with obesity.

Methods: We enrolled healthy, reproductive-age individuals with regular menstrual cycles, body mass index (BMI) higher than 30, and weight at least 176 lbs in a randomized pharmacodynamic study. After confirming ovulation (luteal progesterone level greater than 3 ng/mL), we monitored participants with transvaginal ultrasonography and blood sampling for progesterone, luteinizing hormone, and estradiol every other day until a dominant follicle measuring 15 mm or greater was visualized.

Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB.

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.

Ziritaxestat Drug-Drug Interaction with Oral Contraceptives: Role of SULT1E1 Inhibition.

In vitro signals indicate that ziritaxestat is a weak cytochrome P450 (CYP) 3A4 inhibitor and inducer. Therefore, potential drug-drug interactions (DDIs) with oral contraceptives were examined at a time when ziritaxestat was under development for treatment of fibrotic diseases. This open-label, crossover (fixed sequence) DDI study enrolled healthy, nonpregnant women aged 18-65 years (n = 15) who were using highly effective contraception, such as a nonhormonal intrauterine device, bilateral tubal occlusion, or sexual abstinence.

Evaluation of the potential for pharmacokinetic interaction between tirabrutinib and levonorgestrel/ethinyl estradiol in healthy female volunteers.

Tirabrutinib (TIRA), a potent and nonreversible oral Bruton tyrosine kinase inhibitor, is evaluated for treatment of certain hematological malignancies and inflammatory diseases. A drug-drug interaction study to evaluate the effect of TIRA on the pharmacokinetics of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted in healthy female participants (N = 26). Participants received a single dose of LEVO (150 mcg)/EE (30 mcg) alone (reference), and on day 12 of a 15-day regimen of TIRA 160 mg once-daily (test).

Levonorgestrel butanoate intramuscular injection does not reliably suppress ovulation for 90 days in obese and normal-BMI women: a pilot study.

Background: We performed a pilot evaluation of a new formulation of levonorgestrel butanoate (LB) designed to be a long-acting injectable (6 months) contraceptive to determine pharmacodynamic end points in normal-body mass index (BMI) and obese women.

Study Design: Obese (BMI ≥30 kg/m) and normal-BMI, otherwise healthy, women received a single intramuscular injection of LB after ovulation was confirmed in a baseline cycle. The primary outcome was return of ovulation in days.

Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing.

Objective: To determine if differences exist in the pharmacokinetics (PK) of levonorgestrel-based emergency contraception (LNG-EC) in obese and normal body mass index (BMI) users and test whether doubling the dose of LNG-EC in obese women increases total and free (active) LNG serum concentrations.

Study Design: Healthy, reproductive-age women with obese and normal BMIs received 1.5mg LNG orally (ECx1) and then in a subsequent menstrual cycle, the obese group also received 3mg LNG (ECx2).

Furosemide Pharmacokinetics in Adult Rats become Abnormal with an Adverse Intrauterine Environment and Modulated by a Post-Weaning High-Fat Diet.

Adult individuals born with intrauterine growth restriction (IUGR) have physiological maladaptations that significantly increase risk of chronic disease. We suggested that such abnormalities in organ function would alter pharmacokinetics throughout life, exacerbated by environmental mismatch. Pregnant and lactating rats were fed either a purified control diet (18% protein) or low-protein diet (9% protein) to produce IUGR offspring.

Theophylline Pharmacokinetics in Foetal Sheep: Maternal Metabolic Capacity is the Principal Driver.

Understanding theophylline pharmacokinetics (PK) in the foetus is essential to prevent in utero toxicity and optimize prophylactic therapies. Previous studies in pregnancy have been obfuscated by maternal dosing and inadequate sampling in the foetus; both render modelling of foetal PK difficult. Six ewes carrying singleton foetuses received theophylline (60 mg) into the foetal jugular vein.

A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer.

Introduction: Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells.

Purpose: Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models.

How can we improve oral contraceptive success in obese women?

A rapid increase in obesity rates worldwide further underscores the importance of better understanding the pharmacokinetic alterations in this sub-population and the subsequent effects on pharmacotherapeutics. Pharmacokinetics of contraceptive steroids is altered in obese oral contraceptive users, which may in turn impact efficacy. Our study has identified several dosing strategies that offset these pharmacokinetic changes and may improve effectiveness for obese oral contraception users.

Increased exposure of norethindrone in HIV+ women treated with ritonavir-boosted atazanavir therapy.

Objective: Pharmacokinetics of norethindrone in combination oral contraceptive regimen are well described among HIV+ women treated with ritonavir-boosted protease inhibitor therapies; however, such characterization is lacking in women using progestin-only contraception. Our objective is to characterize pharmacokinetics of norethindrone in HIV+ women using ritonavir-boosted atazanavir treatment during progestin-only contraceptive regimens.

Study Design: An open-label, prospective, nonrandomized trial to characterize the pharmacokinetics of norethindrone in HIV+ women receiving ritonavir-boosted atazanavir (n=10; treatment group) and other antiretroviral therapy known to not alter norethindrone levels (n=17; control group) was conducted.

Correcting oral contraceptive pharmacokinetic alterations due to obesity: a randomized controlled trial.

Objective: To determine if increasing the hormone dose or eliminating the hormone-free interval improves key pharmacokinetic (PK) alterations caused by obesity during oral contraceptive (OC) use.

Study Design: Obese [body mass index (BMI)≥30 kg/m(2)], ovulatory, otherwise healthy, women received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) dosed cyclically (21 days active pills with 7-day placebo week) for two cycles and then were randomized for two additional cycles to the following: continuous cycling (CC, a dose neutral arm using the same OC with no hormone-free interval) or increased dose (ID, a dose escalation arm using an OC containing 30 mcg EE/150 mcg LNG cyclically). During Cycles 2, 3 and 4, outpatient visits were performed to assess maximum serum concentration (Cmax), area under the curve (AUC0-∞) and time to steady state as well as pharmacodynamics.

Are children undergoing cardiac surgery receiving antibiotics at subtherapeutic levels?

Objectives: Perioperative antibiotics have decreased-but not eradicated-postoperative infections. In patients undergoing cardiac surgery with cardiopulmonary bypass, the dilutional effect of the priming and any additional volume given during the procedure may lead to subtherapeutic antibiotic levels. Our aim was to determine if children undergoing cardiac surgery with cardiopulmonary bypass receive perioperative antibiotics at subtherapeutic levels.

Perinatal growth restriction decreases diuretic action of furosemide in adult rats.

Perinatal growth restriction programs higher risk for chronic disease during adulthood via morphological and physiological changes in organ systems. Perinatal growth restriction is highly correlated with a decreased nephron number, altered renal function and subsequent hypertension. We hypothesize that such renal maladaptations result in altered pharmacologic patterns for life.

An ethinyl estradiol-levonorgestrel containing oral contraceptive does not alter cytochrome P4502C9 in vivo activity.

Oral contraceptives have been in wide use for more than 50 years. Levonorgestrel, a commonly employed progestin component of combined oral contraceptives, was implicated in drug-drug interactions mediated via CYP2C9. Although in vitro studies refuted this interaction, there are no confirmatory in vivo studies.

Effect of protease inhibitors on steady-state pharmacokinetics of oral norethindrone contraception in HIV-infected women.

Objective: Pharmacokinetic interactions exist between combined oral contraceptives and protease inhibitors (PI). However, such information is lacking for progestin-only oral contraception. We sought to define the steady-state pharmacokinetic interaction between norethindrone (NET) and PI in HIV-infected women.

Analysis of tacrolimus and creatinine from a single dried blood spot using liquid chromatography tandem mass spectrometry.

Long term therapeutic drug monitoring and assessment of renal function are required in renal transplant recipients on immunosuppressant therapy such as tacrolimus. Dry blood spots (DBS) have been used successfully in the clinic for many years and offers a convenient, simple and non-invasive method for repeated blood tests. We developed and performed a preliminary validation of a method for the analysis of tacrolimus and creatinine from a single DBS using liquid chromatography-tandem mass spectrometric (LC-MS/MS).