Drugs in semen.
ABSTRACT Over the past 50 years, a decline in the quality of semen has been observed, possibly resulting in a reduction in male fertility. Among the factors affecting semen quality, exposure to drugs is of particular importance. It is known that drugs can be transported to the seminal plasma, which is made up of secretions from the various accessory genital glands. There is evidence that many drugs enter the male genitourinary tract by an ion-trapping process. Lipid solubility and the degree of ionisation of the drug, which depend on the pH of plasma and seminal fluid, are important factors in this process. To date, few studies have been conducted on this topic. Pharmacokinetic evaluation of the fluids of the male accessory gland have been performed in the case of chloroquine and caffeine only, while the effects of mesalazine (5-aminosalicylic acid), sulfasalazine, salicylate, propranolol, diltiazem, flunarizine, verapamil, caffeine and nicotine on sperm physiology and morphology have been examined. Although data from the literature are scarce and incomplete, it is evident that many drugs can be excreted into semen. These drugs may interfere with the most common semen characteristics, potentially resulting in a male-mediated teratogenic effect, or local and systemic responses in female recipients. Therefore, it may be advisable to include, in the processes of drug development, pharmacokinetic evaluation of a drug in the semen and analysis of standard microscopic parameters of the semen. This is particularly important for drugs known to concentrate in the semen.
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ABSTRACT: This first in human randomized, double-blind, placebo-controlled, ascending single and multiple oral dose study was designed to evaluate the safety, tolerability and pharmacokinetics in healthy volunteers of KAE609 (cipargamin, formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single dose cohorts (1-300mg, including one 30mg food effect cohort) with 4-10 subjects in each cohort and in multiple dose cohorts (10-150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6-8 days post last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of AUCinf increased in a dose-proportional manner over the dose range of 1-300mg. AUClast and Cmax also increased in an approximately dose-proportional manner. When administered daily for three days, the accumulation ratio on Day 3 (AUC0-24, day3/AUC0-24, day1) was in the range of 1.5-2 in the studied dose range (10-150 mg) and consistent with an elimination half-life of around 24 hours. Urine analysis for unchanged KAE609 revealed negligible amounts (≤ 0.01%) excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC) however Cmax was reduced by around 27%. KAE609 was tolerated within this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses.Antimicrobial Agents and Chemotherapy 08/2014; · 4.57 Impact Factor
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ABSTRACT: Studies in pregnant rabbits were conducted to evaluate if there are any differences in uptake of thalidomide into the intrauterine compartment and developmental toxicity risk following oral and intravaginal administration. Thalidomide concentrations in maternal plasma, yolk sac cavity (YSC) fluid and embryo following intravaginal administration were 2- to 7-fold lower than their respective levels after oral administration. Ratios of thalidomide concentration in YSC fluid to maternal plasma were similar between these two routes, indicating no difference in uptake into the intrauterine compartment. A rabbit embryo-fetal development study using oral and intravaginal thalidomide administration at 2mg/kg/day (a dose >10,000-fold higher than the expected amount of thalidomide in human semen) did not result in any developmental abnormalities. These data demonstrated no preferential transfer mechanism of thalidomide from vagina to conceptus, and no additional embryo-fetal developmental toxicity risks with thalidomide exposure via the vaginal route.Reproductive toxicology (Elmsford, N.Y.). 05/2014;
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ABSTRACT: Studies were conducted in New Zealand White rabbits to assess the seminal transfer, vaginal absorption, and placental transfer of a therapeutic monoclonal antibody (T-IgG4). T-IgG4 was administered by intravenous injection (IV) in males and by IV and intravaginal routes in females. Low levels of T-IgG4 were excreted into seminal plasma (100- to 370-fold lower than serum concentrations) and absorbed following vaginal dosing (3 orders of magnitude lower than IV administration). On gestation day 29 (GD29), fetal serum T-IgG4 levels were 1.5-fold greater than maternal levels following IV dosing. The fetal T-IgG4 exposure ratio for seminal transfer vs. direct maternal IV dosing was estimated to be 1.3*10(-8). Applying human serum T-IgG4 exposure data to the model, the estimated human T-IgG4 serum concentration from seminal transfer was 3.07*10(-7)μg/mL, an exposure level at least 1000-fold lower than the T-IgG4-ligand dissociation constant (Kd) and at least 7 orders of magnitude lower than the in vivo concentration producing 20% inhibition of the target (EC20). These data indicate that excretion of a T-IgG4 into semen would not result in a biologically meaningful exposure risk to the conceptus of an untreated partner.Reproductive Toxicology 05/2014; · 3.14 Impact Factor