Donald R. Mattison

Sex Differences in Pharmacokinetics and Pharmacodynamics

Significant differences that exist between the sexes affect the prevalence, incidence and severity of a broad range of diseases and conditions. Men and women also differ in their response to drug treatment. It is therefore essential to understand these reactions in order to appropriately conduct risk assessment and to design safe and effective treatments. Even from that modest perspective, how and when we use drugs can result in unwanted and unexpected outcomes. This review summarizes the sex-based differences that impact on pharmacokinetics, and includes a general comparison of clinical pharmacology as it applies to men, women and pregnant women. Sex-related or pregnancy-induced changes in drug absorption, distribution, metabolism and elimination, when significant, may guide changes in dosage regimen or therapeutic monitoring to increase its effectiveness or reduce potential toxicity. Given those parameters, and our knowledge of sex differences, we can derive essentially all factors necessary for therapeutic optimization.Since this is a rapidly evolving area, it is essential for the practitioner to review drug prescribing information and recent literature in order to fully understand the impact of these differences on clinical therapeutics.

Environmental exposures and adverse pregnancy outcomes: a review of the science.

To better understand the science linking environmental contaminants exposures with adverse pregnancy outcomes, we reviewed the relevant epidemiologic literature. We searched PubMed (primarily 1995-2006) using the key word combinations for select environmental exposures and pregnancy outcomes. Environmental tobacco smoke is a risk factor for reduced birth weight and preterm delivery. Outdoor air pollution is associated with reduced term birth weight and preterm delivery. Suggestive evidence associates pesticides and polychlorinated biphenyls with decreased fetal growth and length of gestation. Stronger evidence, primarily occupational, links certain birth defects with exposure to organic solvents and chlorophenoxy herbicides. Evidence suggests dichlorodiphenyltrichloroethane and bisphenol-A could be associated with pregnancy loss. Exposures in utero can also increase the risk of developmental delays (ie, impaired neurological function), adult chronic illnesses (ie, heart disease, diabetes, cancer), and next generation effects (ie, reduced reproductive capacity). Further research, education, and improved public health policy are needed to reduce potentially adverse exposures.

The changing epidemiology of multiple births in the United States

OBJECTIVE: To describe changes in the epidemiology of multiple births in the United States from 1980 to 1999 by race, maternal age, and region; and to examine the impact of these changes on birth weight‐specific infant mortality rates for singleton and multiple births. METHODS: Retrospective univariate and multivariable analyses were conducted using vital statistics data from the National Center for Health Statistics. RESULTS: Between 1980 and 1999, the overall multiple birth ratio increased 59% (from 19.3 to 30.7 multiple births per 1000 live births, P < .001), with rates among whites increasing more rapidly than among blacks. Women of advanced maternal age, especially those aged 30‐34, 3539, and 40‐44 experienced the greatest increases (62%, 81%, and 110%, respectively). Although all regions of the United States experienced increases in multiple birth ratios between 1991 and 1999, the Northeast had the highest twin (33.9 per 1000 live births) and higher order birth ratios (280.5 per 100,000 live births), even after adjusting for maternal age and race. Between 1989 and 1999, multiple births experienced greater declines in infant mortality than singletons in all birth weight categories. Consequently, very low birth weight and moderately low birth weight infant mortality rates among multiples were lower than among singletons. CONCLUSION: It is important to understand the changing epidemiology of multiple births, especially for women at highest risk (advanced maternal age, white race, Northeast residents). The attribution of infertility management requires further study. The differential birth weight‐specific infant mortality for singletons and multiples demonstrates the importance of stratifying by plurality when assessing perinatal outcomes. (Obstet Gynecol 2003;101:129‐35.

The effects of smoking on fertility from gametogenesis to implantation

Abstract The literature concerning the effects of cigarette smoking, treatment with nicotine, cigarette smoke condensates, or cigarette smoke constituents on reproductive events from gametogenesis to implanatation is reviewed. Epidemiologic evidence, although scanty, suggests that cigarette smoking decreases fertility in women. Cigarette smoking is also associated with an increased frequency of menstrual abnormalities and a cigarette dose-related decrease in the age of spontaneous menopause. Similar epidemiologic studies assessing reproductive function have not been conducted among men who smoke. Several small studies have demonstrated decreased sperm counts and an increased frequency of abnormal sperm morphology among male smokers. Cessation of smoking in several of these studies has been associated with an increase in sperm number and a decrease in the frequency of sperm shape abnormalities. Treatment of rodents with cigarette smoke or cigarette smoke constituents produces similar effects on sperm number and morphology. Experimental evidence from humans and rodents suggests that cigarette smoke or nicotine can alter hypothalamic-pituitary interrelationships, stimulating growth hormone, cortisol, vasopressin, and oxytocin release and inhibiting luteinizing hormone and prolactin release. These changes may alter hormonal interrelationships necessary for successful reproduction. Studies in rodents and human and nonhuman primates also suggest that cigarette smoke or nicotine alters the motility of the female reproductive tract, and may impair implantation of the embryo. Analysis of the experimental data available concerning the effects of smoking on reproductive processes suggests an adverse influence on reproduction at several sites from gametogenesis to implantation. The literature on smoking and fertility, however, is surprisingly small. Additional experimentation, as well as epidemiological surveys of human populations, are necessary before it will be possible to make unequivocal statements concerning reproductive interference by cigarette smoke or its components.

Exposure to Hurricane Katrina, Post-Traumatic Stress Disorder and Birth Outcomes

Background:Little is known about the effects of natural disasters on pregnancy outcomes. We studied mental health and birth outcomes among women exposed to Hurricane Katrina. Methods:We collected data prospectively from a cohort of 301 women from New Orleans and Baton Rouge. Pregnant women were interviewed during pregnancy about their experiences during the hurricane, and whether they had experienced symptoms of post-traumatic stress disorder (PTSD) and/or depression. High hurricane exposure was defined as having 3 or more of the 8 severe hurricane experiences, such as feeling that ones life was in danger, walking through floodwaters, or having a loved one die. Results:The frequency of low birth weight was higher in women with high hurricane exposure (14.0%) than women without high hurricane exposure (4.7%), with an adjusted odds ratio (aOR): 3.3; 95% confidence interval (CI): 1.13–9.89; P < 0.01. The frequency of preterm birth was higher in women with high hurricane exposure (14.0%) than women without high hurricane exposure (6.3%), with aOR: 2.3; 95% CI: 0.82–6.38; P > 0.05. There were no significant differences in the frequency of low birth weight or preterm birth between women with PTSD or depression and women without PTSD or depression (P > 0.05). Conclusions:Women who had high hurricane exposure were at an increased risk of having low birth weight infants. Rather than a general exposure to disaster, exposure to specific severe disaster events and the intensity of the disaster experience may be better predictors of poor pregnancy outcomes. To prevent poor pregnancy outcomes during and after disasters, future disaster preparedness may need to include the planning of earlier evacuation of pregnant women to minimize their exposure to severe disaster events.

Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs.

IMPORTANCE Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia. OBJECTIVES To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs. DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System. MAIN OUTCOMES AND MEASURES Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs. RESULTS We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P < .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001). CONCLUSIONS AND RELEVANCE Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present, none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings as part of their prescribing information. Our data, and data from prior studies, show the need for more prominent warnings.

The role of epoxidation in 4-vinylcyclohexene-induced ovarian toxicity

4-Vinylcyclohexene (VCH) is present in gases discharged during synthetic rubber production. Chronic treatment of B6C3F1 mice and F-344 rats with VCH by gavage has been shown to induce ovarian tumors in mice but not in rats. Our objective was to understand the mechanism of the species difference in VCH-induced ovarian tumors. Since a critical step in the induction of ovarian tumors is destruction of the small oocyte, small oocyte counts obtained from serially sectioned ovaries were used as an index of toxicity. VCH or its epoxide metabolites [VCH-diepoxide, VCH-1,2-epoxide, and VCH-7,8-epoxide (in mice only)] were given to 28-day-old female mice and rats in corn oil, ip, at doses ranging from 0.07 to 7.4 mmol/kg body wt/day for 30 days. The dose which reduced the small oocyte count to 50% that of control was defined as the ED50. In mice, the ED50 for the reduction in small oocytes by VCH was 2.7 mmol/kg, whereas, no detectable oocyte loss occurred in rats at the highest dose of VCH (7.4 mmol/kg). The potency of the epoxides of VCH was greater than that of VCH in both species. The ED50 for oocyte loss by VCH-1,2-epoxide in mice and rats was 0.5 and 1.4 mmol/kg, respectively. In mice, VCH-7,8-epoxide had comparable potency to VCH-1,2-epoxide (ED50 = 0.7). VCH diepoxide was even more potent with ED50 values of 0.2 and 0.4 mmol/kg, in mice and rats, respectively. The dose response of the blood concentration of VCH-1,2-epoxide in mice after VCH showed that doses of VCH which caused minimal toxicity had the lowest blood level of this ovotoxic epoxide. Pretreatment of mice with the cytochrome P450 inhibitor chloramphenicol (200 mg/kg, ip) inhibited VCH epoxidation in vivo and in vitro and partially protected mice from VCH toxicity. Thus it appears that metabolism of VCH to epoxides and their subsequent destruction of oocytes are critical steps in VCH-induced ovarian tumors. Rats may be resistant to ovarian tumor induction by VCH because the amount of VCH converted to epoxides is insufficient to produce oocyte destruction.

Sex Differences in Drug Disposition

Physiological, hormonal, and genetic differences between males and females affect the prevalence, incidence, and severity of diseases and responses to therapy. Understanding these differences is important for designing safe and effective treatments. This paper summarizes sex differences that impact drug disposition and includes a general comparison of clinical pharmacology as it applies to men and women.

Human Placental Transport of Oxytocin

Oxytocin (OX) has been suggested as a signal for parturition. Although OX is produced by both mother and fetus, concentrations are higher in umbilical than maternal blood. In addition, umbilical artery OX concentrations (15-40 pg/ml) are higher than umbilical vein (4-12 pg/ml) and maternal (1-10 pg/ml) concentrations. The umbilical A-V difference suggests that placental uptake and transport may be one path from fetal (F) to maternal (M) circulation. However, this difference may also reflect placental oxytocinase activity, which is known to metabolize biologically active peptides such as OX. We have investigated placental transport of OX from F to M and M to F circulation using in vitro dually perfused isolated cotyledons from term human placenta. Term human placentae from uncomplicated pregnancies were obtained immediately after delivery. A single peripheral cotyledon and corresponding lobule was cannulated and perfused. After stabilization and demonstration of adequate M to F perfusion-perfusion overlap, we studied the transport of OX (3H) with 14C-inulin (14C-IN) as permeability reference in both M to F (n = 8) and F to M (n = 6) directions during 2 h of perfusion. In addition to the higher tissue uptake observed in M to F than F to M transport direction as measured by the drop in the concentration of both 3H-OX and 14C-IN in the circuits in which both compounds were added, the same trend was found for the transfer rates of both compounds. These transfer rates which reflect the permeability of placental tissue to OX and IN were 15.17 +/- 2.79 (mean +/- SD) and 6.28 +/- 0.93 microliters/min/g (M to F) and 11.79 +/- 1.77 and 4.91 +/- 0.81 microliters/min/g (F to M). Although the permeability of both compounds is higher in the M to F than in the F to M transport direction, comparing these permeability values with respect to their molecular weight (MW) showed a significant correlation when known permeability values of polar compounds between MW 60 and 68,000 daltons were included. This correlation indicates that OX crosses the placenta in both directions by simple diffusion. High-performance liquid chromatography analysis showed that there is little evidence of placental metabolism and degradation of OX over the period of these experiments. Oxytocin is the main therapeutic drug that is frequently used in obstetrics for the induction of labor and parturition. Under such circumstances and with respect to the placental permeability results, oxytocin could reach the fetal circulation.

Phosphoramide mustard is responsible for the ovarian toxicity of cyclophosphamide

Although cyclophosphamide (CPA) is an ovarian toxicant, the responsible metabolite(s) have not been identified. The purpose of these experiments was to determine if phosphoramide mustard or acrolein were the proximate toxicants produced by metabolic activation of CPA. To do this analogs of CPA known to generate either phosphoramide mustard or acrolein in vivo were assessed for their ability to produce ovarian toxicity as measured by differential follicle destruction, ovarian volume loss, and uterine weight loss and compared to the effects produced by CPA. Phosphoramide mustard cyclohexylamine salt (PMC) and trans-4-phenylcyclophosphamide (T4P), both of which generate phosphoramide mustard, and didechlorocyclophosphamide (DCPA) and allyl alcohol (AA) which generate acrolein were administered ip to female C57BL/6N mice, 10-12 weeks old, at doses equimolar to 0, 25, 75, 200, or 500 mg/kg of CPA. Three days later the animals were killed, their uterine weights measured and their ovaries removed, fixed, and serially sectioned. Only PMC and T4P produced ovarian toxicity. On an equimolar basis these compounds were over twice as potent as CPA. Both caused a significant reduction in uterine weight (to 50% of controls) at doses of 200 (PMC) and 150 mg/kg (T4P). PMC and T4P also caused a 50% reduction in ovarian volume at doses above 75 mg/kg. Primordial follicles were most sensitive; ED50s were 76.9, 25.3, and 19.3 mg/kg (0.276, 0.091, and 0.069 mmol/kg) for CPA, PMC, and T4P, respectively. Growing follicle numbers were also reduced by T4P and PMC, an effect not seen with CPA treatment. Finally, antral follicles were significantly reduced by all doses of PMC, and with T4P at doses greater than 75 mg/kg. The highest doses of PMC, T4P, and CPA all caused a reduction in antral follicle numbers to less than one percent of controls. Didechlorocyclophosphamide (DCPA) and allyl alcohol (AA), compounds that generate acrolein but not phosphoramide mustard in vivo, had no effect on any of the parameters measured even when injected directly into the ovary. This suggests that phosphoramide mustard is responsible for CPA ovarian toxicity. The greater potency of PMC and T4P compared to CPA is likely the result of these compounds bypassing important detoxification steps, therefore, more of the parent compound reaches the ovary as the toxic metabolite.