Avinash S. Patil

Cell wall-mediated neuronal damage in early sepsis

ABSTRACT Neuronal dysfunction can occur in the course of sepsis without meningitis. Sepsis-associated neuronal damage (SAND) was observed in the hippocampus within hours in experimental pneumococcal bacteremia. Intravascular challenge with purified bacterial cell wall recapitulated SAND. SAND persisted in PAFr−/− mice but was partially mitigated in mice lacking cell wall recognition proteins TLR2 and Nod2 and in mice overexpressing interleukin-10 (IL-10) in macrophages. Thus, cell wall drives SAND through IL-10-repressible inflammatory events. Treatment with CDP-choline ameliorated SAND, suggesting that it may be an effective adjunctive therapy to increase survival and reduce organ damage in sepsis.

Use of a thrombopoietin mimetic for chronic immune thrombocytopenic purpura in pregnancy.

BACKGROUND: Romiplostim, a thrombopoietin mimetic, is a novel therapeutic option for patients with chronic immune thrombocytopenic purpura. We report on the effects of romiplostim use throughout pregnancy. CASE: A 28-year-old primigravid woman with chronic immune thrombocytopenic purpura initiated a planned pregnancy on romiplostim. The second and third trimesters were marked by a cyclic pattern of thrombocytopenia requiring supplemental corticosteroids or intravenous immunoglobulin and resultant thrombocytosis. Increased romiplostim doses and daily corticosteroids stabilized the platelet count before induction of labor at 33 weeks of gestation. The newborn manifested intraventricular hemorrhage at birth, although no developmental delay was present on follow-up at 10 months of age. CONCLUSION: The decreased efficacy of romiplostim monotherapy is attributed to increased target-mediated drug disposition and the physiologic changes of pregnancy. Safety concerns still exist for the developmental effects of romiplostim on the fetus.

Health care providers’ use of a drug information service for pregnancy-related inquiries

OBJECTIVES To characterize pregnancy and lactation-related medication inquiries to a drug information center to identify classes of medications of most concern to providers. A secondary objective was to identify any trends in provider inquiries over the study period. DESIGN A retrospective descriptive study of pregnancy and lactation-related inquiries to the University of North Carolina Health Care System Drug Information Center database between January 2001 and December 2010. SETTING University of North Carolina Health Care System Drug Information Center. INTERVENTION Provider inquiries and responses were extracted and characterized by indication for treatment and reason for inquiry. Comparison of the first and second 5-year periods was performed to delineate trends. Descriptive statistics, Fishers Exact and χ2 tests were used for analysis. MAIN OUTCOME MEASURES Inquiry origin, time, and subject. RESULTS 433 inquiries were retrieved over the study period from physicians (50%), pharmacists (21%), and nurses (18%). Inquiries were most often made during the antepartum period (34%), followed by the postpartum (28%) and preconception (22%) periods. The most frequent indications for inquiry were psychiatry (15%) and infectious diseases (14%), which remained constant throughout the study period. Safety was the most common reason for inquiry (52%). The responses provided to callers were limited due to lack of information availability 37% of the time. CONCLUSION Psychiatry and infectious disease-related indications are the most frequent subjects of provider inquiry regarding medication use in pregnancy. Rates of inquiry remained constant throughout the past decade in most therapeutic areas. These findings are consistent with previous observations in other developed countries and suggest high-yield areas for pharmacist education.

Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model

Objective: We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility. Study Design: Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2α-hydroxyprogesterone, 6β-hydroxyprogesterone (6β-OHP), 16α-hydroxyprogesterone (16α-OHP), or 17-hydroxyprogesterone caproate (17-OHPC) at 10−9 to 10−6 mol/L. Uterine horns were exposed to progestins (10−6 mol/L), followed by increasing concentrations of oxytocin (1-100 nmol/L) to study oxytocin-induced contractility. Contraction parameters were compared for each progestin and matched vehicle control using repeated measures 2-way analysis of variance. In vitro metabolism of progesterone by recombinant cytochrome P450 3A (CYP3A) microsomes (3A5, 3A5, and 3A7) identified major metabolites. Results: Oxytocin-induced contractile frequency was decreased by 16α-OHP (P = .03) and increased by 6β-OHP (P = .05). Progesterone and 17-OHPC decreased oxytocin-induced contractile force (P = .02 and P = .04, respectively) and frequency (P = .02 and P = .03, respectively). Only progesterone decreased spontaneous contractile force (P = .02). Production of 16α-OHP and 6β-OHP metabolites were confirmed in all CYP3A isoforms tested. Conclusion: Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility.

Is personalized medicine achievable in obstetrics

Personalized medicine seeks to identify the right dose of the right drug for the right patient at the right time. Typically, individualization of therapy is based on the pharmacogenomic makeup of the individual and environmental factors that alter drug disposition and response. In addition to these factors, during pregnancy, a womans body undergoes many changes that can impact the therapeutic efficacy of medications. Yet, there is minimal research regarding personalized medicine in obstetrics. Adoption of pharmacogenetic testing into the obstetrical care is dependent on evidence of analytical validity, clinical validity, and clinical utility. Here, we briefly present information regarding the potential utility of personalized medicine for treating the obstetric patient for pain with narcotics, hypertension, and preterm labor, and discuss the impediments of bringing personalized medicine to the obstetrical clinic.

Uterocervical Angle Measurement Improves Prediction of Preterm Birth in Twin Gestation

Objective Twin pregnancies are associated with an increased risk of spontaneous preterm birth. Our objective was to compare the performance of uterocervical angle to cervical length as predictors of spontaneous preterm birth in this population. Methods We conducted a retrospective cohort study of twin gestations at a single center from May 2008 to 2016 who received a transvaginal ultrasound for the evaluation of the cervix between 16 0/7 and 23 0/7 weeks. The primary outcome was prediction of preterm birth <28 and <32 weeks by uterocervical angle and cervical length. Results Among 259 women with twin gestation, the mean gestational age at birth was 34.83 ± 3.48 weeks. Receiver operator characteristic curves demonstrated optimal prediction of spontaneous preterm birth prior to 32 weeks at a uterocervical angle >110° (80% sensitivity, 82% specificity) [odds ratio (OR), 15.7 (95% confidence interval (CI), 7.2‐34.4)] versus cervical length <20 mm (53% sensitivity, 85% specificity; p < 0.001, OR, 6.4 [95% CI, 2.3‐17.8]) and similarly, prior to 28 weeks at a uterocervical angle >114° (OR, 24.3 [95% CI, 6.7‐88.5]) compared with cervical length <20 mm (OR, 11.4 [95% CI, 3.5‐36.7]). Conclusion Uterocervical angles >110° performed better than cervical length for the prediction of spontaneous preterm birth in twin gestations.

Increased unfractionated heparin requirements with decreasing body mass index in pregnancy

Background Pregnant women receiving low-molecular-weight heparin for therapeutic anticoagulation are often converted to unfractionated heparin in anticipation of labor. We aim to characterize the impact of maternal body mass index on attainment of target anticoagulation during the conversion process. Methods We conducted a five-year retrospective study of a pregnancy cohort converted from low-molecular-weight heparin to unfractionated heparin in the third trimester. Patient demographics, anticoagulation regimens, and clinical outcomes were extracted from the medical record. Nonparametric statistical methods were used for analysis by body mass index (<30, 30–35, and >35). Results Thirty-one subjects were evenly distributed by body mass index (p = 0.97). Linear regression revealed an inverse correlation between patient body mass index and unfractionated heparin dose needed to achieve therapeutic anticoagulation (p = 0.04). Subjects with body mass index > 35 attained therapeutic activated partial thromboplastin time levels at 18 U (Units)/kg/h, while subjects with body mass index < 30 required 25 U/kg/h (p = 0.02). Conclusion Higher doses of unfractionated heparin are needed to achieve anticoagulation in patients with body mass index < 30 during pregnancy. This paradoxical relationship may be explained by physiologic characteristics that increase unfractionated heparin elimination, including diminished adiposity and increased renal clearance.

Principles of Anti-infective Dosing in Pregnancy

PURPOSE Anti-infectives are among the most commonly prescribed medications in pregnancy. However, detailed information on the pharmacokinetics and pharmacodynamics of these medications in pregnancy is limited, leading to uncertainty among clinicians regarding the tolerability and efficacy of treatments. The purposes of this review were to highlight key physiologic changes during pregnancy that influence drug behavior, and to discuss areas of active research related to anti-infective drugs in pregnancy. METHODS A review of literature in PubMed was performed for topics related to physiologic changes of pregnancy, postcesarean surgical site infections, vaccines in pregnancy, and intrauterine infections. The literature was reviewed and pertinent sources were utilized for this article. FINDINGS Physiologic changes during pregnancy may impact drug disposition and efficacy. Cefazolin regimens are the current prophylactic treatment of choice for postcesarean surgical site infections. Vaccines are provided in pregnancy for both maternal and neonatal benefit. Broad-spectrum antibiotics continue to be used as first-line therapy for intrauterine infections. IMPLICATIONS Continued efforts to broaden the knowledge base on anti-infective drug behavior in pregnancy will result in increased therapeutic options for this population.

Fundamentals of Clinical Pharmacology With Application for Pregnant Women

&NA; Medication use is common in pregnancy, yet for most medications the optimal formulation and dosage have not been described specifically for pregnant women. Often, adverse effects are only discovered anecdotally or after extensive off‐label use occurs. Since pharmacologic research that includes pregnant women is sparse and animal studies are often not applicable to the human fetus, providers must use knowledge of drug behavior and normal physiologic changes of pregnancy to personalize treatment for pregnant women. In this review, we present an overview of the basic concepts of clinical pharmacology: pharmacokinetics, pharmacodynamics, and pharmacogenomics. The normal physiologic changes of pregnancy are presented as a framework to understand alterations in drug behavior. A clinical vignette that addresses 4 pregnancy scenarios involving medications—preterm birth, vaccination, herpes simplex virus infection, and codeine toxicity—is provided to illustrate application of core clinical pharmacologic concepts. Discussion of relevant literature illustrates the challenges of offering individualized pharmacologic therapy in pregnancy.

Pseudomonoamniotic Pregnancy: Case Report and Review of Etiologic Considerations

Pseudomonoamniotic gestations are increasingly recognized through sonographic surveillance of monochorionic twins, though etiologic factors remain undefined. We present a case of spontaneous pseudomonoamniotic twins and propose umbilical cord insertion proximity as a sonographic marker. Systematic review of the literature was performed and additional cases with similar findings were noted. Approximately 75% of reported cases (28/37) were deemed spontaneous and several included short inter-cord distances. Shunting of blood away from the membranes in the region between the cord insertions may be responsible for membrane rupture. Further investigation is needed into short inter-cord distance as a marker for monochorionic twins at risk to become a pseudomonoamniotic gestation.