Cyclosporine excretion into breast milk

Although many female patients of childbearing age who are receiving cyclosporine have successful pregnancies, these women may be advised not to breast-feed. During recent years, cases of uneventful pregnancies and subsequent successful breast-feeding have been reported in the literature. The infant's blood cyclosporine concentration was usually very low. Based on these findings and the lack of detectable adverse effects, some investigators have suggested that women on cyclosporine may breast-feed, challenging the conventional view that cyclosporine is contraindicated during breast-feeding. Here, we report our experience with cyclosporine use during breast-feeding in five mother-infant pairs. We show a wide range of infant exposures to the drug in milk, noting that one of the infants had therapeutic blood concentrations of cyclosporine despite relatively low concentrations of the drug in milk.     

Magnetic Resonance Imaging of Ethyl-nitrosourea-induced Rat Gliomas: A Model for Experimental Therapeutics of Low-grade Gliomas

Human low-grade gliomas represent a population of brain tumors that remain a therapeutic challenge. Preclinical evaluation of agents, to test their preventive or therapeutic efficacy in these tumors, requires the use of animal nobreak models. Spontaneous gliomas develop in models of chemically induced carcinogenesis, such as in the transplacental N-ethyl-N-nitrosourea (ENU) rat model. However, without the ability to detect initial tumor formation, multiplicity or to measure growth rates, it is difficult to test compounds for their interventional or preventional capabilities. In this study Fisher-334 rats, treated transplacentally with ENU, underwent magnetic resonance imaging (MRI) examination in order to evaluate this approach for detection of tumor formation and growth. ENU-induced intracranial cerebral tumors were first observable in T2-weighted images beginning at 4 months of age and grew with a mean doubling time of 0.487 ± 0.112 months. These tumors were found histologically to be predominately mixed gliomas. Two therapeutic interventions were evaluated using MRI, vitamin A (all-trans retinol palmitate, RP), as a chemopreventative agent and the anti-angiogenic drug SU-5416. RP was found to significantly delay the time to first tumor observation by one month (P = 0.05). No differences in rates of tumor formation or growth rates were observed between control and RP-treated groups. MRI studies of rats treated with SU-5416 resulted in reduction in tumor growth rates compared to matched controls. These results show that MRI can be used to provide novel information relating to the therapeutic efficacy of agents against the ENU-induced tumor model.     

Polymorphism of the MDR1/ABCB1 C3435T drug-transporter and resistance to anticonvulsant drugs: A meta-analysis

Background:   Approximately one-third of patients with epilepsy patients have recurrent seizures despite therapy. It has been suggested that therapeutic failure is associated with high expression of the multidrug efflux ABCB1 (MDR1) drug-transporter; specifically, that patients with the 3435CC genotype have higher efflux of anticonvulsants out of brain tissue, with correspondingly lower concentrations in the central nervous system.
Methods:   We conducted a meta-analysis to examine the association between MDR1 polymorphisms and the response to anticonvulsants. We included all published studies until September 2007, in which patients with responsive and unresponsive seizure disorders underwent genotyping for ABCB1 C3435T. Individual and summary odds ratios were calculated using a random effects model. A secondary analysis was also performed, stratifying the studies by their ethnic distribution to account for genetic heterogeneity. We also performed a cumulative analysis by date of publication for the included studies using a random effects model.
Results:   We identified 11 case-control studies involving 3,371 patients (1,646 patients with drug-resistant epilepsy and 1,725 controls). We identified no significant association between anticonvulsant drug resistance and MDR1 polymorphism [odds ratio 1.15; 95% confidence interval (CI) 0.78–1.70; p = 0.48). Subanalysis of studies according to ethnicity yielded similar findings [European cohort: OR = 1.31; 95% CI 0.89–1.94, p = 0.18; Asian cohort: OR = 0.99; 95% CI 0.51–1.89, p = 0.96).
Conclusions:   We found no association between ABCB1 genotype and response to anticonvulsant drugs. At the present time, genetic typing for MDR1 polymorphism is not warranted for patients with drug-resistant epilepsy.     

Weight‐related self‐efficacy in relation to maternal body weight from early pregnancy to 2 years post‐partum

Excessive gestational weight gain may lead to long‐term increases in maternal body weight and associated health risks. The purpose of this study was to examine the relationship between maternal body weight and weight‐related self‐efficacy from early pregnancy to 2 years post‐partum. Women with live, singleton term infants from a population‐based cohort study were included (n = 595). Healthy eating self‐efficacy and weight control self‐efficacy were assessed prenatally and at 1 year and 2 years post‐partum. Body weight was measured at early pregnancy, before delivery, and 6 weeks, 1 year and 2 years post‐partum. Behavioural (smoking, breastfeeding) and sociodemographic (age, education, marital status, income) covariates were assessed by medical record review and baseline questionnaires. Multi‐level linear regression models were used to examine the longitudinal associations of self‐efficacy measures with body weight. Approximately half of the sample (57%) returned to early pregnancy weight at some point by 2 years post‐partum, and 9% became overweight or obese at 2 years post‐partum. Body weight over time was inversely related to healthy eating (β = ?0.57, P = 0.02) and weight control (β = ?0.99, P < 0.001) self‐efficacy in the model controlling for both self‐efficacy measures as well as time and behavioural and sociodemographic covariates. Weight‐related self‐efficacy may be an important target for interventions to reduce excessive gestational weight gain and post‐partum weight gain.     

Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization

Thrombin activates endothelial cell signaling by cleaving the protease-activated receptor-1 (PAR1). However, the function of the apparently nonsignaling receptor PAR3 also expressed in endothelial cells is unknown. We demonstrate here the crucial role of PAR3 in potentiating the responsiveness of PAR1 to thrombin. We tested the hypothesis that PAR1/PAR3 heterodimerization and its effect in modifying G protein selectivity was responsible for PAR3 regulation of PAR1 sensitivity. Using bioluminescent resonance energy transfer-2, we showed that PAR1 had comparable dimerization affinity for PAR3 as for itself. We observed increased Galpha(13) coupling between the PAR1/3 heterodimer compared with the PAR1/1 homodimer. Moreover, knockdown of PAR3 moderated the PAR1-activated increase in endothelial permeability. These results demonstrate a role of PAR3 in allosterically regulating PAR1 signaling governing increased endothelial permeability. Because PAR3 is a critical determinant of PAR1 function, targeting of PAR3 may mitigate the effects of PAR1 in activating endothelial responses such as vascular inflammation.     

Pregnancy Outcome Following Gestational Exposure to Fluoroquinolones: a Multicenter Prospective Controlled Study

Concerns regarding the teratogenicity of fluoroquinolones have resulted in their restricted use during gestation. This is despite an increasing need for their use due to emerging bacterial resistance. The objectives of the present investigation were to evaluate pregnancy and fetal outcomes following maternal exposure to fluoroquinolones and to examine whether in utero exposure to quinolones is associated with clinically significant musculoskeletal dysfunctions. We prospectively enrolled and followed up 200 women exposed to fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin) during gestation. Pregnancy outcome was compared with that for 200 controls matched for age and for smoking and alcohol consumption habits. Controls were exposed to nonteratogenic, nonembryotoxic antimicrobial agents matched by indication, duration of therapy (±3 days), and trimester of exposure. Rates of major congenital malformations did not differ between the group exposed to quinolones in the first trimester (2.2%) and the control group (2.6%) (relative risk, 0.85; 95% confidence interval, 0.21 to 3.49). Women treated with quinolones had a tendency for an increased rate of therapeutic abortions compared with the rate among women exposed to nonteratogens (relative risk, 4.50; 95% confidence interval, 0.98 to 20.57), resulting in lower live-birth rates (86 versus 94%; P = 0.02). The rates of spontaneous abortions, fetal distress, and prematurity and the birth weight did not differ between the groups. Gross motor developmental milestone achievements did not differ between the children of the mothers in the two groups. We concluded that the use of fluoroquinolones during embryogenesis is not associated with an increased risk of major malformations. There were no clinically significant musculoskeletal dysfunctions in children exposed to fluoroquinolones in utero. The higher rate of therapeutic abortions observed in quinolone-exposed women compared to that for their controls may be secondary to the misperception of a major risk related to quinolone use during pregnancy.     

The e-MSWS-12: improving the multiple sclerosis walking scale using item response theory

Quality of Life Research - The Multiple Sclerosis Walking Scale (MSWS-12) is the predominant patient-reported measure of multiple sclerosis (MS) -elated walking ability, yet it had not been...