Enhancement of transdermal delivery of 6-beta-naltrexol via a codrug linked to hydroxybupropion.

Naltrexone (NTX) is a potent opioid antagonist used in the treatment of alcohol dependence and heroin abuse. Compared with naloxone, NTX has a longer duration of action largely attributed to its major active metabolite, 6-beta-naltrexol. The purpose of this study was to increase the delivery of 6-beta-naltrexol across human skin in vitro via a novel codrug. A carbonate codrug of 6-beta-naltrexol linked to hydroxybupropion was synthesized and evaluated. In vitro human skin permeation rates were measured using a flow-through diffusion cell system. The drug melting points, solubilities, chemical stability, and skin disposition were determined. The carbonate codrug was hydrolyzed on passing through skin and appeared as a combination of intact codrug and parent drugs, 6-beta-naltrexol and hydroxybupropion, in the receiver solution. The codrug provided a significantly (p<0.05) higher 6-beta-naltrexol flux across human skin than 6-beta-naltrexol base. The extent of parent drug regeneration in the skin ranged from 56 to 86%. A higher stratum corneum partition coefficient and rapid bioconversion of the carbonate codrug in the skin correlated with increased 6-beta-naltrexol delivery rates.     

Pulsed mode versus near-continuous mode delivery of diode laser photocoagulation for high-risk retinopathy of prematurity.

OBJECTIVE: To compare structural and functional outcomes and efficiency of diode laser photocoagulation for retinopathy of prematurity (ROP) when delivered in a pulsed mode versus a near-continuous mode. METHODS: A retrospective study was conducted of 138 patients who underwent diode laser photocoagulation for threshold ROP using either pulsed or near-continuous delivery. Laser-related complications and structural and functional outcomes were analyzed. Prospectively, time efficiency and total energy used were evaluated in nine infants with bilateral symmetric high-risk prethreshold ROP in which one eye of each infant was randomized to pulsed and the fellow eye to near-continuous delivery. RESULTS: There was no significant difference between groups with regards to prevalence of posterior disease (Zone 1 or posterior Zone 2) (p = 0.11), postoperative vitreous haze (p = 0.60), postoperative complications (p = 0.38), retinal detachment (p = 0.90), strabismus (p = 0.73), amblyopia (p = 0.69), or refractive error (p = 0.95). Mean time for treatment was 23 minutes using pulsed delivery versus 14 minutes per eye with near-continuous delivery (p < 0.001). The mean total power used per eye with pulsed mode delivery was 1.5 x 10(5) W versus 1.1 x 10(5) W with near-continuous delivery (p = 0.015). CONCLUSIONS: No differences in complications, functional outcome, or structural outcome were found between using pulsed mode and near-continuous mode diode laser delivery for high-risk ROP. Near-continuous laser delivery, in our hands, was more time-efficient and used less total power.     

A suggested clinical score to predict the severity of adenoid obstruction in children

Chronic nasal obstruction in children is a very common disorder. Obstructing adenoid is usually the first to blame. Though the clinical assessment is essential, it is often considered unreliable or insufficient. We conducted a prospective clinical study to validate a clinical score predicting the severity of adenoid obstruction in symptomatic children. The clinical score (CS) included mouth breathing, snoring, restless sleep, frequent waking-up at night and obstructive breathing during sleep. Each item received a score of 0 or 1. The palatal airway was evaluated on a lateral nasopharyngeal x-ray. The degree of obstruction was assessed intra-operatively by a laryngeal mirror using a 3-grade scale. The volume of each adenoid specimen was measured. Eighty-six patients were enrolled, 51 boys and 35 girls, aged 13–181 months (mean 52, median 45). The CS correlated very well with the intra-operative findings (p < 0.01) and with the degree of palatal airway obstruction (p < 0.05) but not with the volume of the adenoid removed (p > 0.05). The CS was higher in children younger than 3 years (CS > 3 in 85.7% vs. 29.2%), having more frequent obstructive breathing during sleep (71.43% vs. 21.54%). A CS of three or higher, predicted severe obstruction in 96.5% of patients, as detected intra-operatively. The suggested CS is simple to use and is highly reliable in identifying children in need for adenoidectomy, in the context of normal anterior rhinoscopy and tonsils less than grade three.This work was presented at the podium of the XVIII IFOS in Rome, Italy on June 26, 2005.     

Präimplantationsdiagnostik, Pränataldiagnostik und Schwangerschaftsabbruch

Preimplantation genetic diagnosis (PGD) has been vigorously debated in Germany ever since the Bundesärztekammer (BÄK) published a draft of guidelines for PGD in March 2000. Many stakeholders such as churches, medical societies, and diverse associations have participated in the discussion. However, little is known about the attitudes of experts, directly affected patient groups, and the public in Germany. In several studies that are part of the German research program on ethical implications of the Human Genome Project, representative surveys were undertaken to assess the attitudes of the general population (n=1017), five relevant expert groups (n=879), and couples at high risk for genetic disorders(n=324) towards PGD and prenatal diagnosis (PD). All groups favor legislation for PGD. Differences exist in regard to the extent of their approval. For 17% of the high-risk couples with a persisting desire for a child, PGD performed in a neighboring country is the most probable reproductive option. These results should be carefully considered in the ongoing legislation process on human reproduction in our country.     

Does pre-treatment with micronized progesterone affect the ovarian response to a gonadotropin releasing hormone agonist flare-up protocol?

The purpose of this study was to investigate the ovarian response and the receptivity of the endometrium in women pre-treated with micronized progesterone. Eighty-two normogonodotropic women undergoing in vitro fertilization were studied. Thirty received micronized progesterone 1500 mg/day from day 21 of the cycle for a minimum of 2 weeks, and 52 did not receive micronized progesterone (control group). A gonadotropin releasing hormone agonist (GnRH-a) was administered to all the patients in the follicular phase (flare-up). Twenty-five cycles were cancelled for fertilization failure due to male factor, 12 (40%) in the progesterone group and 13 (25%) in the control group (p = 0.271). There was no difference in the number of oocytes retrieved (7.3 +/- 5 vs. 8.2 +/- 4), fertilization rate (50.8% vs. 65%), clinical pregnancy rate (16.6% vs. 25%) or implantation rate (8% vs. 14%). In the progesterone group cases without fertilization, we performed two biopsies to evaluate the receptivity of the endometrium. Pinopode expression was noted 7 days after oocyte retrieval. It seems that the administration of micronized progesterone in the previous cycle does not affect the ovarian response to the combination of follicular phase GnRH-a and gonadotropins, nor the receptivity of the endometrium.     

Score Statistic to Test for Genetic Correlation for Proband-Family Design

In genetic epidemiological studies informative families are often oversampled to increase the power of a study. For a proband‐family design, where relatives of probands are sampled, we derive the score statistic to test for clustering of binary and quantitative traits within families due to genetic factors. The derived score statistic is robust to ascertainment scheme. We considered correlation due to unspecified genetic effects and/or due to sharing alleles identical by descent (IBD) at observed marker locations in a candidate region. A simulation study was carried out to study the distribution of the statistic under the null hypothesis in small data‐sets. To illustrate the score statistic, data from 33 families with type 2 diabetes mellitus (DM2) were analyzed. In addition to the binary outcome DM2 we also analyzed the quantitative outcome, body mass index (BMI). For both traits familial aggregation was highly significant. For DM2, also including IBD sharing at marker D3S3681 as a cause of correlation gave an even more significant result, which suggests the presence of a trait gene linked to this marker. We conclude that for the proband‐family design the score statistic is a powerful and robust tool for detecting clustering of outcomes.     

The impact of mitral valve morphology on the long-term outcome of mitral balloon valvuloplasty.

BACKGROUND: The effect of mitral valve morphology (MVM) on the long-term results of mitral balloon valvuloplasty (MBV) is not well established. The aim of the study was to evaluate the impact of MVM on long-term outcome of MBV. METHODS: Five hundred and eighteen consecutive patients (mean age, 31+/-11 years) who underwent successful MBV were followed up for 0.5-16.5 (mean, 6+/-4.5) years. Patients were divided into two groups according to their mitral echo score (MES) before MBV: group A (n=340; MES8). RESULTS: We report the immediate and long-term clinical and echocardiographic results of the above-mentioned 518 consecutive patients. The mitral valve area was significantly larger in group A than in group B, both immediately after MBV (2.0+/-0.3 vs. 1.82+/-0.3 cm2, respectively; P<0.0001) and also at the last follow-up (1.8+/-0.33 vs. 1.5+/-0.33 cm2, respectively; P<0.0001). Restenosis occurred in 38/340 (11%) in group A vs. 73/178 (41%) in group B (P<0.0001). Actuarial freedom from restenosis at 5, 10, 15 years were 92+/-2%, 85+/-3%, 65+/-6% for group A vs. 72+/-4%, 44+/-5%, 9+/-6% for group B (P<0.001). Event-free survival rates at 5, 10, 15 years for group A were 93+/-1%, 88+/-2%, 66+/-6% vs. 82+/-3%, 59+/-6%, 8+/-7% for group B (P<0.0001). Stepwise Cox multivariate regression analysis identified MES, preprocedure functional class, and postprocedure mitral valve area相似文献