Endogenous estradiol metabolism during treatment with oral contraceptives

OBJECTIVE: Recent clinical studies indicate that an increase in D-ring estradiol metabolites over A-ring metabolites may be a risk factor for breast cancer. The present work was aimed to investigate the effect of oral contraceptives (OC) on the endogenous estradiol metabolism in premenopausal women. METHODS: Two studies were conducted, firstly comparing 2 different progestins, i.e. norethisterone and dienogest, each in combination with a constant ethinyl estradiol dosage (study A) and secondly comparing a single progestin, i.e. levonorgestrel in 2 ethinyl estradiol/progestin dosage combinations (study B). The main A- and D-ring metabolites, i.e. 2-OHE1 and 16-OHE1, were measured by enzyme immunoassay in 8-h night-urine collected before and after 3 cycles of OC administration. RESULTS: In study A, i.e. ethinyl estradiol plus dienogest or norethisterone acetate, the ratios of 16-OHE1 to 2-OHE1 before administration were 0.62 and 0.68, and after 3 months 0.31 and 0.54, respectively. The ratio after ethinyl estradiol and dienogest was significantly lower after treatment. In study B, i.e. ethinyl estradiol plus levonorgestrel (0.03 mg/0.15 mg and 0.02 mg/0.1 mg), the ratios before treatment were 0.71 and 0.75 for the higher and the lower dosages, respectively, which changed not significantly to 0.73 and 0.71 after 3 cycles. CONCLUSION: OCs containing norethisterone acetate, dienogest or levonorgestrel did not have a negative effect on estradiol metabolism, i.e. they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.     

Enhancement of benzodiazepine binding sites following chronic treatment with flumazenil

The aim of this study was to improve our knowledge of the mechanisms leading to adaptive changes in gamma-aminobutyric acid(A) (GABA(A)) receptors following chronic drug treatment. Exposure (48 h) of human embryonic kidney (HEK 293) cells stably expressing recombinant alpha1beta2gamma2S GABA(A) receptors to the antagonist of benzodiazepine binding sites, flumazenil (5 microM), enhanced the maximum number (B(max)) and the equilibrium dissociation constant (K(d)) of [3H]flunitrazepam binding sites. The flumazenil-induced enhancement in B(max) was potentiated by GABA (50 microM) and reduced by the GABA(A) receptor antagonist, bicuculline (100 microM). Flumazenil-induced enhancement in K(d) was affected by neither of these treatments. GABA (50 microM) enhanced the density of [3H]flunitrazepam binding sites, and this enhancement was greater in the presence of diazepam (1 microM). The results suggest that chronic flumazenil treatment up-regulates in a bicuculline-sensitive manner benzodiazepine binding sites at stably expressed GABA(A) receptors.     

From methadone to buprenorphine: Changes during a 10 year period within a national opioid maintenance treatment programme

Opioid maintenance treatment (OMT) is the most widely used treatment for opioid dependence. Maintenance programmes differ in various aspects and may also change over time. This paper investigates the changes in treatment practices within a national OMT programme during a 10 year period (2002–2011), especially with regard to the prescribing of methadone and buprenorphine. Data (n = 34,001) were collected by annual assessments questionnaires. In 2002, only 16% of the OMT patients received buprenorphine as their maintenance medication. By 2011 this percentage had increased significantly (p < .001) to 50.3%. In the same period the number of patients more than tripled (from 1,984 to 6,640, p < .001), and programme attrition rates decreased (p = .020). This relatively rapid shift is a part of the increasing reliance of addiction medicine upon a range of medications administered by different routes which has not been previously charted within a national treatment programme.     

Feasibility of collaborative care treatment of opioid use disorders with buprenorphine during pregnancy

Background: Medication-assisted treatment with buprenorphine or methadone is recommended for pregnant patients with opioid use disorders (OUDs) to minimize adverse maternal and neonatal outcomes. Collaborative care approaches have been successfully utilized with office-based opioid treatment with buprenorphine in primary care settings, but research is significantly limited in the obstetric setting. Our aim with this study is to demonstrate the feasibility of a collaborative care model for pregnant patients with opioid use disorder. Methods: This is a case series of 16 pregnancies in 14 women initiated on office-based opioid treatment with buprenorphine in a perinatal mental health service embedded in 2 obstetric clinics. Patients are treated by a psychiatrist alongside their prenatal care provider and followed for up to 6 months postpartum and referred to ongoing substance abuse treatment to a community prescriber. Results: The average age of the patients was 30.3 years, and an average gestational age of 23.6 weeks at the time of referral. Treatment continued until delivery in 15 (93.8%) pregnancies, with an average duration of treatment of 14.5 weeks. The majority (60%) had a cesarean delivery. Twelve (80%) infants were admitted to the Neonatal Intensive Care Unit (NICU) for monitoring or treatment of neonatal abstinence syndrome, 14 (87.5%) patients continued or resumed treatment with buprenorphine postpartum at the time of discharge from our program, and 13 (81.3%) were referred to a community prescriber. Conclusions: A collaborative care approach to buprenorphine treatment is feasible during pregnancy. Further research is needed to improve the treatment of OUD during pregnancy.     

Severity of pancreatitis-associated gut barrier dysfunction is reduced following treatment with the PAF inhibitor lexipafant

The aim of the present study was to investigate the potential effect of treatment with a platelet-activating factor (PAF) antagonist, lexipafant (BB-882), on gut endothelial and epithelial barrier dysfunction and leukocyte recruitment in rats with acute pancreatitis. Severe acute pancreatitis was induced by the intraductal administration of 5% sodium taurodeoxycholate and pancreatitis-associated gut barrier dysfunction was characterized by increased exudation of radiolabelled albumin into the interstitium and alterations in bidirectional (over both the endothelial and epithelial barrier components) permeability of the intestine at the early stage of bile salt-induced acute pancreatitis. Levels of interleukin 1β and 6, ileal and colonic myeloperoxidase (MPO) content, clearance of radiolabelled albumin from blood to the gut lumen or gut lumen to blood, and leakage of radiolabelled albumin to the ileum or colon were measured 3 and 12 h after induction of acute pancreatitis. Treatment with lexipafant 30 min and 6 h after pancreatitis reduced severity of pancreatitis-associated intestinal dysfunction, associated with a diminish in systemic concentrations of IL-1 and local leukocyte recruitment. The findings imply that PAF plays a critical role in the development of pancreatitis-associated gut barrier dysfunction and that PAF antagonist in some forms may represent potential candidates for future therapeutic intervention.     

Hemodynamic parameters and renal blood flow following stimulation of renal tubular transport processes by treatment with thyroid hormones

In adult rats, renal excretion of p-aminohippurate (PAH) can be stimulated by repeated administration of thyroid hormones. Data on renal cortical slices show clearly that a stimulation of active, carrier-mediated tubular transport processes is the most important cause. In vivo experiments also show an influence of treatment with thyroid hormones on various hemodynamic parameters. The diminution of vascular resistance in cortical and medullary regions of the kidney might contribute to the increased PAH excretion in thyroid hormone-treated rats.     

吡拉米司特在大鼠急性肺损伤模型中降低PDE4活性与TNF-α/IL-10平衡有关

目的观察PDE4活性与TNF-α/IL-10平衡在脂多糖(LPS)诱导的大鼠急性肺损伤模型(ALI)中相互关系,探讨选择性磷酸二酯酶4抑制剂吡拉米司特(piclamilast)对ALI的作用及机制。方法脂多糖(LPS)诱导大鼠ALI模型,设对照组、模型组、吡拉米司特组(1、3、10mg.kg-1)和地塞米松组(1mg.kg-1),常规细胞形态学检测肺泡灌洗液(BALF)和肺组织中中性粒细胞的浸润情况,比色法测定BALF中超氧阴离子自由基(O2.)和中性粒细胞髓过氧化酶(MPO),ELISA法检测肺组织中TNF-α和IL-10含量,高效液相(HPLC)法测定肺组织中PDE4活性。结果①吡拉米司特(1、3、10mg.kg-1)灌胃给予能够抑制BAL中MPO、O2.的增加,改善LPS诱导的大鼠ALI模型BALF中的炎症细胞聚集和肺水肿程度,②吡拉米司特可抑制LPS诱导的大鼠ALI肺组织TNF-α上升(P<0.05～0.01),并能明显提高LPS引起的大鼠ALI肺组织IL-10分泌下降,③大鼠ALI模型肺组织中PDE4活性明显上升(P<0.01),吡拉米司特预处理可抑制PDE4活性的上升,而且其对PDE4活性抑制性变化与TNF-α/IL-10比值的变化基本一致。地塞米松1mg.kg-1也能降低TNF-α和升高IL-10水平,调节TNF-α/IL-10平衡关系,但DXM不能抑制PDE4活性的升高。结论TNF-α/IL-10可能是ALI病理生理学的一对重要的平衡性细胞因子。吡拉米司特可能通过抑制PDE4活性,调节TNF-α/IL-10平衡改善LPS诱导的大鼠ALI。     

Patterns of treatment utilization and methamphetamine use during first 10 years after methamphetamine initiation

The study examined joint trajectories of methamphetamine (MA) use and substance abuse treatment utilization and identified differences among pattern groups for a sample of 348 treated for MA use. Results from group-based trajectory modeling showed that treatment utilization during the first 10 years after initiation of MA use could be categorized into three distinctive patterns: about half the MA users have a pattern of low treatment utilization; one-fourth follow a quicker-to-treatment trajectory with higher probability of treatment during the first 5 years of MA use and less treatment in the next 5 years; and one-fourth have a slower-to-treatment trajectory with more treatment during the second half of the 10-year period. Four MA use patterns were identified: consistently low use, moderate, and high use, as well as a decreasing use pattern. Periods of greater likelihood of treatment participation were associated with periods of decreasing or lower frequency of MA use.     

Tardive dyskinesia during and following treatment with haloperidol,haloperidol + biperiden,thioridazine, and clozapine

In a cross-over trial 16 elderly psychiatric patients with tardive dyskinesia were treated with thioridazine (median dose, 267.5 mg/day) for three months, followed by haloperidol (5.25 mg/day), haloperidol (5.25 mg/day) + biperiden (6 mg/day), thioridazine (267.5 mg/day), and clozapine (62.5 mg/day, only 7 patients), all for periods of 4 weeks with 4-week drug-free intervals. The tardive dyskinesia syndrome and the parkinsonism were evaluated blind according to a self-constructed rating scale and a modified Webster scale from weekly video-tape recordings. At the end of the treatment periods the hyperkinesia score was lower during haloperidol than during either thioridazine for 3 months (total score, 2.2 vs. 3.2, P<0.05), thioridazine for 4 weeks (total score, 2.2 vs. 4.8, P<0.02), or haloperidol + biperiden (score, 2.2 vs. 6.2, P<0.01). Clozapine had no significant antihyperkinetic effect, but in one patient it exerted a clear antiparkinsonian effect. After withdrawal of the initial thioridazine treatment, the hyperkinesia score was lower than after the subsequent haloperidol treatment (6.5 vs. 9.0, P<0.01), but after the second thioridazine period the hyperkinesia was of the same magnitude as after the preceding haloperidol periods. Biperiden increased the tardive dyskinesia syndrome during treatment, but did not significantly influence the syndrome after withdrawal of the treatment.It is concluded that (1) haloperidol (a strong antidopaminergic neuroleptic) has a more pronounced antihyperkinetic effect than thioridazine and clozapine (weaker antidopaminergic neuroleptics); (2) haloperidol might have a greater tendency to induce tardive dyskinesia than thioridazine; (3) administration of anticholinergics concomitant with neuroleptic drugs antagonizes the antihyperkinetic effect of haloperidol, but may not influence the intensity of tardive dyskinesia after withdrawal of the treatment.     

Pharmacokinetics of the S(+) and R(−) enantiomers of vigabatrin during chronic dosing in a patient with renal failure

Aims To study the pharmacokinetics of vigabatrin in a patient affected with tuberous sclerosis who developed major agitation and aggression, while receiving vigabatrin orally (1.5  g every 12  h) and in whom impaired renal function was diagnosed.
Methods The patient received vigabatrin (0.5  g  day⁻¹ ). A pharmacokinetic study of the S(+) and R(−) enantiomers of vigabatrin was performed before and during dialysis. Plasma concentrations were measured at 0, 1, 2, 3, 4, 6, 12, 18 and 24  h by a specific GCMS assay.
Results Before dialysis, the maximum and minimun plasma concentrations of vigabatrin at steady-state were lower for the S(+) than for the R(−) enantiomer, while the apparent oral clearance was higher for the S(+) than for the R(−) enantiomer (2.97 vs 0.48 l  h⁻¹ ). In addition, the haemodialysis clearance was similar for the two enantiomers (4.96 vs 5.15 l  h⁻¹ ).
Conclusions Vigabatrin is an irreversible inhibitor of GABA-transaminase, effective in the treatment of drug-resistant epilepsy and reported to be eliminated unchanged by renal excretion. Although vigabatrin is known to have stereoselective kinetics, the difference in plasma dry concentrations and pharmacokinetics of the S(+) and R(−) enantiomers that we observed during long term administration at high doses in a patient with impaired renal function, has not been reported before. The question remains of the potential toxicity of the high levels of the R(−) enantiomer.     

Serotonin uptake inhibition during treatment of depression with nortriptyline caused by parent drug and not by 10-hydroxymetabolites

Treatment of endogenous depression with nortriptyline (NT), at a daily dose of 150 mg, resulted in a pronounced improvement of seven of ten patients investigated. The concentration of the norepinephrine metabolite HMPG in cerebrospinal fluid (CSF) decreased by 29% (P<0.01) after 3 weeks of treatment. There was no significant effect of treatment on the serotonin and dopamine metabolites 5-HIAA and HVA. In previous larger materials, however, a decrease of 5-HIAA in CSF has been demonstrated.Platelets from the patients showed an increase in K _m for serotonin uptake in response to NT treatment. The IC₅₀ value of NT for serotonin uptake inhibition was 940 nM, while the corresponding value of the major metabolite of NT, i.e. E-10-OH-NT, was much higher (6700 nM). Thus, during treatment, the parent drug and not the metabolite was responsible for the serotonin uptake inhibition in platelets. There was a close correlation between K _m and the plasma concentration of NT after 1 week of treatment (r=0.88, P<0.01) but not after 3 weeks of treatment (r=0.48; ns). There was no uniform effect of NT treatment on V _max. It is concluded that clinical NT treatment results in uptake inhibition not only in norepinephrine but also in serotonin neurons.     

子宫动脉结扎宫腔填纱联合应用治疗剖宫产术中大出血10例分析

目的 探讨子宫动脉结扎与宫腔填纱同时应用在治疗剖宫产术中大出血的应用价值。方法 对10例剖宫产术中大出血患者（出血量在1000～3700ml之间），在施行双侧子宫动脉结扎之后，子宫对宫缩剂反应不良、子宫收缩欠佳或胎盘剥离而仍有较明显的活动性出血患者，即行宫腔大纱垫填塞术。结果 宫腔所填纱垫在术后24～46h于静脉滴注催产素的情况下取出，全部所取出纱垫均无特殊异味，取纱时宫腔出血量在10～30ml之间，10例患者均未造成子宫脏器的丢失。结论 子宫动脉结扎和宫腔填纱均为治疗子宫大出血的有效方法，两者联合应用，疗效明显好于单一方法，并有可能避免因术中大出血而行子宫切除术。     

Ventilation and gas-dynamic work of breathing during CO2 stimulation in patients with airways obstruction prior to and following bronchodilation with reproterol (author's transl)

A new, non-invasive method for measuring chemo-sensitivity of the respiratory center is described, one that may sensibly be applied in patients with airways obstruction. It is used for measurement of ventilation and gas-dynamic work of breathing in body plethysmography during a modified unsteady state of CO2 rebreathing technique. In 9 patients suffering from chronic obstructive bronchitis, a linear correlation between the end-expiratory CO2 partial pressure and the respiratory work rate vs. the airways resistance was established while between the end-expiratory PCO2 and the respiratory minute volume as well as the respiratory minute volume and the respiratory work rate vs. airways resistance, a non-linear correlation exists. In tests with 7-(3[2-(3 5-dihydroxyphenyl)-2-hydroxy-ethyl-amino]-propyl)-theophylline (reproterol, Bronchospasmin), a beta-phenylethyl-amino alkylxanthine, with known bronchodilating effects and a preparation for which pharmacological considerations of central-analeptic effects cannot definitely be excluded, this method revealed in patients with airways obstruction no breathing stimulation. In contrast, however, specific airways resistance in patients afflicted with bronchitis was statistically significantly reduced.     

Postnatal development of young rats following the treatment of the dams with sodium salicylate during late periods of pregnancy

Female albino rats were treated with sodium salicylate dissolved in tap water orally by intubation. The first group received daily doses of 25, 75 or 150 mg/kg from day 15 through day 20 of pregnancy. The second group received daily doses of 4.2, 12.5 or 25 mg/kg on day 20 and on day 21, i.e. the day of parturition. Administration of the intermediate and high doses caused a marked increase in the mortality rates of the young animals. However, the development of the surviving young rats was similar to the controls and no change in behaviour was noted.