Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes.

BACKGROUND: A significant number of women of childbearing age have schizophrenia or other psychoses. This means that there is a considerable risk of in utero exposure to risperidone due to maternal use. OBJECTIVE: To determine whether in utero exposure to the atypical antipsychotic risperidone is associated with poor pregnancy and fetal/neonatal outcomes. METHODS: A search of the Benefit Risk Management Worldwide Safety database, using a selection of preferred terms from the Medical Dictionary of Regulatory Activities, was performed to identify all cases of pregnancy or fetal/neonatal outcomes reported in association with risperidone treatment from its first market launch (international birth date, 1 June 1993) to 31 December 2004. The main measures were the patterns and reporting rates of pregnancy (stillbirth and spontaneous and induced abortion) and fetal/neonatal outcomes (congenital abnormalities, perinatal syndromes and withdrawal symptoms) for women administered risperidone during pregnancy. RESULTS: Overall, 713 pregnancies were identified in women who were receiving risperidone. Data were considered prospective in 516 of these, and retrospective in the remaining 197 cases. The majority of the known adverse pregnancy and fetal/neonatal outcomes were retrospectively reported. Of the 68 prospectively reported pregnancies with a known outcome, organ malformations and spontaneous abortions occurred 3.8% and 16.9% (when the 15 induced abortions were excluded from the denominator, as they were predominantly undertaken for nonmedical reasons), respectively, a finding consistent with background rates of the general population. There were 12 retrospectively reported pregnancies involving major organ malformations, the most frequently reported of which affected the heart, brain, lip and/or palate. There were 37 retrospectively reported pregnancies involving perinatal syndromes, of which 21 cases involved behavioural or motor disorders. In particular, there was a cluster of cases reporting tremor, jitteriness, irritability, feeding problems and somnolence, which may represent a withdrawal-emergent syndrome. CONCLUSION: This comprehensive review of the Benefit Risk Management Worldwide Safety database for case reports of risperidone exposure during pregnancy represents the largest ever published dataset documenting pregnancy outcomes for women taking the atypical antipsychotic risperidone. It indicates that in utero exposure to risperidone does not appear to increase the risk of spontaneous abortions, structural malformations and fetal teratogenic risk above that of the general population. Self-limited extrapyramidal effects in neonates were observed after maternal exposure to risperidone during the third trimester of pregnancy. Risperidone should only be used during pregnancy if the benefits outweigh the potential risks.     

S.S.P.E.: some clues to pathogenesis from epidemiological data

This study is a preliminary report of the national registry of S.S.P.E. cases started in 1987 which continue early epidemiological inquiries concerning incidence in Romania during the decade 1978-1987. The analysis pointed out the high incidence of this disease: a mean incidence rate of 6.35 cases per year per million total population in the last three years. Since 1979 there has been in Romania a sharp decline in the incidence of measles induced by the initiation of compulsory vaccination. As yet this decline is not reflected in S.S.P.E. incidence. The male/female ratio varied between 1.78-3.3 according to the year of observation. The mean age at S.S.P.E. onset increased from 6-7 years at the beginning of the interval to 9.63 years in 1987. The S.S.P.E. incidence is unevenly distributed between rural and urban area and clusters of S.S.P.E. cases were observed in certain countries. Other categories of information which may be relevant to pathogenesis are discussed: immunological history, previous hospitalization and illnesses, family history, recent health problems prior to S.S.P.E. onset, education, vacations, food habits and animal-exposure history.     

Role of drug testing as an early warning programme: the experience of the Republic of Korea

Drug testing plays an important role in the provision of information to health authorities on trends in drug abuse. In the Republic of Korea, the testing of urine and postmortem specimens has been used as part of a programme to monitor and control the abuse of non-controlled drugs, i.e., substances that were not originally included in the lists of controlled substances in that country. Zipeprol, dextromethorphan, carisoprodol and nalbuphine are examples of such drugs, which are widely used as medicines. Increasing levels of abuse of these drugs, including abuse that resulted in fatalities, were confirmed in the Republic of Korea by the results of drug testing. Based on the accumulated data from postmortem specimens, the health authorities in the Republic of Korea subsequently introduced controls on these drugs. A significant drop in fatalities related to the abuse of these non-controlled drugs underlined the importance of timely action for improving community health. In the context of drug testing, the analysis of non-controlled and new drugs always presents a scientific challenge, because specific analytical methods for testing for those drugs are not available. In the Republic of Korea, as part of the drug abuse warning programme, it was necessary to establish methods for the detection and quantification in biological fluids of all four non-controlled drugs and their metabolites in order to monitor the trends in drug abuse. The present paper puts forward epidemiological and clinical data on abuse and fatalities associated with zipeprol, dextromethorphan, carisoprodol and nalbuphine, as well as details of the analytical methods developed.     

RP—HPLC法测定巫山淫羊藿中4种成分的含量

目的:用 HPLC 梯度洗脱法测定巫山淫羊藿中4种主要成分的含量,考察了淫羊藿属苷 A、双藿苷 A、朝藿定 C 和淫羊藿苷在巫山淫羊藿不同部位中的分布。方法:采用 RP-HPLC 法测定,以 BECKMAN COULTER_(TM)-C_(18)(10μm,4.6 mm×250mm)为色谱柱,流动相为乙腈-水,梯度洗脱(0 min,乙腈-水比例为20:80;5 min,比例为30:70;10 min,比例为50:50),流速为1 mL·min~(-1),检测波长270 nm。结果:淫羊藿属苷 A 在0.188μg～1.880μg,淫羊藿苷在0.214μg～2.140μg,双藿苷 A在0.240μg～2.400μg,朝藿定 C 在0.282μg～2.820μg范围内呈良好线性关系;重复性实验的 RSD 分别为1.2%,1.3%,1.2%,1.2%。巫山淫芋藿不同部位双藿苷 A 和朝藿定 C 的含量较大,同一植株的不同部位中朝藿定 C 的分布为根>叶>茎。双藿苷 A 的分布为根>茎>叶,淫羊藿属苷 A 和淫羊藿苷含量较少。结论:巫山淫羊藿根中的化学成分以朝藿定 C 为最高,双藿苷 A 为次,而巫山淫羊藿叶中也以朝藿定 C 含量为最高。     

Safety profile of Lansoprazole: the US clinical trial experience.

OBJECTIVE: Lansoprazole has undergone extensive clinical evaluation for the treatment of acid-peptic diseases. The aim of this study was to define the safety profile of lansoprazole and compare it to that of other therapeutic agents evaluated in the same controlled trials. METHODS: The clinical safety profile of lansoprazole and comparative agents (placebo, ranitidine and omeprazole) was reviewed for 3281 patients who participated in short term (up to 8 weeks) and long term (up to 56 months) clinical trials conducted in the US. Adverse events, laboratory value changes and gastric biopsy changes that occurred during treatment were compared statistically for differences between treatments. RESULTS: The incidence of adverse events and number of patients discontinuing treatment because of adverse events was similar for lansoprazole and comparative agents. Other than elevated serum gastrin levels, a known effect of proton pump inhibitors, no trends in laboratory changes were observed. Median values for gastrin levels remained within the normal range; about 2% of patients had gastrin levels >400 pg/ml at any time, while <1% had 2 or more gastrin values >500 pg/ml. Values returned to baseline levels after therapy was discontinued. No significant changes in gastric endocrine cell growth from baseline to final visit were observed, nor was there evidence of dysplasia or neoplasia. CONCLUSION: Lansoprazole is well tolerated for both short and long term treatment of acid-related disease. The tolerability of lansoprazole is comparable to that of ranitidine, omeprazole and placebo in the treatment of these diseases.     

Risk management strategies in the postmarketing period : safety experience with the US and European bosentan surveillance programmes.

In view of the shortcomings of the current system for postmarketing drug surveillance that is based on voluntary spontaneous adverse drug reaction (ADR) reporting, new approaches are needed.We describe an approach involving a combination of limited distribution, patient and physician education, as well as a novel pharmaco-vigilance system that is capable of promoting the safe and adequate use of a new drug. Importantly, it provides the possibility of calculating true ADR occurrence rates, as the exposed population (denominator) and the number of patients with events (numerator) are known. These measures were taken for the oral dual endothelin ET(A)/ET(B) antagonist bosentan (Tracleer). In recent guidelines issued by the European Society of Cardiology, American College of Chest Physicians and the WHO, this drug is considered as first-line oral treatment for the treatment of pulmonary arterial hypertension, a devastating orphan disease associated with a poor prognosis. Bosentan was approved in 2001/2 on the basis of two pivotal studies that showed improved exercise capacity and haemodynamic parameters while delaying time to clinical worsening. Elevations in serum liver aminotransferase levels of >3 times the upper limit of normal were noted in 10.2% of patients (placebo-subtracted incidence). Therefore, liver function tests have to be performed on a regular basis. In addition, bosentan has potential as a teratogen.In the US, a controlled distribution network for bosentan (Tracleer) Access Program [T.A.P.]) and the development of a patient database to follow patients was set up. Accompanied by comprehensive physician and patient education programmes, T.A.P. was developed to provide a mechanism to assist with the primary risk management goals for bosentan therapy, namely pregnancy prevention and liver enzyme monitoring and prevention of hepatic injury.In Europe, the Tracleer) Excellence (TRAX PMS) database is a novel European non-interventional, prospective, internet-based surveillance system initiated by the manufacturer in cooperation with the European Medicines Agency. It collected potential safety signals associated with bosentan use including adverse events, elevations of liver aminotransferase levels, other abnormal laboratory values, death and hospitalisation. TRAX PMS has accrued 79% of all known patients in the EU and the data provide supportive 'real-life' evidence on the long-term safety of bosentan.The two different systems had similar goals and outcomes. The data received concerning thousands of patient-years of use have confirmed the clinical trial results regarding product safety and the favourable benefit/risk ratio of bosentan, especially with regard to known type A adverse events. The clinical monitoring algorithm has also been confirmed. In addition, no rare type B events were uncovered despite the increased reporting rate. These systems might serve as templates for future pharmaco-vigilance efforts regarding drugs that require particular safety attention.     

Legal issues of addiction assessment: the experience with hair testing in Greece

The purpose of this paper is to present Greek law and legislation for crimes and felonies regarding drugs of abuse and the interpretation of hair testing results with respect to Greek law. Details (such as the process, the decision and the competence of the Court, the police record, the indictment, the expert reports, the defendant's individuality, the crimes and the penal confrontal and many others) from legal cases related to toxicomany and its judicial verification were collected and analysed. Laboratory data of cases concerning the laboratory evaluation of toxicomany in addicts and also occasionally the legal course of cases with addict defendants are presented. In four representative cases segmental hair analysis proved that, for as long as the individuals were imprisoned, findings with drug substances corresponding to that period were lesser or practically absent compared with samples corresponding to the time out of prison, which showed increased drug abuse. Hair analysis provides information on chronic exposure rather than acute poisoning. Its detection window varies from some days to months or even years. The procedure that the law lays down in many cases is insufficient and in most cases impossible to abide by. When the medical examiner is not able to decide if the claim of toxicomany is real, segmental hair analysis may be the only way to prove it. In other cases where the medical examiner is able to diagnose the addiction, a segmental hair analysis is necessary because it can show long-term drug abuse.     

The parents' experience: coping with drug use in the family

The families of drug users are often overlooked in the planning and delivery of services. This paper is based on interviews with parents of heroin users and staff from a support agency that worked with families affected by drug use. Findings highlight the devastation parents experienced in learning that their child was using heroin, and the subsequent impact that this had on their lives. Accessing support from a specialist agency provided tangible benefits for parents. These included a reduced sense of isolation, an increased knowledge of drugs and drug-related issues, and greater empathy for their son or daughter. This resulted in an improved support network for the drug user. However, parents faced many obstacles in accessing support, not least a lack of awareness of their needs amongst appropriate agencies. The paper concludes by highlighting the need to develop further tailored interventions to support families affected by drug use, and to improve the knowledge and awareness of the issue among treatment agencies and a range of other relevant organizations.     

Co-morbidity of substance use disorder and psychopathology in women who use methamphetamine during pregnancy in the US and New Zealand

BackgroundMethamphetamine (MA) abuse is a worldwide problem. Little is known about the co-morbidity of substance use disorders (SUD) and other psychiatric disorders of mothers who use MA prenatally. The Infant Development, Environment and Lifestyle (IDEAL) Study is a prospective, investigation of prenatal MA use and child outcome in the United States (US) and New Zealand (NZ). This study examined prenatal MA use and the co-morbidity of SUD and psychiatric disorders at 1-month postpartum.MethodMothers who used MA (US = 127, NZ = 97) were compared to a matched comparison group (US = 193, NZ = 110). The Substance Abuse Subtle Screening Inventory-3 was used to measure the probability of a SUD. The Brief Symptom Inventory (BSI) was used to measure the likelihood of a positive diagnosis of a psychiatric disorder.ResultsIn the US and NZ, MA groups had lower SES, increased single parenting, delayed prenatal care, and increased polydrug use. In the US only, MA mothers had lower income than the comparison group. MA users were 10 times more likely to have a SUD and twice as likely to meet BSI criteria for a diagnosable psychiatric disorder. In NZ, but not the US, MA users were five times more likely to have co-morbidity of both. This disparity may be due to higher quantities of prenatal alcohol use associated with increased psychiatric symptoms.ConclusionThese findings suggest that addressing both substance abuse and psychiatric disorders in mothers who use MA may be required to effectively treat maternal MA use.     

Evaluation of the UK D.A.R.E. Primary programme

Aims: Results from the first evaluation of the UK Drug Abuse Resistance Education (D.A.R.E.) Primary programme, designed and undertaken by the (independent academic) authors on data collected in late 2015/early 2016 by the UK providers of the programme are presented. The evaluation assessed the programme against its learning outcomes (covering topics including pupils’ ability to communicate and listen, handle relationships and stress, make safe choices, get help from others) as well as their knowledge and use of substances.

Methods: Pre- and post- intervention online surveys of pupils aged 9–11?years from a randomly assigned group of state primary schools in the English East Midlands, split between trial and control samples. Responses from 1496 pupils from 51 schools were analysed and modelled via a set of ordinary least squares regression analyses, controlling for pupils’ and schools’ characteristics.

Findings: An overall positive change between the pre- and the post-survey was found, with significant differences in the extent of change between trial and control samples regarding four of the programme’s nine learning outcomes (getting help from others, improving communication and listening skills, knowledge about alcohol and drugs, and making safe choices).

Conclusions: This evaluation shows this version of D.A.R.E. to be effective regarding four of the programme’s learning outcomes. Further research is needed to measure the programme’s medium and long-term effects and the potential benefits of D.A.R.E. officers and teachers delivering the programme together, identified in this study.     

ET-743: the US experience in sarcomas of soft tissues

Ecteinascidin-743 (ET-743) has shown promise as a new and effective treatment for soft-tissue sarcomas. Two independent, multicenter, Phase II studies have been performed in the USA for patients with unresectable soft-tissue sarcomas (either chemotherapy-na?ve or pretreated patients). The patients received ET-743 at a dose of 1500 micrograms/m2 as a 24 h continuous intravenous infusion every 3 weeks on an outpatient basis. Assessments were conducted every 6 weeks until documented progressive disease, unacceptable toxicity, or withdrawal. Responses were assessed in accordance with conventional oncological criteria and toxicities were graded using the National Cancer Institute common toxicity criteria. A total of 72 patients were enrolled: 36 patients to each study. Confirmed objective response rates were 14% (95% confidence interval (CI) 5 to 30%) and 8% (95% CI 2 to 23%) in chemotherapy-na?ve and pretreated patients, respectively. In chemotherapy-na?ve patients, 12-month progression-free and overall survival rates were 18% (95% CI 4 to 32%) and 49% (95% CI 20 to 78%), respectively. For patients with progressive disease despite prior conventional chemotherapy, 12-month progression-free and overall survival rates were 11% (95% CI 2 to 24%) and 55% (95% CI 35 to 75%), respectively. The median duration of response was 11 months. The durability of major responses in a subset of patients was impressive, as was the number of patients who achieved disease stabilization without showing objective response. Overall, ET-743 had a favorable safety profile. The most common grade 3-4 toxicities included neutropenia and transiently increased transaminase concentrations. ET-743 did not cause alopecia, mucositis, cardiotoxicity or neurotoxicity. The side effects were reversible, non-cumulative and manageable. There were no treatment-associated deaths. In conclusion, ET-743 is an active chemotherapeutic agent that can induce objective responses and clinical benefit in a subset of patients with metastatic or advanced soft-tissue sarcoma.     

Antimalarial drugs in systemic lupus erythematosus: use in pregnancy.

The 4-aminoquinoline radical containing antimalarial drugs are also used in the management of various connective tissue diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis. These agents are particularly useful for the management of inflammatory polyarthritis and skin disease. By raising the pH in intracellular compartments, these drugs interfere with normal phagocytic function which consequently enables them to interfere with antigen processing. Other actions include inhibition of platelet aggregation, this is advantageous in patients with phospholipid antibodies (aPL) which are known to predispose patients to recurrent arterial and venous clinical thrombotic events. Hydroxychloroquine has also been demonstrated to reduce serum lipid levels including cholesterol, triglycerides and low density lipoproteins. As it is now known that patients with SLE are at risk for accelerated artherogenesis and premature heart disease, this action may be an added benefit for these patients. The use of the 4-aminoquinoline radical containing antimalarial drugs during pregnancy is controversial. It is known that these agents can cross the placenta and are deposited in fetal pigmented tissues. These findings have led to the recommendation that these agents should be discontinued in pregnancy for patients with connective tissue diseases even though they have long been recommended for malarial prophylaxis in pregnant women travelling to malarial infested areas. Flares of SLE disease have been documented when these agents are discontinued and as flares of SLE disease activity are known to be detrimental to pregnancy outcome in patients with SLE, it is our opinion that these drugs should not be discontinued during pregnancy in a patient with lupus, particularly when the known terminal elimination half life is 1 to 2 months.