Debrisoquine oxidation phenotype during neuroleptic monotherapy

Summary. The debrisoquine oxidation phenotype was determined in 91 schizophrenic patients on monotherapy with different neuroleptics and in 67 untreated healthy volunteers.The prevalence of poor metabolizers of debrisoquine was significantly higher in the patients (46.2%) than in the healthy subjects (7.5%). Treatment with phenothiazine antipsychotics (chlorpromazine, levomepromazine and thioridazine) was associated with a higher debrisoquine metabolic ratio than treatment with haloperidol. On the other hand, treatment with clothiapine appeared not to interfere with debrisoquine oxidation.Oral administration of 50 mg thioridazine daily to 8 healthy subjects resulted in a marked increase in the debrisoquine metabolic ratio and 4 of them were transformed into phenotypically poor metabolizers.The results confirm the fact that phenothiazines, and to a lesser extent haloperidol, inhibit the oxidative metabolism of debrisoquine. They show also that clothiapine administration does not disturb the debrisoquine metabolic ratio.Data from all the subjects in the study can be obtained from the authors on request     

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics of chlorpropamide

Summary The pharmacokinetics and urinary metabolite pattern of a single oral dose of chlorpropamide 250 mg have been studied in 6 extensive and 5 poor metabolizers of debrisoquine. Ammonium chloride was given orally to acidify the urine in order to make elimination of the parent drug dependent on metabolism alone. The concentration profile in serum and the pharmacokinetic parameters of the parent drug were similar in both groups. However, the ratio in urine of unchanged chlorpropamide to its hydroxylated metabolites was higher in poor than in extensive metabolizers.     

Histamine and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline are competitive inhibitors of debrisoquine 4-monooxygenase in rat liver

The effects of histamine and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline(salsolinol) on debrisoquine 4-monooxygenation, which is catalyzed by cytochrome P-450db1(CYP2D1) in rat liver microsomes, were studied. Both histamine and salsolinol competitively inhibited the activity of debrisoquine 4-monooxygenase (Ki=0.31 and 0.43 mM, respectively). These data demonstrate that histamine and salsolinol bind to the active site of CYP2D1, i.e. histamine and salsolinol have structures (molecular shape) corresponding to the active site of CYP2D1.     

Polymorphic 4-hydroxylation of debrisoquine in chronic discoid psoriasis

Summary 1. The 4-hydroxylation of debrisoquine was measured in 42 patients with chronic discoid psoriasis. 2. The proportion of poor metabolisers (4.8%) and the median metabolic ratio (0.5) in psoriatics were similar to that reported previously in a healthy British population. 3. We conclude that the abnormality of microsomal mono-oxygenase activity which we have found in the skin and other tissues of psoriatics is not due to a generalised (non-specific) impairment of microsomal oxidation and may be enzyme specific.     

老年高血压患者服药后血压控制情况及其不良反应

目的:探讨门诊就诊的老年高血压患者服用降压药物后血压控制情况及其常见的不良反应。方法:采用问卷调查和体格检查相结合的方法,对在我院门诊就诊的955例高血压患者的服药情况及出现的不良反应进行统计分析。结果:被调查者使用较多的降压药物是硝苯地平控释片(伲福达)、硝苯地平片剂(心痛定)和美托洛尔(倍他乐克),分别占所有被调查患者的69.8%、30.8%和27.5%。其次是吲达帕胺(寿比山)、依那普利(怡那林)、特拉唑嗪(高特灵)、贝那普利(洛汀新)和卡托普利。日常血压收缩压控制理想者(<140mmHg)约占患者的50%,舒张压控制理想者多于收缩压控制理想者。服药后不良反应中,钙离子拮抗剂以踝部水肿、利尿剂以低血钾多见,ACEI类药物主要表现为干咳,β受体阻滞剂以心动过缓为主要不良反应,α受体阻滞剂特拉唑嗪的不良反应主要为直立性低血压。治疗依从性的调查还表明约半数高血压患者在服药过程中存在不正确现象。结论:门诊老年高血压患者治疗过程中不良反应较多,且总体血压控制良好率不高。     

Similar effect of oxidation deficiency (debrisoquine polymorphism) and quinidine on the apparent volume of distribution of (±)-metoprolol

Summary The influence of phenotype (debrisoquine type of oxidation polymorphism) and quinidine on (±)-metoprolol distribution parameters was investigated in 7 young male volunteers (4 extensive and 3 poor metabolisers). (±)-Metoprolol tartrate 20 mg was administered as a 20 min infusion i) alone, ii) 12 h after an oral 50 mg quinidine sulphate capsule, and iii) on the last day of 3 days of treatment with 250 mg quinidine sulphate b. d. as a slow-release tablet.No stereoselectivity was apparent in either poor or extensive metabolizers. When (±)-metoprolol was administered alone the apparent volume of distribution at steady-state (V_ss) was higher in extensive than in poor metabolisers (4.84 vs 2.83 1·kg^–1, respectively). Pre-treatment with low or multiple high doses of quinidine decreased V_ss in extensive metabolisers to values comparable to those in poor metabolisers (3.50 and 3.18 l·kg^–1, respectively), but had no significant effect in poor metabolisers (3.24 and 3.42 l·kg^–1, respectively). Estimation of V_ss by noncompartmental analysis or assuming elimination exclusively from the peripheral compartment yielded similar, although somewhat higher, estimates.Despite the small number of subjects, (±)-metoprolol distribution appeared to be different both in genetically and environmentally (quinidine)-determined poor metabolisers, and quinidine inhibition was a good, reversible in vivo model of the genetic deficiency in handling (±)-metoprolol. Differences both in first pass pulmonary elimination or in tissue binding are logically consistent with these observations, but the amplitude of the effect exceeds expections from available biological evidence on selective pulmonary metabolic activity and on specific tissue binding sites.This work was presented in part at the Ninety-first Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Francisco, CA, March 1990     

The adverse effects of antiepileptic drugs in children

Efficacy of antiepileptic drugs (AEDs) are often equivalent, hence selection of an AED is often determined by the adverse effects (AEs). The development of neurocognitive AEs is almost inevitable with use of AEDs, especially in high-risk groups. Teratogenesis with major or minor malformations is of great concern during the first trimester of pregnancy, but an increasing body of information suggests that potential neurocognitive developmental delay may also occur with use of AEDs in the latter part of pregnancy. Decreased bone mineral density has been found in adults and children receiving both enzyme-inducing AEDs and valproate, an enzyme-inhibiting drug. AEDs may influence the lipid profile, body weight, reproductive, hormonal and other endocrine functions, and sleep architecture. There are age-specific AEs related to pharmacokinetic differences that have been highlighted in this review with emphasis on the pediatric population. A classification of AEs using different parameters is also included.     

Efficacy of and adverse effects of disopyramide

Summary The efficacy of disopyramide compared to placebo for exercise induced ventricular arrhythmias was tested in a double-blind randomized controlled clinical trial with cross-over design in 14 patients with coronary heart disease. Disopyramide was given as ordinary capsules (q.i.d.) or as a slow release preparation (b.i.d.) in a total dose of 600 mg per day. The placebo preparations were identical looking capsules and tablets. Each treatment period lasted one week. Efficacy was assessed by a standardized exercise test on a bicycle ergometer and a 6-h Holter monitoring at the end of each period.Plasma levels of disopyramide, measured in conjunction with exercise test, fell within therapeutic range, with a mean value of 7.9 and 8.9 µmol/l for capsules and slow release tablets, respectively.Disopyramide gave a marked and significant reduction of ventricular ectopic beats both at rest and during and after exercise. There was also a significant decrease in the number of ectopic beats recorded on tape during treatment periods compared to during placebo periods. There were no differences between the two preparations with respect to antiarrhythmic effect.Only mild side-effects, mainly mild anticholinergic symptoms, similar for both preparations were reported. No significant cardiovascular changes (heart rate and blood pressure response) were observed.     

The adverse effects of marijuana use: The present state and future directions

Marijuana is recently a subject of a global debate due to potential medical application of cannabis products and the progressive legalization of its recreational use. This situation leads to the need for access to comprehensive and reliable information about the effects of marijuana intake. Our review presents the actual state of knowledge regarding acute and chronic health effects generated by recreational marijuana use. Marijuana smoking can lead to structural and functional alterations in the central nervous system. These effects are especially significant and dangerous at the prenatal, child, and adolescence periods. In contrary to a common myth, cannabis does exhibit an addictive potency, albeit not a strong one. We discuss the “cannabis gateway hypothesis,” which suggests that marijuana use can be the first step before trying more dangerous drugs. However, drawing significant conclusions is difficult due to the strong impact of confounders and often unclear relationships among studied factors, especially in the socioeconomic context. Moreover, we point to the need for the unbiased assessment of the harm generated by marijuana in comparison with other drugs.     

Saxagliptin overview: special focus on safety and adverse effects

Adverse drug reactions (ADRs) have long been recognised as a significant cause of morbidity and mortality. They account for a substantial number of clinical consultations, hospital admissions and extended duration of in-patient stay as well as mortality. By far the most common ADRs are the concentration-dependent pharmacological reactions, the majority of which ought to be preventable. As a result of high concentrations of the parent drug and/or its metabolite(s), there is an augmentation of primary pharmacological activity and/or appearance of new and undesirable secondary pharmacological activity. Typically, these high concentrations result from administration of high doses in an attempt to maximise efficacy and/or modulation of the pharmacokinetics of a drug by either genetic or non-genetic factors. High plasma concentrations of parent drug may result from inherited impairment or drug-induced inhibition of its pharmacokinetic disposition. Conversely, inherited overcapacity or drug-induced induction of the metabolism of a drug may result in low concentrations of parent drug and frequently, rapid accumulation of its metabolites. Environmental, dietary and phytochemical factors may also influence the activity of drug metabolising enzymes. As with inherited polymorphisms of acetylation and cytochrome P450-based drug metabolising enzymes, polymorphisms of other conjugation reactions, such as glucuronidation, increasingly appear to be associated with drug toxicity. Diseases of organs involved in elimination of a drug also alter its pharmacokinetics, plasma concentration and, therefore, the profile of its concentration-dependent ADRs. Inherited mutations, concurrently administered drugs or presence of certain diseases may also alter the sensitivity of some pharmacological targets, accounting for a substantial number of ADRs and interactions. When there is enhanced pharmacodynamic sensitivity, plasma drug concentrations that are apparently within the normal ‘non-toxic’ range give rise to ADRs. Recent advances have also provided important insights into the wider scope of drug–drug interactions. Interactions that occur at P-glycoproteins, drug transporters and efflux pumps, at various transmembrane interfaces such as the gastrointestinal wall, renal tubules, hepatobiliary border and blood–brain barrier, are beginning to explain many non-metabolic interactions. These alter the systemic exposure to drugs and have so far, begun to explain unexpected neurotoxicity and hepatotoxicity. The function of these transporters is also genetically modulated. These advances, together with continued increased awareness and education of prescribers and pharmacists, offer great opportunities for substantially minimising concentration-related ADRs.     

高血压药物的不良反应与药物基因组学关系的研究进展

近来,个体差异造成降压药物不良反应的不同越来越受到重视,通过药物基因组学的研究,基因多态性已被认为是造成药物不良反应的首要原因。从基因水平揭示高血压药物不良反应的个体差异是一种有效的方法。本文综述了常用降压药物的不良反应与药物基因组学关系的研究进展,为高血压药物个体化应用于临床治疗应用提供参考依据。     

The attenuating effect of carteolol hydrochloride, a β-adrenoceptor antagonist, on neuroleptic-induced catalepsy in rats

It is known that β-adrenoceptor antagonists are effective in the treatment of akathisia, one of the extrapyramidal side effects that occur during neuroleptic treatment. Neuroleptic-induced catalepsy, a model of neuroleptic-induced extrapyramidal side effects, was considered suitable as a model for predicting neuroleptic-induced akathisia in humans, although neuroleptic-induced catalepsy was not considered a specific test for neuroleptic-induced akathisia. Therefore, the effects of carteolol, a β-adrenoceptor antagonist, on haloperidol-induced catalepsy in rats were behaviorally studied and compared with those of propranolol and biperiden, a muscarinic receptor antagonist. Carteolol, as well as propranolol and biperiden, inhibited the haloperidol-induced catalepsy. The inhibitory effect of carteolol was almost comparable to that of propranolol, but was weaker than that of biperiden. Carteolol did not evoke postsynaptic dopamine receptor-stimulating behavioral signs such as stereotypy and hyperlocomotion in rats. Carteolol did not antagonize the inhibitory effects of haloperidol on apomorphine-induced stereotypy and locomotor activity in rats. In addition, carteolol did not evoke 5-HT_1A receptor-stimulating behavioral signs such as flat body posture and forepaw treading and did not inhibit 5-hydroxytryptophan-induced head twitch in rats. Finally, carteolol did not inhibit physostigmine-induced lethality in rats. These results strongly suggest that carteolol improves haloperidol-induced catalepsy via its β-adrenoceptor antagonistic activity and is expected to be effective in the treatment of akathisia without attenuating neuroleptic-induced antipsychotic effects due to its postsynaptic dopamine receptor antagonistic activity. Received: 7 March 1996/ Final version: 27 November 1996     

国产与进口羟乙基淀粉溶液的临床疗效与不良反应比较

目的评价国产羟乙基淀粉溶液的临床疗效和不良反应。方法选择124例创伤及大、中手术患者,64例(A组)给予国产羟乙基淀粉溶液治疗,60例(B组)输入进口羟乙基淀粉溶液,观察并比较用药前、后生命体征变化及对血常规,肝、肾功能,血流动力学,凝血功能的影响。结果不同时相点上P、R、SBP、DBP指标变化前后比较及组间比较均无临床意义(P>0.05)。ITT和PP人群中,A、B组的疗效积分均≥12分,总有效率≥98%(P>0.05),2组药物对血常规、肝肾功能、血流动力学及凝血功能的影响相同(P>0.05),未发现不良反应。结论国产与进口羟乙基淀粉溶液作用一致,为一有效的血浆代用品。     

孟鲁司特钠致儿童患者精神系统不良反应临床分析

目的：了解我国儿童患者中孟鲁司特钠所致精神系统不良反应（ PAE）的临床特点,为临床合理用药提供参考。方法对1010年1月至1013年11月在华中科技大学附属同济医院过敏反应科就诊并服用孟鲁司特钠的门诊患儿进行随访,收集服药后出现PAE患儿的临床资料,就患儿的疾病诊断、合并用药情况、不良反应具体表现、不良反应出现时间、不良反应程度以及停药后症状消失时间等进行汇总分析。结果共收集到符合入选标准的患儿1481例,男性1015例,女性466例;年龄3~17岁,其中3~6岁者613例,7~11岁603例,13~17岁155例;过敏性哮喘780例,过敏性鼻炎701例。1481例患儿中17例服药后出现PAE,发生率为1.15%。男性患儿PAE发生率为1.18%（13/1015）,女性患儿为0.86%（4/466）;3~6岁患儿PAE发生率为1.61%（10/613）,7~11岁患儿为0.83%（5/603）,13~17岁患儿为0.78%（1/155）;过敏性哮喘患儿 PAE 发生率为1.15%（9/780）,过敏性鼻炎患儿为1.14%（8/701）;不同性别、年龄段和疾病间PAE发生率差异无统计学意义（均P﹥0.05）。17例发生PAE患儿中睡眠障碍者9例（噩梦7例,失眠1例）,行为异常5例（攻击性强4例,多动1例）,焦虑1例,噩梦合并多动1例。不良反应呈轻度者14例,中度者3例。PAE发生在服药后1周内者15例,1周及3个月者各1例。17例患儿均在停用孟鲁司特钠后1周内恢复正常。结论儿童患者服用孟鲁司特钠后出现的PAE以睡眠障碍尤其是噩梦较为多见。不良反应程度多较轻微,停药后恢复快。     

免疫检查点抑制剂致神经系统不良反应

免疫检查点抑制剂（ICBs）释放机体对肿瘤的"免疫刹车",掀起了肿瘤免疫治疗的热潮,临床已用于治疗黑色素瘤、非小细胞肺癌、转移性肾癌和转移性尿路上皮癌。ICBs所致的免疫相关的神经系统不良反应（nAEs）,严重性不容忽视。本文将针对ICBs所致的nAEs发生率、临床表现和诊断、危险因素、发生机制及治疗进行阐述。     

Pargyline reduces/prevents neuroleptic-induced acute dystonia in monkeys

The neuropharmacologic mechanisms underlying neuroleptic-induced extrapyramidal syndromes (EPS) were studied using a nonhuman primate model. Twenty-six Cebus albifrons monkeys were given weekly challenges of haloperidol (0.025 mg/kg IM), and half of the animals received the monoamine oxidase (MAO) inhibitor pargyline (5 mg/kg PO) daily for 17 consecutive days during the protocol. Pargyline caused no changes in baseline behaviors, but significantly reduced haloperidol-induced acute dystonia (AD) (-67%, P<0.002) and parkinsonism (-56%, P<0.005). The majority (8 of 13) of the experimental group had complete prevention of neuroleptic-induced EPS during cotreatment with pargyline. Behavioral scores returned to baseline levels after stopping pargyline, and did not show the further sensitization to haloperidol-induced AD that occurred in the control group. The possible mechanisms by which an MAO inhibitor might influence neuroleptic-induced AD were considered. The most likely explanation would appear to involve facilitation of striatal dopamine (DA) neurotransmission by inhibition of intra- and extraneuronal MAO, thus supporting the hypothesis that AD is due to decreased striatal DA function with secondary cholinergic hyperfunction.     

International monitoring of adverse health effects associated with herbal medicines

Herbal medicines are used in health care around the world and may increase in importance. There is much uncertainty, however, with regard to their composition, efficacy and safety. There is substantial evidence that herbal medicines can cause serious adverse reactions, but more data are needed as regard their nature, frequency and preventability. In this respect the Uppsala Monitoring Centre of the World Health Organization can play a crucial role. Better reporting of adverse reactions to herbal medicines is needed, in particular with regard to the precise identity and composition of these products. A consistent use by producers, regulators and reporters of the international Latin binomial nomenclature and the use of the new Herbal Anatomical Therapeutic Chemical (ATC) classification are recommended. Copyright © 2000 John Wiley & Sons, Ltd.