Evaluation of the prevalence and economic burden of adverse drug reactions presenting to the medical emergency department of a tertiary referral centre: a prospective study

Background  

Adverse drug reactions (ADRs) are now recognized as an important cause of hospital admissions, with a proportion ranging from 0.9–7.9%. They also constitute a significant economic burden. We thus aimed at determining the prevalence and the economic burden of ADRs presenting to Medical Emergency Department (ED) of a tertiary referral center in India     

双膦酸盐类药物致不良反应回顾性分析

目的:分析双膦酸盐类药物所致不良反应情况。方法:检索中国期刊全文数据库(CNKI)、万方数据库(Wan Fang)、中文科技期刊数据库(VIP)2004年1月至2013年8月国内有关双膦酸盐致不良反应的个案报道,按年龄、性别、原发病、药物名称、给药途径、不良反应发生时间、临床表现症状、治疗与转归等进行分类统计分析。结果:48例不良反应包括运动系统、消化系统、感官系统、循环系统、神经系统及全身性损害,高年龄段与女性发生率较高。结论:临床上应重视双膦酸盐类药物所致不良反应,坚持合理用药。     

Therapeutic evaluation of free and liposome-encapsulated atovaquone in the treatment of murine leishmaniasis

The use of drug delivery systems may reduce the toxicity and improve the activity of anti-leishmanial compounds. The activity of atovaquone (ATV)-loaded liposomes was compared by determination of median effective doses (ED(25) and ED(50)), with that of free ATV in a murine model of visceral leishmaniasis induced by Leishmania infantum. On day 0, mice were infected intravenously with 4.10(7) promastigotes and treated via the tail vein on days 15, 17 and 19 by free drug in a DMSO/cremophor/water solution (0.2 to 1.6 mg/kg body weight) or by liposomal drug (0.04 to 0.32 mg/kg body weight). Mice were killed and livers and spleens were removed and weighed on day 21 p.i. and liver parasite burdens evaluated using the Stauber method. Effective doses were determined using the Hill representation relating the percentage of parasite suppression to the dose. Liposomal ATV was significantly more effective than the free drug in reducing liver parasites (61.6% of parasite suppression at a dose of 0.32 mg/kg vs 34.9% at a dose of 1.6mg/kg). Liposomal ATV was 23 times more active than the free drug (ED(25) value=0. 02+/-0.01 mg/kg vs 0.46+/-0.15 mg/kg for free drug). It was not possible to obtain the ED(50) for free ATV because the dose-response curve reached a plateau around 33% of parasite suppression. Conversely, the ED(50) for liposomal ATV was 0.17+/-0.05 mg/kg. 100% efficacy of bound ATV could be obtained with a concentration of 1. 77+/-0.35 mg/kg. A significant decrease in spleen weights was also observed reflecting a leishmanicidal activity of ATV. These results suggest that liposome loaded ATV is more efficacious than the free drug against Leishmania infantum in this murine model.     

A rapid and automated colorimetric assay for evaluating the sensitivity of herpes simplex strains to antiviral drugs

A rapid and sensitive colorimetric assay has been developed to evaluate the sensitivity of herpes simplex viruses (HSV) to antiviral agents. The chessboard titration of viruses and antiviral drugs and the automatic reading and analysis of the data allows objective and accurate results to be rapidly obtained. Virus sensitivity was expressed as an ED50 value which was the concentration of drug (micrograms/ml) reducing viral cpe by 50%. The ED50 values of antiviral drugs [acetylguanosine (ACV), idoxuridine (IDU), deoxycytidine (IDC) and bromovinyl deoxyuridine] for several HSV reference strains were determined and the method was then applied to clinical specimens. The selection of ACV and IDU resistant mutants was performed on a cloned sensitive HSV 1 ocular strain. We observed cross-resistance between ACV and IDU for the mutants isolated. The resistance to thymidine-kinase-dependent antiviral agents varied in inverse ratio to the thymidine kinase activity induced by HSV strains.     

孕烷X受体的翻译后修饰及其功能调控作用研究进展

孕烷X 受体（PXR）是一类配体依赖性的核受体亚家族,可感受外源物质,被多种药物激活。PXR 可转录调控多种与药物代谢 相关的药物代谢酶和药物转运体的表达,参与药物代谢调控。PXR 转录活性的变化可改变药物在体内的代谢过程,继而诱发潜在药物不 良反应,与药物药代动力学研究和临床药物治疗密切相关,并有潜力成为防治药物介导的肝损伤和逆转化疗药物耐药的新型药物靶标。 综述了目前已发现的PXR 翻译后修饰及其对PXR 功能调控机制的研究进展。     

154例药品不良反应监测报告分析

目的:分析我院2009和2010年收集的154例药品不良反应(ADR)报告,以期了解不良反应发生的特点和规律,减少或避免不良反应的重复发生,为临床科室合理用药提供参考。方法:采用回顾性分类统计方法,对我院2009和2010两年上报的154例报告就ADR分布与年龄、给药途径、药物分类、累及系统及器官等方面的关系进行统计分析。结果:154例不良反应报告中以抗微生物药物和中药注射剂为主,分别占44.81%和20.78%。ADR临床表现以变态反应为主,其中儿童和老年患者居多(33.12%和48.05%),以静脉滴注方式为主(91.55%),临床表现主要以皮肤及其附件损伤最常见(75.97%)。结论:应加强ADR监测上报工作,并及时向临床科室反馈,提高临床安全用药意识,确保临床用药安全。     

Analysis of interaction between etoricoxib and tramadol against mechanical hyperalgesia of spinal cord injury in rats

Drug combinations have the potential advantage of greater analgesia over monotherapy. The present study was aimed to assess any possible interaction (additive or potentiation) in the antinociceptive effects of etoricoxib; a novel cyclooxygenase-2 inhibitor, and tramadol; a typical opioid agonist when administered in combination against mechanical hyperalgesia induced by spinal cord injury in rats. The nature of interaction was analyzed using surface of synergistic interaction (SSI) analysis and an isobolographic analysis. Etoricoxib or tramadol when administered alone to rats, exhibited different antihyperalgesic potencies (ED50 etoricoxib: 0.58+/-0.19 mg/kg, po; ED50 tramadol: 9.85+/-0.57 mg/kg, po). However, both the drugs were found to be long acting against this model of hyperalgesia. Further, etoricoxib and tramadol were co-administered in fixed ratios of ED50 fractions. One combination (0.29/4.79 mg/kg, po: etoricoxib/tramadol) exhibited additivity and other three combinations (0.15/2.39, 0.08/1.19, and 0.04/0.59 mg/kg, po: etoricoxib/tramadol) resulted in potentiation when analyzed by SSI. The SSI was calculated from the total antihyperalgesic effect produced by the combination after the subtraction of the antihyperalgesic effect produced by each of the individual drug. In the isobolographic analysis, the experimental ED50 was found to be far below the line of additivity also indicating a significant (P < 0.05) synergistic antihyperalgesic effect when etoricoxib and tramadol was co-administered to rats. The synergistic antihyperalgesic effect of etoricoxib and tramadol combination suggests that these combinations may have clinical utility in mechanical hyperalgesia associated with spinal injury.     

Modern problems of drug allergy to antibiotics in the clinical aspects of skin and venereal diseases]

Allergic dermatoses induced by antibiotics amounted to 45.2 per cent of all determined drug reactions according to the data of the Kharkov Research Institute of Dermatology and Venerology. The data on the factors favouring development of the drug dermatoses are presented. Difficulties in differential diagnosis by means of clinical and laboratory methods are indicated. The modern immunological tests of etiological diagnosis of drug resistance and the results of studying non-specific reactivity in patients with medicamentous dermatoses were analyzed. The principles of therapy and prophylaxis are summarized.     

Drug metabolism in the newborn

The duration and intensity of drug action depend not only on the dose of the drug but also on the rates at which drugs are transformed to products that can be excreted readily by the kidney. Two general categories of drug metabolism occur in the liver: phase 1 reactions (oxidations-reductions and hydrolyses) and phase 2 reactions (synthetic conjugations). Phase 1 reactions produce functional groups that can participate in phase 2 reactions. Phase 1 reactions are almost nonexistent in the fetuses of laboratory animals; however, many appear in primates during the first trimester of gestation. Phase 2 reactions are deficient prenatally in both rodents and primates. Parturition triggers a surge of both phase 1 and phase 2 reactions. The lack of uniformity of the development of phase 1 oxidative reactions during the early neonatal period reflects the multiplicity of cytochrome P-450 hemoproteins, the terminal oxidases responsible for most hepatic oxidative biotransformations. The rate of recovery of chemically induced losses of cytochrome P-450 systems is age dependent.     

Recognizing and reporting adverse drug reactions.

Although physicians in practice are most likely to see patients with adverse drug reactions, they may fail to recognize an adverse effect or to attribute it to a drug effect and, when recognized, they may fail to report serious reactions to the US Food and Drug Administration (FDA). To recognize and attribute an adverse event to a drug effect, physicians should review the patient''s clinical course, looking at patient risk factors, the known adverse reactions to the suspected drug, and the likelihood of a causal relationship between the drug and the adverse event-based on the temporal relationship, response to stopping or restarting the drug, and whether other factors could explain the reaction. Once an adverse drug reaction has been identified, the patient should be informed and appropriate documentation made in the patient''s medical record. Serious known reactions and all reactions to newly released drugs or those not previously known to occur (even if the certainty is low) should be reported to the FDA.     

Specific ethanol withdrawal seizures in genetically selected mice

We are selectively breeding mice prone (WSP) and resistant (WSR) to ethanol withdrawal seizures assessed by handling induced convulsions (HIC). The possibility that differences between the lines in HIC scores are a result of differences in general CNS excitability not specific to ethanol withdrawal was examined. Using treatments which produce generalized seizures (electroconvulsive shock, strychnine, and flurothyl) and gamma amino-butyric acid (GABA) antagonists (picrotoxin, bicuculline, and pentylentetrazol), the ED50 for seizures was determined in the selected lines. In addition, the sensitivity of WSP and WSR mice to the anticonvulsant actions of ethanol against each treatment was determined. Neither the convulsant amperage 50 (CA50) for ECS nor the ED50 for any drug treatment differed for the selected lines. When ethanol (1.5 g/kg) was administered prior to ECS, there was a dramatic differential suppression of ECS in the lines: the CA50 of WSR mice was elevated 5-fold, whereas the CA50 of WSP mice increased only two fold. Ethanol pretreatment also elevated the ED50 for strychnine and flurothyl in WSR mice significantly more than WSP mice, but the line difference was smaller than for the anticonvulsant effect against ECS. The ED50s for the GABA antagonists were not different between the WSR and WSP lines after ethanol pretreatment. We conclude that genetic selection is producing lines of mice that differ specifically in the degree of seizure severity caused by withdrawal from ethanol physical dependence and not in generalized CNS excitability. An increased sensitivity to the anticonvulsant effects of ethanol against some convulsant treatments has appeared as a correlated response to selection in the WSR line.     

Advanced glycation end-products: a common pathway in diabetes and age-related erectile dysfunction

Abstract

Reactive derivatives of non-enzymatic glucose-protein condensation reactions integrate a heterogeneous group of irreversible adducts called advanced glycation end-products (AGEs). Numerous studies have investigated the role of the AGEs in cardiovascular system; however, its contribution to erectile dysfunction (ED) that is an early manifestation of cardiovascular disease has been less intensively investigated. This review summarizes the most recent advances concerning AGEs effects in the cavernous tissue of the penis and in ED onset, particularly on diabetes and aging, conditions that not only favor AGEs formation, but also increase risk of developing ED. The specific contribution of AGE on intra- and extracellular deposition of insoluble complexes, interference in activity of endothelial nitric oxide (NO) synthase, NO bioavailability, endothelial-dependent vasodilatation, as well as molecular pathways activated by receptor of AGEs are presented. Finally, the interventional actions that prevent AGEs formation, accumulation or activity in the cavernous tissue and that include nutritional pattern modulation, nutraceuticals, exercise, therapeutic strategies (statins, anti-diabetics, inhibitors of phosphodiesterase-5, anti-hypertensive drugs) and inhibitors of AGEs formation and crosslink breakers, are discussed. From this review, we conclude that despite the experiments conducted in animal models pointing to the AGE/RAGE axis as a potential interventional target with respect to ED associated with diabetes and aging, the clinical data have been very disappointing and, until now, did not provide evidence of benefits of treatments directed to AGE inactivation.     

Angio-oedema in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE--To evaluate and describe the clinical course of angio-oedema reactions induced by angiotensin converting enzyme inhibitors. DESIGN AND METHODS--All reports of angio-oedema reactions associated with angiotensin converting enzyme inhibitors submitted to Swedish Adverse Reactions Advisory Committee were reviewed and the clinical courses summarised. Numbers of cases judged to be induced by angiotensin converting enzyme inhibitors were related to their annual usage, estimated from total sales of defined daily doses, as well as to the estimated number of new patients. All cases of angio-oedema associated with angiotensin converting enzyme inhibitors reported to the World Health Organisation''s international drug information system were also summarised. RESULTS--36 of the 38 reported cases in Sweden between 1981 and 1990 were judged to be related to angiotensin converting enzyme inhibitors. During 1981 through 1990, altogether 1309 cases of angio-oedema associated with angiotensin converting enzyme inhibitors were registered with the international drug information system. The incidence of reported cases of angio-oedema increased largely in parallel with the increased sales (usage) of angiotensin converting enzyme inhibitors. Of the 36 Swedish patients, 77% experienced the reaction within the first three weeks after starting treatment. 10 patients needed hospitalisation, two of whom had life threatening laryngeal obstruction. With one exception all 36 patients were free of symptoms within one week after discontinuing the drug. CONCLUSIONS--Angio-oedema induced by angiotensin converting enzyme inhibitors is a rare but potentially life threatening reaction, which in most instances occurs shortly after the start of treatment. Any patient in whom the reaction is suspected should have the treatment interrupted and, if necessary, be admitted for observation.     

Diabetes impairs endothelium-dependent relaxation of human penile vascular tissues mediated by NO and EDHF

Standard treatments for erectile dysfunction (ED) (i.e., PDE5 inhibitors) are less effective in diabetic patients for unknown reasons. Endothelium-dependent relaxation (EDR) of human corpus cavernosum (HCC) depends on nitric oxide (NO), while in human penile resistance arteries (HPRA) endothelium-derived hyperpolarizing factor (EDHF) and NO participate. Here we show that diabetes significantly reduced EDR induced by acetylcholine (ACh) in HCC and HPRA. Relaxation attributed to EDHF was also impaired in HPRA from diabetic patients. The PDE5 inhibitor, sildenafil (10nM), reversed diabetes-induced endothelial dysfunction in HCC, but not in HPRA. Calcium dobesilate (DOBE; 10 microM) fully reversed diabetes-induced endothelial dysfunction in HPRA by specifically potentiating the EDHF-mediated component of EDR. Impairment by diabetes of NO and EDHF-dependent responses precluded the complete recovery of endothelial function in HPRA by sildenafil. This could explain the poor clinical response to PDE5 inhibitors of diabetic men with ED and suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men.     

Cortexolone as a modulator of diazepam activity

The influence of ACTH (200 micrograms/kg), corticosterone (20 mg/kg) and cortexolone (20 mg/kg) on the anxiolytic activity of diazepam was studied. ACTH partly and corticosterone completely blocked the action of diazepam. Cortexolone injection 30 min before the administration of diazepam induced a 100% anxiolytic effect of diazepam in the range of doses from 0.1 to 0.3 mg/kg (ED50 of anxiolytic diazepam effect is 0.2 mg/kg). The role of stress hormones in the regulation of psychotropic drug activity is discussed.     

Anticonvulsant profile of nimodipine and nitrendipine against pentylenetetrazole induced seizures in rats

The activity of nimodipine and nitrendipine against pentylenetetrazole (PTZ) induced seizures in Albino rats was studied alone and in combination with valproate. The median effective dose [ED50] of valproate, nimodipine and nitrendipine were initially determined. All the 3 drugs were injected i.p. 30 min before the induction of seizures. Seizures were induced by PTZ 85 mg/kg i.p., and subsequently the effect of combining ED50 doses of nimodipine and nitrendipine with ED50 dose of valproate was evaluated. ED50 of valproate and nitrendipine were 129 and 2.5 mg/kg respectively. ED50 of nimodipine could not be established since a dose-response relationship was not obtained. Hence, for the purpose of combination studies, 4 mg/kg of nimodipine was used. Both nimodipine (4 mg/kg) and nitrendipine (2.5 mg/kg) decreased the ED50 of valproate from 129 to 40 mg/kg. Both nimodipine and nitrendipine potentiate the activity of valproate against PTZ induced seizures and can be considered as potential adjuvant anticonvulsants which merit further study.     

Safety of autologous bone marrow-derived mesenchymal stem cells in erectile dysfunction: an open-label phase 1 clinical trial

Background aimsThe efficacy of phosphodiesterase type 5 inhibitors (PDE5Is), which are commonly used to treat erectile dysfunction (ED), is not satisfactory in patients with denervation of the cavernous nerve due to pelvic surgeries and diabetes mellitus (DM). Pre-clinical studies using bone marrow-derived mesenchymal stem cells (BMSCs) to treat ED have shown promising results. The authors conducted a phase 1 clinical trial with autologous BMSCs in patients with ED due to radical prostatectomy or DM.MethodsTen patients (five with post-prostatectomy ED and five with DM-associated ED) who could not perform sexual activity despite taking the maximum dose of a PDE5I were enrolled. The brief clinical trial protocol was registered with the US National Institutes of Health on ClinicalTrials.gov (NCT02344849). The primary outcome was the safety of stem cell therapy, and the secondary outcome was the improvement of erectile function.ResultsOf the 13 patients screened, 10 were registered in the clinical trial and received autologous BMSCs and nine completed the clinical trial. One patient with post-prostatectomy ED experienced two treatment-emergent adverse events (TEAEs) (pyrexia and back pain), and two patients with DM-associated ED experienced a total of five TEAEs (one case each of viral upper respiratory tract infection, prostatitis and pruritus and two cases of hyperglycemia). Of these patients, one with DM-associated ED experienced two serious TEAEs (two instances of hyperglycemia). All TEAEs were considered not to be related to autologous BMSC therapy. In addition, no clinical significance was identified related to other safety measures, such as laboratory tests and vital signs. The mean International Index of Erectile Function score increased significantly at 1 month versus baseline (24.9 versus 18.1, P = 0.0222).ConclusionsThis phase 1 clinical trial confirmed the safety and potential efficacy of autologous BMSC therapy in patients with ED. The authors’ results need to be confirmed by a phase 2 clinical trial.     

Tolerated drugs in subjects with severe cutaneous adverse reactions (SCARs) induced by anticonvulsants and review of the literature

Background

Anticonvulsant hypersensitivity syndrome represents a rare but potentially fatal kind of adverse drug reaction. This clinical picture often hampers the flexibility with which alternative anticonvulsants or even other classes of drugs are prescribed in these patients, negatively affecting the efficacy of treatment and the course of the disease. The aim of this study was to analyse a group of six patients with severe cutaneous drug reactions induced by anticonvulsants and to report which alternative antiepileptic drugs and which drugs of other classes were tolerated.

Case presentation

A total of six patients (2 males and 4 females, age 11–73 years) are described in this study. In all the patients the onset of the severe cutaneous drug reactions was 2–4 weeks after initiating the anticonvulsant therapy: 2 out of 6 patients presented with a drug reaction with eosinophilia and systemic symptoms under therapy with phenytoin; 2 out of 6 presented with Stevens–Johnson syndrome under therapy with lamotrigine; and 2 out of 6 presented with a toxic epidermal necrolysis, one of them under therapy with valproic acid, and the other one under therapy with lamotrigine. Alternative anticonvulsants tolerated after the reaction were: clonazepam, levetiracetam, diazepam, delorazepam and lormetazepam.

Conclusions

In our cases we observed that non aromatic anticonvulsants and benzodiazepines were well tolerated as alternative treatments in six patients with reactions to aromatic anticonvulsivants and that the risk of hypersensitivity reactions to other drug classes was not increased as compared to general population.

     

Selective action of fluoroquinolones against intracellular amastigotes of Leishmania (Viannia) panamensis in vitro

We have demonstrated that fluoroquinolones, a class of antibacterial agents that act through inhibition of type II DNA topoisomerases, exert selective action against intracellular amastigotes of Leishmania (Viannia) panamensis at concentrations that are achievable in vivo. Drug cytotoxicity assays employing the luciferase reporter gene revealed that intracellular amastigotes were 6.6- to 25.9-fold more sensitive than human macrophages (P < 0.05) to second-generation fluoroquinolones in vitro. The most selective agents (enoxacin and ciprofloxacin) exhibited 2 orders of magnitude greater potency against parasites (50% effective dose [ED50] = 54.9-83.4 microM) than host cells (ED50 = 1,425-1,740 microM). Linear regression analysis of ED50 data confirmed a complete lack of correlation (r = 0.001) between the relative drug sensitivities of parasites and host cells. A potential relationship between the structures of fluoroquinolones and their relative leishmanicidal activities was observed. The key substituents of the basic pyridone beta-carboxylic acid nucleus accounting for enhanced antiparasite potency and selectivity appear to be a nitrogen at position 8 of the bicyclic nucleus (enoxacin), a cyclopropyl substituent at the R1 site (ciprofloxacin), and linkage of the R1 and X8 groups by a CH3CHO bridge to form a tricyclic compound (ofloxacin). These findings support the potential of fluoroquinolones and derivatives as novel antileishmanials and encourage their clinical evaluation.     

Response of Schistosoma mansoni isolates having different drug sensitivity to praziquantel over several life cycle passages with and without therapeutic pressure

The stability of praziquantel (PZQ)-insusceptible S. mansoni isolates and the possible selection of PZQ-insusceptible parasites upon applying therapeutic pressure were examined over several life cycle passages (snails to mice). To test isolate stability, 3 PZQ-susceptible and 7 PZQ-insusceptible isolates were used to establish infection in mice, and they were passaged each for 2-5 life cycles. After each passage, 6 groups of mice were used to assess the PZQ dose at which the worm burden was decreased by 50% (ED50). Five of them were treated with doses of PZQ (12.5, 25, 50, 100, and 200 mg/kg for 5 days) 7 wk after infection; the last group represented infected, but untreated, controls. Possible selection of PZQ-insusceptible parasites under therapeutic pressure was examined by subjecting 1 PZQ-susceptible and 1 PZQ-insusceptible S. mansoni isolate to therapeutic pressure by PZQ for 8 passages. After the final passage, PZQ ED50 was estimated. All PZQ-susceptible S. mansoni isolates showed stable susceptibility to PZQ (mean PZQ ED50 = 85 mg/kg) over all passages. Two of the 7 PZQ-insusceptible S. mansoni isolates (847 and ER5) showed normal sensitivity to PZQ in 1-2 passages (although not the last passage, and without a declining ED50 profile), whereas the remaining passages kept a sustained insusceptibility to the drug (mean PZQ ED50 = 217 mg/kg). Worm maturity and sex were irrelevant to variability in drug ED50 within an individual isolate over different passages, revealing the heterogeneous nature of the parasite. Therapeutic pressure for limited life cycle passages did not result in a significant increase in drug ED50. The fact that reversion of some of the PZQ-insusceptible S. mansoni isolates to normal drug-sensitive state is not long lasting and that the therapeutic pressure by PZQ in the field is not comparable with that in the laboratory (unlimited), make monitoring the response of patients to the drug in the field an integral part of schistosomiasis control measures.