Incidence Of Severe Adverse Reactions Research Articles

Incidence and Predictors of Severe Adverse Drug Reactions among Patients on Antiretroviral Drugs in Harari Regional State, Eastern Ethiopia.

The introduction of combination antiretroviral therapy improves the quality and longevity of people living with HIV/AIDS. However, adverse drug reactions associated with antiretroviral therapy compromise the resulting benefits and have been reported differently worldwide, including Ethiopia. Severe adverse drug reactions are one of the major public health concerns for the reason that they can potentially impede the benefit of antiretroviral therapy and put the patient's survival at risk. Despite many successes achieved with the introduction of the combined antiretroviral therapy, the majority of the patients on antiretroviral therapy experience adverse drug reactions associated with the drugs. Consequently, little is known about the problem in the current study area. This is, therefore, to study incidence and predictors of severe adverse drug reactions among patients on antiretroviral drugs in the Harari region, Eastern Ethiopia. The aim of this study was to assess the incidence and predictors of severe adverse drug reactions among patients on antiretroviral therapy from February 25, 2022, to March 25, 2022, in the Harari region, Eastern Ethiopia. A hospital-based retrospective cohort study was conducted among 449 randomly selected medical records of people living with HIV on first-line antiretroviral therapy. Collected data were entered into EpiData version 3.1 and exported to STATA version 15 for analysis. Kaplan-Meier survival curve with log-rank test was used to compare survival curves for categorical independent variables. A p value ≤0.05 was declared as significant, and an adjusted hazard ratio was used to report the effect size using the multivariate Cox proportional hazard model. The overall incidence density of the severe adverse reactions was 7.22 per 1000 months (95% CI: 5.5, 9.6). After adjusting for all potential confounders using multivariable Cox proportional hazard ratio, advanced clinical diseases (AHR = 3.44; 95% CI: 1.54, 7.65), HIV/tuberculosis confections (AHR = 2.38; 95% CI: 1.23, 4.62), and being female (AHR = 3.12; 95% CI: 1.57, 6.18) were significantly associated with the experience of severe adverse drug reactions. In this study, the incidence of severe adverse reactions was consistent with the previous studies, and advanced World Health Organization (WHO) clinical stage, HIV/TB confection, and being female were the independent predictors of the severe adverse drug reactions.

Clinical Evaluation of Bexagliflozin and Other SGLT2 Inhibitors for Type 2 Diabetes Management

To assess the clinical effectiveness and safety of Bexagliflozin and Cagglitazone (Cagelin) in the management of type 2 diabetes, we conducted a study involving three hundred type 2 diabetes patients admitted to the hospital from May 2022 to May 2023. The patients were randomly allocated into two study groups. The Bexagliflozin treatment group consisted of 150 patients, while the control group included 150 patients who were administered Cagelin. During a 4-month intervention period, both cohorts were subjected to a rigorous evaluation. We conducted a comprehensive analysis encompassing their demographic data, glycemic fluctuations, pre- and post-treatment body weight variations, as well as vigilantly monitored for any potential adverse events. The results indicate a significant decrease in FPG, 2HPG, HbA1c, and body weight indicators in both groups after drug treatment. Notably, the Bexagliflozin group demonstrated a significantly greater reduction in blood glucose and body weight indices compared to the control group. The incidence of severe adverse reactions was slightly higher in the Bexagliflozin group at 7.33% compared to 6.67% in the control group, but this difference was not statistically significant (P>0.05). When compared to other SGLT2 inhibitors, Bexagliflozin demonstrates a more pronounced effect in regulating blood sugar levels and inhibiting weight gain in the treatment of type 2 diabetes.

Effectiveness and safety of Inclisiran in hyperlipidemia treatment: An overview of systematic reviews.

This paper aimed to comprehensively evaluate the effectiveness and safety of Inclisiran in treating hyperlipidemia through an overview of systematic reviews (SRs). The Cochrane Library, EMBASE, PubMed, CNKI, WANGFANG database, VIP database, ClinicalTrials.gov, and ICRT were searched electronically to collect SRs and meta-analysis of Inclisiran in hyperlipidemia treatment from the establishment of the database till May 2022. Two researchers independently screened the relevant literature, then the assessment of multiple systematic reviews tool was made into assess the methodological quality of the included studies. Data extracted were used to perform the study through RevMan5.3 software. The grading of recommendations assessment, development, and evaluation tool was used to grade the quality of the evidence of the outcomes included in the SRs. Prospero ID: CRD 42022326845. A total of 10 relevant SRs were included, involving 7 randomized controlled trials. The assessment results of the assessment of multiple systematic reviews tool suggested that the quality of the SRs included needed to be improved. The reduced level of low-density lipoprotein cholesterol of the experimental group was lower than the control group, and the difference in the amount of effectiveness was statistically significant (MD = -50.13, 95%CI: -56.2 to -44.06, P < .00001). The grading of recommendations assessment, development, and evaluation results showed that out of 27 outcomes, 8 were high-quality, 3 were of medium quality, 6 were of low quality, and 10 were of the most inferior quality. 300mg Inclisiran with 2 injections a year has the best therapeutic effect, which can significantly reduce low-density lipoprotein cholesterol and total cholesterol, and increase high-density lipoprotein cholesterol levels in patients with hyperlipidemia. Inclisiran has a favorable safety profile, with no significant difference in the incidence of adverse reactions compared to a placebo. Most of the adverse effects were associated with the reaction on the injection site.

INNV-21. EFFECTIVE REGIMEN OF HIGH-DOSE METHOTREXATE PLUS TEMOZOLOMIDE FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A SINGLE-CENTER RETROSPECTIVE STUDY

Abstract OBJECTIVE To evaluate the efficacy and safety of high-dose methotrexate combined with temozolomide in the treatment of newly diagnosed primary central nervous system lymphoma. METHODS A retrospective study was performed to analyze the clinical data of patients with primary central nervous system lymphoma treated with high-dose methotrexate plus temozolomide in the Department of Neuro-oncology, Capital Medical University, Sanbo Brain Hospital from May 2010 to December 2018. RESULTS A total of 41 patients were identified. Median age was 57 years (range, 27–76 years). The maximal extent of surgery was total resection in 6, partial resection in 8, and biopsy in 27 patients. Of the 35 patients with evaluable lesions, 32 achieved complete response (CR) and 3 achieved partial response. CR rate was 91.4%. The median follow-up time was 36.5 months (range, 4.9–115.4 months). After treatment, the median progression-free survival (PFS) was 45.1 months. PFS rate at 1, 2, 5 years were 85.4%, 70.1% and 43.8%, respectively. The OS rate at 1, 2, 5 years were 92.7%, 82.4% and 66.5%, respectively. The median PFS of patients younger than 65 years was better than that of patients ≥65 years (98.8 months vs 27.9 months, p=0.039). There was no association between efficacy and extent of resection (p=0.836). After disease progression, 6 of the 21 patients received radiotherapy. There was no statistical difference in OS between the patients with or without radiotherapy (36.9 months vs 28.4 months). The main severe adverse events were myelosuppression (36.6%) and elevated transaminase (34.1%). Three patients were discontinued due to drug-related toxicities. CONCLUSIONS High-dose methotrexate combined with temozolomide is effective in the treatment of primary central nervous system lymphoma, with a low incidence of severe adverse reactions. This efficacy may be better than the historical control of methotrexate alone or methotrexate plus rituximab.

Anaphylactic Reaction Rates to Blue Dyes Used for Sentinel Lymph Node Mapping: Systematic Review and Meta-analysis.

The primary objective of this study was to quantify the risk of anaphylaxis to blue dyes used in SLNB for cancer. Secondary outcomes included the identification of factors that may influence this risk. Blue dyes are widely used to help identify sentinel lymph nodes in oncological surgery. The rate of severe allergic reactions to blue dyes remains a controversial topic, with the true incidence and influencing factors uncertain. A systematic review and meta-analysis was performed to identify all studies which report on the incidence of severe adverse reactions and anaphylaxis to blue dyes (patent blue, isosulfan blue, methylene blue, and indigo carmine), when used for SLNB. Collected data included cancer and dye type, volume, and method of injection. Incidence was estimated using the arcsine method of statistical analysis. One hundred nine studies documenting 94 episodes of anaphylaxis in a total of 61,951 SLNB procedures, resulting in a weighed anaphylaxis rate of 0.061%. SLNB for breast cancer carries an anaphylaxis risk of 0.083%, with the risk markedly lower in melanoma surgery (0.0043%). Low dye volume (<2 mL) and intradermal injection are both associated with lower rates of anaphylaxis (0.031% and 0.0068%). Isosulfan blue seems to be the most anaphylactogenic amongst blue dyes with a rate of 0.16%. There were no reported cases of death in this cohort. Anaphylaxis to blue dyes in SLNB is rare. Methylene blue, patent blue, lower dye volumes, and intradermal administration are all associated with a lower incidence of anaphylaxis.

Acute adverse reactions observation of craniospinal irradiation with helical tomotherapy in patients with medulloblastoma

Objective To investigate the acute adverse reactions of craniospinal irradiation with helical tomotherapy in medulloblastoma patients and its risk factors. Methods A total of 20 patients with medulloblastoma who received craniospinal irradiation with helical tomotherapy between October 2012 and September 2016 in Air Force General Hospital were selected. The acute adverse events of 20 patients during the treatment were record. According to National Cancer Institute Common Terminology Criteria Adverse Events (NCI-CTCAE) version 4.0, the adverse reactions were divided into the mild group (grade 0-Ⅱ) and severe group (grade Ⅲ-Ⅳ) adverse reactions. And the risk factors were also analyzed. Results The non-hematological adverse reactions included fatigue (55%), vomiting (45%) and headache (25%). The hematological adverse reactions included leukopenia (95%), thrombocytopenia (55%) and lower hemoglobin (45%), and the incidence of severe adverse reactions was 35% (7/20), 20% (4/20) and 0 (0/20), respectively. Leukopenia occurred in 18 patients (90%) at the beginning of radiotherapy within 2 weeks, and thrombocytopenia occurred in 8 patients (40%) at the beginning of radiotherapy after 2 weeks. Single factor analysis showed that there were no statistical differences in hematological adverse events of gender, age and radiation dose of spinal cord (all P > 0.05). The incidence of leukopenia for the patients who received the chemotherapy before the radiotherapy was higher than that for the patients without the chemotherapy before the radiotherapy (P < 0.05). Conclusions The hematological adverse reactions were the major acute adverse events during the craniospinal irradiation with helical tomotherapy in patients with medulloblastoma. The incidence of leukopenia and thrombocytopenia is common, and the incidence of hematological adverse reactions is higher after the chemotherapy. Thus, the close monitoring of hemogram change and treatment of hematological adverse reactions in time during the radiotherapy should be taken into the consideration. Key words: Medulloblastoma; Tomography, spiral computed; Adverse reactions

Relationship between UGT1A1 gene polymorphisms and irinotecan-induced severe adverse events

Objective: To investigate the relationship between UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A1*93 polymorphisms and irinotecan-induced severe adverse reactions(grade 3-4 delayed diarrhea and neutropenia) in Chinese cancer patients. Methods: A total of 141 cancer patients treated with irinotecan were enrolled in this study. Peripheral venous blood was collected and genomic DNA was extracted. The genetic polymorphisms of UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A1*93 were analyzed by PCR and direct sequencing. The adverse reactions during chemotherapy were observed and recorded. The incidence of severe adverse reactions was compared among patients with different genotypes. Results: Among 141 patients, the cases with UGT1A1*6 GG, GA and AA genotypes were 71, 54 and 16, while those with UGT1A1*28 TA6/6, TA6/7 and TA7/7 genotypes were 105, 33 and 3, respectively. The cases with UGT1A1*60 AA, AC and CC genotypes were 52, 80 and 9, while those with UGT1A1*93 GG, GA and AA genotypes were 105, 32 and 4, respectively. The patients with grade 3-4 delayed diarrhea and neutropenia were 23 and 56, respectively. Multivariate logistic regression analysis showed that UGT1A1*6 and UGT1A1*60 genetic polymorphisms were independent factors influencing the occurrence of grade 3-4 delayed diarrhea. The risk of grade 3-4 delayed diarrhea in homozygous AA carriers of UGT1A1*6 increased 3.79 times compared with that in wild-type GG carriers (95%CI: 1.35-10.67). Moreover, the risk of grade 3-4 delayed diarrhea in homozygous CC carriers of UGT1A1*60 was 20.42 times compared with that in wild-type AA carriers (95%CI: 3.52-118.33). In addition, UGT1A1*28 genetic polymorphism was an independent factor of the occurrence of grade 3-4 neutropenia. The patients with homozygous TA7/7 carriers of UGT1A1*28 had an 1.61 times higher risk of grade 3-4 neutropenia compared with those with wild-type TA6/6 carriers (95%CI: 1.44-12.65). There was no correlation between UGT1A1*93 genetic polymorphism and severe adverse reactions caused by irinotecan. Conclusion: The cancer patients who carried UGT1A1*6, UGT1A1*28 and UGT1A1*60 gene polymorphisms have high risk of severe adverse events caused by irinotecan-based chemotherapy.

Severe Adverse Reactions Induced by the Chest Injection of Elemene: An Analysis of 7 Cases

背景与目的恶性胸腔积液（malignant pleural effusion, MPE）指胸膜原发恶性肿瘤或其他部位恶性肿瘤转移至胸膜引起的胸腔积液。胸腔内注射榄香烯对MPE有良好的治疗效果，在临床中应用较普遍，同时存在一些不良反应，但文献缺乏对严重不良反应的报道及处理。本研究旨在观察榄香烯注射液治疗恶性胸腔积液导致不良反应发生情况，探讨严重不良反应发生原因和应对方案。方法回顾性分析14例胸腔注射榄香烯病例，对其中7例发生严重不良反应病例进行详细报道。结果榄香烯注射液胸腔注射所致严重不良反应主要表现为剧烈胸痛、呼吸困难、喘憋、意识模糊和凝血功能障碍，经临床对症治疗后均可缓解。结论胸腔注射榄香烯榄香烯对MPE有一定治疗价值，使用时应严格把握适应证、筛选患者、严密监测。

Clinical pharmacological management of polypharmacy in old age depression

Polypharmacy is the rule in psychogeriatric patients, as they present frequently comorbidities such as depression, dementia [often including Behavioral and Psychological Symptoms of Dementia (BPSD)] and somatic diseases. Recommended treatments for geriatric depression are antidepressant medications, psychotherapy and psychosocial interventions [1]. Besides antidepressants, other psychotropic drugs are often co-prescribed, but somatic drugs are also needed for the treatment of other concomitant diseases. This situation increases the risk for adverse effects due to pharmacokinetic and pharmacodynamic interactions, especially since the organism of elderly patients displays a lowered homeostatic reserve and a decrease of functions, which allows resisting to xenobiotic influences.On the other hand, there are also studies which suggest that in hospitalized psychogeriatric patients, the incidence of severe adverse reactions is lower in patients &gt; 60 y than in those &lt; 60 y [2]. This is one of the results of the AMSP-study group, which in German speaking countries has developed a pharmacovigilance program in psychiatric hospitals.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Development of an S-1 dosage formula based on renal function by a prospective pharmacokinetic study.

BackgroundS-1 is an oral anticancer drug, containing tegafur (a prodrug of 5-fluorouracil, 5-FU), 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. As renal dysfunction is known to increase exposure of 5-FU following S-1 administration, the incidence of severe adverse reactions is increased in patients with impaired renal function. However, no reliable information on its dose modification for patients with renal dysfunction has been provided.MethodsWe conducted a prospective pharmacokinetic study to develop an S-1 dosage formula based on renal function. Sixteen cancer patients with various degrees of renal function received a single dose of S-1 at 40 mg/m2. A series of blood samples were collected at predefined times within 24 h to assess the plasma concentration profiles of 5-FU, 5-chloro-2,4-dihydroxypyridine, and tegafur. A mathematical model for the relationship between renal function and exposure of 5-FU was constructed by a population pharmacokinetic analysis.ResultsThe clearance of 5-FU following S-1 administration was related to body surface area and creatinine clearance in the range 15.9–108.8 mL/min as estimated by the Cockcroft–Gault equation. The S-1 dosage formula was derived as follows:\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{dose}} = {\ ext{target AUC}} \ imes \\left( {21.9 + 0.375 \ imes {\ ext{CLcr}}} \\right) \ imes {\ ext{BSA}},$$\\end{document}dose=target AUC×21.9+0.375×CLcr×BSA,where AUC is the area under the concentration–time curve, CLcr is creatinine clearance, and BSA is body surface area. The recommended daily doses of S-1 in Asia and Europe were also proposed as nomograms according to exposure matching to the previously reported area under the concentration–time curve of 5-FU, which confirmed the efficacy and toxicity in pivotal registration studies.ConclusionsWe have developed a novel formula for determining the S-1 dosage on the basis of renal function. Further validation is needed to confirm the formula for practical application.Electronic supplementary materialThe online version of this article (doi:10.1007/s10120-015-0536-6) contains supplementary material, which is available to authorized users.

Risks associated with exercise testing and sports participation in cystic fibrosis

Background Severe adverse reactions (SARs) associated with physical exercise have not been systematically studied in cystic fibrosis (CF). Methods Two surveys were conducted to assess the incidence of exercise-related SARs: a caregiver survey asking for complications associated with exercise testing and in-hospital training therapy and a web-based patient survey asking for problems with exercise. Results 78 of 107 CF facilities caring for 4208 patients responded to the caregiver survey, 256 patients answered the web-based survey. No SARs were reported for 713 exercise tests. With in-hospital training, the yearly incidence of exercise-related SARs such as pneumothorax, cardiac arrhythmia, injury or hypoglycaemia was < 1% each, the respective lifetime incidences reported by the patients were 0.8–6.3%. 67% of the patients reported no SARs with exercise. Conclusions Exercise testing is safe in patients with CF. Despite the limitations in quality of data, the incidence of exercise-related SARs appears low in this population.

The Safety of Definity and Optison for Ultrasound Image Enhancement: A Retrospective Analysis of 78,383 Administered Contrast Doses

The purpose of this retrospective analysis was to define the incidence of severe adverse events after exposure to ultrasound contrast agents. Data between January 1, 2001, and September 30, 2007, were collected using invited responses to an on-line web-based questionnaire from 1 general and 12 cardiac ultrasound laboratories. During a period of 4.5 +/- 2.4 years, a total of 66,164 doses of Definity (Lantheus Medical Imaging, North Billerica, MA) and 12,219 doses of Optison (GE Healthcare, Buckinghamshire, UK) were administered, reflecting contrast use in 5% of transthoracic and 28% of stress echocardiographic procedures. More than 10,000 doses were given to critically ill patients in intensive care unit settings or to patients with acute chest pain of suspected cardiac origin. The median age of patients who received an ultrasound contrast agent was 60 years, 49% were male, and the mean body mass index was 32 +/- 1.4 g/m(-2). Severe reactions that were considered "probably" related to an ultrasound contrast agent developed in 8 patients (0.01%), all of whom were outpatients, and 4 (0.006%) of these were consistent with anaphylactoid reactions. There were no deaths reported. All patients recovered with treatment. No serious events were seen in inpatients. This multicenter, retrospective analysis includes the largest number of doses of ultrasound contrast agents ever published and a large number of patients evaluated in a wide variety of settings, including the critically ill. It shows that these agents have a good safety profile in both cardiac and abdominal ultrasound applications. The incidence of severe adverse reactions to ultrasound contrast agents is no greater, and may be lower, than that reported for contrast agents commonly used in other cardiac imaging tests.

Treatment of eclampsia with magnesium sulphate in Aba, South-Eastern

Context : Eclampsia is a major contributor to maternal and perinatal morbidity and mortality in Nigeria. While it has been widely reported that its prognosis can be greatly improved by effective treatment with magnesium sulphate, experience with this drug for the treatment of eclampsia in Nigeria has been scantily reported. Objective : To determine the effectiveness and safety of magnesium sulphate in the control of eclamptic convulsion and its influence on maternal and perinatal outcome. Design, Setting and Subjects : A prospective descriptive study carried out at Nigerian Christian Hospital, Aba, Nigeria from 1 January, 2002 to 29 February, 2004. The study group consisted of 40 consecutive cases of eclampsia seen at the maternity unit during the study period. They were given magnesium sulphate as the only anticonvulsant. Results : The incidence of eclampsia was 1 in 41 deliveries (2.45%). Magnesium sulphate effectively controlled eclamptic convulsions as 87.5% of cases did not have any further fits after commencement of the drug. There was no incidence of severe adverse reactions to the drug. The only complications of magnesium sulphate observed was depression of deep tendon reflexes which occurred in two patients. There was 1{2.5%} maternal death and a high perinatal mortality of 55.26%. Conclusion : Magnesium sulphate is effective in the control of eclamptic fits and has a good maternal outcome. These findings support the use of magnesium sulphate as the drug of choice for control of convulsions in eclamptic women. Keywords : eclampsia, magnesium sulphate, South Eastern Nigeria Tropical Journal of Obstetrics and Gynaecology Vol. 23(1) 2006: 20-22

A systematic review of the use of atypical antipsychotics in autism.

Conventional antipsychotic medication is commonly prescribed to patients with autistic spectrum disorder. However, a high incidence of severe adverse reactions highlights the need to find more favourable treatments. Atypical antipsychotics may combine efficacy in ameliorating some autistic symptoms with a lower incidence of some adverse reactions. This article reviews the use of atypical antipsychotics in autistic disorder, with particular focus on behaviour, cognition and physical well-being. Thirteen studies using risperidone, three using olanzapine, one using clozapine, one using amisulpride and one using quetiapine were identified. Few firm conclusions can be drawn due to the limitations of the studies; however, there is an indication that risperidone may be effective in reducing hyperactivity, aggression and repetitive behaviours, often without inducing severe adverse reactions. Olanzapine and clozapine may also be effective; however, there is little evidence for using amisulpride or quetiapine in this population. Randomized trials are required to clarify the effectiveness of these agents.

Mizoribine and Mycophenolate Mofetil

Both mizoribine (MZR) and mycophenolate mofetil (MMF) are immunosuppressive agents that inhibit the proliferation of lymphocytes selectively, via inhibition of IMPDH. MZR is a nucleoside of the imidazole class, isolated from the culture medium of the mold Eupenicillium brefeldianum M-2166. Although this compound has been found to have weak antimicrobial activity against Candida albicans, it has proved ineffective against experimental candidiasis. Unlike azathioprine, this compound is not taken up by nucleic acids in the cell. Instead, after phosphorylation MZR-5 -monophosphate inhibits GMP synthesis by the antagonistic blocking of IMPDH (Ki = 10(-8)M) and GMP- synthetase (Ki =10(-5) M). The drug has been found to inhibit both humoral and cellular immunity, and on this basis it was developed in Japan as an immunosuppressant. MZR has been shown in animal experiments to lack oncogenicity, and has been shown clinically to be associated with a low incidence of severe adverse reactions. MZR has been registered in Japan for the prevention of rejection in renal transplantation, and for the treatment of lupus nephritis, rheumatoid arthritis and the nephrotic syndrome. MMF is the morpholinoethyl ester prodrug of mycophenolic acid (MPA), which was first isolated in 1896 from the culture media of several Penicillium species. MPA has been evaluated for its unique properties as an anticancer, antiviral, antifungal and antibacterial agent, as well as for its therapeutic use in psoriasis and rheumatoid arthritis. MMF was designed to enhance the oral bioavailability of the parent compound. After beneficial effects were observed in animals, the clinical efficacy of MMF as an immunosuppressant in renal transplantation was studied in the United States. In 1995 the US Food and Drug Administration (FDA) approved the use of MMF for the prevention of rejection in renal transplantation, the drug also available on a number of European markets.

Adverse effects of neuromuscular blockers and their antagonists.

Among all the drugs used for general anaesthesia, neuromuscular blockers appear to play a prominent role in the incidence of severe adverse reactions. It now seems likely that most serious adverse drug reactions occurring during anaesthesia are immunological in type. The frequency of life-threatening anaphylactic or anaphylactoid reactions occurring during anaesthesia has been estimated to be between 1 in 1000 and 1 in 25,000 anaesthetic procedures, with the neuromuscular blockers being involved in 80% of cases. The mortality from such serious reactions is reported to be in the range of 3.4 to 6%. The highly immunogenic drug, suxamethonium chloride (succinylcholine), was found to be the most hazardous agent. Drug-specific immunoglobulin E antibodies to suxamethonium chloride and other neuromuscular blockers have been demonstrated. This sensitivity to neuromuscular blockers seems to be a long-lasting phenomenon. During anaesthesia, the clinical features of an allergic reaction are often masked. Tachycardia and circulatory collapse may be the only signs of an allergic reaction, and they are easily misdiagnosed. Bronchospasm is reported to be present in about 40% of cases. Successful management of these patients includes stabilisation during the acute reaction and avoidance of future reactions. The latter is based on the identification of the causative drug and potentially cross-reacting compounds. The use of suxamethonium chloride is associated with many other adverse effects, such as fasciculations, myalgia, potassium release, changes in the heart rate, increases in intragastric and intraocular pressures, and malignant hyperthermia. Because of the dangers of hyperkalaemic cardiac arrest after suxamethonium chloride administration in children with unrecognised muscular dystrophy, there have now been moves to limit the use of this drug in children. Although neuromuscular blockers are designed to specifically block nicotinic cholinergic receptors at the neuromuscular junction, many bind to muscarinic cholinergic receptors on ganglia and smooth muscle, and alter parasympathetically mediated heart rate and airway calibre. Most benzylisoquinolinium muscle relaxants can induce histamine release, especially when they are administered rapidly, which can lead to disturbances of cardiovascular function. In addition, nondepolarising neuromuscular blockers have been implicated in causing generalised weakness following their long term administration to patients on an intensive care unit. The problem with these adverse drug reactions is their unpredictable nature. Therefore, prompt recognition with appropriate therapy can help to improve the outcome.

Disposition and covalent binding of ibuprofen and its acyl glucuronide in the elderly*

Ibuprofen is an over-the-counter nonsteroidal anti-inflammatory drug with a low incidence of severe adverse reactions. It is metabolized by oxidation to carboxyibuprofen and hydroxyibuprofen and by conjugation to an acyl glucuronide. In vitro studies have indicated that ibuprofen glucuronide is labile and reactive, forming covalent adducts with proteins. To verify the formation of ibuprofen-protein adducts in vivo, the pharmacokinetics of ibuprofen glucuronide and its covalent binding to plasma proteins were studied in five elderly patients who received long-term administration of oral doses of ibuprofen. Plasma levels of ibuprofen glucuronide were low relative to those of ibuprofen; the ratio of area under the plasma concentration versus time curve for the glucuronide relative to the parent drug was only 4%. Covalent binding of ibuprofen to plasma protein was observed in all patients, correlating well with the area under the plasma concentration versus time curve of ibuprofen glucuronide (r = 0.966). Compared with reports for other nonsteroidal anti-inflammatory drugs that form acyl glucuronides, plasma levels of ibuprofen-protein adduct are low during long-term administration. The observed lower reactivity in vivo is probably attributable to the greater stability of ibuprofen glucuronide relative to other acyl glucuronides.

The incidence of severe adverse reactions to food in Colorado

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Prediction of severe adverse reactions to ionic and nonionic contrast media in Japan: evaluation of pretesting. A report from the Japanese Committee on the Safety of Contrast Media.

In a nationwide prospective study of adverse reactions to intravenous contrast media (CM), the Japanese Committee on the Safety of Contrast Media compared high-osmolar ionic CM with low-osmolar nonionic CM. A total of 337,647 cases were analyzed. The reliability of pretesting with an intravenous injection of a small amount of CM as a means of predicting severe or fatal reactions was also evaluated. The predictive values of the pretest were 1.2% for ionic and 0.0% for nonionic CM, and the sensitivity values were 3.7% and 0.0%, respectively. Such low values render this test meaningless for predicting which patients are at risk of a severe adverse reaction. A comparison of the incidence of severe adverse reactions between the nonpretested and pretested patients, as well as between the nonpretested and pretested patients with negative results, disclosed no statistically significant differences. Also, no beneficial effects of premedication in patients with a positive pretest were proved. The authors therefore conclude that pretesting with an intravenous injection of a small amount of CM is not useful in predicting severe reactions to ionic or nonionic CM.

UNCOUPLING THE TOXICOLOGICAL MORASS IN THE DEVELOPMENT OF NEW ANTIRHEUMATIC DRUGS—IS THERE ANY HOPE?

ALL classes of anti-arthriti c drugs are very toxic. The high incidence of severe adverse reactions among these drugs is well known, and the mortality and morbidity therefrom is among the highest of all drugs reported to national drug regulatory authorities [1—4]. This is related, partly, to their widespread use, untoward reactions from combinations with other drugs (e.g. antihypertensives, antidiuretic agents), and patterns of use [1-5]. It is also possible that there is a lack of respect on the part of the medical community resulting from the apparently innocuous appearance of the various pills and capsules readily prescribed at the stroke of the pen; the influence of sales techniques and the demands from patients for a quick cure all.giving the ingredients to this lack of respect for the drugs being nothing more than poisons. Aside from these aspects, there is no doubt we have reached the stage where something has to be done about preventing the occurrence of toxic reactions to anti-arthriti c drugs, especially the newer range of agents in development which are perched on the horizon to join the large and, to many, an everbewildering therapeutic armamentarium. Thus, some major re-thinking is required in the ways in which preclinical and early-stage clinical toxicology is undertaken in drug development; the evaluating criteria employed by drug-regulatory authorities (DRAs); and the political and legal criteria set by government agencies which form the inevitable umbrella under which DRAs, industry, and the medical and scientific professions are forced to act. On the latter aspect, it must be said that the politicolegal criteria are too often enforced from without the medicoscientific community and that it is high time that more appropriate sound scientific criteria be established, the more realistically and critically to set the basis upon which the toxicology and overall therapeutic evaluation of drugs is performed by DRAs. Admittedly, some efforts have been made in the past few years to inject more science into the decision-making progress, but the progress is slow and inflexible. Some 3-4 years ago at a symposium on rheumatoid arthritis in London I espoused some of these ideas, and one of my close colleagues who is a senior vice-president of a research division of a large US company quickly pointed out to me afterwards that if I thought there was any prospect of changing the way of thinking of the US Food and Drug Administration (FDA) then I had no hope. The same comments could be addressed,