Specific features of amoxicillin-associated Drug Reaction with Eosinophilia and Systemic Symptoms syndrome: a nationwide study.

BACKGROUND: Growing evidence indicates that amoxicillin induces herpesvirus replication in vitro. As these play a central pathophysiological role in Drug Reaction with Eosinophilia and Systemic Symptoms syndrome (DRESS), amoxicillin could present with specific DRESS features. OBJECTIVE: To characterize the onset patterns of amoxicillin-associated DRESS. METHODS: All cases of DRESS (Kardaun score ≥4) involving amoxicillin and reported in the French Pharmacovigilance Database between January 1, 2004 and November 30, 2019 were included. Onset circumstances for these cases were categorized considering the onset delay from amoxicillin initiation, and the presence of concomitant medications with a compatible time to onset. RESULTS: A total of 146 probable cases or definite cases of DRESS were included. Three onset circumstances were identified: (i) 'amoxicillin clear culprit' where amoxicillin was the sole suspect drug or when concomitant drugs of compatible time to onset were not reported to cause DRESS (n = 62); (ii) 'amoxicillin possible culprit' in the presence of other potentially culprit drugs in addition to amoxicillin (n = 44) and (iii) 'flare' where amoxicillin, used after DRESS onset, induced flare-up reactions (n = 40). The median time to onset was 5 days (IQR 2-11) in 'clear culprit', and 18 days (IQR 7-26) in 'possible culprit' cases. In 'flare' cases, the median latency between amoxicillin initiation and flare-up reactions was 3 days (IQR 2-5). CONCLUSIONS: Amoxicillin can induce DRESS with a specific early onset and exacerbate DRESS from another drug.

Clomiphene citrate and neural tube defects: a meta-analysis of controlled observational studies.

BACKGROUND: At the end of the 1980s, several studies suggested a potential increased risk of neural tube defects (NTDs) with ovulation induction/fertility drugs, especially with clomiphene citrate (CC). A previous meta-analysis of observational studies evaluating the risk of NTDs associated with the use of CC performed in 1995 found a risk ratio of 1.08 (95% CI 0.76-1.51). Since then, additional studies have been published and the risk of NTDs associated with periconceptional CC exposure may have changed. OBJECTIVE: To perform an updated quantitative meta-analysis of the risk of NTDs associated with periconceptional CC exposure. SEARCH STRATEGY: MEDLINE, Web of Science, and Scopus were searched (October 2018). SELECTION CRITERIA: Comparative cohort and case-control studies investigating the risk of NTDs after periconceptional CC exposure. DATA COLLECTION AND ANALYSIS: Pooled effect sizes with corresponding 95% CIs were calculated using random effects models, comparing the risk of NTDs between pregnancies exposed and not exposed to CC. MAIN RESULTS: Thirteen studies met the inclusion criteria, totalling 218 819 pregnancies. Periconceptional exposure to CC was not significantly associated with an increased risk of NTDs (pooled odds ratio 1.21, 95% CI 0.88-1.66). No heterogeneity between studies was observed (I2  = 26%). A funnel plot and asymmetry test were not suggestive of publication bias. CONCLUSION: Our meta-analysis confirms that exposure to CC before or in early pregnancy was associated with a 21% increased risk of NTD in relation to CC exposure; however, this increased risk is not statistically significant. TWEETABLE ABSTRACT: A new meta-analysis finds that clomiphene citrate exposure before or in early pregnancy is not associated with an increased risk of NTDs.

Severe adverse effects of bromocriptine in lactation inhibition: a pharmacovigilance survey.

OBJECTIVE: To assess the nature and conditions of the occurrence of adverse drug reactions (ADRs) of bromocriptine, which is used to inhibit lactation. DESIGN: Observational study. SETTING: Cases from the French pharmacovigilance database and the marketing authorisation holders. SAMPLE: Serious ADRs reported between 1994 and 2010 in association with bromocriptine used for lactation inhibition in France. METHODS: Each case was checked to confirm the bromocriptine indication, the seriousness of the ADR, the modalities of bromocriptine use, and to identify possible associated predisposing factors. MAIN OUTCOME MEASURES: Number and description of serious ADRs, with a particular focus on misuse and associated predisposing factors. RESULTS: Among 105 serious ADRs, including two fatal cases, the most frequent were cardiovascular (70.5%), neurological (14.3%), and psychiatric (8.6%) disorders. Cardiovascular disorders primarily consisted of ischaemic manifestations (n = 47): acute ischaemic stroke (n = 18, one death), myocardial infarction (n = 11, one death), and reversible postpartum cerebral angiopathy (n = 10). Misuse was identified in 52 cases (70.3%) of cardiovascular disorders, and mostly consisted of bromocriptine continuation despite the occurrence of first symptoms suggesting an ADR or the absence of a progressive titration of bromocriptine. About half of these women had cardiovascular predisposing factors, mainly tobacco smoking, overweight or obesity, or a history of hypertension or pre-eclampsia. CONCLUSIONS: This survey, together with published data, provides further evidence that serious ADRs still occur after bromocriptine use in lactation inhibition, and that most of these ADRs could have been avoided. The use of bromocriptine should therefore be limited to cases where no other options are available to inhibit lactation.

Safety of oseltamivir during pregnancy: a comparative study using the EFEMERIS database.

OBJECTIVE: To compare pregnancy outcome between women exposed and unexposed to oseltamivir during pregnancy. DESIGN: A comparative observational cohort study of women exposed to oseltamivir during pregnancy. SETTING: A French prescription database (EFEMERIS) that includes data for pregnant women was used. EFEMERIS records prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes in Haute-Garonne, South West France. POPULATION: Women who delivered from 1 July 2004 to 31 December 2010. METHODS: The study compared exposed and unexposed pregnant women. Two women unexposed to oseltamivir were individually matched, by maternal age, month, and year of delivery, with one women exposed to oseltamivir. Multivariable conditional logistic regression and multivariable Cox proportional hazards regression were used to evaluate associations between each outcome and exposure to oseltamivir during pregnancy. MAIN OUTCOME MEASURES: Pregnancy loss for any cause, preterm delivery, low birthweight, neonatal pathology, and congenital malformation. RESULTS: A cohort of 337 (0.58% of women included in EFEMERIS) women exposed to oseltamivir were compared with 674 unexposed women. The risk for pregnancy loss (HR 1.52; 95% CI 0.80-2.91), for preterm birth (adjusted OR 0.64; 95% CI 0.31-1.27), and for neonatal pathology (adjusted OR 0.62; 95% CI 0.23-1.54) did not differ between exposed and unexposed groups. When exposure during organogenesis was considered, one case of congenital anomaly (2.0%) among 49 exposed women and one case (1.0%) among 99 unexposed women were observed (crude OR 2.00; 95% CI 0.13-32.00). CONCLUSIONS: There was no significant association between adverse pregnancy outcomes and exposure to oseltamivir during pregnancy.

Continuation of pregnancy after first-trimester exposure to mifepristone: an observational prospective study.

OBJECTIVE: To report the follow-up of continuing pregnancies after first-trimester exposure to mifepristone. DESIGN: Observational prospective study. SETTING: France. SAMPLE: Patients exposed to mifepristone during the first 12 weeks of pregnancy. METHODS: Women were included in the study when they or their doctors asked a French pharmacovigilance centre or the Paris Teratogen Information Service about the risk of mifepristone exposure in early pregnancy. Exclusion criteria were requests received after 22 weeks of gestation or subsequent elective termination of pregnancy without a pathological examination of the fetus. Data on maternal history and drug exposure were collected on first contact, and pregnancy outcomes were documented at follow-up. MAIN OUTCOME MEASURES: Rate of major congenital malformations. RESULTS: A total of 105 pregnancies were included, with 46 exposed to mifepristone alone, and 59 exposed to both mifepristone and misoprostol. There were 94 live births (90.4%) and 10 (9.6%) miscarriages (including one with major malformation). Elective termination of pregnancy was performed after the subsequent diagnosis of trisomy 21 in one case. The overall rate of major congenital malformations was 4.2% (95% CI 1.2-10.4%), with two cases among 38 patients exposed to mifepristone alone, and two cases among 57 patients exposed to both mifepristone and misoprostol. CONCLUSIONS: This first prospective study found that the rate of major malformations after first-trimester exposure to mifepristone is only slightly higher than the expected 2-3% rate in the general population. Such findings provide reassuring data for risk evaluation for continuation of pregnancy after mifepristone exposure.

Pregnancy outcome following maternal exposure to statins: a multicentre prospective study.

OBJECTIVE: This contribution addresses the risk associated with exposure to statins during pregnancy. DESIGN: Multicentre observational prospective controlled study. SETTING: European Network of Teratology Information Services. POPULATION: Pregnant women who contacted one of 11 participating centres, seeking advice about exposure to statins during pregnancy, or to agents known to be nonteratogenic. METHODS: Pregnancies exposed during first trimester to statins were followed up prospectively, and their outcomes were compared with a matched control group. MAIN OUTCOME MEASURES: Rates of major birth defects, live births, miscarriages, elective terminations, preterm deliveries and gestational age and birthweight at delivery. RESULTS: We collected observations from 249 exposed pregnancies and 249 controls. The difference in the rate of major birth defects between the statin-exposed and the control groups was small and statistically nonsignificant (4.1% versus 2.7% odds ratio [OR] 1.5; 95% confidence interval [95% CI] 0.5-4.5, P = 0.43). In an adjusted Cox model, the difference between miscarriage rates was also small and not significant (hazard ratio 1.36, 95% CI 0.63-2.93, P = 0.43). Premature birth was more frequent in exposed pregnancies (16.1% versus 8.5%; OR 2.1, 95% CI 1.1-3.8, P = 0.019). Nonetheless, median gestational age at birth (39 weeks, interquartile range [IQR] 37-40 versus 39 weeks, IQR 38-40, P = 0.27) and birth weight (3280 g, IQR 2835-3590 versus 3250 g, IQR 2880-3630, P = 0.95) did not differ between exposed and non-exposed pregnancies. CONCLUSIONS: This study did not detect a teratogenic effect of statins. Its statistical power remains insufficient to challenge current recommendations of treatment discontinuation during pregnancy.

[Suspected allergy to COVID-19 vaccines: A retrospective study of 320 patients]. / Suspicion d'allergie aux vaccins anti COVID-19 : étude rétrospective sur 320 patients.

Introduction: The health context with COVID-19 pandemic has led to fast development of many vaccines against the SarS-Cov-2 virus. Four of them are currently available in France and contain polyethylene glycol (PEG) or polysorbate 80 as excipients, already described as causing anaphylaxis. French recommendations have been suggested by allergology authorities and proposed a course of action in the event of a suspected allergy to these vaccines. Thus, allergies to excipients were the only contraindication to COVID-19 vaccination. Our main objective was to determine the impact of these allergology vaccine recommendations on the management of these patients. Our secondary objective was to determine prevalence of true allergies to these vaccines. Materials and methods: We conducted a unicentric descriptive retrospective study with all patients over 18 years of age referred for an allergological opinion before or after an injection of one of the anti-COVID-19 vaccines. Nineteen patients were classified into different interest groups, based on french recommendations. Results: The vast majority of patients did not require a pre-vaccination allergological assessment. Indeed, only 25 patients received skin tests prior to vaccination. The rest of patients were able to be vaccinated without allergological assessment. Patients not vaccinated due to allergy to excipients represent less than 1% of the population (n = 3/320). Conclusion: French recommendations made it possible to vaccinate the vast majority of patients included in our study. Allergy to PEG, polysorbate or their derivatives, the only contraindication to anti-COVID vaccination, according to the recommendations of February 2021, remains rare. Today, several authors propose tolerance inductions allowing the vaccination of patients allergic to PEGs or their derivatives with good tolerance.

Suspicion of drug-drug interaction between high-dose methotrexate and proton pump inhibitors: a case report - should the practice be changed?

We report a case of a potential drug-drug interaction in a woman treated by a first injection of high-dose methotrexate for a T-lymphoblastic lymphoma. Valaciclovir, fluoxetine and pantoprazole were given concomitantly. A methotrexate overdosage was shown at 36 h after infusion associated with a severe renal failure. Alkaline hyperhydration, folinic acid and carboxypeptidase G2 were given. Prescription analyses by pharmacists and literature research have permitted us to suggest that a drug-drug interaction between methotrexate and proton pump inhibitors (PPI) was responsible for this renal failure. Several mechanisms of interaction were suggested and might be related to the inhibition of renal methotrexate transporters by PPI, an increase in the methotrexate efflux to the blood by an upregulation of multidrug resistance protein 3 by PPI or genetic polymorphisms. This case shows that pharmacists can help physicians to optimize patient treatment: they consensually decided on the systematic discontinuation of PPI or a switch to ranitidine when patients were treated by high-dose methotrexate.

[The relevance of diagnostic criteria for latent tuberculosis before initiation of TNF-alpha inhibitors in psoriasis patients]. / Pertinence des critères diagnostiques de tuberculose latente avant traitement du psoriasis par anti-TNF-alpha.

BACKGROUND: Initiation of anti-TNF-alpha therapy requires prior screening for and treatment of tuberculosis. Diagnosis of relating to tuberculosis is based primarily on measurement of the papule induced by intradermal reaction to tuberculin (IDR). In this article, we discuss the validity of this criterion and the potential consequences of its use in relation to 15 patients. PATIENTS AND METHODS: This was a retrospective case study of patients presenting psoriasis and eligible for antibiotic therapy in whom latent tuberculosis was diagnosed and who received combined prophylactic antitubercular treatment for three months. All patients underwent thorough questioning and clinical examination, chest x-ray and QuantiFERON (QTF) testing, and all except one were tested for IDR. RESULTS: Thirteen patients were considered carriers of latent tuberculosis based on IDR greater than 5 mm, and on positive QTF for two others, one of whom had a documented history of primary tubercular infection. Six of these 15 patients (40%) developed hepatic cytolysis ascribable to their antitubercular treatment. DISCUSSION: Analysis of the respective characteristics of the IDR and QTF tests showed that only five of the 15 patients in our study were in fact presenting authentic latent tuberculosis, thereby suggesting that the diagnostic criteria for latent tuberculosis recommended by the French Medicines Agency (AFSSAPS), which are based solely on the size of the papule arising from IDR, are unsuitable for patients with psoriasis pending anti-TNF therapy. In our view, screening for latent tuberculosis in this patient population should involve both IDR for its sensitivity and QTF for its specificity, thereby avoiding overdiagnosis of tuberculosis leading to pointless exposure of patients to the risk of hepatic toxicity associated with antitubercular medication. CONCLUSION: We strongly recommend a change in the recommendations for prevention of tuberculosis by antibiotic therapy in patients with psoriasis, and that the review panels should include at least one dermatologist.

[Active drug monitoring of adverse drug reactions in pediatric emergency department]. / Recueil systématique et actif des évènements indésirables médicamenteux chez les enfants admis aux urgences pédiatriques.

OBJECTIVES: The aim of this study was to systematically evaluate adverse drug reactions (ADRs) in children consulting at the pediatric emergency unit during a 6-month period. METHOD: The regional pharmacovigilance center (CRPV) and the department of clinical pharmacology prospectively and systematically recorded all potential ADRs among patients younger than 18 years of age in the pediatric emergency unit reported at the daily staff meetings. All cases were then screened and validated by the CRPV. For validated cases, preventability, seriousness, and off-label use were evaluated. RESULTS: During the study period, from 1 March to 1 September 2005, 90 children presented potential adverse drug events. ADRs were confirmed in 43 patients, 19 females and 24 males. Thirty-four patients (79%) were under the age of 5. According to the European definition, 14 patients (33%) had serious ADRs. One anaphylactic shock after amoxicillin injection; antimalarial prophylaxis misuse leading to convulsive status epilepticus, convulsion, and coma after hepatitis B and MMR vaccines were deemed life-threatening. Three ADRs were considered avoidable. Antibiotics and vaccines were the most common possible cause of ADRs (76%). Skin reactions (n=27), fever (n=8), and gastric disorders (n=5) were the most common clinical manifestations. CONCLUSIONS: Because ADRs were reported by clinicians on a voluntary basis, serious ADRs were probably reported more systematically. Compared to a similar period without active monitoring, active drug monitoring of ADRs doubled the number of confirmed cases 43 vs 17, p<0.001. Close collaboration between the pharmacovigilance center, pharmacologists, and clinicians is necessary and seems feasible for improving the monitoring of ADRs in children.

[Pharmacokinetic risk factors of beta-blockers overdose in the elderly: Case report and pharmacology approach]. / Facteurs de risque pharmacocinétiques de surdosage en bêta-bloquants chez les patients âgés : cas clinique et rationnel pharmacologique.

Beta-blockers are widely prescribed in elderly patients and may induce severe adverse drug reactions. We report a case of bisoprolol-induced bradycardia in an elderly patient with impaired renal function and use of cytochrome P450 inhibitors. A literature review has been performed in order to analyze pharmacokinetic risk factors of beta-blockers overdosing in geriatrics. Various mechanisms can result in decreased elimination of beta-blockers. These mechanisms vary according to the beta-blocker agent and may be combined in some individuals, especially elderly patients. This can lead to unexpected overexposure. Knowledge about drug interactions and pharmacokinetic elimination pathways is important for preventing overexposure and adverse drug reactions when using beta-blockers.

[Ambroxol-induced immune hemolytic anemia]. / Anémie hémolytique immunoallergique due à l'ambroxol.

INTRODUCTION: Drug-induced immune hemolytic anemia is a rare cause of hemolytic anemia. CASE RECORD: A 68-year-old male patient developed an acute intravascular hemolysis with acute renal failure. Common causes of hemolysis were ruled out and the patient rapidly improved. An immune mechanism was confirmed by the positivity of the direct antiglobulin test with anti-IgA in the presence of ambroxol only, one of the drug the patient had received during 6 days before hospitalization. DISCUSSION: To our knowledge, this is the first report of ambroxol-induced immune hemolytic anemia. This case also underlined that the direct antiglobulin test should also be performed with anti-IgA to rule out any false negative.

[Lower limb edema during valpromide treatment: case report and literature review]. / Œdèmes des membres inférieurs au cours d'un traitement par valpromide : cas clinique et revue de la littérature.

INTRODUCTION: Valpromide and sodium divalproate are indicated in the treatment of maniac episodes of bipolar disorder. These drugs are metabolized into valproic acid. The occurrence of peripheral edema has been described as a very rare adverse reaction of those drugs. CASE REPORT: We report the case of a patient treated with valpromide who presented edema of the lower limbs. The increase in furosemide dose allowed regression of edema, and valpromide discontinuation resulted in rapid normalization. Recurrence of mood disorders led to the reintroduction of valpromide, which was associated with recurrence of edema. The definitive withdrawal of valpromide resulted in resolution of edema. CONCLUSION: Edema of the lower limbs can be induced by valproate. The mechanism of this reaction is unknown. These edema appear to be reversible upon discontinuation of the drug. Clinicians should be aware of a possible relationship between valproate-derived drugs and peripheral edema.

Clinical toxicity of interleukin-2.

Interleukin-2 (IL-2) is increasingly used to treat patients with cancers refractory to conventional treatment. Flu-like syndromes are extremely frequent but usually mild. A variety of skin complications (mostly erythema and mucositis) have been reported. Life-threatening skin reactions have also been described. Acute reactivation of psoriasis can also occur. Immediate hypersensitivity reactions have so far not been described, but IL-2 treatment has been shown to predispose to acute hypersensitivity reactions to iodine-containing contrast media. Hypothyroidism is the major endocrine complication and antithyroid antibodies have been detected in approximately 50% of patients. Neurological and psychiatric disturbances with moderate or severe mental status changes are common and sometimes treatment-limiting. The occurrence of peritumoural oedema in patients with brain metastases can also be a major practical problem. Musculoskeletal disorders are transient and resolve spontaneously. The vascular leak syndrome is the most frequent and severe complication of IL-2 of which weight gain, generalised oedema, hypotension and impaired renal function are the main features. Even though a damaging effect on vascular endothelium cells by various cytokines released by activated lymphoid cells or mediated by non-lymphocyte-dependent factors has been proposed to be involved, the mechanism remains unclear. Other cardiovascular injuries, possibly life-threatening, including myocarditis, angina pectoris and myocardial infarction, can occur during the first days of treatment. Supraventricular arrhythmias are the most common rhythmic disorder. Decreases in myocardial contractility and haemodynamic pattern similar to those of septic shock have been encountered in most cases. Acute renal dysfunction is common but resolves with symptomatic management. Intrahepatic cholestasis with hyperbilirubinaemia is observed in most patients but permanent liver damage has not been described. Several cases of pancreatitis have been reported. Anaemia, thrombocytopenia, lymphocytopenia and eosinophilia are frequent and occur in most if not all patients. Some data suggest a high incidence of infectious complications, particularly in patients with surgically tunnelled catheters, but marked flu-like syndromes may be confounding. Finally, death directly related to IL-2 treatment has been noted in less than 1% of all patients. Investigations are under way to minimise IL-2 toxicity with varying dose regimens and combined treatments.

Clinical toxicity of cytokines used as haemopoietic growth factors.

A number of cytokines are used as haemopoietic growth factors and this review focuses on toxicities associated with granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1, IL-3, IL-4, IL-6 and macrophage colony-stimulating factor (M-CSF). Both GM-CSF and G-CSF, currently approved for clinical use, are generally well tolerated by the majority of patients during short term administration. Constitutional symptoms and bone pain are the most frequently reported adverse effects, but they are rarely treatment-limiting. Reactivation of rheumatoid symptoms, and exacerbation of autoimmune thyroiditis or autoimmune haematological disorders have sometimes been described. Severe cardiovascular complications include the possibility for arterial thromboses and the vascular leak syndrome, which is more specifically observed with GM-CSF. Reports of several cases and small series of patients have suggested that growth factors might increase the pulmonary toxicity of chemotherapy, a possibility that remains debated and requires further attention. Generalised or local cutaneous reactions are frequently noted with GM-CSF. Leukocytoclastic vasculitis was observed with both growth factors, while neutrophilic dermatoses have been mostly described with G-CSF. Exacerbation of psoriasis and isolated anaphylactic reactions have appeared with GM-CSF and G-CSF. The hepatotoxic potential of the growth factors is not clearly established, but the occurrence of coagulation abnormalities has recently been reported. Renal and biological disturbances are usually transient. Long term treatment with GM-CSF and G-CSF also seems to be well tolerated, but the possible occurrence of several adverse events, i.e. bone disorders, leukaemia, unmasking or acceleration of underlying disease, require further investigation in patients receiving prolonged treatment, as in myelodysplasia. Finally, antibodies against growth factors have been reported only with GM-CSF. Other cytokines are still under investigation. Flu-like and constitutional symptoms, sometimes dose-limiting, have been reported with IL-1, IL-3, IL-4 and IL-6, while M-CSF was occasionally associated with such adverse effects. More specific adverse events, also frequently considered as dose-limiting toxicities, include hypotension with IL-1, severe headache or skin rash with IL-3, and nasal congestion and gastroduodenal lesions with IL-4. Severe capillary leak syndrome has been reported only with IL-4. M-CSF toxicity is minimal and limited to reversible but sometimes dose-limiting thrombocytopenia and ophthalmological symptoms with the recombinant product. Again, the safety of long term administration of these cytokines has not yet been determined, and IL-3-induced disease progression in myelodysplastic patients has been suggested.

Clinical toxicity of the interferons.

Since their initial description in 1957, the interferons (IFNs) have been increasingly used to treat a wide array of diseases. Acute adverse effects, i.e. 'flu-like' syndromes, hypo- or hypertension, tachycardia, headache, myalgias and gastrointestinal disorders, occur within the first hour or day after starting treatment. They are seldom treatment-limiting and are easily manageable. Sub-acute and chronic effects develop after several days, usually within 2 and 4 weeks of therapy. The most typical is neurological toxicity, including fatigue/asthenia, and behavioural and cognitive changes. Such symptoms may seriously impair quality of life and result in treatment discontinuation. Seizures have seldom been described. Other infrequent central nervous system adverse effects include vertigo, cramp and oculomotor nerve paralysis. Distal paraesthesias and peripheral neuropathy have been reported. IFN-associated autoimmunity is quite rare but a matter of concern. Biological or clinical manifestations usually require several months to become apparent. Autoantibodies have been shown to develop in most patients but have been inconsistently associated with clinical symptoms of systemic lupus erythematosus, rheumatoid-like arthritis and thyroiditis. Both hypo- and hyperthyroidism have been described but are usually reversible. Other infrequent autoimmune reactions include diabetes, pemphigus and worsening of multiple sclerosis. Although several patients present with a pre-existing autoimmune disorder, no predisposing factor has been clearly established. While hypotension and tachycardia are the most frequent acute cardiovascular complications, a few additional cases of cardiac arrhythmias and myocardial ischaemia have been reported after a short course or several weeks of treatment. These latter complications do not appear to be dose-dependent or age-related. Isolated cases of congestive heart failure have also been described. Mild proteinuria has been observed in 15 to 25% of patients, but acute renal toxicity is uncommon. A transient rise in serum aminotransferase levels is frequently noted during the first stage of therapy, especially in patients receiving the highest dosages. Direct hepatotoxicity is extremely rare. Autoimmune hepatitis, which is ill-diagnosed as chronic viral hepatitis, and de novo induction of autoimmune hepatitis, account for the majority of liver diseases. Haematotoxicity is relatively common but mild to moderate, and develops gradually during the first weeks of treatment. Neutropenia is the most common haematological toxicity, but is usually not dose-limiting and resolves rapidly upon drug discontinuation. Myelosuppression, autoimmune and immune allergic haemolytic anaemias and thrombocytopenias have seldom been described. Cutaneous adverse effects comprised nonspecific erythema and hair loss and, less frequently, vasculitis, local ulcerations at the site of injection and exacerbation of psoriasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Side effects of ranitidine.

Ranitidine was first marketed in 1981; since then many patients have been treated such that much experience has been accumulated on the safety of this histamine H2-receptor antagonist in the treatment of gastroduodenal disease. A wide array of ranitidine-associated side effects has been described, but infrequently. As so much information is now available, the aim of this review is to assess the weight of evidence for a causal link between ranitidine and the reported side effects. Overall, ranitidine is well tolerated. The incidence of general side effects at less than 2% is very similar to placebo. Headaches, tiredness, dizziness and mild gastrointestinal disturbance (e.g. diarrhoea, constipation and nausea) are among the most frequent complaints, but have very seldom resulted in stopping treatment. Cardiovascular side effects are extremely rare and unpredictable with the usual doses of oral ranitidine (at most 1 in 1 million patients). They mostly comprise sinusal bradycardia and atrioventricular blockade, especially after rapid intravenous administration, receding after cessation of the drug. Clinical studies, however, have not shown a significant pharmacological effect of ranitidine on the cardiovascular system via H2-receptors, even though individual sensitivities cannot be ruled out in a few isolated reports. Ranitidine is unlikely to be directly hepatotoxic: a transient change in liver function tests has been noted in only 1 in 100 to 1 in 1000 patients. Several cases of mixed hepatitis have been reported, but very few were fully documented. The incidence of ranitidine-associated acute hepatitis has been estimated to be less than 1 in 100,000 patients. Neuropsychiatric complications may be less common and clinically quite similar to those reported with cimetidine, i.e. confusion, disorientation, hallucinations, delirium. These side effects have occurred especially in critically ill and multiple-therapy patients, or patients with chronic renal or hepatic failure, so that the direct causal link with ranitidine treatment was often difficult to ascertain. Even though an H2-receptor-mediated effect is an attractive hypothesis (since similar complications were noted with other H2-receptor antagonists), other mechanisms have been suggested to play a role, e.g. cholinergic or histaminic effects. The overall incidence of neuropsychiatric complications is probably markedly less than 1%. White cell injury (i.e. agranulocytosis) appears to be the most frequent haematological complication, even though case reports are very few and poorly documented.(ABSTRACT TRUNCATED AT 400 WORDS)

Dual control by purines and pyrimidines of the expression of the pyrD gene of Salmonella typhimurium.

Expression of the Salmonella typhimurium pyrD gene was found to be repressed two-fold when cells were grown in the presence of hypoxanthine. Purine-mediated repression was evident for reporter plasmids containing pyrD-lacZ transcriptional or translational fusions, indicating that regulation was being exercised at the level of transcriptional initiation. In a strain harbouring a purR6::Tn10 mutation inactivating the purine regulon repressor (PurR), expression of pyrD was not repressed by hypoxanthine. Gel retardation experiments provided evidence that PurR binds to a PUR box centered 27 base pairs upstream of the -35 region of the pyrD promoter. Site-directed mutagenesis was used to decrease the similarity of the putative PUR box to the consensus sequence; each mutation eliminated binding of PurR to the mutated DNA in vitro and abolished repression by hypoxanthine in purR+ cells in vivo. Regulation by pyrimidines was unaffected by either of the two PUR box mutations, showing that purine and pyrimidine control of pyrD expression can operate independently.

Treatment of drug-induced agranulocytosis with haematopoietic growth factors: a review of the clinical experience.

Although drug-induced agranulocytosis is infrequent, it is of concern as the mortality rate ranges from 6 to 10%. Since the approval of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), these drugs have been increasingly used in the management of drug-induced agranulocytosis. Unfortunately, most of the data regarding the use of these agents in patients with drug-induced agranulocytosis comes from case reports. In light of the low incidence of drug-induced agranulocytosis, the large variety of offending drugs with potentially different toxic mechanisms and the wide range of neutropenia duration among patients with agranulocytosis, randomised, double-blind studies are unlikely to be performed. Case reports provide promising results with a shortening in the duration of agranulocytosis, a possible reduction in the duration of hospitalisation and the fatality rate in patients treated with haematopoietic growth factors (HGF) compared with historical controls. A therapeutic effect is also suggested by reports of reductions in the neutrophil count after HGF discontinuation following an initial increase. The results of recent case series are less positive, with only a moderate, but usually not significant, reduction in the duration of neutropenia in patients treated with HGF, as compared with those receiving routine care. A Japanese study indicated that G-CSF was effective in patients with mild-to-moderate antithyroid drug-induced neutropenia, whereas no clear benefit was apparent in those with severe neutropenia. Several factors, for example, early recognition and improved management of individual cases with better supportive care, have contributed to a decrease in the overall mortality of drug-induced agranulocytosis. HGF are expected to further reduce mortality. Guidelines for the use of HGF in patients with febrile neutropenia, as established by the American Society of Clinical Oncology, are probably valuable for the management of drug-induced agranulocytosis. In accordance with these recommendations, the use of HGF may be recommended in patients with severe neutropenia and/or poor prognostic factors. Whether the absence of myeloid precursors or presence of promyelocytes or myelocytes in bone marrow examination represents optimal conditions for HGF treatment is still unknown. Most authors agree that treatment should be administered early in the course of the disease. An interesting approach, in which treatment decisions are based on the granulocyte count 4 hours after a single dose of G-CSF in patients with anthithyroid drug-associated neutropenia should be more extensively evaluated.