Karim Aouam

Les effets indésirables des antituberculeux : épidémiologie, mécanismes et conduite à tenir

Tuberculosis, what ever its localization, is an infectious disease which can be totally cured by combining antitubercular drugs. Current therapeutic regimens with isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin have proved successful in treating tuberculosis. However, they are associated to a high rate of adverse effects that can lead to therapeutic failure. Understanding the nature and the severity of these adverse effects allows for their appropriate management. Toxic neuropathy and hepatitis are the most common adverse reactions to isoniazid. Rifampicin is generally well tolerated but some severe immuno-allergic reactions may occur in case of intermittent regimen. Pyrazinamide-induced liver injury is rare but sometimes lethal. Joint affections, usually due to hyperuricemia, are more frequent but easily manageable. The major adverse effect related to ethambutol is ocular optic neuropathy. It occurs dose-dependently and can be irreversible. Finally, administration of streptomycin is potentially associated with renal and cochleo-vestibular toxicity that might be milder than when induced by other aminoglycosides. The management of antituberculosis-induced adverse effects depends on parameters related to the adverse effect itself and to the administrated drug.

Carbamazepine-induced DRESS and HHV6 primary infection : The importance of skin tests

A 34‐year‐old male with a 20‐year history of epilepsy was treated with valproic acid and phenobarbital. As he had frequent convulsive fits, carbamazepine (CBZ) was added. Thirty‐four days later, the patient developed hyperthermia, (39.5°C), cervical lymphadenopathy and generalized cutaneous exfoliated maculae and papulae. Biochemical investigation was characterized by a white cell count of 16.1 × 103/μl (17% eosinophils) and increased levels of aspartate aminotransferase and alanine aminotransferase (50 and 116 IU/L, respectively). HHV6 serological tests performed on day 21, detected anti HHV6 IgM, suggesting a HHV6 primary infection. Hence, CBZ was discontinued. One month later, the skin eruption, fever, lymph node swelling, liver dysfunction, and eosinophilia were progressively relieved. Six weeks after complete recovery, prick and patch skin tests were performed. They were strongly positive at 48‐h reading. This report suggests the usefulness of skin tests in diagnosing CBZ‐induced‐DRESS, as well as s possible association between DRESS and HHV6 primary infection.

Revue généraleLes effets indésirables des antituberculeux : épidémiologie, mécanismes et conduite à tenirAdverse effects of antitubercular drugs: epidemiology, mechanisms, and patient management

Tuberculosis, what ever its localization, is an infectious disease which can be totally cured by combining antitubercular drugs. Current therapeutic regimens with isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin have proved successful in treating tuberculosis. However, they are associated to a high rate of adverse effects that can lead to therapeutic failure. Understanding the nature and the severity of these adverse effects allows for their appropriate management. Toxic neuropathy and hepatitis are the most common adverse reactions to isoniazid. Rifampicin is generally well tolerated but some severe immuno-allergic reactions may occur in case of intermittent regimen. Pyrazinamide-induced liver injury is rare but sometimes lethal. Joint affections, usually due to hyperuricemia, are more frequent but easily manageable. The major adverse effect related to ethambutol is ocular optic neuropathy. It occurs dose-dependently and can be irreversible. Finally, administration of streptomycin is potentially associated with renal and cochleo-vestibular toxicity that might be milder than when induced by other aminoglycosides. The management of antituberculosis-induced adverse effects depends on parameters related to the adverse effect itself and to the administrated drug.

Hypersensitivity Syndrome Induced by Anticonvulsants: Possible Cross-Reactivity Between Carbamazepine and Lamotrigine

A 14‐year‐old male presents with erythroderma and fever 44 days after carbamazepine intake. Laboratory exams show eosinophilia and elevated liver enzymes, and thoracic imaging reveals interstitial pneumonitis. All symptoms disappear after carbamazepine withdrawal. A patch test to carbamazepine performed 6 weeks after recovery is positive. About 8 months later, the patient exhibits the same clinical and biological picture 52 days after lamotrigine intake. Lamotrigine is stopped and all symptoms disappear. A patch test to LMG is positive. This case illustrates a possible cross‐reactivity between carbamazepine and lamotrigine, which are aromatic and nonaromatic anticonvulsants, respectively.

Acute generalized exanthematous pustulosis (AGEP) induced by cefotaxime

We report a case of acute generalized exanthematous pustulosis (AGEP) after cefotaxime use confirmed by a positive patch test. A 30‐year‐old woman received cefotaxime, fosfomycin and ciprofloxacin for sinusitis. Twelve days after drug initiation, she developed an extending pustular erythema associated with fever. Laboratory investigations showed marked leukocytosis. His blood chemistry was normal. The histological examination showed parakeratosis, spongiosis and nonfollicular intra‐epidermal pustules consistent with AGEP. All medications were withdrawn. The symptoms resolved within 11 days after cefotaxime discontinuation. Patch tests were positive to cefotaxime after 48 h, while ciprofloxacin and fosfomycin yielded negative findings. Based on the Naranjo algorithm, it is probable that AGEP reaction was caused by cefotaxime. To our knowledge, this is the first reported case of AGEP associated with positive cefotaxime patch testing.

Circadian variation of Valproic acid pharmacokinetics in mice

Valproic acid (VPA) is currently one of the most commonly used antiepileptic drugs. This study aims to investigate whether VPA pharmacokinetics varied according to circadian dosing-time. A single dose of VPA (350 mgkg(-1)) was administered by intraperitonally (i.p.) route to a total of 132 mice synchronized for 3 weeks to 12h light (rest span) and 12 h dark (activity span). Four different circadian times (1, 7, 13 and 19 HALO) of drug injection were used (33 mice/circadian time). At each circadian time, blood samples were withdrawn at (0 h) and at 0.083, 0.166, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2 and 3h after VPA injection. Plasma VPA concentrations were determined by an EMIT method. There were no significant differences in T(max) of VPA whatever the circadian-time of injections (T(max)=0.166 h). However, there were relevant differences in C(max) between the four circadian groups (p<0.005), it varied between 386 ± 30.86 mg L(-1) in mice treated at 7 HALO and 824 ± 39.85 mg L(-1) in mice treated at 19 HALO. The AUC(0-∞) was significantly two times higher when VPA was administered at 19 HALO as compared to the injection at 7 HALO. Drug dosing at 7 HALO resulted in highest Cl(T) value: 0.405 ± 0.006 L h(-1)kg(-1), whereas Cl(T) was significantly slower when VPA was administered at 19 HALO (0.157 ± 0.009 L h(-1)kg(-1)) (p<0.0001). The AUC(0-∞) was significantly 2-fold higher when VPA was administered at 19 HALO (2216.65 ± 138.91 mg h(-1)L(-1)) as compared to the injection at 7 HALO (864.09 ± 16.82 mg h(-1)L(-1)) (p<0.0001). Cosinor analysis showed circadian rhythm in different pharmacokinetic parameters. C(max) and AUC(0-∞) have a significant circadian rhythm with an acrophase located at 20.16 HALO ± 0.16 h (the middle of the active span) (p<0.001), whereas Cl(T) and Vd showed a significant circadian rhythm with an acrophase located respectively at 7.86 HALO ± 0.57 h and 6.13 HALO ± 0.07 h (the middle of the rest span) (p<0.001). The large circadian variation of VPA pharmacokinetic processes might be involved in the mechanisms of circadian rhythm in murine toxicity since the optimal tolerance corresponded to the time which induces lowest C(max) and AUC values.

Hypersensitivity to amoxicillin after drug rash with eosinophilia and systemic symptoms (DRESS) to carbamazepine and allopurinol: a possible co‐sensitization

Hypersensitivity syndrome, also known as drug rash with eosinophilia and systemic symptoms (DRESS), is a serious idiosyncratic drug reaction. It is associated with fever, skin eruption, eosinophilia and multiple organ involvement (lymph node enlargement, hepatitis, pneumonitis, renal dysfunction, pancreatitis, myositis, myocarditis, central nervous system manifestations and hyper- and/or hypothyroidism) [1].

Severe ranitidine-induced anaphylaxis: a case report and literature review

What is known and Objective:  Ranitidine is a generally well‐tolerated drug, and serious side effects are rare. However, ranitidine‐induced anaphylaxis has been reported on rare occasions. We report on such a case and review other cases reported in the literature.

Circadian Time‐Dependent Differences in Murine Tolerance to the Antihistaminic Agent Loratadine

Loratadine is a second‐generation histamine H1‐receptor antagonist used in the treatment of allergic diseases. The aim of the study was to assess whether lethal toxicity and motor incoordination (neurotoxicity) of loratadine is circadian rhythm‐dependent. A total of 210 male Swiss mice, aged 10 wk, were synchronized for 3 wk to 12 h light (rest span)/12 h dark (activity span). The drug was administered per os. The choice of the sublethal (TD50=82 mg/kg body weight) and the lethal (LD50=4 g/kg body weight) dosage was based on preliminary studies. Each of these two doses was administered to comparable groups of animals at six different circadian time points (1, 5, 9, 13, 17, and 21 Hours After Light Onset [HALO]). The survival duration was dosing time‐dependent (χ2=16.96; p<0.001). Drug dosing at 17 HALO resulted in best (67%) survival rate; whereas, dosing at 9 HALO resulted in poorest (21%) survival rate. Cosinor analyses (with a trial period τ=24 h) validated a statistically significant circadian rhythm in survival rate (p<0.04) with an acrophase (peak time Ø of best tolerance to loratadine) being at 17.5 HALO±4.65 h. Troughs of motor incoordination were located at the administration times of 5 and 17 HALO (60% and 32% of animals affected, respectively), whereas peaks were located at 9 and 21 HALO (87% and 68% of animals affected, respectively). The 24 h mean of the motor incoordination was 61%, the mean proportion of animals affected by the treatment for the six different circadian times studies. The extent of this neurotoxic effect varied as a function of loratadine dosing time (p<0.001). A statistically significant ultradian component rhythm (p<0.01) with a trial period τ=12 h was also validated. The obtained results show that the dosing time of loratadine at the mid‐activity (dark) span seems to be optimal, since it corresponds to the longest (21 vs. 12 days) survival span and to least neurotoxicity.

Chronotolerance study of the antiepileptic drug valproic acid in mice

Background Valproic acid (VPA) is an antiepileptic drug widely used for the treatment of absence seizures and generalized tonic-clonic seizures. The present work aims to study whether VPA-induced toxicity varies according to the dosing-time in the 24 hour-scale. Methods The influence of dosing-time on tolerance to VPA was investigated in 120 male Swiss mice synchronized under a light-dark cycle (12:12). The mean VPA lethal dose was first determined to be 850 ± 0.2 mg/kg, i.p.. Such a dose was administered by i.p. route to a total of 90 mice divided in six circadian stages [1, 5, 9, 13, 17 and 21 Hours After Light Onset (HALO)] (15 mice/circadian time); 30 mice were used as control (5 mice / circadian time). Results The surviving treated mice exhibited a significant circadian variation in rectal temperature and body weight loss (p < 0.001). The least rectal temperature change and body weight loss occurred when VPA was injected at 9 HALO. Drug dosing at 9 HALO resulted in -9 % weight loss whereas drug dosing at 17 HALO was -15 % (Ø = 20.3 HALO ± 1.1 h, p ≤ 0.0001). Lethal toxicity also varied according to circadian dosing-time (χ2 = 42.1, p < 0.0001). The highest (60 %) and the lowest (6.67 %) survival rates were observed at 9 HALO and 17 HALO respectively. Cosinor analyses validated a significant circadian rhythm in survival duration with an acrophase at 8.4 HALO ± 0.75 h (p < 0.001). Conclusions With regards to these data the optimal tolerance to VPA occurred when the drug was administered in the second half of the light-rest span of mice which is physiologically analogous to the second half of the night for human patients.