Naceur A. Boughattas

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.

Antihyperglycemic, antihyperlipidemic and antioxidant activities of traditional aqueous extract of Zygophyllum album in streptozotocin diabetic mice.

OBJECTIVE The aim of this work was to investigate the antihyperglycemic, antioxidant and antihyperlipidemic effects of the aqueous extract of Zygophyllum album on streptozotocin (STZ)-induced diabetic mice. METHODS Diabetes was induced in Swiss albino mice by the administration of STZ (45mg/kg b.w.) intraperitoneally. Aqueous extract of Z. album (100 and 300mg/kg b.w.) was administered by oral gavage once a day for a period of 15days. The effect of the extract on blood glucose, lipids, cholesterol levels in plasma, and also on enzymatic and non enzymatic antioxidants of defence systems such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) enzyme activities, and vitamin C, vitamin E and glutathione reductase (GSH) levels in liver and pancreas were studied. RESULTS Our results showed that Z. album extract reduced the blood glucose, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels in STZ-diabetic mice. It also significantly abolished the increase in MDA level, and GPx, SOD and CAT activities in both liver and pancreas. The levels of GSH, vitamin C and high-density lipoprotein (HDL) were significantly augmented in Z. album treated diabetic mice in comparison with control group. Our findings suggest that Z. album aqueous extract prevented the diabetic induced MDA levels via the enhancement of the tissue GSH and blood vitamin C levels. CONCLUSIONS These results suggest that Z. album extract exerts the anti-diabetic and antihypercholesterolemic activities through its antioxidant properties.

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.

MALONDIALDEHYDE CONTENT AND CIRCADIAN VARIATIONS IN BRAIN, KIDNEY, LIVER, AND PLASMA OF MICE

In aerobic organisms, the use of oxygen (O2) to produce energy is associated with the production of Reactive Oxygen Species (ROS), which reacts with biological molecules to produce oxidized metabolites such as malondialdehyde (MDA). This experiment focused on male Swiss mice 12 weeks of age synchronized for 3 weeks by the 12 h light (rest)/12 h dark (activity) span. Different and comparable groups of animals (n=10) were sacrificed at six different circadian stages: 1, 5, 9, 13, 17, and 21 h after light onset (HALO). The 24 h mean MDA level varied among organs of mice in non‐stress conditions and was comparable in brain and liver but lower than in kidney. As the MDA 24 h status constitutes only a part of ROS damages in sites differing by their oxygen use, lipid composition, and detoxification capacity, the temporal patterns of their MDA content were comparatively studied in relationship to the animal rest‐activity cycle. The results revealed significant circadian rhythms with the peak time located during the rest span (5 HALO) for both brain and liver, but during the activity span for the kidney (21 HALO) and plasma (13 HALO). This chronobiological study showed that under physiological conditions, lipid peroxidation depends on several factors. The MDA peak/trough might be used as a tool to detect moments of high/low sensitivity of tissues to ROS attack in rodents.

Antiulcerogenic and antibacterial activities of Apium graveolens essential oil and extract

This study investigates the antiulcerogenic and antibacterial activities of Apium graveolens extracts. The antiulcerogenic activity was evaluated in rats by the HCl/EtOH method. Inhibition of gastric lesions by A. graveolens extracts was dose-dependent for both aerial part (53–76%) and seeds (51–95%). The methanolic extract as well as the aqueous extracts used at 300 mg kg−1 dose exhibited a highly significant inhibition of gastric lesions (91% and 95%, respectively) which was similar to that induced by omeprazole (94%). Essential oil and aqueous extract prepared from the aerial parts of A. graveolens were tested to determine their antibacterial activity using the paper disc-diffusion method, the minimal inhibitory concentration and the minimal bactericidal concentration. Essential oil of A. graveolens was strongly inhibitory against Escherichia coli and moderately inhibitory against Pseudomonas aeruginosa and Staphylococcus aureus. The chemical composition of the volatile oil was investigated by gas chromatography analysis. The major components identified were β-pinene, camphene, cumene, limonene, α-thuyene, α-pinene, β-phellendrene, p-cymene, γ-terpinene, sabinene and terpinolene.

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].

Time-of-day dependence of neurological deficits induced by sodium nitroprusside in young mice

Sodium nitroprusside (SNP) is widely used in pharmacological studies as a potent vasodilator or a nitric oxide donor. SNP-induced ataxic effects were assessed in mice by the Joulou-Couvoisier test. Swiss albino mice of both genders, 2-8 weeks of age, were acclimated at least for 2 weeks to 12 h light (rest span)/12 h dark (activity span). In 2 and 4 week old mice, maxima of ataxia were found following intraperitoneal administration of a dose ranging from 3 to 3.6 mg.kg-1 SNP at ≈ 1 and 13 HALO (Hours After Light Onset). The sublethal toxicity was statistically dosing-time dependent (χ2 test: P < 0.005). No rhythm was validated in neurotoxicity by cosinor analyses. At the 8th week of post-natal development (PND), SNP-induced ataxia was greatest at ≈ 1 HALO (69% in males vs. 49% in females) and lowest at ≈ 13 HALO (21% in males vs. 11% in females) (χ2 test: P < 0.00001). Cosinor analysis also revealed no statistically significant rhythm in mice injected with 3 or 3.3 mg.kg-1. However, a significant circadian (τ = 24 h) rhythm was detected by adjusted cosinor in 3.6 mg.kg-1-treated mice (P < 0.004). In all studied groups, SNP-induced motor impairment (expressed in %) was lower during the dark than the light phase. Furthermore, there was a non-significant gender-related difference in SNP-induced neuronal toxicity with the males more sensitive than females at every studied PND. The ataxic effects were inversely proportional to the lag time from injection and to the age of animals (with P < 0.05 only between 2 and 8 week old mice). These data indicate that both the administration time and age of the animal significantly affect the neurotoxic effects of SNP.

General unknown screening procedure for the characterization of human drug metabolites: Application to loratadine phase I metabolism

This article describes the application of a recently developed general unknown screening (GUS) strategy based on LC coupled to a hybrid linear IT-triple quadrupole mass spectrometer (LC-MS/MS-LIT) for the simultaneous detection and identification of drug metabolites following in vitro incubation with human liver microsomes. The histamine H1 receptor antagonist loratadine was chosen as a model compound to demonstrate the interest of such approach, because of its previously described complex and extensive metabolism. Detection and mass spectral characterization were based on data-dependent acquisition, switching between a survey scan acquired in the ion-trapping Q3 scan mode with dynamic subtraction of background noise, and a dependent scan in the ion-trapping product ion scan mode of automatically selected parent ions. In addition, the MS(3) mode was used in a second step to confirm the structure of a few fragment ions. The sensitivity of the ion-trapping modes combined with the selectivity of the triple quadrupole modes allowed, with only one injection, the detection and identification of 17 phase I metabolites of loratadine. The GUS procedure used in this study may be applicable as a generic technique for the characterization of drug metabolites after in vitro incubation, as well as probably in vivo experiments.