Levamisole-induced vasculopathy: A systematic review.

OBJECTIVE: To characterize levamisole-induced vasculopathy. METHODS: We performed a systematic review searching MEDLINE for articles published from 1972 to 2016. RESULTS: We retrieved 357 references and abstracts and selected 111 articles. Levamisole-induced vasculopathy was reported in 192 patients, with a female predominance (n = 122, 63.5%). Median [interquartile range] age was 44 [38-50]. Skin was the most frequently involved organ (n = 182, 94.8%). Cutaneous lesions were mostly on the face (n = 136, 70.8%), especially the ears. Purpura (n = 131, 68.2%) was the most reported cutaneous lesion. Organ involvement included acute renal failure (n = 24, 12.5%), and pulmonary involvement (n = 20, 10.4%). Anti-neutrophil cytoplasmic antibodies (ANCAs) were found in 167/178 patients (93.8%), with both anti-myeloperoxydase and anti-proteinase 3 specificity reported in 51/118 patients (43.2%). Anti-phospholipid (APL) antibodies were found in 93/137 patients (67.9%). Leukopenia was detected in 69/138 patients (50%). Skin biopsies identified vasculitis and thrombotic vasculopathy in 73/148 (49.3%) and 62/148 (41.9%) patients, respectively. The outcome was favourable in 116/134 patients (86.6%), but relapses were reported in 33 (28.4%), mainly on levamisole re-exposure. CONCLUSION: Levamisole-induced vasculopathy is characterized by a female predominance, skin involvement, ANCA and/or APL antibody positivity, leukopenia, vasculitis or vascular thrombotic histological lesions, and despite possible systemic involvement, a favourable outcome with levamisole interruption.

Staphylococcus aureus osteo-articular infection: usefulness of the determination of daptomycin serum concentration to explain a treatment failure.

We report two cases of treatment failure in patients with osteoarticular infection associated with Staphylococcus aureus bacteremia and receiving daptomycin. Using a published population-pharmacokinetic model and daptomycin blood level in these patients, area under the curve (AUC) was calculated and compared to the pharmacological target. For the first patient, treated with 6 mg/kg every 48 hours due to acute renal failure and then every 24 hours, the AUC was 820 mg×h×L-1, with a minimal concentration of 23.5 mg/L confirming the right dose adjustment and the absence of underdosing. The methicillin-resistant Staphylococcus aureus (MRSA) strain was still susceptible to daptomycin, but it was not sufficient to observe a favorable outcome. For the second patient, treated with 10 mg/kg/d, the steady state residual concentration was 10.4 mg/L, and the calculated AUC value was 550 mg×h×L-1. AUC/MIC values evolved during treatment to be under the cut-off for bactericidal effects (> 800 hours), and the Staphylococcus aureus (SA) strain became daptomycin resistant. This study highlights the inter-individual pharmacokinetic variation leading sometimes to drug underdosing. Drug monitoring should be encouraged in order to avoid treatment failure.

Disulfiram ethanol reaction mimicking anaphylactic, cardiogenic, and septic shock.

Shock is a common reason for medical intensive care unit admission, with septic and cardiogenic accounting for most of the etiologies. However, the potential severity of adverse side effects of drugs indicates that any medication should be carefully scrutinized for potential pharmacokinetic and pharmacodynamic interactions that may result. We herein report the case of a life-threatening shock mimicking successively anaphylactic, cardiogenic, and septic shock, which was finally related to disulfiram ethanol reaction. Indeed, disulfiram ethanol reaction is known to provoke unpleasant symptoms through vasodilatation in various organs. However, extreme manifestations of vasodilatory shock may lead to circulatory failure and lactic acidosis. Because of large prevalence of alcoholism and disulfiram medication, emergency physicians and medical specialists should be aware of this life-threatening condition, with its misleading presentation.

Safety profile of enantiomers vs. racemic mixtures: it's the same?

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The physicochemical properties of racemates and stereoisomers of medicines can differ significantly, and this may affect the side-effect profile in addition to the pharmacokinetics and intended pharmacology. WHAT THIS STUDY ADDS: This is a study to investigate the profile of adverse drug reactions of racemic and enantiomeric forms of drugs. Our data suggest differences in the safety profile for ofloxacin and omeprazole. This area requires more work to investigate this for other compounds. AIMS: The objective was to investigate the safety profile of four drugs marketed as racemic and enantiomeric forms in France. METHODS: Data from the French PharmacoVigilance Data Base (January 2005 to June 2010) were analysed for four pairs of racemic/isomeric drugs. A case-noncase approach was used to measure the disproportionality of combination between adverse drug reaction (ADR) and exposure to drug. RESULTS: No significant difference in the number of ADRs was observed between Rac-cetirizine/(R)-cetirizine or Rac-citalopram/(S)-citalopram pairs. (S)-Omeprazole induced more haematological effects than Rac-omeprazole. Rac-Ofloxacin induced more haematological, renal and neuropsychiatric ADRs than (S)-ofloxacin, whereas levofloxacin was associated with more reports of musculoskeletal ADRs. CONCLUSIONS: The profile of ADRs could differ for some drugs marketed as racemic and enantiomeric forms. Further studies would be necessary to confirm these data.

Drug-induced hypersensitivity syndrome: clinical and biologic disease patterns in 24 patients.

Drug-induced hypersensitivity syndrome (DIHS), also called drug rash with eosinophilia and systemic symptoms (DRESS), is a severe reaction usually characterized by fever, rash, and multiorgan failure, occurring 1-8 weeks after drug introduction. It is an immune-mediated reaction involving macrophage and T-lymphocyte activation and cytokine release, although no consensus has been reached as to its etiology. The skin, hematopoietic system, and liver are frequently involved. DIHS can mimic severe sepsis, viral infection, adult-onset Still disease (AOSD), or lymphoproliferation.We describe 24 consecutive patients with DIHS who were hospitalized between September 2004 and March 2008. Criteria for inclusion in this observational study were suspected drug reaction, eosinophilia >or=500/microL and/or atypical lymphocytes, involvement of at least 2 organs (skin being 1 of them), with suggestive chronology and exclusion of other diagnoses. Our cohort of 12 women and 12 men had a median age of 49 years (range, 22-82 yr), and 11 had skin phototype V or VI. Patients with mild or no rash were immunocompromised (7/24)- defined as treatment with prednisone (>or=10 mg/d) and another immunosuppressant drug, or human immunodeficiency virus infection. All patients were febrile (>38 degrees C), 14 had localized or generalized edema, 7 had pharyngitis, 8 had lymphadenopathy, 22 had hepatitis, 4 had nephritis, 2 had noninfectious and nonlithiasic angiocholitis or cholecystitis. Ten patients were hypotensive, 5 of whom had associated laboratory signs and/or imaging findings suggestive of acute myocardial dysfunction. Half of the patients had hemogram abnormalities, including eosinophilia. Nine DIHS patients fulfilled the Fautrel criteria for AOSD diagnosis, including glycosylated ferritin <20% in 4/11, with or without laboratory characteristics of hemophagocytosis. Twenty DIHS episodes occurred during the less sunny months of October to March.We determined 25-hydroxyvitamin D3 (25[OH]D3) levels in 18 patients and found that 9 patients had vitamin D deficiency (<25 nmol/L or <10 microg/L) and 5 had vitamin D insufficiency (25-50 nmol/L). Moreover, 25(OH)D3 levels were inversely correlated with ferritin values. After culprit-drug withdrawal, outcomes were favorable for all patients, including those with cardiac abnormalities under slow tapering of glucocorticoids.We recommend looking for the frequent but underdiagnosed hypersensitivity myocarditis with noninvasive diagnostic tools, such as N-terminal probrain natriuretic peptide, and promptly withdrawing the culprit drug and starting glucocorticoids. Vitamin D deficiency might be a DIHS risk or severity factor, especially for patients with high skin phototype and during the winter. Because DIHS clinical and laboratory patterns share similarities with AOSD and hemophagocytosis, DIHS should be included in their differential diagnoses.

Acute pancreatitis related to tigecycline: case report and review of the literature.

Tigecycline is a new broad-spectrum antibiotic. Nausea and vomiting are its most common side-effects. We describe here a case of severe acute pancreatitis related to tigecycline in order to highlight the possible occurrence of this adverse event and to remind clinicians to measure the lipase rate if in any doubt.

Severe uveitis in an HLA-B27-positive patient with ankylosing spondylitis.

BACKGROUND: A 36-year-old male presented with bilateral, anterior, chronic uveitis, with cystoid macular edema. Decimal visual acuity was 0.25 in the right eye and 0.20 in the left eye. Ankylosing spondylitis had been diagnosed 13 years previously, with peripheral and axial involvement. He had no history of extra-articular manifestations of ankylosing spondylitis before this uveitis attack. Treatment with the anti-tumor necrosis factor agent etanercept was initiated 5 months before the attack of uveitis. INVESTIGATIONS: Slit-lamp biomicroscopy, laser-flare photometry, optical coherence tomography, chest radiography, angiotensin-converting-enzyme test, mycobacterial culture from gastric lavage, serology tests for syphilis, brucellosis, toxoplasmosis, toxocarosis, antinuclear antibodies, rheumatoid factor, antineutrophil cytoplasmic antibodies, antimyeloperoxydase antibodies and antiproteinase 3 antibodies. DIAGNOSIS: Atypically severe HLA-B27-positive uveitis, in a patient with ankylosing spondylitis treated with etanercept. MANAGEMENT: Intensive topical corticosteroid and cycloplegic treatment, subtenon triamcinolone acetonide injection, switch in treatment from etanercept to infliximab followed by discontinuation of tumor necrosis factor inhibitors, intravenous pulses of methylprednisolone followed by oral corticosteroids, and intravenous cyclophosphamide.

Population pharmacokinetics of tenofovir in human immunodeficiency virus-infected patients taking highly active antiretroviral therapy.

The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (V(c)/F), peripheral distribution volume (V(p)/F), intercompartmental clearance (Q/F), and plasma clearance (CL/F) were 297 +/- 28.5 [corrected] liters, 848 +/- 209 [corrected] liters, 80 +/- 15 [corrected] liters/h and 50.5 +/- 3.1 [corrected] liters/h, respectively. Apparent plasma clearance was related to body weight/serum creatinine ratio (BW/S(CR)) and to the existence of a tubular dysfunction. Concomitant treatment with lopinavir/ritonavir was found to decrease tenofovir clearance. Individual Bayesian estimates of CL/F were used to calculate the tenofovir area under the concentration-time curve from time zero to 24 h (AUC(0-24)). In patients without tubular dysfunction, AUC(0-24) values markedly decreased from 6.7 to 1.4 mg . h/liter for BW/S(CR) increasing from 0.44 to 1.73. The relevance of a dosage adjustment based on BW/S(CR) should be further evaluated.

Acute colchicine intoxication during clarithromycin administration.

OBJECTIVE: To report a case of colchicine intoxication occurring with institution of clarithromycin. CASE SUMMARY: A 76-year-old man with familial Mediterranean fever (FMF) had received colchicine 1.5 mg daily for 6 years. The patient underwent 7 days of clarithromycin, amoxicillin, and omeprazole treatment for Helicobacter pylori-associated gastritis. Fever, abdominal pain, and diarrhea occurred 3 days after treatment initiation. On day 8, dehydration, pancytopenia, metabolic acidosis, and increased lipase level necessitated hospitalization. Alopecia was observed 2 weeks later. The patient recovered fully after the colchicine dosage was reduced to 0.5 mg/day and rehydration was performed. The previous dosage was then reinstituted without adverse reaction. An objective causality assessment revealed that the adverse event was probable. DISCUSSION: Continuous colchicine administration is used in treatment of microcrystalline arthritis, Behcet's disease, and FMF. Colchicine is primarily eliminated through biliary excretion. Renal elimination and cytochrome P450 metabolism play a less significant role. Colchicine is also a substrate of P-glycoprotein, a transporter involved in cellular efflux and elimination of numerous drugs. Three cases of intoxication have been reported when colchicine was combined with erythromycin, josamycin, or clarithromycin. Macrolides are inhibitors of P-glycoprotein and cytochrome P450-dependent enzymes and may decrease colchicine's biliary excretion through P-glycoprotein inhibition. CONCLUSIONS: Coadministration of colchicine and macrolides may impair colchicine elimination, resulting in excess drug exposure and toxicity. To this end, colchicine should be used with extreme caution in patients receiving P-glycoprotein inhibitors, particularly if they are elderly and/or renally compromised.

Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases.

We describe 7 cases of renal tubular injury in HIV-infected patients receiving an antiretroviral regimen containing tenofovir. Our patients (5 women and 2 men) developed renal tubular dysfunction, with hypophosphatemia, normoglycemic glycosuria, proteinuria, and decrease of creatinine clearance. The first biologic signs of renal toxicity were observed after duration of tenofovir treatment from 5 weeks to 16 months, and they resolved less than 4 months after discontinuation of tenofovir. Six patients had a low body weight (<60 kg). Five patients received low doses of ritonavir, and 1 received didanosine. In 5 patients, the signs resolved with the discontinuation of only the tenofovir. A renal biopsy performed in 1 patient was consistent with tubulointerstitial injury. Proximal tubulopathy appears to be a rare adverse effect of long-term tenofovir therapy. In patients with low weight or mild preexisting renal impairment, regular monitoring of tubulopathy markers could lead to early detection of this dysfunction.