Current Drug Safety - Volume 7, Issue 5, 2012

Toxic epidermal necrolysis (TEN) is a severe mucocutaneous drug-induced syndrome that causes massive keratinocyte apoptosis and therefore hydro-electrolytic disorders and systemic infection. TEN approximately affects one to two cases per million per year. Mortality rate may reach thirty percent of cases. Thus, TEN constitutes a therapeutic emergency at diagnosis. Typically, clinical examination shows a mucocutaneous detachment involving more than thirty percent of body area. Definitive diagnosis is made on cutaneous biopsy with histological exam that shows the blister of necrotic keratinocytes. Main differential diagnosis are acute staphylococcus epidermis, acute generalized exanthematous pustulosis, linear IgA bullous dermatosis, paraneoplastic pemphigus, bullous fixed pigmented erythema, acute lupus erythematosus. In the early days, SCORTEN gives a good estimation and is now widely used as prognostic score. Drugs are generally considered as the main etiology of TEN but in some cases bacterial or viral infections could be involved. Physiopathology remains unclear even if recent advances have reported the possible implication of immune pathways based on activation of T and NK cells. Treatment of TEN requires to be instituted as soon as the diagnosis is made and the patient is preferentially referred to a specialized unit. Supportive care consist of covering areas of cutaneous detachment. No other therapy has demonstrated its efficiency, but high-dose intravenous immunoglobulin might improve the prognosis.

Drug-induced toxic epidermal necrolysis (TEN) is a rare but potentially lethal bullous disease whose complex pathomechanisms remain uncertain. The aim of the study was an exploratory attempt to assess TEN pathobiology using a combination of immunohistochemistry and proteomics. Skin blister fluid (BF) and serum were collected in a patient in the early TEN stage at day (D) +4 of evolution and three days later (D +7). Intravenous cyclosporine A (CsA) treatment was initiated since D +4. Immunohistochemistry was performed on skin blister biopsies. In addition, proteomic analyses compared the BF protein content before and at the issue of the 3-day CsA treatment. Proteins were selected according to their prominent differential abundance in BF between D+4 and D+7, when influenced by lesional skin cells, but not in serum. Among 300 proteins, four were considered. Glutathione transferase π was related to oxidative stress in TEN epidermis. The monocyte differentiation antigen CD14 and myeloperoxidase indicated macrophage activation. The proinflammatory S100-A8 protein probably originated from activated keratinocytes and/or macrophages. These proteomic findings were in line with immunohistochemistry and supported the prominent involvement of keratinocytes and macrophages in TEN pathomechanism. As opposed to CD14, other proteins were mainly present in BF at D+7, confirming that CsA expressed little effect, if any, on the activity of keratinocytes and macrophages in the present TEN patient. Of note, the present exploratory study using proteomic analyses in a single TEN case supports a pathogenic hypothesis without establishing any firm conclusion.

Human epidermal keratinocytes (EKs) are metabolically involved in various drug transport mechanisms, as well as in detoxification or activation processes. The overall cell mechanisms of drug metabolization, and more specifically drug processing are reviewed in normal EKs. The overall drug metabolism involves different phases corresponding to the uptake, biotransformation and anti-transport steps. In EKs, both the enzymes and transportassociated proteins are different from those involved in the hepatocyte metabolism. Some cytochrome P450 enzymes and the flavin-containing mono-oxygenases are particularly involved in EKs. Basically, EKs represent key cells likely involved during the initial stage of drug-induced toxic epidermal necrolysis (TEN). Only limited advances have been made so far in this field. Nevertheless, mitigating EKs metabolic disturbances in TEN probably represent a promising specific treatment of the disease.

Folates are one-carbon donors essential for synthesizing purines, pyrimidines, serine, and methionine. They correspond to anionic hydrophilic molecules essential for DNA synthesis in mammalian cells. The latter cells lack the capacity to synthesize folates. In some patients, high dosages of antifolate drugs (eg: methotrexate, pemetrexed) used in cancer chemotherapy alter the keratinocytes, endothelial cells and Factor XIIIa+ dermal dendrocytes in a range of various severities. Such conditions clinically designed under the heading antifolate cytotoxic skin reaction (ACSR) occasionally resemble the toxic epidermal necrolysis (TEN) / Stevens-Johnson syndrome (SJS) spectrum. Whether or not the TEN/SJS presentation of ACSR is a regular condition similar to that induced by other drugs or a variant condition supported by a unique pathomechanism is unsettled.

Toxic epidermal necrolysis (TEN) is a dreadful life-threatening syndrome typically induced by an adverse drug reaction. This condition is characterized by the sudden and extensive destruction of the epidermis. The patient should be promptly addressed to a burn unit where three types of treatment should be administered, namely, (a) specific topical care of the bullous/eroded skin areas, (b) systemic anti-apoptotic/necrotic treatments, and (c) supportive care preventing secondary internal organ failures. This latter aspect is covered by the present review and focuses on (a) early withdrawal of the causative drug, (b) airway management, (c) hydro-electrolytic control, (d) nutritional support, (e) antibiotherapy, (f) prevention of venous thrombosis and gastroduodenal ulcers, and (g) analgesia and anesthesia.

Benzodiazepines are World Health Organisation essential medicines used in the treatment of alcohol withdrawal, anaesthesia, sedation, anxiolysis, behavioural disturbance, epilepsy, insomnia, palliative care, and muscle spasm. Despite their widespread use concerns remain over their long-term safety through both neuronal and non-neuronal effects. We conducted a systematic review to identify vulnerable populations of patients who may be at increased risk of harm from benzodiazepines. We identified three potentially “at risk” groups of patients, those with renal disease, lung disease and those recently hospitalised. However methodological limitations including selection bias, vague descriptors of benzodiazepine use and inappropriate grouping together of benzodiazepines with other medications, precluded definitive conclusions. Future studies should concentrate on these groups to identify the long-term safety of benzodiazepines in these patient groups.

Objectives: To report the case of a patient with diffuse large B-cell lymphoma (DLBCL) who developed vincristine (VCR)-induced seizure after R-CHOP chemotherapy. Case Summary: A 22-year-old boy with DLBCL developed generalized tonic clonic seizures following R-CHOP chemotherapy. After receiving the third cycle of chemotherapy, he developed Aspergillus pneumonia; therefore, itraconazole was started 18 days before the administration of cycle 4 of chemotherapy. Seven days after the administration of the fifth doses of vincristine, the patient reported symptoms of gastrointestinal toxicity (abdominal cramps and constipation). Subsequently, he developed three episodes of generalized tonic-clonic seizure which lasted for 2-3 minutes during one day and became unconsciousness. His serum electrolytes were normal with the exception of low serum sodium (128mEq/L). Blood glucose, blood urea nitrogen, the complete blood count, and a cerebrospinal fluid study were also normal. A computed tomography scan of the brain did not show any abnormalities. He had no previous history of convulsion. Occurrence of seizure due to central nervous system invasion of DLBCL was ruled out with a normal cerebrospinal fluid examination, computed tomography scan, and magnetic resonance imaging of the head. Therefore, the patient's neurotoxicity has been attributed to vincristine, the effects of which were likely potentiated by itraconazole therapy. Discussion: Vincristine is a naturally occurring vinca alkaloid used in various chemotherapy regimens. Neurotoxicity is a known and commonly encountered side effect of vincristine. Peripheral neuropathy is the most common form of vincristine neuropathy whereas central effects are rarer. Enhanced VCR neurotoxicities from drug interactions with several azole antifungals such as itraconazole and voriconazole have been reported. Our case represents a drug possible adverse drug effect based on the Naranjo ADR Probability Scale. Conclusion: Administration of vincristine in conjunction with azole antifungals should be with caution and after carefully considering the risks and benefits. Also, it is important to rule out other causes of seizure in these patients.

Background: Pharmacokinetics (PK), pharmacodynamics and optimal dosing of vancomycin in obese children is not known. Higher trough levels of vancomycin may improve outcomes. This prospective study evaluated the appropriateness of twice-daily regimen for the adherence to guidelines, among obese and non obese children. Methods: Children receiving vancomycin, (20 mg/kg BID) were included. Patients were divided into 3 groups. Adequacy was defined as trough level ≥ 10mg/L and AUC/MIC > 400. An alternative-dosing regimen was calculated based on individual PK parameters. Results: Seventy-seven pairs (trough, peak) were taken from 51 children. Mean trough level was 3.36±2.58, only 3% fell in therapeutic range, no statistical difference was observed between obese, normal weight or underweight groups. One child had an AUC/MIC > 400. All children recovered. Conclusion: PK properties of all weight groups were similar. More frequent and higher doses are needed to achieve the goals of current guidelines.

Angiotensin converting enzyme inhibitors (ACEI) are widely used to treat benign hypertension. These drugs are generally well tolerated. Serious side effects such as angio-oedema are very rare. The authors report a 64-year-old Caucasian woman with a history of liver transplant on Mammalian Target Of Rapamycin (mTOR) inhibitor, who attended Emergency department with angio-oedema only on the left side of her tongue. Her airway was patent and she was haemodynamically stable. Trauma was denied. Her physician had 2 days earlier commenced her on Lisinopril for newly diagnosed benign hypertension. Intravenous steroids and anti-histamine were immediately administered. A good response of oedema subsidence was noted. In general, angio-oedema can present in a spectrum of severity. Precipitating factors are often difficult to pre-determine and avoid. Early recognition of risk factors for and diagnosis of angio-oedema can often be life-saving.

Background: Pharmacovigilance (PV) System is an integral part of drug therapy which helps in detection, monitoring and designing strategies to minimize the occurrence of adverse drug reaction (ADRs). Present study was planned to study the patterns of ADRs in a tertiary care government hospital. Methods: The present study was carried out for a period of one year. Suspected adverse drug reaction reports due to medications submitted to the Department of Pharmacology under the Pharmacovigilance Programme of India were included. The reports were analyzed for their type, severity, organ system involvement, and the causality assessment was performed using Naranjo Probability Scale. Results: A total of 520 ADRs were received. The highest percentage (66.2%) of ADRs was seen in adult patients. Female patients experienced more (57.5%) ADRs. 95% of ADRs occurred in patients receiving 5 or more drugs. Medicine department reported the maximum number (38.46%) of ADRs. Antimicrobial agents (AMA) (35.7%) were the commonest group of drugs causing ADRs. Amongst the organ systems affected, skin constituted a major component (40.4%). Causality assessment revealed that 55% of the ADRs were possible. Majority of the ADRs were non-serious and only 7 cases were serious and required hospitalization. Conclusion: The results suggest that healthcare professionals (HCP) at this institution are cognizant of PV. However a closer liaison between the HCPs and the hospital PV centre, periodic reinforcement of the HCPs regarding the need for PV can further improve spontaneous reporting. The data will also help in designing strategies for framing policies towards safer use of drugs in future.

In the past 10 years there has been an emphasis on the risk of upper gastrointestinal bleeding in patients taking SSRI antidepressants. Few studies have concurrently examined the possible risk of traditional antidepressants or atypical antidepressants such as venlafaxine, classified as a serotonin-norepinephrine reuptake inhibitor. In order to promote debate about possible risk of upper gastrointestinal bleeding in elderly patients taking antidepressants different from SSRIs, we report a case of venlafaxine-induced upper gastrointestinal bleeding in a 84 years old woman. Discussion about safer drugs and protective factors is provided.

A single pill daily fixed dose combination of Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) provides a potent and convenient treatment option for HIV/AIDS. The components have been shown to be well tolerated and are effective in randomized controlled trials. A literature search revealed no case of hepatic failure reported with this drug combination. We here in describe the 1st case of acute hepatic failure developing after 3 months of treatment with EFV/FTC/TDF in a 41 year old African American male without pre-existing liver disease or risk factors.