Response to Modified Antitubercular Drug Regime and Antiretroviral Therapy in a Case of HIV Infection With Disseminated Tuberculosis With Isoniazid Induced Toxic Epidermal Necrolysis.

Response to Modified Antitubercular Drug Regime and Antiretroviral Therapy in a Case of HIV Infection with Disseminated Tuberculosis with Isoniazid Induced Toxic Epidermal Necrolysis.

Filed under: Drug and Alcohol Rehabilitation

Case Rep Infect Dis. 2012; 2012: 626709
Swami A, Gupta B, Bhattacharjee P

Toxic epidermal necrolysis (TEN) is a potentially life-threatening disorder characterized by widespread erythema, necrosis, and bullous detachment of the epidermis and mucous membranes. Without proper management,TEN can cause sepsis leading to death of the patient. Though TEN is commonly drug induced, Isoniazid (INH) has been uncommonly associated with TEN. As INH is one of the first line drugs in treatment of tuberculosis, TEN induced INH needs modification of antitubercular therapy (ATT) with withdrawal of INH from the treatment regime along with other supportive treatments. Patients with HIV infection and disseminated tuberculosis need to be urgently initiated on an effective ATT on diagnosis of tuberculosis. However, if the patient develops potential life-threatening toxicity to first line antitubercular drugs like INH, an alternative effective ATT combination needs to be started as soon as the condition of the patient stabilizes as most of these patients present in advanced stage of HIV infection and this is to be followed by antiretroviral therapy (ART) as per guidelines. The present case reports the effectiveness of an ATT regime comprising Rifampicin, Pyrazinamide, Ethambutol, and Levofloxacin along with ART in situations where INH cannot be given in disseminated tuberculosis in HIV patients.
HubMed – drug

Combination of infliximab and high-dose intravenous immunoglobulin for toxic epidermal necrolysis: successful treatment of an elderly patient.

Filed under: Drug and Alcohol Rehabilitation

Case Rep Dermatol Med. 2012; 2012: 915314
Patmanidis K, Sidiras A, Dolianitis K, Simelidis D, Solomonidis C, Gaitanis G, Bassukas ID

Toxic epidermal necrolysis (TEN) is a rare, severe cutaneous adverse drug reaction with average mortality 25-35%, especially among elderly multimorbid patients. Established therapeutic guidelines do not exist and controversies underlie many of the presently suggested treatment regimens. Herein we present the use of the recently described combination scheme of methylprednisolone (500?mg methylprednisolone bolus i.v.) followed by infliximab (5?mg/kg i.v.) and high-dose intravenous immunoglobulin (2?g/kg over 5 days) to treat an elderly, 74-year-old female patient with TEN (SCORTEN 3) within the premises of a district hospital. Already from the second day of hospitalization the skin condition markedly stabilized and the patient’s status improved rapidly thereafter. She was discharged after 19 days in stationary care in excellent general condition and remained without any sequels 9 months afterwards. The present paper further supports the feasibility, efficacy, and safety of the proposed combination modality for the treatment of elderly patients with TEN, a population susceptible to more severe TEN.
HubMed – drug

The Interface between BCR-ABL-Dependent and -Independent Resistance Signaling Pathways in Chronic Myeloid Leukemia.

Filed under: Drug and Alcohol Rehabilitation

Leuk Res Treatment. 2012; 2012: 671702
Nestal de Moraes G, Souza PS, Costas FC, Vasconcelos FC, Reis FR, Maia RC

Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML.
HubMed – drug

Chemical Modification of the M(1) Agonist VU0364572 Reveals Molecular Switches in Pharmacology and a Bitopic Binding Mode.

Filed under: Drug and Alcohol Rehabilitation

ACS Chem Neurosci. 2012 Dec 19; 3(12): 1025-36
Digby GJ, Utley TJ, Lamsal A, Sevel C, Sheffler DJ, Lebois EP, Bridges TM, Wood MR, Niswender CM, Lindsley CW, Conn PJ

We previously reported the discovery of VU0364572 and VU0357017 as M(1)-selective agonists that appear to activate M(1) through actions at an allosteric site. Previous studies have revealed that chemical scaffolds for many allosteric modulators contain molecular switches that allow discovery of allosteric antagonists and allosteric agonists or positive allosteric modulators (PAMs) based on a single chemical scaffold. Based on this, we initiated a series of studies to develop selective M(1) allosteric antagonists based on the VU0364572 scaffold. Interestingly, two lead antagonists identified in this series, VU0409774 and VU0409775, inhibited ACh-induced Ca(2+) responses at rat M(1-5) receptor subtypes, suggesting they are nonselective muscarinic antagonists. VU0409774 and VU0409775 also completely displaced binding of the nonselective radioligand [(3)H]-NMS at M(1) and M(3) mAChRs with affinities similar to their functional IC(50) values. Finally, Schild analysis revealed that these compounds inhibit M(1) responses through a fully competitive interaction at the orthosteric binding site. This surprising finding prompted further studies to determine whether agonist activity of VU0364572 and VU0357017 may also engage in previously unappreciated actions at the orthosteric site on M(1). Surprisingly, both VU0364572 and VU0357017 completely displaced [(3)H]-NMS binding to the orthosteric site of M(1)-M(5) receptors at high concentrations. Furthermore, evaluation of agonist activity in systems with varying levels of receptor reserve and Furchgott analysis using a cell line expressing M(1) under control of an inducible promotor was consistent with an action of these compounds as weak orthosteric partial agonists of M(1). However, consistent with previous studies suggesting actions at a site that is distinct from the orthosteric binding site, VU0364572 or VU0357017 slowed the rate of [(3)H]-NMS dissociation from CHO-rM(1) membranes. Together, these results suggest that VU0364572 and VU0357017 act as bitopic ligands and that novel antagonists in this series act as competitive orthosteric site antagonists.
HubMed – drug

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