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otenet.gr
In continuous ambulatory peritoneal dialysis (CAPD) patients, acyclovir-induced neurotoxicity is reported to be associated with high serum drug levels even when following the recommended reduced doses for this renal failure population. In view of the high oral bioavailability of valaciclovir (the L-valyl ester of acyclovir) the risk of neurotoxicity becomes more prominent. The present study was conducted in 12 CAPD patients who were administered a single oral dose of 500 mg valaciclovir. Acyclovir was analyzed by high-performance liquid chromatography. Relative pharmacokinetic parameters were estimated based on acyclovir concentrations at 8, 12 and 24 h post-dose. High inter-patient variations were observed with acyclovir apparent total clearance 7.238 +/- 4 l/h and half-life (T1/2) 22.27 +/- 16.82 h. However, dosage simulations confirmed supratherapeutic acyclovir concentrations for all participants when following the recommended dose of 1,000 mg valaciclovir/24 h for varicella zoster infections. Copyright 2002 S. Karger AG, Basel
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12021536&dopt=Abstract
virginia.edu
The clinician must maintain a high level of suspicion for central nervous system infections even if not all of the classic signs are present, because prompt treatment may make a difference in patient outcome. If bacterial meningitis is suspected, a CT scan of the head should be obtained prior to lumbar puncture if there is papilledema, a focal neurologic exam, or if the patient is comatose. In bacterial meningitis, empiric antibiotics should be chosen based on a patient's risk factors and should be started immediately. Depending on the resistance patterns of the institution, Streptococcus pneumoniae may be resistant to penicillins and cephalosporins. Corticosteroids are of uncertain benefit in bacterial meningitis and may decrease the penetration of antibiotics into the central nervous system. The dosage for acyclovir treatment in herpes simplex encephalitis is 10 to 15mg/kg every 8 hours. Subdural empyema is a neurosurgical emergency. Brain abscesses should be surgically drained if they exceed 2.5 centimeters.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12036506&dopt=Abstract [PubMed - as supplied by publisher]
J Biol Chem. 2002 Aug 16;277(33):30236-43. Epub 2002 May 29.
Structural characterization of the closed conformation of mouse guanylate kinase.
Sekulic N, Shuvalova L, Spangenberg O, Konrad M, Lavie A.
University of Illinois at Chicago, Department of Biochemistry and Molecular Biology, Chicago, Illinois 60612 and the Max Planck Institute for Biophysical Chemistry, Department of Molecular Genetics, Am Fassberg 11, 37077 Gottingen, Germany.
Guanylate kinase (GMPK) is a nucleoside monophosphate kinase that catalyzes the reversible phosphoryl transfer from ATP to GMP to yield ADP and GDP. In addition to phosphorylating GMP, antiviral prodrugs such as acyclovir, ganciclovir, and carbovir and anticancer prodrugs such as the thiopurines are dependent on GMPK for their activation. Hence, structural information on mammalian GMPK could play a role in the design of improved antiviral and antineoplastic agents. Here we present the structure of the mouse enzyme in an abortive complex with the nucleotides ADP and GMP, refined at 2.1 A resolution with a final crystallographic R factor of 0.19 (R(free) = 0.23). Guanylate kinase is a member of the nucleoside monophosphate (NMP) kinase family, a family of enzymes that despite having a low primary structure identity share a similar fold, which consists of three structurally distinct regions termed the CORE, LID, and NMP-binding regions. Previous studies on the yeast enzyme have shown that these parts move as rigid bodies upon substrate binding. It has been proposed that consecutive binding of substrates leads to "closing" of the active site bringing the NMP-binding and LID regions closer to each other and to the CORE region. Our structure, which is the first of any guanylate kinase with both substrates bound, supports this hypothesis. It also reveals the binding site of ATP and implicates arginines 44, 137, and 148 (in addition to the invariant P-loop lysine) as candidates for catalyzing the chemical step of the phosphoryl transfer.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12036965&dopt=Abstract
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