Using gabapentin to treat neuropathic pain.
(33/2065)
OBJECTIVE: To review use of gabapentin as an adjuvant agent to treat neuropathic pain. QUALITY OF EVIDENCE: MEDLINE was searched from 1995 to October 1998 for reports. There were approximately 20 citations. Additional articles from Pain and other medical journals were reviewed. No double-blind studies have examined gabapentin and its use as an analgesic adjuvant agent. MAIN MESSAGE: Gabapentin is an anticonvulsant medication used recently as an effective adjuvant agent for treating neuropathic pain. It is a structural analogue of gamma-aminobutyric acid (GABA), but its receptor and biochemical function remain unknown. Gabapentin has desirable pharmacokinetic properties and acceptable side effects, which simplify its use. There are very few interactions between gabapentin and other medications, and gabapentin is well tolerated. CONCLUSION: Gabapentin could be an effective adjuvant agent for many neuropathic pain states. (+info)
Evaluation of interaction between gabapentin and ibuprofen on the formalin test in rats.
(34/2065)
BACKGROUND: Gabapentin is active in the regulation of facilitated pain states evoked by tissue injury. The mechanism of this action is believed to be through a specific binding site, likely at the spinal level. Nonsteroidal antiinflammatory drugs have a comparable behavioral profile, although their actions are believed to be mediated by cyclooxygenase inhibition at the spinal level. This study was undertaken to determine the nature of the interaction of these two mechanistically distinct antihyperalgesic agents in rats in a model of facilitated processing, the formalin test. METHODS: The effects of intraperitoneal gabapentin and ibuprofen were examined on flinching behavior and cardiovascular response (mean arterial blood pressure [MABP] and heart rate measured in the tail artery) evoked by the injection of formalin (5%; 50 microl). Their interaction was characterized using an isobolographic analysis. RESULTS: Injection of formalin into the hind paw caused a biphasic flinching and parallel increases in MABP. Gabapentin and ibuprofen produced a limited effect on the flinching in phase 1, but both drugs produced dose-dependent suppression of the flinching observed during phase 2 (gabapentin ED50 = 88 mg/kg; ibuprofen ED50 = 19 mg/kg). Gabapentin similarly showed a dose-dependent suppression of the MABP and heart rate response only during phase 2; ibuprofen showed dose-dependent reduction of MABP response in both phases. The isobolographic analysis carried out using equipotent dose ratios in phase 2 revealed an additive interaction between the two drugs. Neither gabapentin nor ibuprofen affected the baseline cardiovascular measures. CONCLUSION: Gabapentin and ibuprofen independently alter the facilitated state as measured by somatomotor and autonomic response. Together these agents interact in an additive fashion if delivered concurrently. This combination may prove useful in managing postinjury pain states in humans. (+info)
Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.
(35/2065)
BACKGROUND: Safe and effective antiviral agents are needed to prevent infection with influenza A and B virus. Oseltamivir (GS4104), which can be administered orally, is the prodrug of GS4071, a potent and selective inhibitor of influenzavirus neuraminidases. We studied the use of oseltamivir for long-term prophylaxis against influenza in two placebo-controlled, double-blind trials at different U.S. sites during the winter of 1997-1998. METHODS: We randomly assigned 1559 healthy, nonimmunized adults 18 to 65 years old to receive either oral oseltamivir (75 mg given once or twice daily, for a total daily dose of 75 or 150 mg) or placebo for six weeks during a peak period of local influenzavirus activity. The primary end point with respect to efficacy was laboratory-confirmed influenza-like illness (defined as a temperature of at least 37.2 degrees C accompanied by at least one respiratory and at least one systemic symptom). RESULTS: In the two studies combined, the risk of influenza among subjects assigned to either once-daily or twice-daily oseltamivir (1.2 percent and 1.3 percent, respectively) was lower than that among subjects assigned to placebo (4.8 percent; P<0.001 and P=0.001 for the comparison with once-daily and twice-daily oseltamivir, respectively). The protective efficacy of oseltamivir in the two active-treatment groups combined was 74 percent (95 percent confidence interval, 53 to 88 percent) at all the sites combined and 82 percent (95 percent confidence interval, 60 to 93 percent) at sites in Virginia, where the rate of influenza infection was higher than the overall rate. For culture-proved influenza, the rate of protective efficacy in the two oseltamivir groups combined was 87 percent (95 percent confidence interval, 65 to 96 percent). The rate of laboratory-confirmed influenza infection was lower with oseltamivir than with placebo (5.3 percent vs. 10.6 percent, P<0.001). Oseltamivir was well tolerated but was associated with a greater frequency of nausea (12.1 percent and 14.6 percent in the once-daily and twice-daily groups, respectively) and vomiting (2.5 percent and 2.7 percent, respectively) than was placebo (nausea, 7.1 percent; vomiting, 0.8 percent). However, the frequency of premature discontinuation of drug or placebo was similar among the three groups (3.1 to 4.0 percent). CONCLUSIONS: Oseltamivir administered daily for six weeks by the oral route is safe and effective for the prevention of influenza. (+info)
Role of polyamine structure in inhibition of K+-Cl- cotransport in human red cell ghosts.
(36/2065)
1. K+-Cl- cotransport in human red cell ghosts is inhibited by divalent inorganic cations, soluble polycations and amphipathic organic cations. These findings suggest a common mechanism of inhibition, namely, binding of the cations to negative charges at the surface of a hydrophobic structure. 2. We have characterized the inhibitory capacity of a number of polyamines in order to obtain information about the nature of the charges with which they interact. Neomycin inhibited swelling-stimulated cotransport. The diquaternary amines dimethonium and decamethonium were relatively ineffective inhibitors. These compounds are thought to shield negative charges, but not bind to them. 3. Comparison of a homologous series of polyamines indicated that primary amines were better inhibitors than secondary amines, that inhibition increased with the charge of the polyamine, and that inhibition increased as the distance separating the amines increased. 4. The results indicate that the negative charges to which polycations bind are multiple and mobile. Since they must be associated with a hydrophobic environment, it is likely that they are negatively charged phospholipids located in the inner leaflet of the bilayer membrane. 5. Heating red cells or ghosts to 49 C denatures spectrin. Heating markedly increased K+ uptake in swollen ghosts but not in shrunken ghosts. The increase in uptake was reversed when swollen ghosts were shrunk even though denaturation of spectrin was not reversed. Polyamines, which inhibited swelling-activated K+ uptake in control ghosts, similarly inhibited the increased uptake in heated ghosts. 6. We speculate that spectrin, which is closely associated with the inner bilayer leaflet, shields negative charges in a volume-dependent manner and so regulates volume-sensitive K+ transport. (+info)
Heterocyclic aromatic amines (HAs) represent a class of potent bacterial mutagens and rodent carcinogens which gain their biological activity upon metabolic conversion by phase I and phase II enzymes. Subsequent to cytochrome P450 (CYP)-dependent hydroxylation, mainly catalyzed by CYP1A2, acetylation mediated by the activity of N-acetyltransferase, NAT2, produces the ultimate electrophilic product that may react with DNA. In addition to point mutations observed in HA-exposed cells as genotoxic endpoint in vitro, loss of heterozygosity (LOH) has often been identified in HA-related rodent tumors as another endpoint in vivo. LOH may reflect a chromosomal deletion, a chromosome loss or a previous mitotic recombination event and it represents a prominent mechanism for the inactivation of tumor suppressor alleles. In this study we have investigated whether LOH observed in several HA-induced rodent tumors is related to a recombinogenic activity of HA compounds, and to address this question we have studied the genotoxic activity of several HAs in metabolically competent Saccharomyces cerevisiae strains. For this purpose expression vectors have been constructed providing simultaneous expression of three human enzymes, CYP1A2, NADPH-cytochrome P450 oxidoreductase and NAT2 in different genotoxicity tester strains. Evidence for functional expression of all three enzymes has been obtained. One strain allowed us to monitor HA-induced gene conversion, another one HA-induced chromosomal translocation. A third strain allowed us to study HA-induced forward mutations in the endogenous URA3 gene. It was found that 2-amino-3-methylimidazo-[4,5-f]quinoline and 2-amino-3, 8-dimethylimidazo-[4,5-f]quinoxaline produced a strong recombinogenic response in either recombination tester strain. The recombinogenic activity was comparable with the mutagenic activity of the compounds. The other HAs, 2-amino-3, 4-dimethyl-imidazo-[4, 5-f]quinoline, 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole, 2-aminodipyrido-[1,2-a:3', 2'-d]imidazole, 3-amino-1-methyl-5H pyrido-[4,3-b]indole and 2-amino-1-methyl-6-phenyl-imidazo-[4, 5-b]pyridine, produced weak or no increases in the genotoxic endpoints of interest. The described strains may provide a suitable tool to characterize the genotoxic potential of HAs in more detail. (+info)
O-phthalaldehyde: fluorogenic detection of primary amines in the picomole range. Comparison with fluorescamine and ninhydrin.
(38/2065)
O-Phthalaldehyde, in the presence of 2-mercaptoethanol, reacts with primary amines to form highly fluorescent products. Picomole quantities of amino acids, peptides, and proteins can be detected easily. o-Phthalaldehyde is five to ten times more sensitive than fluorescamine and is soluble and stable in aqueous buffers. (+info)
Structure of a soluble super-active insulin is revealed by the nature of the complex between cyanogen-bromide-activated sepharose and amines.
(39/2065)
Insulin-like material with elevated insulin specific acitivity is released from insulin-Sepharose in the presence of bovine-serum albumin. The mechanism of release and the chemical nature of this insulin-like material are revealed by the finding that amine-Sepharose is O-Sepharose-N-substituted isourea. Nucleophilic attack by amino groups releases N-1-N-2-disubstituted guanidines. Correspondingly, it is shown that the super-active insulin-like material is an N-1-N-2-disubstituted guanidine in which insulin and bovine-serum albumin are the substituents. (+info)
Pulmonary inflammation alters the lung disposition of lipophilic amine indicators.
(40/2065)
Many lipophilic amine compounds are rapidly extracted from the blood on passage through the pulmonary circulation. The extent of their extraction in normal lungs depends on their physical-chemical properties, which affect their degree of ionization, lipophilicity, and propensity for interacting with blood and tissue constituents. The hypothesis of the present study was that changes in the tissue composition that occur during pulmonary inflammation would have a differential effect on the pulmonary extraction of lipophilic amines having different properties. If so, measurement of the extraction patterns for a group of lipophilic amines, having different physical-chemical properties, might provide a means for detecting and identifying lung tissue abnormalities. To evaluate this hypothesis, we measured the pulmonary extraction patterns for four lipophilic amines, [(14)C]diazepam, [(3)H]alfentanil, [(14)C]lidocaine, and [(14)C]codeine, along with two hydrophilic compounds, (3)HOH and [(14)C]phenylethylamine, after the bolus injection of these indicators into the pulmonary artery of isolated lungs from normal rabbits and from rabbits with pulmonary inflammation induced by an intravenous injection of complete Freund's adjuvant. The pulmonary extraction patterns, parameterized using a previously developed mathematical model, were, in fact, differentially altered by the inflammatory response. For example, the tissue sequestration rate, k(seq) (ml/s), per unit (3)HOH accessible extravascular lung water volume significantly increased for diazepam and lidocaine, but not for codeine and alfentanil. The results are consistent with the above hypothesis and suggest the potential for using lipophilic amines as indicators for detection and quantification of changes in lung tissue composition associated with lung injury and disease. (+info)