Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new tagamet research articles will be listed here shortly after becoming available to us.
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Medical research on tagamet
Dig Dis Sci. 2008 Jul 2;
Murashima Y, Kotani T, Hayashi S, Komatsu Y, Nakagiri A, Amagase K, Takeuchi K
We investigated the influence of 5-fluorouracil (5-FU), an anti-tumor agent, on the healing of gastric lesions generated by 0.6 M HCl in rats and the effect of lafutidine, a histamine H(2) receptor antagonist, on the impaired healing. Animals fasted for 18 h were given 1 ml of 0.6 M HCl p.o., fed normally from 1 h later, and killed 1-96 h thereafter. 5-FU was given i.v. twice, 1 h and 24 h after the HCl. The gastric lesions healed spontaneously within 96 h. Although it decreased acid secretion, 5-FU markedly delayed the healing. Lafutidine, but not cimetidine, given p.o. immediately after each dosing of 5-FU significantly reversed the delay in healing by 5-FU, and this effect was attenuated by the chemical ablation of capsaicin-sensitive afferent neurons. Capsaicin also significantly reversed the delay in healing. The mucosal application of 50 mM HCl did not affect gastric mucosal blood flow (GMBF) in the normal stomach, but significantly increased it in the stomach damaged by 0.6 M HCl. The increases in GMBF were attenuated by 5-FU; however, the co-administration of lafutidine significantly restored the response. In addition, 5-FU inhibited both cell proliferation and migration in rat gastric epithelial cells (RGM1) in vitro. These results suggest that 5-FU delayed the healing of gastric lesions generated by 0.6 M HCl, probably through the inhibition of cell migration and proliferation, as well as the impairment of GMBF, and lafutidine reversed the delay in healing, mainly through the amelioration of the GMBF response mediated by capsaicin-sensitive afferent neurons.
A mechanism for the inhibition of neural progenitor cell proliferation by cocaine.
PLoS Med. 2008 Jun 10; 5(6): e117
Lee CT, Chen J, Hayashi T, Tsai SY, Sanchez JF, Errico SL, Amable R, Su TP, Lowe RH, Huestis MA, Shen J, Becker KG, Geller HM, Freed WJ
BACKGROUND: Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation. METHODS AND FINDINGS: Microarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum (ER) stress response, as indicated by increased phosphorylation of eIF2alpha and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A. CONCLUSIONS: Our results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development.
Successful treatment of florid cutaneous warts with intravenous cidofovir in an 11-year-old girl.
Pediatr Dermatol. 2008 May-Jun; 25(3): 387-9
Cusack C, Fitzgerald D, Clayton TM, Irvine AD
Cutaneous warts, commonly seen in children and the immunosuppressed are socially distressing and are often resistant to traditional treatments. Here, we report an 11-year-old girl with bilateral florid verrucous lesions on her hands, feet and chin, which were refractory to a number of standard treatments including cryotherapy, cantharidin preparations, topical salicylic acid, surgical debulking techniques, oral Cimetidine, and topical and intralesional Cidofovir. As the disfiguring lesions had a marked adverse effect on her quality of life, a trial of IV Cidofovir was instituted. We administered five cycles of IV Cidofovir with a 1-week interval between the first and second treatment, followed by 2-week intervals thereafter. This regime was well tolerated and we report dramatic resolution of the lesions with persistent clearance 6 months after completion of the fifth infusion. Resolution of recalcitrant warts with IV Cidofovir has been reported in a limited number of cases. Our experience supports its efficacy in this setting, and to the best of our knowledge this is the first report of successful treatment of cutaneous warts with IV Cidofovir in a pediatric case.
Eur J Pharmacol. 2008 May 27;
Campbell CA, Gaskin PJ, Darton J, Chiu P, Lee K, McLean PG
Identification of novel drug molecules requires the extensive evaluation in vitro and in vivo. Following in vitro evaluation it is necessary to efficiently screen numerous novel molecules in vivo using relatively simple methodology that requires small numbers of animals, is rapid to perform, and provides results that can definitely discriminate potential candidates for further investigation. Herein, we describe the results of three standard compounds (omeprazole, a proton pump inhibitor; cimetidine, an histamine H(2) receptor antagonist; and AR-H047108, a potassium competitive acid blocker) in the rat aspiration model (under both basal and stimulated conditions), and compared the effects with those in the pyloric ligation model with a view to comparing the results in terms of sensitivity, robustness and simplicity of the methodology. In the aspiration model, drug or vehicle was administered orally 1 h prior to administration of pentagastrin or dimaprit. Ten minutes later 0.9% NaCl was administered orally and immediately recovered by aspiration. In the pyloric ligation model, drugs or vehicle were administered orally 2 h before ligation in a volume of 10 ml/kg. For each model, the volume of each sample was measured and the acidity was determined. In the aspiration model under basal acid secretion or following stimulation with pentagastrin omeprazole, cimetidine and AR-H047108 produced dose related inhibition of acidity. Omeprazole and cimetidine inhibited acid secretion following stimulation with dimaprit. In the pyloric ligation model omeprazole, cimetidine and AR-H047108 inhibited acid secretion. The profile of each of 3 inhibitors of acid secretion exhibited similar effects irrespective of the degree of stimulation (dimaprit, pentagastrin or pyloric ligation). Thus, based on these robust effects and ease of methodology we would recommend the use of the rat aspiration model with pentagastrin stimulation of gastric acid secretion as the primary in vivo methodology to screen novel inhibitors of acid secretion.
Sheng Li Xue Bao. 2008 Jun 25; 60(3): 397-402
Qi Y, Qian ZB, Wu ZH
The present study was carried out to determine the role of histamine H(1) and H(2) receptors in the generation of basic respiratory rhythm. Neonatal (aged 0-3 d) Sprague-Dawley rats of either sex were used. The medulla oblongata slice containing the medial region of the nucleus retrofacialis (mNRF) and the hypoglossal nerve rootlets was prepared and the surgical procedure was performed in the modified Kreb's solution (MKS) with continuous carbogen (95% O2 and 5% CO2), and ended in 3 min. Respiratory rhythmical discharge activity (RRDA) of the rootlets of hypoglossal nerve was recorded by suction electrode. Thirty medulla oblongata slice preparations were divided into 5 groups. In groups I, II and III, histamine (5 mumol/L), H(1) receptor specific antagonist pyrilamine (10 mumol/L) and H(2) receptor specific antagonist cimetidine (5 mumol/L) was added into the perfusion solution for 15 min separately. In group IV, after application of histamine for 15 min, additional pyrilamine was added into the perfusion for another 15 min. In group V, after application of histamine for 15 min, additional cimetidine was added into the perfusion for another 15 min. The discharges of the roots of hypoglossal nerve were recorded. Signals were amplified and band-pass filtered (100-3.3 kHz). Data were sampled (1-10 kHz) and stored in the computer via BL-420 biological signal processing system. Our results showed that histamine significantly decreased the respiratory cycle (RC) and expiratory time (TE), but changes of integral amplitude (IA) and inspiratory time (TI) were not statistically significant. Pyrilamine induced significant increases in RC and TE, but changes of TI and IA were not statistically significant. Cimetidine had no effects on RC, TE, TI and IA of RRDA. The effect of histamine on the respiratory rhythm was reversed by additional application of pyrilamine but not cimetidine. Taken together, with the results mentioned above, histamine H(1) receptors but not H(2) receptors may play an important role in the modulation of RRDA in the medulla oblongata slice preparation of neonatal rats.
OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine.
Pharmacogenet Genomics. 2008 Jul; 18(7): 637-45
Wang ZJ, Yin OQ, Tomlinson B, Chow MS
PURPOSE: Genetic polymorphisms of organic cation transporter 2 (OCT2) have been recently described, but their genotype-phenotype relationship in humans is unknown. We performed this study to (i) characterize genetic variations of the OCT2 gene in the Chinese population and (ii) investigate the potential functional significance of OCT2 polymorphisms using metformin (an OCT2 substrate) alone or in the presence of its transport inhibitor (cimetidine). METHOD: Direct sequencing of all OCT2 exons and the surrounding introns was performed using genomic DNA from 112 healthy Chinese participants. To evaluate the potential functional change of a common 808G>T variant (Ala270Ser) identified in this population, 15 healthy participants with different 808G>T mutation status were recruited in a pharmacokinetic study of metformin with or without cimetidine. RESULTS: A total of 14 genetic variants were identified and 13 had frequency more than 1%. The renal tubular clearance (CLt) of metformin averaged 8.78+/-1.75, 7.68+/-0.672, and 6.32+/-0.954 ml/min/kg for participants with GG (n=6), GT (n=5), and TT (n=4) genotypes, respectively (P=0.037, one-way analysis of variance). In the presence of cimetidine, metformin CLt was decreased in all participants, but the decrease was significantly lower in TT than GG group (18.7 vs. 48.2%, P=0.029). CONCLUSION: Our study results demonstrated for the first time the existence of genetic polymorphisms of OCT2 in the Chinese population, and further showed that the 808G>T polymorphism is associated with a reduced metformin renal or tubular clearance. Moreover, the inhibition of metformin renal tubular secretion by cimetidine also appeared to be dependent on this mutation.
Ontogenetic Noradrenergic Lesion Alters Histaminergic Activity in Adult Rats.
Neurotox Res. 2008 Apr; 13(2): 79-83
Nowak P, Jochem J, Zwirska-Korczala K, Josko J, Noras L, Kostrzewa RM, Brus R
To determine whether noradrenergic nerves might have a modulatory role on the sensitivity or reactivity of histaminergic receptor systems in brain, behavioral effects of the respective histamine H1, H2 and H3 antagonists S(+)chlorpheniramine, cimetidine and thioperimide in control adult rats were compared to the effects in adult rats that had been lesioned as neonates with the noradrenergic neurotoxin DSP-4. On the 1st and 3rd days after birth rat pups were treated with either saline or DSP-4 (50 mg/kg sc), then returned to their home cages with the dam. At 8 weeks when rats were tested, S(+)chlorpheniramine (10 mg/kg ip) was found to increase locomotor activity in intact and DSP-4 lesioned rats, while cimetidine (5 mg/kg, ip) and thioperimide (5 mg/kg, ip) increased activity several-fold solely in the DSP-4 group. Exploratory activity, nociceptive activity, and irritability were little altered by the histamine antagonists, although oral activity was increased by thioperimide in intact and lesioned rats, and by cimetidine or S(+)chlorpheniramine in DSP-4 rats. High performance liquid chromatography with electrochemical detection was used to determine that DSP-4 produced a 90% reduction in frontal cortex, hippocampus and hypothalamus, with a 90% elevation of NE in cerebellum - reflecting reactive sprouting of noradrenergic fibers consequent to lesion of noradrenergic tracts projecting to proximal brain regions. These findings indicate that perinatal noradrenergic fiber lesioning in rat brain is associated with an altered behavioral spectrum by histamine H1, H2 and H3 receptor antagonists, thereby implicating histaminergic systems as modulators of noradrenergic systems in brain.
Mol Endocrinol. 2008 May 29;
Willets JM, Taylor AH, Shaw H, Konje JC, Challiss RA
Histamine stimulates uterine contraction, however little is known regarding the mechanism or regulation of uterine histamine receptor signaling. Here we investigated the regulation of Galphaq/11-coupled histamine receptor signaling in human myometrial smooth muscle cells using the inositol 1,4,5-trisphosphate (IP3) biosensor eGFP-PHPLCdelta and the Ca(2+)-sensitive dye Fluo-4. Histamine addition caused concentration-dependent increases in IP3 and [Ca(2+)]i in the ULTR human uterine smooth muscle cell line and primary human myometrial cells. These effects were completely inhibited by the H1 histamine receptor antagonist, diphenhydramine, and were unaffected by the H2 histamine receptor antagonist, cimetidine. ULTR and primary myometrial cells were transfected with either dominant-negative G protein-coupled receptor kinases (GRKs) or siRNAs targeting specific GRKs to assess the roles of this protein kinase family in H1 histamine receptor desensitization. Dominant-negative GRK2, but not GRK5 or GRK6, prevented H1 histamine receptor desensitization. Similarly, transfection with siRNAs (that each caused > 70% depletion of the targeted GRK) for GRK2, but not GRK3 or GRK6, also prevented H1 histamine receptor desensitization. Our data suggest that histamine stimulates phospholipase C-signaling in myometrial smooth muscle cells through H1 histamine receptors and that GRK2 recruitment is a key mechanism in the regulation of H1 histamine receptor signaling in human uterine smooth muscle. These data provide insights into the in situ regulation of this receptor subtype and may inform pathophysiological functioning in pre-term labor and other conditions involving uterine smooth muscle dysregulation.
Pharmacotherapy for Inappropriate Sexual Behaviors in Dementia: A Systematic Review of Literature.
Am J Alzheimers Dis Other Demen. 2008 May 28;
Ozkan B, Wilkins K, Muralee S, Tampi RR
The aim of this study is to systematically review the published literature on pharmacotherapy for inappropriate sexual behaviors in dementia. Literature search of the 5 databases (PubMed, MEDLINE, EMBASE, PsychINFO, and COCHRANE collaboration) and the analysis of the data available for the pharmacotherapeutic treatments of inappropriate sexual behaviors in dementia were carried out.There are no published randomized controlled trials of pharmacotherapy for inappropriate sexual behaviors in dementia, but available data from uncontrolled trials, case series, and individual case reports suggest efficacy for antidepressants, antipsychotics, mood stabilizers, hormonal agents, cimetidine, and pindolol for the treatment of these behaviors. Although there are no controlled data for the treatment of inappropriate sexual behaviors in dementia, available data suggest efficacy for some commonly used pharmacotherapeutic agents.
Biochem Biophys Res Commun. 2008 Aug 1; 372(3): 491-6
Wang J, Su B, Ding Z, Du X, Wang B
Cimetidine (CIM), a histamine 2-receptor antagonist, is postulated to enhance immune responses owing to its inhibitory effects on suppressor T cells. In this report, we evaluated effects of cimetidine on the potency of antigen-specific immunity generated by DNA vaccine encoding hepatitis B surface antigen (HBsAg, pcD-S2). Our data demonstrate that CIM as adjuvant significantly increased HBsAg-specific cell-mediated and humoral immunities that were characterized by higher Ig2a/IgG1 ratio. In addition, CIM significantly promotes an elevated level of IL-4 and IFN-gamma in antigen-specific CD4(+) T cells and a robust antigen-specific cytotoxic response in the animals immunized with pcD-S2 plus CIM. Further, CIM induces pro-inflammatory cytokine expression such as the IL-12 and down-regulates anti-inflammatory cytokine expression such as IL-10 and TGF-beta, which may lead to an impairment of CD4(+)CD25(+) Treg cell-mediated suppression. Collectively these findings suggest that CIM enhances the immune responses of HBV DNA vaccine through the stimulation of pro-inflammatory and inhibition of anti-inflammatory cytokine expression patterns.