Effect of cimetidine and ranitidine on bronchial reactivity in patients with asthma

The results of studies on the effect of cimetidine and ranitidine on the bronchial reactivity in a group of 10 patients with atopic bronchial asthma are discussed. The patients received 800 mg of cimetidine daily for 6 days and, after a three-day interval, 300 mg of ranitidine daily for a further 6 days. Bronchial reactivity was determined with the histamine test, according to Spector and Farr, before the administration of each drug and on the third and sixth days of each course of the treatment. A comparison of the effect of cimetidine and ranitidine on the bronchial reactivity in the same patients revealed that a 3-day exposure to each of the two drugs, cimetidine enhanced bronchial reactivity to a greater extent than ranitidine; the difference between the action of the two drugs being statistically significant (p less than 0.05). Bronchial reactivity was found to increase significantly after a 6-day treatment with each of the drugs but no statistically significant differences were noted comparing the effect of these drugs.     

Effects of cimetidine and ranitidine on high density lipoprotein cholesterol concentrations.

To assess the effect of cimetidine and ranitidine on high density lipoprotein (HDL) cholesterol concentration two groups of eight patients with duodenal ulcer or oesophagitis matched for age, sex, and cigarette consumption were given either cimetidine 1 g daily or ranitidine 300 mg daily for one month. There was no significant change in the cholesterol content of HDL and its subfraction HDL3 after treatment with ranitidine or cimetidine, or in the cholesterol content of the subfraction HDL2 after treatment with ranitidine; the HDL2 cholesterol concentration was, however, significantly increased after treatment with cimetidine. Further studies are being undertaken to establish the mechanism of this effect.     

Effect of cimetidine, ranitidine and omeprazole on postprandial gastrin and somatostatin release in conscious dogs

During a first series of experiments, the gastrin responses to a meal were measured and compared to the responses seen after administration of cimetidine (2.5 mg/kg/h) or omeprazole (2 mg/kg). During a second series of experiments the effects of cimetidine (2.5 mg/kg/h), ranitidine (0.5 mg/kg/h) and omeprazole (2 mg/kg) on post-prandial gastrin and somatostatin release were determined in experiments during which the intragastric pH was maintained close to 6.4. During a third series of experiments, the effects of cimetidine (2.5 mg/kg/h) and omeprazole (2 mg/kg) on basal gastrin and somatostatin release were estimated. Postprandial gastrin release was increased by cimetidine and by omeprazole. When acidification of the gastric content was prevented by intragastric titration, postprandial gastrin release was increased by about 100%. No further increase was observed when the animals were concomitantly treated with cimetidine, ranitidine or omeprazole. Intragastric titration did not alter postprandial somatostatin release. Concomitant administration of H2 blockers decreased the somatostatin response to the meal, while concomitant administration of omeprazole did not alter this release. No significant changes were observed in basal gastrin or somatostatin levels after administration of cimetidine or omeprazole.(ABSTRACT TRUNCATED AT 250 WORDS)     

Simple and universal HPLC-UV method to determine cimetidine, ranitidine, famotidine and nizatidine in urine: application to the analysis of ranitidine and its metabolites in human volunteers

A validated, simple and universal HPLC-UV method for the determination of cimetidine, famotidine, nizatidine and ranitidine in human urine is presented. This is the first single HPLC method reported for the analysis of all four H(2) antagonists in human biological samples. This method was also utilized for the analysis of ranitidine and its metabolites in human urine. All calibration curves showed good linear regression (r(2)>0.9960) within test ranges. The method showed good precision and accuracy with overall intra- and inter-day variations of 0.2-13.6% and 0.2-12.1%, respectively. Separation of ranitidine and its metabolites using this assay provided significantly improved resolution, precision and accuracy compared to previously reported methods. The assay was successfully applied to a human volunteer study using ranitidine as the model compound.     

Differences in electrostatic properties at antibody-antigen binding sites: implications for specificity and cross-reactivity

Antibodies HyHEL8, HyHEL10, and HyHEL26 (HH8, HH10, and HH26, respectively) recognize highly overlapping epitopes on hen egg-white lysozyme (HEL) with similar affinities, but with different specificities. HH8 binding to HEL is least sensitive toward mutations in the epitope and thus is most cross-reactive, HH26 is most sensitive, whereas the sensitivity of HH10 lies in between HH8 and HH26. Here we have investigated intra- and intermolecular interactions in three antibody-protein complexes: theoretical models of HH8-HEL and HH26-HEL complexes, and the x-ray crystal structure of HH10-HEL complex. Our results show that HH8-HEL has the lowest number and HH26-HEL has the highest number of intra- and intermolecular hydrogen bonds. The number of salt bridges is lowest in HH8-HEL and highest in HH26-HEL. The binding site salt bridges in HH8-HEL are not networked, and are weak, whereas, in HH26-HEL, an intramolecular salt-bridge triad at the binding site is networked to an intermolecular triad to form a pentad. The pentad and each salt bridge of this pentad are exceptionally stabilizing. The number of binding-site salt bridges and their strengths are intermediate in HH10-HEL, with an intramolecular triad. Our further calculations show that the electrostatic component contributes the most to binding energy of HH26-HEL, whereas the hydrophobic component contributes the most in the case of HH8-HEL. A "hot-spot" epitope residue Lys-97 forms an intermolecular salt bridge in HH8-HEL, and participates in the intermolecular pentad in the HH26-HEL complex. Mutant modeling and surface plasmon resonance (SPR) studies show that this hot-spot epitope residue contributes significantly more to the binding than an adjacent epitope residue, Lys-96, which does not form a salt bridge in any of the three HH-HEL complexes. Furthermore, the effect of mutating Lys-97 is most severe in HH26-HEL. Lys-96, being a charged residue, also contributes the most in HH26-HEL among the three complexes. The SPR results on these mutants also highlight that the apparent "electrostatic steering" on net on rates actually act at post-collision level stabilization of the complex. The significance of this work is the observed variations in electrostatic interactions among the three complexes. Our work demonstrates that higher electrostatics, both as a number of short-range electrostatic interactions and their contributions, leads to higher binding specificity. Strong salt bridges, their networking, and electrostatically driven binding, limit flexibilities through geometric constrains. In contrast, hydrophobic driven binding and low levels of electrostatic interactions are associated with conformational flexibility and cross-reactivity.     

Habitat conditions at beaver settlement sites: implications for beaver restoration projects

Recognition that beavers are integral components of stream ecosystems has resulted in an increase in beaver‐mediated habitat restoration projects. Beaver restoration projects are frequently implemented in degraded stream systems with little or no beaver activity. However, selection of restoration sites is often based on habitat suitability research comparing well‐established beaver colonies to unoccupied stream sections or abandoned colonies. Because beavers dramatically alter areas they occupy, assessing habitat conditions at active colonies may over‐emphasize habitat characteristics that are modified by beaver activity. During 2015–2017, we conducted beaver activity surveys on streams in the upper Missouri River watershed in southwest Montana, United States, to investigate habitat selection by beavers starting new colonies in novel areas. We compared new colony locations in unmodified stream segments to unsettled segments to evaluate conditions that promoted colonization. Newly settled stream segments had relatively low gradients (β ± SE = ?0.72 ± 0.27), narrow channels (β = ?1.31 ± 0.46), high channel complexity (β = 0.76 ± 0.42), high canopy cover of woody riparian vegetation (β = 0.56 ± 0.21), and low‐lying areas directly adjacent to the stream (β = 0.36 ± 0.24), where β denotes covariate effect sizes. Habitat selection patterns differed between our new settlement site analysis and an analysis of occupied versus unoccupied stream segments, suggesting that assessing habitat suitability based on active colonies may result in misidentification of suitable site conditions for beaver restoration. Our research provides recommendations for beaver restoration practitioners to select restoration sites that will have the highest probability of successful colony establishment.     

Effect of H2-receptor antagonists, cimetidine and ranitidine on reproductive functions in male mice.

Na+,K(+)-ATPase and Ca(2+)-ATPase in testis were inhibited with an oral administration of cimetidine and ranitidine. Cimetidine at dose level of 100 and 30 mg while ranitidine at 70 and 10 mg per kg body wt inhibited the enzyme activities, 24 hr after single administration or daily administration for 15-days. Mg(2+)-ATPase activity was increased with cimetidine while ranitidine inhibited the enzyme. Michaelis-Menten kinetic characteristics revealed mixed type of inhibition for Na+,K(+)-ATPase with cimetidine, whereas it was noncompetitive for Ca(2+)-ATPase with cimetidine as well as ranitidine administration. Inhibition of Na+,K(+)-ATPase with ranitidine was also of noncompetitive type. Mg(2+)-ATPase behaved differently with administration of ranitidine at both the time points used i.e. noncompetitive type of inhibition after 24 hr and mixed type after 15-days. Histologically, signs of degeneration of testicular elements appeared after administration of cimetidine with a significant decrease in tubular diameter and germinal epithelial cell height. Ranitidine administration did not produce any change in the seminiferous tubules of testis. Scanning electron microscopy of spermatozoa from cimetidine-treated mice exhibited distinct departure from the normal morphology such as, (i) breaks at various places along distal portion of the tail, (ii) roughening, wrinkling and disorganization of plasma membrane of the head region, (iii) decapitation of the head and (iv) changes in shape of cytoplasmic droplet. Ranitidine administration showed normal morphology of the spermatozoa.     

Comparative evaluation of the effects of intravenous administration of cimetidine and ranitidine on several cardiovascular parameters

We have compared the effects of intravenous administration of cimetidine and ranetidine on some cardiovascular parameters. Five healthy volunteers received both cimetidine (3, 5 mg/Kg) and ranetidine (1, 5 mg/Kg). Heart rate, blood pressure and PEP/LVET were recorded at baseline and 5, 10, 30, 45 minutes after administration of both drugs. Intravenous administration of cimetidine and ranetidine did not induce any significant alterations in cardiovascular variables.     

In vitro toxicology of fumonisins and the mechanistic implications

The effects of fumonisins B₁FB₁, B₂(FB{2}), and the backbone of fumonisin B₁ remaining after hydrolysis of the tricarballylic groups with base (HFB₁) on sphingolipid biosynthesis were studied in both primary rat hepatocytes and pig kidney epithelial cells (LLC-PK₁). Fumonisins were potent inhibitors of sphingolipid biosynthesis in hepatocytes (IC₅₀ of FB₁=0.1 M), but overt toxicity was not observed. In renal cells, fumonisins also inhibited sphingosine biosynthesis (IC₅₀ for FB₁=35 M), and caused decreased cell proliferation as well. Higher doses (70 M) killed renal cells after exposure for 3 days. The inhibition of de novo sphingolipid biosynthesis was specific, and appeared to be at the site of ceramide synthase, which catalyzes the formation of dihydroceramide or ceramide by the addition of the amide-linked fatty acid to sphinganine or sphingosine. These results may account for the ability of fumonisins to cause equine leucoencephalomalacia and to promote tumor formation.     

The binding characteristics of cholinergic sites in rabbit spermatozoa

Binding of neurotrophic ligands to rabbit spermatozoa was studied. Nicotinic cholinergic antagonists, [3H]alpha-bungarotoxin and [3H]dihydro-beta-erythroidine (DE), bound with high affinity to different sites in the tails of rabbit spermatozoa with the former binding to 10,207 sites/cell and the latter to 562 sites/cell. alpha-Bungarotoxin and DE sites resemble nicotinic sites in brain in binding affinity and specificity. [3H]Quinuclidinyl benzilate (QNB), a muscarinic cholinergic antagonist, also bound with high affinity to a single class of sites located in the heads and tails of rabbit spermatozoa. The binding characteristics of the sperm muscarinic site are similar to muscarinic sites in both innervated and noninnervated cells. Rabbit spermatozoa incubated for 16-18 h in a medium which supported motility for an extended period possessed fewer binding sites than nonincubated spermatozoa for [3H] alpha-bungarotoxin and [3H]QNB and the KD for the latter ligand was also lower. Ligands specific for the kappa and delta opiate receptors showed no affinity for rabbit spermatozoa.     

TRP channels as target sites for insecticides: physiology,pharmacology and toxicology

Transient receptor potential (TRP) channels are attracting attention from various research areas including physiology, pharmacology and toxicology. Our group has focused on TRPA1 channels and revealed their expression pattern, ion channel kinetics and pharmacological characteristics. From Integrated Pest Management point of view, TRP channels could be a possible new target site of pest control agents as well as the primary or secondary target site for known insecticides. We have examined expressed TRPA1 channels using physiological and pharmacological methods to clarify the function of these channels. Here, we show that the TRPA1 is activated by the insecticide and natural toxin allyl isothiocyanate which is known as insecticide.     

Actions of amantadine at synaptic and extrasynaptic cholinergic receptors in the central nervous system of the cockroach Periplaneta americana

The effects of amantadine were investigated on cercal afferent, giant interneurone synapses and on the cell body membrane of the fast coxal depressor motoneurone (D_f), in the cockroach Periplaneta americana. Bath-applied amantadine at concentrations above 2.0 × 10^?5 M significantly reduced the amplitude of unitary and compound epsps recorded by sucrose-gap methods from cercal afferent, giant interneurone synapses in the desheathed sixth abdominal ganglion. Complete block of synaptic transmission was achieved at 1.0 × 10^?3 M amantadine. Synaptic blockade, which was not accompanied by changes in resting potential, was almost fully reversed by washing the ganglion in normal saline. From the dose-dependence of the synaptic blocking action, a Hill coefficient of 0.94 was estimated, indicating that there is no co-operativity in the binding of amantadine to its site of action.Bath-application of amantadine (5.0 × 10^?5 M) resulted in a parallel shift to the right of the dose-response curve for the depolarizing postsynaptic actions of acetylcholine. Nevertheless, even at a concentration of 2.0 × 10^?3 M, amantadine failed to protect the synaptic acetylcholine receptor/ion channel complex from the blocking action of α-bungarotoxin (5.0 × 10^?7 M). In addition, the block by amantadine of the acetylcholine-induced current recorded from the cell body membrane of the fast coxal depressor motoneurone (D_f), was strongly dependent on membrane potential in the range ? 120mV to ? 70mV. An action of amantadine at the open acetylcholine receptor/ion channel complex is proposed.     

Effects of restraint stress in gestation: implications for rodent developmental toxicology studies

Restraint has been used as a procedure to study the effects of stress on gestation outcome in rodents. The effects of restraint could potentially be used as a model for the impact of general stress produced by high doses of toxicants and other interventions. In mice, restraint in the peri-implantation period leads to implantation failure, and restraint at appropriate times in organogenesis produces cleft palate, supernumerary ribs, and resorption. In rats, there is some evidence for an association with restraint for implantation failure, but not for the morphological anomalies. Restraint in late gestation alters adult sexual behavior of male rat offspring, but consequences for their fertility are not known. Intrauterine growth retardation is not commonly associated with gestational restraint. In the few studies where they have been directly compared, different restraint procedures produced graded, qualitatively different, or no effects. Adrenocortical hormones have been implicated as mediating the effect of restraint on cleft palate, but not on supernumerary ribs, implantation failure, or sexual differentiation. Given the variety of restraint procedures and the varying species-dependent consequences, it is not possible to infer a generalizable pattern of developmental effects due to gestational stress from the restraint literature. As an alternative approach, contemporary methods in gene expression and developmental biology could profitably be applied to understanding different patterns of stress-mediated effects of toxicant exposures on intrauterine development.     

Detection and quantification of Geobacter lovleyi strain SZ: implications for bioremediation at tetrachloroethene- and uranium-impacted sites

Geobacter lovleyi strain SZ reduces hexavalent uranium, U(VI), to U(IV) and is the first member of the metal-reducing Geobacter group capable of using tetrachloroethene (PCE) as a growth-supporting electron acceptor. Direct and nested PCR with specific 16S rRNA gene-targeted primer pairs distinguished strain SZ from other known chlorinated ethene-dechlorinating bacteria and closely related Geobacter isolates, including its closest cultured relative, G. thiogenes. Detection limits for direct and nested PCR were approximately 1 x 10(6) and 1 x 10(4) 16S rRNA gene copies per mul of template DNA, respectively. A quantitative real-time PCR (qPCR) approach increased the sensitivity to as few as 30 16S rRNA gene copies per mul of template DNA but was less specific. Melting curve analysis and comparison of the shapes of amplification plots identified false-positive signals and distinguished strain SZ from G. thiogenes when analyzed separately. These indicators were less reliable when target (strain SZ) DNA and nontarget (G. thiogenes) DNA with high sequence similarity were mixed, indicating that the development of qPCR protocols should not only evaluate specificity but also explore the effects of nontarget DNA on the accuracy of quantification. Application of specific tools detected strain SZ-like amplicons in PCE-dechlorinating consortia, including the bioaugmentation consortium KB-1, and two chlorinated ethene-impacted groundwater samples. Strain SZ-like amplicons were also detected in 13 of 22 groundwater samples following biostimulation at the uranium- and chlorinated solvent-contaminated Integrated Field-Scale Subsurface Research Challenge (IFC) site in Oak Ridge, TN. The numbers of strain SZ-like cells increased from below detection to 2.3 x 10(7) +/- 0.1 x 10(7) per liter groundwater, suggesting that strain SZ-like organisms contribute to contaminant transformation. The G. lovleyi strain SZ-specific tools will be useful for monitoring bioremediation efforts at uranium- and/or chlorinated solvent-impacted sites such as the Oak Ridge IFC site.