The influence of cimetidine and ranitidine on basophil histamine release and bronchial reactivity in asthmatic patients

Anti-IgE induced histamine release from isolated basophils after Cimetidine and Ranitidine administration was evaluated in 22 patients with atopic bronchial asthma. The histamine provocation test after Ranitidine treatment in 10 patients with atopic bronchial asthma and 10 patients with peptic ulcer was also performed. Investigations in vitro revealed that Cimetidine and Ranitidine in low concentrations had an inhibitory effect whereas in concentrations of over 10(-6) M and 10(-4) M, respectively, they enhanced histamine release. Investigations in vivo after administration of Ranitidine showed that it does not cause marked changes in the bronchial reactivity in patients with bronchial asthma and any change in patients with peptic ulcer. These preliminary studies seem to suggest that in patients with atopic bronchial asthma and concomitant peptic ulcer Ranitidine is preferable to Cimetidine in the treatment of digestive tract disorders.     

In-vitro Interaction between H2 Antagonists and Vecuronium

Abstract— The interaction between histamine H₂ antagonists and the neuromuscular blocking drug vecuronium was investigated in the rat phrenic nerve-hemidiaphragm preparation. Cimetidine alone, in the concentration range 800–4000 μm produced between 14 and 74% neuromuscular paralysis with an EC50 (mean ± s.e.) of 2900 ± 100 μm . Ranitidine augmented the indirectly-evoked muscle response at concentrations between 30 and 160 μm but at higher concentrations, between 300 and 1800 μm , produced neuromuscular paralysis. Famotidine produced negligible and statistically insignificant (0–5%) neuromuscular paralysis at concentrations between 0·3 and 300 μm . Cimetidine (800 μm ) shifted the neuromuscular concentration-effect curve of vecuronium to the left in a parallel manner, while ranitidine (160 μm ) shifted it to the right. The potentiation ratio was 1·90 ± 0·14 for cimetidine and 0·62 ± 005 for ranitidine. Famotidine (30 μm ) did not alter the response to vecuronium. These data indicate that higher than clinically relevant concentrations of cimetidine and ranitidine produce neuromuscular paralysis and may potentiate the action of vecuronium. Low concentrations of ranitidine may antagonize the action of vecuronium. Famotidine, in contrast, lacks significant neuromuscular effects.     

Effect of ranitidine on ileal myenteric plexus preparation and on acetyl- and butyrylcholinesterase

Ranitidine at concentrations from 1 microM to 0.1 mM brought about a dose-dependent potentiation of the twitch responses elicited by electrical stimulation of the ileal myenteric preparation. At higher concentrations (0.3-3 mM) ranitidine also caused irregular slow contractions of the unstimulated ileal preparation which were potentiated by eserine and blocked by atropine and tetrodotoxin. In order to identify the mechanism of these apparently cholinomimetic actions, the effects of ranitidine on AChE and BuChE were studied. Ranitidine showed an instantaneous and promptly reversible inhibitory action at concentrations between 0.5 and 30 microM. Double reciprocal plots were prepared and equilibrium dissociation constants calculated. It appears that ranitidine exerts an inhibition of the "mixed" type on both AChE and BuChE, but the dissociation constants for BuChE were markedly higher than those for AChE. Since AChE inhibition occurs in the same concentration range potentiating the twitch responses on the ileal myenteric preparation, it may explain the cholinomimetic effect of ranitidine.     

The reversible cholinesterase inhibitor physostigmine has channel-blocking and agonist effects on the acetylcholine receptor-ion channel complex

The actions of the carbamate cholinesterase inhibitors, physostigmine (Phy) and physostigmine methiodide (MetPhy), were studied on the acetylcholine receptor-ion channel complex (AChR) of skeletal muscles. Low concentrations of these agents produced cholinesterase inhibition which resulted in potentiation of nerve-elicited muscle twitches and an increased peak amplitude and prolongation of the decay time constant (tau EPC) of endplate currents (EPCs) elicited in frog (Rana pipiens) sartorius muscles. However, increasing concentrations of Phy depressed the peak amplitude and shortened the decay phase of the EPC with an apparent loss in the voltage dependence of tau EPC. At higher concentrations and depolarized potentials, EPC decays were double exponential. The effects of both Phy and MetPhy on the postsynaptic AChR complex were also evident in preparations pretreated with diisopropylfluorophosphate. Under these conditions, a linear relationship between the reciprocal of tau EPC and the concentration of these agents was observed. Single channel studies revealed that Phy (20-600 microM) shortened channel lifetime and decreased channel conductance at very high concentrations. In addition, Phy (0.5 microM) induced the appearance of channel openings with conductance similar to that of acetylcholine. High concentrations (greater than 50 microM) of this agent activated channel openings with decreased conductance. Similar results were obtained with MetPhy. Thus, the reversible cholinesterase inhibitors Phy and MetPhy altered the properties of the AChR by interacting as agonists capable of inducing desensitization and blockade.     

Disposition kinetics of cimetidine and ranitidine in endotoxin pretreated rats

Cimetidine and ranitidine are used in patients with life-threatening gram-negative infections, endotoxemia and acute stress erosions. Disposition kinetics of cimetidine and ranitidine in endotoxin pretreated rats was investigated. The H2-antagonists were administered intravenously 24 h after endotoxin (10 mg/kg) pretreatment. This endotoxin dosage resulted in 50% mortality in rats. Blood samples (0.25 ml) were collected at different timed intervals. No significant differences were observed in plasma clearance, half-life and volume of distribution between endotoxin pretreated and control rats. Cimetidine is eliminated extensively by the renal route in animals and man with metabolism being a minor process. Ranitidine is metabolized to a large extent (70%) in rats, while in humans this represents a minor process. No significant changes in cimetidine and ranitidine disposition parameters in endotoxin pretreated rats were observed. These results suggest that cimetidine and ranitidine may be used in normal dosages in endotoxemia patients since their pharmacokinetic parameters would not be affected under these circumstances.     

Different effects of cimetidine and ranitidine on gastric emptying in rats and man

Cimetidine and ranitidine were tested for their effect on gastric emptying in the rat. At low doses, cimetidine was inactive, whereas it significantly delayed emptying rate when administered at higher doses. Ranitidine always accelerated gastric emptying. At variance with rats, ranitidine delayed human gastric emptying whereas cimetidine was completely inactive. All these data are consistent with the idea that these effects of H2-antagonists are independent of H2-receptor blockade.     

Excretion of high concentrations of cimetidine and ranitidine into rat milk and their effects on milk composition and mammary gland nucleic acid content.

The excretion of cimetidine and ranitidine into rat milk following single or multiple oral doses and the subsequent effects on their suckling pups and on milk composition and milk synthesis were investigated. Following a single dose of [3H]cimetidine, peak milk cimetidine concentrations were maintained from 1 until 4 hr, while plasma concentrations peaked at 10% of the milk level at 30 min and then declined. Multiple doses of cimetidine (18 or 180 mg/kg/day) on Days 13-16 of lactation led to milk cimetidine concentrations of 17 and 113 micrograms/ml. The milk/plasma ratios far exceeded the theoretical milk/plasma ratio of 2.0. Ranitidine concentrations in rat milk following ranitidine treatment (4.5 or 45 mg/kg/day) were also greater (6.8-15 times) than in plasma, but only slightly greater than the predicted ratio of 5.0. There were no changes in liver weight or in hepatic aminopyrine N-demethylase activity in the cimetidine- or ranitidine-treated dams or their pups. Cimetidine treatment had no effect on milk lipid, solid, or protein content, but at 180 mg/kg/day, caused a significant increase in milk lactose. The RNA/DNA ratio in the mammary gland was significantly increased by cimetidine, suggesting increased milk synthesis. Ranitidine had no effect on milk composition or on mammary gland RNA, DNA, or RNA/DNA. Therefore, high concentrations of cimetidine and ranitidine were excreted into rat milk, but no deleterious effects on the suckling pups, or the composition of the milk, or on the milk synthetic activity were observed.     

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

The anesthetic propofol is thought to induce rapid hypnotic sedation by facilitating a GABAergic tonic current in forebrain neurons. The depression of cardiovascular and respiratory regulation often observed during propofol suggests potential additional actions within the brainstem. Here we determined the impacts of propofol on both GABAergic and glutamatergic synaptic mechanisms in a class of solitary tract nucleus (NTS) neurons common to brainstem reflex pathways. In horizontal brainstem slices, we recorded from NTS neurons directly activated by solitary tract (ST) axons. We identified these second-order NTS neurons by time-invariant ("jitter"<200 micros), "all-or-none" glutamatergic excitatory postsynaptic currents (EPSCs) in response to shocks to the ST. In order to assess propofol actions, we measured ST-evoked, spontaneous and miniature EPSCs and inhibitory postsynaptic currents (IPSCs) during propofol exposure. Propofol prolonged miniature IPSC decay time constants by 50% above control at 1.8 microM. Low concentrations of gabazine (SR-95531) blocked phasic GABA currents. At higher concentrations, propofol (30 microM) induced a gabazine-insensitive tonic current that was blocked by picrotoxin or bicuculline. In contrast, total propofol concentrations up to 30 microM had no effect on EPSCs. Thus, propofol enhanced phasic GABA events in NTS at lower concentrations than tonic current induction, opposite to the relative sensitivity observed in forebrain regions. These data suggest that therapeutic levels of propofol facilitate phasic (synaptic) inhibitory transmission in second-order NTS neurons which likely inhibits autonomic reflex pathways during anesthesia.     

Anti-acid secretion activity of drugs cimetidine, ranitidine, tiotidine D 15,144 in dogs fixed with gastric fistulae

1. Acid secretion for each dog has reached a near maximum (100%) at the 6th samples, 90 min after the intravenous infusion of histamine (10 mu ghr-1, or approximately equal to 0.3 mghr-1). 2. 0.5 mgkg-1 Cimetidine had produced a mean inhibition of 47% on the stomach. 3. 0.1 mgkg-1 Ranitidine (D 14,951) could only inhibit a maximum of 28%, and the secretion had return to normal in just 30 min. 4. 0.025 mgkg-1 Tiotidine (D 15,104) had inhibited 53% acid secretion within 15 min of exposure. Recovery was quite similar to that of Cimetidine, at 150 min. 5. At a dosage one fifth of Cimetidine (0.1 mgkg-1) D 15,144 had depressed 35% of acid secretion at the first 15 min. The inhibition is gradually increased to about 43% (at 30 min), and was maintained for the next 105 min.     

A comparison of the effect of cholinesterase inhibitors on end-plate current and on cholinesterase activity in frog muscle

The effect of various cholinesterase inhibitors on the end-plate current was studied in glycerol-treated frog skeletal muscle. In the same muscle, the activity of cholinesterases was estimated histochemically and measured quantitatively.By using the irreversibile cholinesterase inhibitor methanesulphonyl fluoride, cholinesterases were completely inhibited. This resulted in an increase of the amplitude, of the rise time and half-time of the end-plate current.By using the reversible cholinesterase inhibitors eserine and prostigmine, the changes of the end-plate current seemed complex and not well understood. At concentrations of these drugs which did not inhibit the activity of cholinesterases completely, the amplitude, the rise time and the half-time of the end-plate current were increased by a variable extent. At a higher concentration, which almost completely inhibited the cholinesterases, the amplitude and the half-time of the end-plate current were depressed. This was particularly well pronounced with the cholinesterase inhibitor BW284C51.The changes in the end-plate current, observed at a relatively high concentration of reversible inhibitors, are thought to be related either to a presynaptic, or to a postsynaptic “curare-like” action of these drugs.     

Effects of Cimetidine,Ranitidine and Omeprazole on Tolbutamide Pharmacokinetics

This randomized, four-way crossover study in 16 healthy subjects compared the effects of cimetidine 800 mg, ranitidine 300 mg and omeprazole 40 mg against placebo given daily after breakfast for seven days on the pharmacokinetics of a single oral dose of tolbutamide (500 mg) given on day 4. Plasma tolbutamide and urinary hydroxytolbutamide and carboxytolbutamide concentrations were determined by HPLC. Ranitidine had no significant effects on tolbutamide metabolism. Cimetidine produced a 20% increase in AUC (P < 0·001) and a 14% increase in t 1/2 (P < 0·01), while omeprazole produced a 10% increase in AUC (P < 001). The effect of these agents on urinary concentrations of the tolbutamide metabolites was small. These results do not indicate that interactions of major clinical significance occur in healthy subjects.     

Desensitization of P2X2 receptor/channel pore mutants

Properties of five mutants of P2X2 receptor/channel having amino acid residue-substitution at the pore region were examined by expressing the channels in Xenopus oocytes. When the concentration-response relationship for ATP-evoked current was obtained, the current amplitude was increased along with the concentrations of ATP for the wild type channel whereas the amplitude was rather decreased with highest concentrations for four of the five mutants as if an "inactivation-like" mechanism occurs to these mutants. Upon a long exposure (30 s) to ATP, time-dependent decay in the ATP-evoked current was observed for three of the five mutants, suggesting that desensitization occurs to these mutants. The time course of the desensitization was well fitted with a single exponential time whereas that of the recovery from the desensitization could be better fitted with multiple exponentials than with a single exponential. The relationship between the desensitization and the "inactivation-like" mechanism was discussed.     

Pharmacological treatment of Alzheimer disease: from psychotropic drugs and cholinesterase inhibitors to pharmacogenomics

For the past 20 years the scientific community and the pharmaceutical industry have been searching for treatments to neutralize the devastating effects of Alzheimer disease (AD). During this period important changes in the etiopathogenic concept of AD have occurred and, as a consequence, the pharmacological approach for treating AD has also changed. During the past 2 decades only 3 drugs for AD have been formally approved by the FDA, although in many countries there are several drugs which are currently used as neuroprotecting agents in dementia alone or in combination with cholinesterase inhibitors. The interest of the pharmaceutical industry has also shifted from the cholinergic hypothesis which led to the development of cholinesterase inhibitors to enhance the bioavailability of acetylcholine at the synaptic cleft to a more "molecular approach" based on new data on the pathogenic events underlying neurodegeneration in AD. In our opinion, the pharmacological treatment of AD should rely on a better understanding of AD etiopathogenesis in order to use current drugs that protect the AD brain against deleterious events and/or to develop new drugs specifically designed to inhibit and/or regulate those factors responsible for premature neuronal death in AD. The most relevant pathogenic events in AD can be classified into main categories: primary events (genetic factors, neuronal apoptosis), secondary events (beta-amyloid deposition in senile plaques and brain vessels, neurofibrillary tangles due to hyperphosphorylation of tau proteins, synaptic loss), tertiary events (neurotransmitter deficits, neurotrophic alterations, neuroimmune dysfunction, neuroinflammatory reactions) and quaternary events (excitotoxic reactions, calcium homeostasis miscarriage, free radical formation, primary and/or reactive cerebrovascular dysfunction). All of these pathogenic events are potential targets for treatment in AD. Potential therapeutic strategies for AD treatment include palliative treatment with nonspecific neuroprotecting agents, symptomatic treatment with psychotropic drugs for noncognitive symptoms, cognitive treatment with cognition enhancers, substitutive treatment with cholinergic enhancers to improve memory deficits, multifactorial treatment using several drugs in combination and etiopathogenic treatment designed to regulate molecular factors potentially associated with AD pathogenesis. This review discusses the conventional cholinergic enhancers (cholinesterase inhibitors, muscarinic agonists), noncholinergic strategies that have been developed with other compounds, novel combination drug strategies and future trends in drug development for AD treatment. Stem-cell activation, genetically manipulated cell transplantation, gene therapy and antisense oligonucleotide technology constitute novel approaches for the treatment of gene-related brain damage and neuroregeneration. The identification of an increasing number of genes associated with neuronal dysfunction along the human genome together with the influence of specific allelic associations and polymorphisms indicate that pharmacogenomics will become a preferential procedure for drug development in polygenic complex disorders. Furthermore, genetic screening of the population at risk will help to identify candidates for prevention among first-degree relatives in families with transgenerational dementia.     

The effect of two lubricants (magnesium stearate and pruv) in the formation of tablets of four anti-ulcer agents/ by means of direct compression]

In this research we study the influence of two lubricants-Magnesium Stearate and Pruv--on the tablets elaboration of Cimetidine, Ranitidine, Famotidine and Pirenzepine by direct compression. The presence of 0.5% of lubricants improved the flow of all the formulations, but especially the Famotidine's formulation. The formulations with Magnesium Stearate had the worst results in tests of friability and tensile strength. All tablets with drugs and Pruv had high data in indentation hardness. The tablets of Cimetidine, Famotidine and Pirenzepine with Magnesium Stearate had less time of disintegration.     

Acetylcholinesterase and cholinesterase activities in the mouse cerebellum following misonidazole treatment

The acetylcholinesterase and cholinesterase activities in the mouse cerebellum were unchanged following misonidazole treatment. Inhibition of acetylcholinesterase activity only occurred at concentrations of misonidazole which were in excess of those obtained clinically. These findings indicate that the clinical neurotoxicity of the drug cannot be attributed to an effect on cholinesterases.     

Effects of ranitidine and cimetidine on plasma lipoproteins in healthy subjects

Serum lipoproteins were monitored in 24 healthy subjects receiving either ranitidine or cimetidine for four weeks. Ranitidine produced a significant (P less than .05) reduction in high-density lipoprotein (HDL)-cholesterol in both men and women. Cimetidine caused a nonsignificant increase in HDL-cholesterol and a reduction in LDL-cholesterol that was significant (P less than .05) only in women. As these drugs had opposite effects on HDL-cholesterol levels, the mechanism of action is unlikely to be medicated by H2-receptor blockade.     

Review of the toxicology of chlorpyrifos with an emphasis on human exposure and neurodevelopment

This review examines the large body of toxicological and epidemiological information on human exposures to chlorpyrifos, with an emphasis on the controversial potential for chlorpyrifos to induce neurodevelopmental effects at low doses. The results of this review demonstrate that the use of urinary 3,5,6-trichlorpyridinol (TCPy), a metabolite of chlorpyrifos as a biomarker of nonoccupational exposure is problematic and may overestimate nonoccupational exposures to chlorpyrifos by 10-to 20-fold because of the widespread presence of both TCPy and chlorpyrifos-methyl in the food supply. Current "background" (nonoccupational) levels of exposure to chlorpyrifos are several orders of magnitude lower than those required to inhibit plasma cholinesterase activity, which is a more sensitive target than nervous system cholinesterase. However, several in vitro studies have identified putative neurodevelopmental mechanisms that are altered at concentrations of chlorpyrifos below those that inhibit cholinesterases. Although one human cohort study reported an association between maternal and cord blood chlorpyrifos levels and several measures of neurodevelopment, two other cohort studies that utilized urinary TCPy as a surrogate for chlorpyrifos exposure did not demonstrate an association. Although the weight of the scientific evidence demonstrates that current levels of chlorpyrifos exposure will not have any adverse effects on neurodevelopment that might result from inhibition of nervous system cholinesterases, several recent studies propose alternative mechanisms. Thus, further in vivo investigation on neurodevelopment in an appropriate animal model is needed; additional epidemiological studies may be warranted if a suitable, chlorpyrifos-exposed cohort can be identified and more rigorous measures of exposure are utilized.     

The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease

Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recent in vitro studies suggest that memantine abrogates beta-amyloid (Abeta) toxicity and possibly inhibits Abeta production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of channel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.     

Cimetidine and ranitidine: their interaction with human and pig liver microsomes and with purified cytochrome P-450

Cimetidine and ranitidine interact with microsomes from human and pig liver and with purified cytochrome P-450 in the ligand-type manner. The affinity for cimetidine is about 10 times as high as that for ranitidine. Accordingly amplitudes of the specta are much higher for cimetidine. These results are in accordance with those obtained earlier with rat liver microsomes. The inhibitory potency of either compound with regard to dealkylation of 7-ethoxycoumarin appears to be less in the human preparation.     

The influence of H2-receptor antagonists on steady-state concentrations of propranolol and 4-hydroxypropranolol

Twelve healthy male volunteers were treated with 1200 mg/day cimetidine, 300 mg/day ranitidine, or no H2-receptor antagonist (control) for seven days in a sequence determined by Latin-square design. Each treatment period was separated by a seven-day washout. On the third day of each treatment period, 80 mg propranolol every 12 hours for nine doses was initiated. Whole blood concentrations of propranolol and 4-hydroxypropranolol were measured at 12 time points during the 12-hour period following administration of the last propranolol dose. Heart rate was measured before each blood sample was withdrawn. Cimetidine treatment was associated with a 47 per cent increase in the area under the propranolol concentration-time curve and a 17 per cent increase in elimination half-life of propranolol. Ranitidine had no significant effect on the concentration-time profile of propranolol. There were no significant differences in the 4-hydroxypropranolol pharmacokinetic parameters during any of the treatments. There was, however, a significant decrease in the average 4-hydroxypropranolol-to-propranolol steady-state concentration ratio during the cimetidine treatment. There was no significant difference in heart rate between any of the treatments. The elevation of propranolol concentrations during cimetidine treatment is likely due to metabolic inhibition by cimetidine.