Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Famotidine (Pepcid, a histamine-2 receptor blocker, is marketed for the treatment of peptic ulcer disease, gastroesophageal reflux, and the treatment of pathological hypersecretory conditions, including the Zollinger-Ellison syndrome. Recent reports indicate that it is also effective in relieving the deficit (or withdrawal) symptoms of adults with schizophrenia. Autism, a neuropsychiatric disorder which presents within the first few years of life, is defined by deficient social interaction, communication, language, play, and a markedly restricted repertoire of activities and interests. Similarities between the deficit symptoms of schizophrenia and the social deficit symptoms of autism suggest the hypothesis that famotidine may be useful in treating children with autism. Histamine serves as a neurotransmitter and neuromodulator in the brain. H2-receptors in the brain predominantly transmit inhibitory signals; when these receptors are stimulated in animals, spontaneous activity and exploratory behavior decrease; blockade of H2-receptors would therefore be expected to reverse this inhibition.
 ...
PMID:Oral famotidine: a potential treatment for children with autism. 1041 59

Metabotropic glutamate (mGlu) receptors were discovered in the mid 1980s and originally described as glutamate receptors coupled to polyphosphoinositide hydrolysis. Almost 6500 articles have been published since then, and subtype-selective mGlu receptor ligands are now under clinical development for the treatment of a variety of disorders such as Fragile-X syndrome, schizophrenia, Parkinson's disease and L-DOPA-induced dyskinesias, generalized anxiety disorder, chronic pain, and gastroesophageal reflux disorder. Prof. Erminio Costa was linked to the early times of the mGlu receptor history, when a few research groups challenged the general belief that glutamate could only activate ionotropic receptors and all metabolic responses to glutamate were secondary to calcium entry. This review moves from those nostalgic times to the most recent advances in the physiology and pharmacology of mGlu receptors, and highlights the role of individual mGlu receptor subtypes in the pathophysiology of human disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
 ...
PMID:Metabotropic glutamate receptors: from the workbench to the bedside. 2103 82

Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated that type 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson's disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability to enhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.
 ...
PMID:Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders. 2136 21

Clozapine (CLZ) is the drug of choice for the treatment of resistant schizophrenia; however, its suitable use is limited by the complex adverse effects' profile. The best-described adverse effects in the literature are represented by agranulocytosis, myocarditis, sedation, weight gain, hypotension, and drooling; nevertheless, there are other known adverse effects that psychiatrists should readily recognize and manage. This review covers the "rare" and "very rare" known adverse effects of CLZ, which have been accurately described in literature. An extensive search on the basis of predefined criteria was made using CLZ and its combination with adverse effects as keywords in electronic databases. Data show the association between the use of CLZ and uncommon adverse effects, including ischemic colitis, paralytic ileus, hematemesis, gastroesophageal reflux disease, priapism, urinary incontinence, pityriasis rosea, intertriginous erythema, pulmonary thromboembolism, pseudo-pheochromocytoma, periorbital edema, and parotitis, which are influenced by other variables including age, early diagnosis, and previous/current pharmacological therapies. Some of these adverse effects, although unpredictable, are often manageable if promptly recognized and treated. Others are serious and potentially life-threatening. However, an adequate knowledge of the drug, clinical vigilance, and rapid intervention can drastically reduce the morbidity and mortality related to CLZ treatment.
...
PMID:Rare and very rare adverse effects of clozapine. 2627 2

Clozapine is a second-generation antipsychotic which has proven efficacy in treating the symptoms of schizophrenia. Although clozapine therapy is associated with a number of adverse drug reactions, it is frequently used. One of the most common adverse drug reactions is gastroesophageal reflux disease which is an indication for treatment with proton pump inhibitors (PPIs). Coadministration of clozapine and PPIs increases the risk of hematological adverse drug reactions, including neutropenia and agranulocytosis. The mechanism in idiosyncratic agranulocytosis is not dose related and involves either a direct toxic or an immune-allergic effect. It is suspected that the clozapine metabolites nitrenium ion and N-desmethylclozapine may cause apoptosis or impair growth of granulocytes. Formation of N-desmethylclozapine is correlated with activity of the cytochrome P450 enzymes 1A2 and 3A4 (CYP1A2 and CYP3A4). Nitrenium ion is produced by the flavin-containing monooxygenase system of leukocytes. A drug interaction between clozapine and a PPI is a consequence of the induction of common metabolic pathways either by the PPI or clozapine. Findings to date suggest that indirect induction of flavin-containing monooxygenase by omeprazole through the aryl hydrocarbon receptor increases the expression of the enzyme mRNA and in the long term may cause the increase in activity. Moreover, induction of CYP1A2, especially by omeprazole and lansoprazole, may increase the serum concentration of N-desmethylclozapine, which can accumulate in lymphocytes and may achieve toxic levels. Another hypothesis that may explain hematological adverse drug reactions is competitive inhibition of CYP2C19, which may contribute to increased serum concentrations of toxic metabolites.
 ...
PMID:Potential Mechanisms of Hematological Adverse Drug Reactions in Patients Receiving Clozapine in Combination With Proton Pump Inhibitors. 2829 Oct 36

A low level, inflammatory phenotype is prevalent in individuals with schizophrenia, but the source of this inflammation is not known. Studies of the gut-brain axis indicate that this inflammation may be related to the translocation of intestinal microbes across a permeabilized gut-vasculature barrier. In addition, studies of the endocrine system support that this inflammation may derive from effects of stress hormones and metabolic imbalances. Gastrointestinal (GI) and endocrine conditions are not mutually exclusive, but rather may have additive effects to produce this inflammatory phenotype in schizophrenia. Here, we examined a series of plasma biomarkers used to measure general inflammation and presumably microbial, gut-derived inflammation in 409 individuals with schizophrenia: c-reactive protein (CRP), lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14), and IgG antibodies to S. cerevisiae, bovine milk casein, and wheat gluten. Individuals were stratified according to whether or not they had a comorbid GI or endocrine condition, both, or neither. In multivariate regression models, the presence of GI and endocrine conditions was additive for the GI-based marker, LBP, with significant associations only when both conditions were present compared to when both conditions were absent (OR = 2.32, 95th% CI 1.05-5.13, p < 0.03). In contrast, the marker of general inflammation, CRP, was strongly associated with primarily endocrine conditions (OR = 3.64, 95th% CI 1.35-9.84, p < 0.05). Overall associations were largely driven by the GI condition, gastroesophageal reflux disease (GERD), and by the endocrine condition, obesity. In univariate comparisons, S. cerevisiae IgG levels were significantly elevated only in persons with GI conditions (p < 0.02), whereas antibodies to the food antigens were elevated in the presence of either or both conditions (p < 0.005-0.04). More severe psychiatric symptoms were associated only with GI conditions (p < 0.01-0.04). In conclusion, both GI and endocrine abnormalities may contribute to inflammation in schizophrenia, sometimes independently and sometimes as part of interactions which may represent complex integrated pathways. The accumulating evidence for multisystem inflammation in schizophrenia may lead to the development of new strategies to prevent and treat this devastating disorder.
 ...
PMID:Complex Gastrointestinal and Endocrine Sources of Inflammation in Schizophrenia. 3262 21