Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

St. John's wort (Hypericum perforatum L.) is widely used for the treatment of mild to moderately severe depression. However, the nature of its active principles and the exact mode of antidepressant action are still unknown. It has been suggested repeatedly in preclinical and clinical studies that the content of the acylphloroglucinol hyperforin decisively contributes to the antidepressant efficacy of St. John's wort extracts. Experimental studies in vivo also indicate that the naphthodianthrone hypericin may reduce the activity of the hypothalamic-pituitary-adrenal axis. Exacerbated hypothalamic-pituitary-adrenal activity has often been associated with depressive states in patients. Corticotropin-releasing factor (CRF) seems to be a major determinant in the regulation of the hypothalamic-pituitary-adrenal activity via activation of CRF(1) receptors. In the present study, we investigated the CRF(1) receptor antagonist activity of three main constituents of St. John's wort (hypericin, pseudohypericin and hyperforin) by measuring their effect on CRF-stimulated cAMP formation in recombinant Chinese hamster ovary (CHO) cells. As a selectivity test, the compounds were also tested against calcitonin in the same cells. Of the three compounds tested, only pseudohypericin selectively antagonised CRF (K(B) 0.76 microM). Hypericin and hyperforin affected both CRF and calcitonin with similar potencies and the same type of behaviour (competitive antagonism for hypericin, noncompetitive for hyperforin). It is concluded that pseudohypericin is the only real CRF(1) receptor antagonist of the three constituents tested. In addition, evidence is provided that beside hyperforin, both pseudohypericin and hypericin are implicated in the antidepressant efficacy of St. John's wort.
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PMID:Antagonist effect of pseudohypericin at CRF1 receptors. 1250 80

Osteoporosis is a silent disease that affects 10 million Americans; 80% of those affected are women. Although the disease is more common in postmenopausal Caucasian women, all ages and races are at risk. Osteoporosis can be a debilitating disease that can cause pain, fractures, depression, and social withdrawal. Signs of osteoporosis include kyphosis, loss of height, and protrusion of the abdomen. Because symptoms generally do not occur until after the disease has progressed, clinicians should include osteoporosis screening and preventative education as part of the regular gynecologic care. Diagnosis is typically made by a dual energy x-ray absorptiometry (DEXA) scan. Treatment consists of dietary and lifestyle changes, along with pharmacologic intervention. Although hormone therapy has been shown to be effective in preventing osteoporosis, the risks of long-term treatment with HRT are discussed. The following effective treatment options for women who have been diagnosed with the disease are discussed: bisphosphonates, calcitonin, and selective estrogen receptor modulators (SERMs). Because midwives regularly care for women of all ages, they are ideal candidates to provide women with preventative education, screening, counseling, and treatment.
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PMID:Pharmacotherapeutics for osteoporosis prevention and treatment. 1258 4

Nitroxyl anion (HNONO(-)), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO/NO(-) augments systolic and diastolic function of failing hearts, and whether contrary to NO/nitrates such modulation enhances rather than blunts beta-adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO/NO(-) generated by Angelis' salt (AS) was infused (10 microg/kg per min, i.v.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P < 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine(DEA)NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed beta-adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA/NO blunted beta-stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA/NO or NTG, supporting a proposed role of this peptide to HNO/NO(-) cardiotropic action. Thus, HNO/NO(-) has positive inotropic and lusitropic action, which unlike NO/nitrates is independent and additive to beta-adrenergic stimulation and stimulates CGRP release. This suggests potential of HNO/NO(-) donors for the treatment of heart failure.
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PMID:Positive inotropic and lusitropic effects of HNO/NO- in failing hearts: independence from beta-adrenergic signaling. 1270 27

An intestinal ischemia-reperfusion injury (IIR) may induce renal tubular dysfunction and a reduction in renal blood flow that may be related to the alteration of renal-nerve activity. A rat model of IIR injury was established. The superior mesenteric artery was clamped for 120 min, constituting the ischemic period, and was then released for 60 min, thus constituting the reperfusion period. Renal-nerve activity, renal function, and hemodynamic changes were recorded during the different periods. The levels of calcitonin gene-related peptide (CGRP) in portal-vein blood and intestinal tissue were investigated here. In the reperfusion period, the efferent renal-nerve activity (ERNA) was markedly elevated (94.3% +/- 21.6% higher than the baseline value), such an elevation being only partially reversed by fluid expansion (29.3% +/- 5.2% higher than the baseline value). The elevation of ERNA contributed to the renal blood-flow reduction from 6.8 +/- 0.3 mL/min/g to 2.0 +/- 0.4 mL/min/g, and decreased diuretic and natriuretic responses. The afferent renal nerve activity (ARNA) was markedly depressed (45.7% +/- 8.1% lower than the baseline value) during the reperfusion period. This depression was not reversed by fluid expansion, suggesting that the baroreflex was not responsible for this effect. The blunted ARNA also contributed to the elevation of ERNA by way of a renorenal reflex. The potent vasodilator neuropeptide in the gut, CGRP, revealed an increased level in the portal-vein blood (92.2 +/- 4.4 pg/mL vs. 57.8 +/- 0.6 pg/mL) and also in intestinal tissue (655.8 +/- 115.9 pg/mL vs. 60.5 +/- 9.4 pg/mL) with a time-matched related pattern with the change to renal-nerve activity, suggesting CGRP's role regarding changes in renal-nerve activity. This study indicates that the elevated ERNA level associated with IIR injury is related to a systemic hypotension-induced baroreflex, the contra-lateral inhibition of ARNA, and possibly also gut-released CGRP. In regards to an IIR injury, the depressed ARNA reflects the involvement of a renal sensory- impairment mechanism.
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PMID:The effect of an intestinal ischemia-reperfusion injury on renal nerve activity among rats. 1274 94

Until now, our understanding of migraine pathophysiology has been fairly incomplete. So far no animal model has allowed an explanation of all facets of the clinically heterogeneous condition migraine. However, it is now generally accepted that the migraine headache is due to activation of the trigeminal system. The model of neurogenic inflammation after stimulation of the trigeminal ganglion or systemic administration of capsaicin allows study of the inhibitory interactions between antimigraine compounds and peripheral trigeminal fibre terminals that sustain a sterile meningeal inflammation through release of allogenic and vasoactive neuropeptides, such as substance P and calcitonin gene-related peptide. Studies with the model of superior sagittal sinus stimulation have revealed central actions of antimigraine agents such as ergotamine and sumatriptan, but also acetylsalicylic acid on neurotransmission of trigeminal nociceptive input in the brainstem. A likely explanation for the slowly progressing neurological deficits is cortical spreading depression (CSD), which can easily be elicited in many species. However, CSD has not been observed in vivo in humans. The described models strongly influenced the development of new medications for migraine treatment and have improved our understanding of migraine pathophysiology.
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PMID:[Animal models and their results in relation to the therapy of migraine]. 1279 56

Arachidonylethanolamide (anandamide, AEA) is believed to be the endogenous ligand of the cannabinoid CB(1) and CB(2) receptors. CB(1) receptors have been found localized on fibers in the spinal trigeminal tract and spinal trigeminal nucleus caudalis. Known behavioral effects of anandamide are antinociception, catalepsy, hypothermia, and depression of motor activity, similar to Delta(9)-tetrahydocannanbinol, the psychoactive constituent of cannabis. It may be a possible therapeutic target for migraine. In this study, we looked at the possible role of the CB(1) receptor in the trigeminovascular system, using intravital microscopy to study the effects of anandamide against various vasodilator agents. Anandamide was able to inhibit dural blood vessel dilation brought about by electrical stimulation by 50%, calcitonin gene-related peptide (CGRP) by 30%, capsaicin by 45%, and nitric oxide by 40%. CGRP(8-37) was also able to attenuate nitric oxide (NO)-induced dilation by 50%. The anandamide inhibition was reversed by the CB(1) receptor antagonist AM251. Anandamide also reduced the blood pressure changes caused by CGRP injection, this effect was not reversed by AM251. It would seem that anandamide acts both presynaptically, to prevent CGRP release from trigeminal sensory fibers, and postsynaptically to inhibit the CGRP-induced NO release in the smooth muscle of dural arteries. CB(1) receptors seem to be involved in the NO/CGRP relationship that exists in causing headache and dural blood vessel dilation. It also seems that some of the blood pressure changes caused by anandamide are mediated by a noncannabinoid receptor, as AM251 was unable to reverse these effects. It can be suggested that anandamide is tonically released to play some form of modulatory role in the trigeminovascular system.
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PMID:Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. 1471 91

We investigated the antagonistic effect of 1-piperidinecarboxamide, N-[2-[[5amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) on the calcitonin gene-related peptide (CGRP)-induced responses by using isometric myograph and FURA-2 technique in human subcutaneous arteries removed in association with abdominal surgery. BIBN4096BS, at the concentration of 1 pm, had no significant effect on the CGRP-induced relaxation in these vessels. At the concentration of 10 pM, BIBN4096BS had a competitive antagonistic-like behaviour characterized by parallel rightward shift in the log CGRP concentration-tension curve with no depression of the E(max). At the higher concentrations (0.1 and 1 nM), BIBN4096BS had a concentration-dependent noncompetitive antagonistic effect on the CGRP-induced responses. The efficacy and potency of CGRP was significantly greater in the smaller (lumen diameter approximately 200 microM) human subcutaneous arteries compared to the larger ones. The apparent agonist equilibrium dissociation constant, K(A), for CGRP(1) receptors in the human subcutaneous arteries was approximately 1 nM. Analysis of the relationship between receptor occupancy and response to CGRP indicates that the receptor reserve is relatively small. Using reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of mRNA sequences encoding the calcitonin receptor-like receptor, receptor activity modifying protein (RAMP1, RAMP2, RAMP3) and receptor component protein were demonstrated in human subcutaneous arteries, indicating the presence of CGRP(1)-like receptor and the necessary component for the receptor activation. In conclusion, the inhibitory action of BIBN4096BS at the low concentration (10 pM) on the CGRP-tension curve (but not intracellular calcium concentration ([Ca(2+)](i)) resembles what is seen with a reversible competitive antagonist. However, at the higher concentrations (0.1 and 1 nM), BIBN4096BS acts as a selective noncompetitive inhibitor at CGRP(1) receptors in human subcutaneous arteries.
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PMID:Noncompetitive antagonism of BIBN4096BS on CGRP-induced responses in human subcutaneous arteries. 1547 23

The sigma(1) receptor is a 223 amino acid protein sharing no homology with other mammalian protein. It is an intracellular protein present on the endoplasmic reticulum membrane, which can translocates to other organelles and plasma membranes after activation. Activation of the sigma(1) receptor results in modulation of calcium mobilization from inositol trisphosphate receptor-gated intracellular pools and, at the plasma membrane, in modulation of several neurotransmitter responses. Behaviorally, sigma(1) receptors are involved in learning and memory, response to stress and depression, psychostimulant-induced sensitization, vulnerability to addiction and pain perception. Numerous synthetic compounds bind to sigma(1) receptor, playing the role of activator/agonist or blocker/antagonist, and these include benzomorphans, neuroleptics, antidepressants, cocaine, peptides related to neuropeptide Y or calcitonin gene-related peptide. It is also the case of neuro(active)steroids, i. e., circulating neuroactive steroids and neurosteroids synthesized de novo by the brain, which appear as the most important endogenous modulators of sigma(1) receptor. Pregnenolone and dehydroepiandrosterone act as sigma(1) receptor agonists and progesterone is a potent antagonist. The present paper will review the molecular and biochemical features concerning the sigma(1) receptor and focus on the recent studies examining the impact of the neuro(active)steroid/sigma(1) receptor interaction on the antidepressant activity of sigma(1) receptor agonists in the context of neurodegenerative diseases.
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PMID:Neurosteroids and sigma1 receptors, biochemical and behavioral relevance. 1554 83

Daily treatment of systemic mastocytosis with high-dose interferon-alfa often is not tolerated because of clinical or hematologic side effects. We report successful treatment of a patient with systemic mastocytosis, who was positive for the D816V mutation, with interferon alfa-2b at 10 million units three times per week. During 5 years of treatment, bone marrow infiltration by mast cells decreased from 50 to < or =5%, and there was a decrease (urinary N-methylhistamine excretion, 75%; serum tryptase concentration, 98%) or normalization (serum calcitonin value, urinary prostaglandin F2alpha excretion) of mast cell mediators. Side effects included mild depression (untreated) and biochemical hypothyroidism easily managed with supplemental levothyroxine.
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PMID:Successful treatment of systemic mastocytosis with high-dose interferon-alfa: long-term follow-up of a case. 1560 59

Uncorrected hypercalcemia can cause clinical signs such as polyuria, polydipsia, vomiting, diarrhea, lethargy, and depression and contributes to the development of primary renal failure and soft tissue mineralization. Treatment of hypercalcemia includes diagnosis and treatment of the underlying disease process and some combination of excracellular fluid volume expansion by administration of fluids intravenously and administration of glococorticosteroids, salmon calcitonin, and furosemide. Bisphosphonates such as pamidronate disodium also may be safe and effective in the treatment of hypercalcemia. The purpose of our study was to characterize the efficacy and safety of pamidronate in the treatment of hypercalcemia attritutable to several different disease processes in the dog and cat. Seven dogs and 2 cats were administered pamidronate at a dose of 1.05-2.0 mg/kg IV for a variety of disease processes, including neoplasia (n = 4), calcipotriene toxicity (n = 3), nocardiosis (n = 1), and idiopathic hypercalcemia with chronic renal failure (n = 1). In all the animals, IV pamidronate administration rapidly decreased serum calcium concentrations without evident toxicosis. Two animals received pamidronate several times without obvious toxicosis. On the basis of the findings in our retrospective study, pamidronate may be a safe and effective drug with which to lower both serum total and ionized calcium concentrations in patients with hypercalcemia arising from a wide variety of underlying disease processes.
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PMID:Uses and effectiveness of pamidronate disodium for treatment of dogs and cats with hypercalcemia. 1571 44


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