Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
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The bisphosphonates are the treatment of choice in hypercalcaemia of malignancy. However, plicamycin (mithramycin) an calcitonin treatment may still be of value should bisphophonate treatment fail, and gallium nitrate has recently been introduced as an alternative therapy. We analysed the tolerability of different treatments based on articles identified in a Medline search covering the period 1979 through September 1998. Articles were included if they met two criteria: (i) quantitative assessment of adverse effects; (ii) inclusion of > or = 10 patients. Although bisphosphonates are generally well tolerated, elevation of serum creatinine level, nausea/vomiting and fever have been reported following their application. Patients receiving etidronate (n = 268) or clodronate (n = 127) more frequently experienced creatinine elevation (8 and 5%, respectively) than did patients receiving pamidronate (n = 424; 2%), aledronate (n = 79; 0%), or ibandronate (n = 203; <1%). The difference in the frequency of reported creatinine level elevations reached statistical significance only for etidronate (z-test: p < 0.001 versus pamidronate; p < 0.02 versus alendronate; p < 0.001 versus ibandronate). With regard to the frequency of creatinine level elevations, clodronate treatment did not differ significantly from treatment with pamidronate, alendronate and ibandronate. An exception among the bisphosphonates is tiludronate, which has been reported on s a treatment of hypercalcaemia in only 1 study (n = 19) resulting in 1 case of lethal and 1 case of manageable acute renal failure. Nausea and vomiting are rare adverse effects of bisphosphonate treatment but seem to be more frequent with first generation drugs: etidronate (8%) and clodronate (7%) versus pamidronate (2%) [p < 0.001 and 0.009, respectively] and versus ibandronate (<1%) [p< 0.002 and 0.02, respectively]. Bisphosphonates containing a nitrogen atom were associated with an acute phase reaction leading to reported fever in 16% of pamidronate, 20% of aledronate, and 11% of ibandronate-treated patients. The most frequently reported adverse effects of treatment with the cytostatic drug plicamycin were hepatotoxicity (26%), nausea/vomiting (23%), and serum creatinine level elevation (5%). Furthermore. plicamycin application was associated with bone marrow suppression and a bleeding tendency due to abnormalities in multiple clotting factors and platelet dysfunction. The use of calcitonin is limited more by the short duration of its therapeutic effect than by toxicities (most frequent: nausea/vomiting in 16% of treated cases). The few publications on gallium nitrate in the treatment of hypercalcaemia of malignancy characterise it as an efficient drug, which is, however, associated with a higher frequency of renal toxicity (10%) and of nausea and vomiting (14%) than are the bisphosphonates.
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PMID:Comparative tolerability of drug therapies for hypercalcaemia of malignancy. 1055 53

Migraine is one of the most common neurological disorders, involving periodical attacks of headache and nausea as well as a plethora of other symptoms. Although considerable progress has been made, the pathophysiology of migraine is still not understood. However, several observations point to an involvement of calcitonin gene-related peptide (CGRP). Migraine headache involves the activation of the trigeminal system and dilatation of cranial vessels. CGRP is localized to neurons in the trigeminal ganglia and CGRP levels are increased during a migraine attack, presumably causing the vasodilation observed. Accordingly, it is conceivable that inhibition of CGRP-evoked dilatation of the cranial vessels may provide a novel treatment for migraine headache. The non-peptidic CGRP antagonist BIBN-4096BS (Boehringer Ingelheim) is presently under clinical investigation to assess the importance of CGRP in migraine headache and to answer the question of whether the concept of CGRP antagonists may offer advantages, e.g., higher efficacy, lower recurrence rate or improved side-effect profile, compared to the currently used antimigraine drugs.
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PMID:Development of CGRP antagonists for the treatment of migraine. 1171 13

Hypercalcemia is one of the metabolic complications associated with cancer. To assess the frequency of hypercalcemia in patients with squamous cell carcinoma (SCC), 242 patients who were evaluated as having SCC in the oral cavity between July 1995 and June 2001 were investigated. All patients were periodically monitored for their serum level of calcium (Ca). Hypercalcemia was defined as a serum Ca concentration higher than 11 mg/dl. By this definition, hypercalcemia was detected in 12 of the 242 patients (5.0%). All 12 patients were at an advanced stage of oral SCC. In these 12 patients, the serum level of parathyroid hormone-related protein (PTH-rP) was also significantly elevated. Therefore, we diagnosed these diseases as humoral hypercalcemia of malignancy (HHM). Moreover, we studied the efficacy of anti-hypercalcemic therapy on the quality of life (QOL). The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 was used for estimation of QOL. The patients with HHM who were administrated drugs such as bisphosphonate and calcitonin showed a reduction in their Ca and PTH-rP levels, and the six of ten EORTC QLQ-C30 subscales (emotional functioning, cognitive functioning, fatigue, dyspnoea, nausea/vomiting and appetite loss) were also improved after the anti-hypercalcemic therapy. However, these suppressive effects were temporary. The median survival time after the diagnosis of HHM was only 54.9+/-18.3 days (range 27-86 days). Therefore, HHM in SCC appears to be an ominous prognostic sign. Although anti-hypercalcemic therapy has a palliative role, the patients may be in less discomfort during the terminal stage of their illness.
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PMID:Hypercalcemic complication in patients with oral squamous cell carcinoma. 1272 78

Hypercalcemia is a common, life-threatening metabolic disorder that can be associated with cancer. Its pathophysiology includes enhanced osteoclastic bone resorption and decreased renal excretion of extracellular calcium. Symptoms of hypercalcemia include nausea, vomiting, bone pain, polyuria, renal insufficiency, bradycardia, and arrhythmia. The goals of medical therapy are to inhibit bone resorption and promote renal calcium excretion. Hydration is the first step in management. Treatments for hypercalcemia include phosphates, calcitonin, bisphosphonates, and gallium nitrate. Although intravenous phosphates prevent intestinal calcium absorption and inhibit mineral and bone matrix resorption, serious adverse events include renal failure, hypotension, extraskeletal calcification, and severe hypocalcemia. Calcitonin has a rapid onset of action and can lower serum calcium concentrations within hours, but its usefulness is limited by its short duration of effect and the development of tachyphylaxis. Bisphosphonates are effective inhibitors of bone resorption but appear to have decreased response rates in hypercalcemic patients with high levels of parathyroid-related protein. Gallium nitrate, an antitumor agent noncytotoxic to osteoclasts and bone cells, appears to be more effective than pamidronate, etidronate, and calcitonin in the treatment of cancer-related hypercalcemia. Importantly, unlike bisphosphonates, gallium nitrate is effective in both parathyroid-related protein-mediated and non-parathyroid-related protein-mediated hypercalcemia.
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PMID:Treatment of cancer-related hypercalcemia: the role of gallium nitrate. 1277 55

The bowel exhibits reflexes in the absence of CNS input. To do so, epithelial sensory transducers, such as enterochromaffin (EC) cells, activate the mucosal processes of intrinsic (IPANs) and extrinsic primary afferent (sensory) neurons. EC cells secrete serotonin (5-HT) in response to mucosal stimuli. Submucosal IPANs, which secrete acetylcholine and calcitonin gene-related peptide, initiate peristaltic and secretory reflexes and are activated via "5-HT1P" receptors. Release of neurotransmitters is enhanced by 5-HT4 receptors, which are presynaptic and strengthen neurotransmission in prokinetic pathways. 5-HT3 receptors mediate signaling to the CNS and thus ameliorate cancer chemotherapy-associated nausea and the visceral hypersensitivity of diarrhea-predominant irritable bowel syndrome (IBS-D); however, because 5-HT3 receptors also mediate fast ENS neurotransmission and activate myenteric IPANs, they may be constipating. 5-HT4 agonists are prokinetic and relieve discomfort and constipation in IBS-C and chronic constipation. 5-HT4 agonists do not initiate peristaltic and secretory reflexes but strengthen pathways that are naturally activated. Serotonergic signaling in the mucosa and the ENS is terminated by a transmembrane 5-HT transporter, SERT. Mucosal SERT and tryptophan hydroxylase-1 expression are decreased in experimental inflammation, IBS-C, IBS-D, and ulcerative colitis. Potentiation of 5-HT due to the SERT decrease could account for the discomfort and diarrhea of IBS-D, while receptor desensitization may cause constipation. Similar symptoms are seen in transgenic mice that lack SERT. The loss of mucosal SERT may thus contribute to IBS pathogenesis.
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PMID:Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. 1579 84

Primary headaches such as migraine and cluster headache are neurovascular disorders. Migraine is a painful, incapacitating disease that affects a large portion of the adult population with a substantial economic burden on society. The disorder is characterised by recurrent unilateral headaches, usually accompanied by nausea, vomiting, photophobia and/or phonophobia. A number of hypothesis have emerged to explain the specific causes of migraine. Current theories suggest that the initiation of a migraine attack involves a primary central nervous system (CNS) event. It has been suggested that a mutation in a calcium gene channel renders the individual more sensitive to environmental factors, resulting in a wave of cortical spreading depression when the attack is initiated. Genetically, migraine is a complex familial disorder in which the severity and the susceptibility of individuals are most likely governed by several genes that vary between families. Genom wide scans have been performed in migraine with susceptibility regions on several chromosomes some are associated with altered calcium channel function. With positron emission tomography (PET), a migraine active region has been pointed out in the brainstem. In cluster headache, PET studies have implicated a specific active locus in the posterior hypothalamus. Both migraine and cluster headache involve activation of the trigeminovascular system. In support, there is a clear association between the head pain and the release of the neuropeptide calcitonin gene-related peptide (CGRP) from the trigeminovascular system. In cluster headache there is, in addition, release of the parasympathetic neuropeptide vasoactive intestinal peptide (VIP) that is coupled to facial vasomotor symptoms. Triptan administration, activating the 5-HT(1B/1D) receptors, causes the headache to subside and the levels of neuropeptides to normalise, in part through presynaptic inhibition of the cranial sensory nerves. These data suggest a central role for sensory and parasympathetic mechanisms in the pathophysiology of primary headaches. The positive clinical trial with a CGRP receptor antagonist offers a new promising way of treatment.
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PMID:Neurobiology in primary headaches. 1591 51

Opiates are the primary treatment for pain management in cancer patients reporting moderate to severe pain, and are being increasingly used for non-cancer chronic pain. However, prolonged administration of opiates is associated with significant problems including the development of antinociceptive tolerance, wherein higher doses of the drug are required over time to elicit the same amount of analgesia. High doses of opiates result in serious side effects such as constipation, nausea, vomiting, dizziness, somnolence, and impairment of mental alertness. In addition, sustained exposure to morphine has been shown to result in paradoxical pain in regions unaffected by the initial pain complaint, and which may also result in dose escalation, i.e. 'analgesic tolerance'. A concept that has been gaining considerable experimental validation is that prolonged use of opioids elicits paradoxical, abnormal pain. This enhanced pain state requires additional opioids to maintain a constant level of antinociception, and consequently may be interpreted as antinociceptive tolerance. Many substances have been shown to block or reverse antinociceptive tolerance. A non-inclusive list of examples of substances reported to block or reverse opioid antinociceptive tolerance include: substance P receptor (NK-1) antagonists, calcitonin gene-related peptide (CGRP) receptor antagonists, nitric oxide (NO) synthase inhibitors, calcium channel blockers, cyclooxygenase (COX) inhibitors, protein kinase C inhibitors, competitive and non-competitive antagonists of the NMDA (N-methyl-D-aspartate) receptor, AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) antagonists, anti-dynorphin antiserum, and cholecystokinin (CCK) receptor antagonists. Without exception, these substances are also antagonists of pain-enhancing agents. Prolonged opiate administration indeed induces upregulation of substance P (SP) and calcitonin gene-related peptide (CGRP) within sensory fibers in vivo, and this is accompanied by an enhanced release of excitatory neurotransmitters and neuropeptides from primary afferent fibers upon stimulation. The enhanced evoked release of neuropeptides is correlated with the onset of abnormal pain states and opioid antinociceptive tolerance. Importantly, the descending pain modulatory pathway from the brainstem rostral ventromedial medulla (RVM) via the dorsolateral funiculus (DLF) is critical for maintaining the changes observed in the spinal cord, abnormal pain states and antinociceptive tolerance, because animals with lesion of the DLF did not show enhanced evoked neuropeptide release, or develop abnormal pain or antinociceptive tolerance upon sustained exposure to opiates. Microinjection of either lidocaine or a CCK antagonist into the RVM blocked both thermal and touch hypersensitivity as well as antinociceptive tolerance. Thus, prolonged opioid exposure enhances a descending pain facilitatory pathway from the RVM that is mediated at least in part by CCK activity and is essential for the maintenance of antinociceptive tolerance.
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PMID:Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? 1621 2

A 78-year-old man with severe chronic obstructive pulmonary disease presented to our pain medicine clinic for treatment of post herpetic neuralgia. Pharmacotherapy with tricyclic antidepressants, anticonvulsants, tramadol and traditional analgesics had failed, primarily due to adverse drug effects, particularly sedation, dizziness and nausea. Consequently, intravenous salmon calcitonin was administered, based on evidence of efficacy in the treatment of other neuropathic pain syndromes and its relatively benign side-effects profile. The patient reported immediate and sustained improvement in his post herpetic neuralgia for over two months, without adverse effects from the calcitonin therapy.
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PMID:Salmon calcitonin in the treatment of post herpetic neuralgia. 1706 47

Adjuvant analgesics are drugs that are not primarily used as analgesics but can produce analgesia in certain types of pain. Adjuvant analgesics can be administered together with non-opioid and opioid analgesics on each step of the WHO analgesic ladder. They should be given when an additional or specific indication exists, but should not be used as a substitute for a thorough treatment with opioids and nonopioids. Adjuvant analgesics can be classified into groups according to the type of pain to be treated: continuous neuropathic pain or lancinating neuropathic pain, sympathetically maintained pain, bone pain and those for multipurpose use. Adjuvant drugs used for continuous neuropathic pain include local anaesthetics, clonidine, capsaicin, and antidepressants. Tricyclic antidepressants are the group that have been best investigated, and are therefore the drugs of choice. An analgesic effect is probably produced via enhancement of transmitter concentrations in pain-modulating pathways. This occurs at lower doses than those necessary to treat depression. Anticholinergic actions, acute glaucoma, constipation, orthostatic hypotension and cardiac arrhythmias are adverse effects that are seen predominantly with teritiary amine drugs and less often with secondary amine compounds. Initial doses should be small to avoid these adverse effects. Local anaesthetics are used less often, because of the high incidence of side effects (especially with tocainide, flecainide). An analgesic effect has been described in neuropathic pain, however, probably due to membrane stabilization and reduction of aberrant signal conduction. Mexiletine is considered to be the safest local anaesthetic, and should be used initially in small doses (100-150 mg/d). If side effects do not occur, doses can be increased step-wise up to 900 mg/d. Local anaesthetics are indicated for the treatment of severe neuropathic pain; this treatment is contraindicated in patients with cardiac arrhythmias. Systemic or intrathecal clonidine can be tried in neuropathic pain refractory to opioid therapy. The same stands for the topical application of capsaicin in certain types of pain. Lancinating neuropathic pain is an indication for anticonvulsant drugs. Carbamazepine, clonazepam, valproate and phenytoin seem to reduce aberrant signal conduction in damaged nerves in a manner similar to the supression of epileptiform activities in the brain. Common side effects include sedation, dizziness and nausea. Of greater concern are the more severe side effects, such as bone marrow depression (carbamazepine) and hepatotoxicity (phenytoin, valproate). Low initial doses and stepwise increases in dosage, repeated blood counts, and monitoring of plasma levels are helpful in recognizing and avoiding these adverse effects. Baclofen, a GABA agonist primarily used for spasticity, is effective in the treatment of trigeminal neuralgia and is often used in the management of lancinating pain of unspecific origin. The initial dosage is 10-15 mg/d, increasing to 30-90 mg/d, or higher. If neural blockade fails to reduce sympathetically maintained pain sufficiently specific adjuvants can be used. Sympatholytic drugs, e.g. phenoxybenzamine (60-120 mg/d) or prazosin, can be administered to patients without major cardiovascular dysfunction. There is experimental evidence of the involvement of calcium channels in nociception, and a beneficial clinical effect of nifidepine in reflex sympathetic dystrophy (RDS) has been demonstrated. Bone pain is common in tumor patients and can often be treated effectively with non-steroidal anti-inflammatory drugs. Biphosphonates (etidronate, clodronate, pamidronate derivates) also produce analgesic effects in patients with bone metastases. However, differences among the various compounds have not been clearly evaluated yet. Potent and specific radioisotopes are still under development and the use of calcitonin in bone pain is considered controversial.
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PMID:[Pharmacotherapy of cancer pain. 3. Adjuvant drugs.]. 1841 35

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, alpha-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT(1B/1D) receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT(2) receptor antagonists, Ca(2+) channel blockers, and beta-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT(1-7)), adrenergic (alpha(1), alpha(2,) and beta), calcitonin gene-related peptide (CGRP(1) and CGRP(2)), adenosine (A(1), A(2), and A(3)), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.
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PMID:Current and prospective pharmacological targets in relation to antimigraine action. 1862 30


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