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)

For particles to be useful medicinal aerosols, not only their aerodynamic diameter has to be on the order of a few micrometers but also they have to be chemically and physically stable. Manufacture of respirable particles is a technical challenge because as particles are reduced in size by conventional milling techniques, their cohesiveness greatly increases and physical and chemical stability is often compromised by the formation of amorphous material. In the present study, we describe the use of trileucine for the preparation of dry powders suitable for inhalation via spray drying of a wide range of drugs (i.e., asthma therapeutics such as albuterol and cromolyn, and anti-infectives such as netilmicin and gentamicin, as well as therapeutic proteins and peptides such as human growth hormone and salmon calcitonin). The glass transition of spray-dried trileucine is dependent on the pH and can be correlated with the proportion of the anion, cation, and zwitterion concentration in solution. Trileucine glass transition is relatively high ( approximately 104 degrees C) enabling long-term room temperature stability. The solubility of trileucine is dependent on the pH and is lowest at neutral pH ( approximately 6.8 mg/mL). Trileucine's low aqueous solubility enables the formation of low-density corrugated particles and promotes the formation of trileucine coated spray-dried particles, resulting in superior aerosol performance. Trileucine is surface active and promotes the formation of spray-dried powders with a reduced cohesiveness as demonstrated by a decrease in the measured surface energy which correlates with an observed improvement in aerosol performance. Additionally, trileucine competes with the protein on the air/water interface resulting in an additional depression of surface tension in solution which correlates with a decreased denaturation and aggregation in the solid state.
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PMID:Trileucine improves aerosol performance and stability of spray-dried powders for inhalation. 1782 50

Complex regional pain syndrome (CRPS), formerly known as "reflex sympathetic dystrophy," is a chronic neurological disorder characterized by disabling pain, swelling, vasomotor instability, sudomotor abnormality, and impairment of motor function. The disorder usually develops after minor trauma or surgery. No specific diagnostic test is available and, hence, diagnosis is based mainly on history, clinical examination, and supportive laboratory findings. This review gives a synopsis of CRPS and discusses the principles of management based on the limited available literature in the area. A literature search was conducted using electronic bibliographic databases (Medline, Embase, Pubmed, CENTRAL) from 1970 to 2006. Keywords complex regional pain syndrome, reflex sympathetic dystrophy, neuropathic pain, and causalgia were used for the search. Relevant articles from the reference lists in retrieved articles were also studied. There were 3,771 articles published in the area. Seventy-six randomized controlled trials were identified. Most studies were on the role of sympathetic blockade in the treatment of CRPS (n = 13). The role of sympathectomy is unclear, with some studies showing transient benefit and others showing no beneficial effects, with most studies containing only a small number of patients. Nine studies were on bisphosphonates or calcitonin. Studies involving bisphosphonates showed benefit, but studies involving calcitonin showed no definite benefit. Four studies were on cognitive behavioral therapy, physiotherapy, or occupational therapy, all of which demonstrated a potential beneficial effect. Three studies on spinal cord stimulation and two studies each on acupuncture, vitamin C, and steroid all showed a potential beneficial effect in pain reduction. The remaining studies were on miscellanous therapy or combination therapy, making it difficult to draw any conclusions on the effect of treatment. There is very little good evidence in the literature to guide treatment of CRPS. Early recognition and a multidisciplinary approach to management seems important in obtaining a good outcome. Treatments aimed at pain reduction and rehabilitation of limb function form the mainstay of therapy. Comorbidities, such as depression and anxiety, should be treated concurrently.
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PMID:Complex regional pain syndrome: a review. 1834 83

Nociceptive stimuli are modulated at the dorsal horn of the spinal cord. This modulation is performed by various systems working independently complementarily, additively or supra-additively. Non-opioid analgesics relieve pain without a motor blockade. In contrast to spinal opioids a reduced risk of respiratory depression is expected. In the therapy of chronic pain non-opioid analgesics may be an alternative, given alone or in combination with an opioid. Clinically relevant dosages for antinociception mediated by the alphaadrenoceptoragonistclonidine are >/=150 mug epidurally. Clonidine is effective in reducing acute and chronic pain. In combination with opioids the action of the opioids is intensified. Clonidine intensifies and prolongs the action of local anesthetics. If opioid tolerance occurs, epidural clonidine alone or in combination with an opioid has good antinociceptive action.Midazolam, a water-soluble benzodiazepine, was injected spinally for the reduction of pain for various indications (postoperative, malignancy, chronic back pain, spinal spasticity). Spinal benzodiazepine should not be injected into the spine in patients until it has been proven that there are no neurotoxic effects. Intrathecally injectedbaclofen is a well-known means of reducing spinal spasticity. Used in this way, it may have a secondary analgesic effect. No significant direct analgesic effect has so far been demonstrated. Spinalcalcitonin often leads to insufficient pain relief when given alone. Combination with an opioid may reduce the dosage of the opioid. Nausea and vomiting are frequent side effects of spinal calcitonin. Intrathecalsomatostatin produces antinociception. However, in animal studies neurotoxic action has been observed. Administration in man has not yet been proved to be safe. Spinalketamine has procluted controversial results in clinical studies, and has not yet been excluded that the substance is not neurotoxic.Lysine acetylsalicylic acid (L-ASA) has been given intrathecally for the therapy of severe cancer pain and chronic back pain. In most patients good analgesia was observed up to 2 months after a single injection. If neurotoxity can be excluded, L-ASA may be an alternative in the therapy of cancer pain before neurodestructive therapy is done.
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PMID:[Intrathecal and epidural administration of non-opioid analgesics in acute and chronic pain treatment.]. 1841 40

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 and depression coincide in some 20-30% of patients. Although antidepressants (namely tricyclics) are not considered as first-line prophylactic compounds in patients with migraine alone, several clinical trials support a remarkable benefit in the treatment of migraine and related headache disorders. However, treatment with one antidepressant alone often does not suffice to treat both disorders effectively. Therefore, combinations of classical antidepressants with both newer antidepressants and established prophylactic drugs (e.g. beta-adrenergic receptor antagonists [beta-blockers], topiramate and sodium valproate) are required. In addition, acute attack medication (such as triptans, ergotamines or analgesics) is regularly combined with the preventive medication, thus requiring elaborate knowledge about the complex network of potential interactions and contraindications. Fear of potentially serious interactions can frequently lead to insufficient treatment of both underlying disorders, with an enormous impact on the patient's life. Pathophysiologically, multiple neurotransmitters have been attributed an important role in the aetiology of migraine (mainly serotonin and calcitonin gene-related peptide) and depression (among others, serotonin, dopamine and noradrenaline [norepinephrine]). Most drugs used to treat both disorders influence at least one of these transmitter systems, such as classical tricyclics. This review discusses the efficacy of antidepressants in migraine prevention. In addition, recommended combinations in patients with concomitant depression and migraine are presented with regard to their proposed pharmacological mechanism of action and their potential interactions.
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PMID:Antidepressants in long-term migraine prevention. 1919 33

Migraine is a multifactorial and heterogeneous disorder. Diagnostic criteria have been established by the International Headache Society, however these are only supportive in terms of definition. The pathophysiology involves neuronal and vascular phenomena. The former is supported by the cortical spreading depression being the aura correlate and by brainstem and hypothalamic activation during the pain phase; the latter is suggested by the association between migraine and cardiovascular disease and findings of pathological vasoreactivity and endothelial dysfunction. Triptans and calcitonin gene-related peptide receptor antagonists show only a relative migraine-specific action; up to 30% of patients are nonresponders. Despite a clear genetic component, the discovery of specific genes for common forms of migraine remains elusive. Electrophysiological studies consistently indicate a characteristic "dyshabituation" concurring with clinical features of altered sensory perception. The age- and sex-specific pattern along with the effect of external factors on the course of migraine argue in favor of the involvement of epigenetic mechanisms. Knowledge about migraine is still limited, which hampers a definition.
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PMID:[What is migraine?]. 1932 54

We have previously shown that, in AKR and C57BL/6 mice, a genetic polymorphism results in differential expression of the peptide, calcitonin gene-related polypeptide (CGRP), explaining a strain difference in thermal pain sensitivity. Although CGRP is widely distributed in the brain, little is known about the effects of supraspinal CGRP. We used AKR and C57BL/6 mice as a model to explore the effects of centrally (intracerebroventricular) injected CGRP and the CGRP receptor antagonists, CGRP(8-37) and BIBN4096BS, in a series of behavioral assays. Locomotor activity was significantly increased in C57BL/6 mice following the injection of BIBN4096BS and in both strains after the administration of CGRP(8-37) into the third ventricle. CGRP increased paw-withdrawal latencies in C57BL/6 mice only, while decreasing depression-like behaviors in both strains in the forced-swimming test. CGRP and CGRP receptor antagonists failed to modulate activity in the elevated plus maze, a model of anxiety. Taken together, these results suggest a complex role for supraspinal CGRP systems in the regulation of locomotion, nociception, and depression-like behaviors.
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PMID:Role of central calcitonin gene-related peptide (CGRP) in locomotor and anxiety- and depression-like behaviors in two mouse strains exhibiting a CGRP-dependent difference in thermal pain sensitivity. 1938 79

Migraine is a largely inherited disorder of the brain characterized by a complex, but stereotypical, dysfunction of sensory processing. Often the most obvious clinical symptom is head pain, but non-headache symptoms such as photophobia, phonophobia and nausea are clearly part of the typical presentation. This review discusses the current pathophysiological concepts of migraine and migraine aura, such as a possible brainstem dysfunction and cortical spreading depression. Acute and preventive migraine treatment approaches are briefly covered with a focus on shortcomings of the currently available treatment options. A number of different receptors, such as calcitonin gene-related peptide (CGRP), TRPV1 and glutamate receptors, are currently being targeted by potential novel migraine therapeutics. The prospects of this research are exciting and are likely to improve patient care.
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PMID:Migraine pathogenesis and state of pharmacological treatment options. 1991 94

Alpha-calcitonin gene-related peptide (alphaCGRP) is a neuropeptide that is expressed in motor and sensory neurons. It is a powerful vasodilator and has been implicated in diverse metabolic roles. However, its precise physiological function remains unclear. In this study, we investigated the role of alphaCGRP in lipid metabolism by chronically challenging alphaCGRP-specific knockout (alphaCGRP(-/-)) and control mice with high-fat diet regimens. At the start of the study, both animal groups displayed similar body weights, serum lipid markers, and insulin sensitivity. However, alphaCGRP(-/-) mice displayed higher core temperatures, increased energy expenditures, and a relative daytime (nonactive) depression in respiratory quotients, which indicated increased beta-oxidation. In response to fat feeding, alphaCGRP(-/-) mice were comparatively protected against diet-induced obesity with an attenuated body weight gain and an overall reduction in adiposity across all the three diets examined. AlphaCGRP(-/-) mice also displayed improved glucose handling and insulin sensitivity, lower im and hepatic lipid accumulation, and improved overall metabolic health. These findings define a new role for alphaCGRP as a mediator of energy metabolism and opens up therapeutic opportunities to target CGRP action in obesity.
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PMID:Mice lacking the neuropeptide alpha-calcitonin gene-related peptide are protected against diet-induced obesity. 2061 May 63

Cortical spreading depression (CSD) is believed to be a phenomenon underlying migraine auras. The mutations of hemiplegic migraine genes are demonstrated to cause a reduction of CSD threshold. Consistently, tonabersat, which was developed for its ability to inhibit CSD, showed a preventive effect on attacks of migraine with aura. Besides, CSD has also been reported to activate the trigemino-vascular system, which subsequently causes migraine headache. The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) receptor is known as one of the nociceptive receptors, and exists in the dura mater and the trigeminal ganglion. We demonstrated that the dural TRPV1 receptor conducts pain sensation to the trigeminal nucleus caudalis via the trigeminal ganglion, which implies possible contribution of the TRPV1 receptor to migraine headache. Also our recent data have raised the possibility that the TRPV1 receptor may play a pivotal role for the chronification of migraine. Furthermore, the TRPV1 receptor regulates the release of calcitonin gene-related peptide (CGRP). CGRP has been recognized to be associated with migraine because of its potent effect for dilation of intracranial and extracranial blood vessels. Some newly developed CGRP receptor antagonists have revealed the efficaciousness for acute migraine attacks. The present review discusses the relevance of recent advance of basic migraine research to future migraine treatment.
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PMID:[Migraine: advances in the pathophysiology and treatment]. 2140 9


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