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)

Treatment of migraine presents special problems in the elderly. Co-morbid diseases may prohibit the use of some medications. Moreover, even when these contraindications do not exist, older patients are more likely than younger ones to develop adverse events. Managing older migraine patients, therefore, necessitates particular caution, including taking into account possible pharmacological interactions associated with the greater use of drugs for concomitant diseases in the elderly. Paracetamol (acetaminophen) is the safest drug for symptomatic treatment of migraine in the elderly. Use of selective serotonin 5-HT(1B/1D) receptor agonists ('triptans') is not recommended, even in the absence of cardiovascular or cerebrovascular risk, and NSAID use should be limited because of potential gastrointestinal adverse effects. Prophylactic treatments include antidepressants, beta-adrenoceptor antagonists, calcium channel antagonists and antiepileptics. Selection of a drug from one of these classes should be dictated by the patient's co-morbidities. Beta-adrenoceptor antagonists are appropriate in patients with hypertension but are contraindicated in those with chronic obstructive pulmonary disease, diabetes mellitus, heart failure and peripheral vascular disease. Use of antidepressants in low doses is, in general, well tolerated by elderly people and as effective, overall, as in young adults. This approach is preferred in patients with concomitant mood disorders. However, prostatism, glaucoma and heart disease make the use of tricyclic antidepressants more difficult. Fewer efficacy data in the elderly are available for selective serotonin reuptake inhibitors, which can be tried in particular cases because of their good tolerability profile. Calcium channel antagonists are contraindicated in patients with hypotension, heart failure, atrioventricular block, Parkinson's disease or depression (flunarizine), and in those taking beta-adrenoceptor antagonists and monoamine oxidase inhibitors (verapamil). Antiepileptic drug use should be limited to migraine with high frequency of attacks and refractoriness to other treatments. Promising additional strategies include ACE inhibitors and angiotensin II type 1 receptor antagonists because of their effectiveness and good tolerability in patients with migraine, particularly in those with hypertension. Because of its favourable compliance and safety profile, botulinum toxin type A can be considered an alternative treatment in elderly migraine patients who have not responded to other currently available migraine prophylactic agents. Pharmacological treatment of migraine poses special problems in regard to both symptomatic and prophylactic treatment. Contraindications to triptan use, adverse effects of NSAIDs, and unwanted reactions to some antiemetics reduce the list of drugs available for the treatment of migraine attacks in elderly patients. The choice of prophylactic treatment (beta-adrenoceptor antagonists, calcium channel antagonists, antiepileptics, and more recently, some antihypertensive drugs) is influenced by co-morbidities and should be directed at those drugs that are believed to have fewer adverse effects and a better safety profile. Unfortunately, for most of these drugs, efficacy studies are lacking in the elderly.
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PMID:Practical considerations for the treatment of elderly patients with migraine. 1687 31

We report the case of a premature newborn (gestational age 33 weeks) with congenital glaucoma. After a trabeculotomy high intraocular pressure persisted, leading to adjuvant treatment with timolol and--when the infant was 3 weeks old--with brimonidine. After the first application of topical brimonidine the infant developed such severe apnoeic spells that intubation and temporary ventilation were necessary. A review of the literature reveals that when used in young infants brimonidine eye drops can potentially have toxic effects on the central nervous system (e.g. respiratory depression). The use of topical brimonidine is therefore not advised in this age group.
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PMID:[Depression of respiration via toxic effects on the central nervous system following use of topical brimonidine in an infant with congenital glaucoma]. 1733 44

Alzheimer's disease (AD) and Vascular dementia represent the most common forms of dementia. If left unabated, the economic cost of caring for patients with these maladies would consume the entire gross national product of the industrialized world by the middle of this century. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. Many potential neuroprotective drugs tested in clinical trials failed because of intolerable side effects. However, after our discovery of its clinically-tolerated mechanism of action, one putatively neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of dementia. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of both mild and moderate-to-severe Alzheimer's disease and possibly Vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell damage is mediated in part by overactivation of N-methyl-D-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca(2+) influx through the receptor associated ion channel and subsequent free radical formation. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with subsequent normal synaptic transmission. Clinical use has corroborated the prediction that memantine is well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including HIV-associated dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention.
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PMID:Pathologically-activated therapeutics for neuroprotection: mechanism of NMDA receptor block by memantine and S-nitrosylation. 1750 5

Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) isoforms present in the eyes (CA I, II, IV and XII), with sulfonamides such as acetazolamide, methazolamide, ethoxzolamide and dichlorophenamide, is still widely used for the systemic treatment of glaucoma. The mechanism of action of these drugs consists in inhibition of CA isozymes present in ciliary processes of the eye, with the consequent reduction of bicarbonate and aqueous humour secretion, and of elevated intraocular pressure (IOP) characteristic of this disease. As isoforms CA II/IV/XII are present in many other tissues/organs, generally, systemic CAIs possess undesired side effects such as numbness and tingling of extremities; metallic taste; depression; fatigue; malaise; weight loss; decreased libido; gastrointestinal irritation; metabolic acidosis; renal calculi and transient myopia. For avoiding these side effects, recently, topically effective CAIs have been developed in the last 10 years, with two drugs available clinically: dorzolamide and brinzolamide. Both these drugs are applied topically as water solutions/suspensions, alone or in combination with other agents (beta-blockers, prostaglandin derivatives, etc) and produce a consistent and prolonged reduction of IOP. Furthermore, recent reports show both the systemically as well as topically acting sulfonamide CAIs to be effective in the treatment of macular edema, macular degeneration disease, or diabetic retinopathy, for which pharmacological treatment is unavailable up to now. Much research is in act in the search of more effective topically acting CAIs, free of the inconveniences and side effects of the presently available drugs. For achieving this goal, two recently reported strategy, the tail approach and its variant, the sugar-tail approach, were extensively applied for the synthesis of large numbers of derivatives possessing desired physico-chemical properties. Many such new sulfonamides showed promising antiglaucoma activity in animal models of the disease.
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PMID:The development of topically acting carbonic anhydrase inhibitors as antiglaucoma agents. 1833 10

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

The ergot alkaloid derivative nicergoline became clinically available about 35 years ago in the 1970s. Nicergoline has a broad spectrum of action: (i) as an alpha(1)-adrenoceptor antagonist, it induces vasodilation and increases arterial blood flow; (ii) it enhances cholinergic and catecholaminergic neurotransmitter function; (iii) it inhibits platelet aggregation; (iv) it promotes metabolic activity, resulting in increased utilization of oxygen and glucose; and (v) it has neurotrophic and antioxidant properties. Acting on several basic pathophysiological mechanisms, nicergoline has therapeutic potential in a number of disorders. This article provides an overview of the published clinical evidence relating to the efficacy and safety of nicergoline (30 mg twice daily) in the treatment of dementia (including Alzheimer's disease and vascular dementia) and vascular and balance disorders. For dementia of different aetiologies, the therapeutic benefit of nicergoline has been established, with up to 89% of patients showing improvements in cognition and behaviour. After as little as 2 months of treatment, symptom improvement is apparent compared with placebo, and most patients are still improved or stable after 12 months. Concomitant neurophysiological changes in the brain indicate (after only 4-8 weeks' treatment) improved vigilance and information processing. In patients with balance disorders, mean improvements of 44-78% in symptom severity and quality of life have been observed with nicergoline. Although clinical experience with nicergoline in vascular disorders is limited to relatively short-term, small-scale studies, it has been successfully used in rehabilitation therapy of patients with chronic ischaemic stroke. Open-label evaluations suggest that nicergoline may also be valuable in glaucoma, depression and peripheral arterio-pathy. Adverse events of nicergoline, if any, are related to the central nervous system, the metabolic system and the overall body. Most are considered typical symptoms of ergot derivatives. Because of their generally mild and transient nature, treatment discontinuations occur relatively infrequently. The efficacy of nicergoline combined with a favourable safety and tolerability profile at commonly applied doses (60 mg/day) make this agent a valuable therapy in patients with mild to moderate dementia, vascular diseases and balance disorders.
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PMID:Therapeutic use of nicergoline. 1866 1

Alpha(2)-adrenoceptors mediate diverse functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. To determine whether alpha(2)-adrenoceptors on adrenergic neurons or alpha(2)-adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of alpha(2)-agonists, we used the dopamine beta-hydroxylase (Dbh) promoter to drive expression of alpha(2A)-adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-alpha(2A) transgenic mice were crossed with double knockout mice lacking both alpha(2A)- and alpha(2C)-receptors to generate lines with selective expression of alpha(2A)-autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express alpha(2A)- and alpha(2C)-receptors in both adrenergic and nonadrenergic cells, and alpha(2A)/alpha(2C) double-knockout mice, which do not express these receptors in any cell type. We were surprised to find that only a few functions previously ascribed to alpha(2)-adrenoceptors were mediated by receptors on adrenergic neurons, including feedback inhibition of norepinephrine release from sympathetic nerves and spontaneous locomotor activity. Other agonist effects, including analgesia, hypothermia, sedation, and anesthetic-sparing, were mediated by alpha(2)-receptors in nonadrenergic cells. In dopamine beta-hydroxylase knockout mice lacking norepinephrine, the alpha(2)-agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of alpha(2)-adrenoceptor stimulation is not mediated via autoreceptor-mediated inhibition of norepinephrine release. The present study paves the way for a revision of the current view of the alpha(2)-adrenergic receptors, and it provides important new considerations for future drug development.
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PMID:Genetic dissection of alpha2-adrenoceptor functions in adrenergic versus nonadrenergic cells. 1925 26

Family physicians have an essential role in assessing, identifying, treating, and preventing or delaying vision loss in the aging population. Approximately one in 28 U.S. adults older than 40 years is visually impaired. Vision loss is associated with depression, social isolation, falls, and medication errors, and it can cause disturbing hallucinations. Adults older than 65 years should be screened for vision problems every one to two years, with attention to specific disorders, such as diabetic retinopathy, refractive error, cataracts, glaucoma, and age-related macular degeneration. Vision-related adverse effects of commonly used medications, such as amiodarone or phosphodiesterase inhibitors, should be considered when evaluating vision problems. Prompt recognition and management of sudden vision loss can be vision saving, as can treatment of diabetic retinopathy, refractive error, cataracts, glaucoma, and age-related macular degeneration. Aggressive medical management of diabetes, hypertension, and hyperlipidemia; encouraging smoking cessation; reducing ultraviolet light exposure; and appropriate response to medication adverse effects can preserve and protect vision in many older persons. Antioxidant and mineral supplements do not prevent age-related macular degeneration, but may play a role in slowing progression in those with advanced disease.
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PMID:Vision loss in older persons. 1951 94

The increase in serotonin (5-HT) neurotransmission is considered to be one of the most efficacious medical approach to depression and its related disorders. The selective serotonin reuptake inhibitors (SSRIs) represent the most widely antidepressive drugs utilized in the medical treatment of depressed patients. Currently available SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. The primary SSRIs pharmacological action's mechanism consists in the presynaptic inhibition on the serotonin reuptake, with an increased availability of this amine into the synaptic cleft. Serotonin produces its effects as a consequence of interactions with appropriate receptors. Seven distinct families of 5-HT receptors have been identified (5-HT(1) to 5-HT(7)), and subpopulations have been described for several of these. The interaction between serotonin and post-synaptic receptors mediates a wide range of functions. The SSRIs have a very favorable safety profile, although clinical signs of several unexpected pathologic events are often misdiagnosed, in particular, those regarding the eye. In all cases reported in the literature the angle-closure glaucoma represents the most important SSRIs-related ocular adverse event. Thus, it is not quite hazardous to hypothesize that also the other reported and unspecified visual disturbances could be attributed - at least in some cases - to IOP modifications. The knowledge of SSRIs individual tolerability, angle-closure predisposition and critical IOP could be important goals able to avoid further and more dangerous ocular side effects.
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PMID:Selective serotonin reuptake inhibitors: a review of its effects on intraocular pressure. 1958 51

Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K(i)=13.2nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.
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PMID:Characterization of a novel non-steroidal glucocorticoid receptor antagonist. 2003 23


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