Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zonisamide is an antiepileptic drug used as adjunctive therapy for refractory partial seizures in adults. Because of the multiple mechanisms of action, it shows a broad spectrum of anticonvulsant activity and has been effective in several types of seizures, including partial and generalized seizures, tonic-clonic seizures and absence seizures in patients unresponsive to other anticonvulsants. Myoclonic epilepsy, Lennox-Gastaut syndrome and infantile spasms have also been treated effectively with zonisamide. Recent clinical studies have demonstrated additional potential for therapeutic use in neuropathic pain, bipolar disorder, migraine, obesity, eating disorders and Parkinson's disease. Despite adverse events, zonisamide is relatively safe and well tolerated in patients, and shows low discontinuation rate. It has a good pharmacokinetic profile and a low drug interaction potential. Zonisamide is considered as a drug that effectively reduces the frequency of partial seizures.
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PMID:Zonisamide: review of its use in epilepsy therapy. 1634 Dec 90

Zonisamide and topiramate are two antiepileptic drugs known to induce weight loss in epilepsy patients. These molecules were recently shown to act as carbonic anhydrase (CA) inhibitors, being presumed that the weight loss may be due to the inhibition of the mitochondrial isozymes CA VA and CA VB involved in metabolic processes, among which lipid biosynthesis. To better understand the interaction of these compounds with CAs, here, we report a homology modeling and molecular dynamics simulations study on their adducts with human carbonic anhydrase VA (hCA VA). According to our results, in both cases the inhibitor sulfamate/sulfonamide moiety participates in the canonical interactions with the catalytic zinc ion, whereas the organic scaffold establishes a large number of van der Waals and polar interactions with the active site cleft. A structural comparison of these complexes with the corresponding homologues with human carbonic anhydrase II (hCA II) provides a rationale to the different affinities measured for these drugs toward hCA VA and hCA II. In particular, our data suggest that a narrower active site cleft, together with a different hydrogen bond network arrangement of hCA VA compared to hCA II, may account for the different Kd values of zonisamide and topiramate toward these physiologically relevant hCA isoforms. These results provide useful insights for future design of more isozyme-selective hCA inhibitors with potential use as anti-obesity drugs possessing a novel mechanism of action.
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PMID:Molecular modeling study for the binding of zonisamide and topiramate to the human mitochondrial carbonic anhydrase isoform VA. 1742 Jan 32

Obesity is widespread disease both in the developed and developing world, which currently affects over 300 million individuals worldwide and is associated with premature mortality and chronic morbidity. Although diet, physical activity and behavioral modifications should theoretically help in controlling this condition, very often these strategies are insufficient to normalize the multiple risks associated with this condition. Thus, pharmacological interventions for the treatment of this disease are essential. Paradoxically, the currently available drugs for the treatment of obesity are very few, their mechanism of action is hardly understood and their side effects are generally quite serious. Therefore, novel effective anti-obesity drugs possessing different mechanisms of action are needed. In this review we describe in detail a possible new approach for the treatment and prophylaxis of this disease based on the inhibition of Carbonic Anhydrases (CAs, EC 4.2.1.1), enzymes involved in several steps of de novo lipogenesis. In particular, we summarize here a series of kinetic and structural studies recently reported on Topiramate (TPM) and Zonisamide (ZNS), two antiepileptic drugs showing strong CA inhibitory properties, that were shown to induce persistent weight loss in obese patients. On the basis of the reviewed studies we suggest that the use of TPM and ZNS as lead molecules for the design of CA inhibitors targeting isozymes involved in lipogenesis could represent the beginning of a very promising approach for the treatment of obesity.
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PMID:Are carbonic anhydrase inhibitors suitable for obtaining antiobesity drugs? 1833 11

Zonisamide (ZNS), a sulfonamide antiepileptic drug, is indicated as an adjunct therapy for partial seizure disorders with and without secondary generalization. ZNS has a favorable pharmacokinetic profile because of its rapid absorption and high bioavailability. Its activity is related to the blockade of voltage gated sodium and calcium channels, modulation of central dopaminergic, GABAergic, and serotonergic functions, as well as inhibition of carbonic anhydrase and monoamine oxidase B. ZNS has potential efficacy for an array of neuropsychiatric disorders including migraine and other headache syndromes, neuropathic pain, Parkinson's disease, essential tremor, stroke, obesity, anxiety, bipolar and binge-eating disorders.
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PMID:Therapeutic role of zonisamide in neuropsychiatric disorders. 1878 51

Insomnia is a sleep trouble in which the patient has difficulties in falling or in staying asleep. There are patients who fall asleep easily, but wake up too early; others have troubles in falling asleep and a third category has troubles with both falling and staying asleep. Independent of the type of insomnia, the final result is a poor-quality sleep, responsible for depressive or irritable mood, loss in concentration, learning and memory capacities. Sleep is essential to emotional and physical health. Inadequate sleep over a period of time is increasing the risks for obesity, diabetes, heart disease and depression. People suffering of chronic insomnia show an increased predisposition for psychiatric problems. People who had sleep troubles reported impaired ability to fulfill tasks involving memory, learning, logical reasoning and mathematical operations. New studies show that insomnia might be a result of the decrease of gamma-aminobutyric acid (GABA), a neurochemical responsible for the decrease of activity in many brain areas. Lower brain GABA levels were also found in people with major depressive disorder and anxiety disorders. Hypnotics, such as benzodiazepines are acting increasing the activity of the GABA neurons. Exposure to stress is associated with a greater risk for insomnia, with individual differences. Stress activates the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. Increased activity of HPA axis is stimulating the secretion of corticotropin-releasing hormone, further inducing sleep disruption. Insomnia is also associated with depression and anxiety disorders, in which the HPA axis is characteristically overactive. People who show predisposition to sleep troubles have a hyperactive sympathetic nervous system, they are usually suffering from hyperarousal and they have a more intense response to stressful events. Primary sleep troubles (insomnia) has no apparent causes, is lasting more than one month, and is affecting approximately a quarter of the adult population. Secondary insomnia is associated with chronic heart and/or lung diseases, medication which interfere with onset or duration of sleep, constant change of the sleep habits, restless leg syndrome, etc. Besides lifestyle changes and cogn itive-behavioral therapy, in the treatment of insomnia are used hypnotic medicines, advised to be prescribed on short-term cures of one or two weeks. Benzodiazepines are inducing and maintaining sleep. Longer use is responsible for severe side effects--dependency and withdrawal syndrome, daytime drowsiness and dizziness, low blood pressure, memory troubles and change in the melatonin secretion during night-time period. For these reasons were created non-benzodiazepines hypnotics--zolpidem, zaleplon, which are as effective as benzodiazepines, but have fewer side effects. Nevertheless the use of these hypnotics is also restricted to 7-10 days. Zopiclone (Imovane) another short-acting non-benzodiazepine hypnotic has a different chemical structure, but a pharmacologic profile similar to that of the benzod iazepines; the treatment should be of maximum four weeks. Besides generally known concerns related to the use of hypnotics (residual sedative effects, memory impairment, rebound insomnia, abuse, dose escalation, dependency and withdrawal problems) it was signaled a risk of death associated with the use of current hypnotic medications.
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PMID:Main neuroendocrine features and therapy in primary sleep troubles. 2327 43