Wiley
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Mildronate: An Antiischemic Drug for Neurological Indications ABSTRACT Mildronate (3‐(2,2,2‐trimethylhydrazinium)propionate; MET‐88; meldonium, quaterine) is an antiischemic drug developed at the Latvian Institute of Organic Synthesis. Mildronate was designed to inhibit carnitine biosynthesis in order to prevent accumulation of cytotoxic intermediate products of fatty acid β‐oxidation in ischemic tissues and to block this highly oxygen‐consuming process. Mildronate is efficient in the treatment of heart ischemia and its consequences. Extensive evaluation of pharmacological activities of mildronate revealed its beneficial effect on cerebral circulation disorders and central nervous system (CNS) functions. The drug is used in neurological clinics for the treatment of brain circulation disorders. It appears to improve patients' mood; they become more active, their motor dysfunction decreases, and asthenia, dizziness and nausea become less pronounced. Since the brain does not utilize fatty acids as fuel other mechanisms of action of mildronate in CNS should be considered. Several reports indicate the possible existence of an alternative, non‐carnitine dependent mechanism of action of mildronate. Our recent findings suggest that CNS effects of mildronate could be mediated by stimulation of the nitric oxide production in the vascular endothelium by modification of the γ‐butyrobetaine and its esters pools. It is hypothesized that mildronate may increase the formation of the γ‐butyrobetaine esters. The latter are potent cholinomimetics and may activate eNOS via acetylcholine receptors or specific γ‐butyrobetaine ester receptors. This article summarizes known pharmacological effects of mildronate, its pharmacokinetics, toxicology, as well as the proposed mechanisms of action.
Wiley - Tập 11 Số 2 - Trang 151-168 - 2005
MDL 100,907: A Selective 5‐HT<sub>2A</sub> Receptor Antagonist for the Treatment of Schizophrenia
Wiley - Tập 3 Số 1 - Trang 49-67 - 1997
Glatiramer Acetate in Multiple Sclerosis: A Review ABSTRACT Multiple sclerosis (MS) is considered to be primarily an inflammatory autoimmune disease. Over the last 5 years, our view of the pathogenesis of MS has evolved considerably. The axonal damage was recognized as an early event in the disease process and as an important determinant of long‐term disability. Therefore, the antiinflammatory and neuroprotective strategies are thought to represent promising approach to the therapy of MS. The therapeutic potential of glatiramer acetate (GA), a synthetic amino acid polymer composed of a mixture of l ‐glutamic acid, l ‐lysine, l ‐alanine, and l ‐tyrosine in defined proportions, in MS has been apparent for many years. GA has been shown to be effective in preventing and suppressing experimental allergic encephalomyelitis (EAE), the animal model of MS. GA has been, therefore, evaluated in several clinical studies and found to alter the natural history of relapsing‐remitting (RR)MS by reducing the relapse rate and affecting disability. These findings were confirmed in open‐label follow‐up trials covering more than 10 years of treatment. The trials demonstrated sustained efficacy for GA in slowing the progression of disability. The clinical therapeutic effect of GA is consistent with the results of magnetic resonance imaging (MRI) findings from various clinical centers. At a daily standard dose of 20 mg, s.c., GA was generally well tolerated. The induction of GA‐reactive T‐helper 2‐like regulatory suppressor cells is thought to be the main mechanism of the therapeutic action of this drug. In addition, it was recently shown that GA‐reactive T cells produce neurotrophic factors (e.g., brain‐derived neurotrophic factor [BDNF]) that protect neurons and axons in the area of injury.
Wiley - Tập 13 Số 2 - Trang 178-191 - 2007
Ethosuximide: From Bench to Bedside ABSTRACT Ethosuximide, 2‐ethyl‐2‐methylsuccinimide, has been used extensively for “petit mal” seizures and it is a valuable agent in studies of absence epilepsy. In the treatment of epilepsy, ethosuximide has a narrow therapeutic profile. It is the drug of choice in the monotherapy or combination therapy of children with generalized absence (petit mal) epilepsy. Commonly observed side effects of ethosuximide are dose dependent and involve the gastrointestinal tract and central nervous system. Ethosuximide has been associated with a wide variety of idiosyncratic reactions and with hematopoietic adverse effects. Typical absence seizures are generated as a result of complex interactions between the thalamus and the cerebral cortex. This thalamocortical circuitry is under the control of several specific inhibitory and excitatory systems arising from the forebrain and brainstem. Corticothalamic rhythms are believed to be involved in the generation of spike‐and‐wave discharges that are the characteristic electroencephalographic signs of absence seizures. The spontaneous pacemaker oscillatory activity of thalamocortical circuitry involves low threshold T‐type Ca2+ currents in the thalamus, and ethosuximide is presumed to reduce these low threshold T‐type Ca2+ currents in thalamic neurons. Ethosuximide also decreases the persistent Na+ and Ca2+ ‐activated K+ currents in thalamic and layer V cortical pyramidal neurons. In addition, there is evidence that in a genetic absence epilepsy rat model ethosuximide reduces cortical γ‐aminobutyric acid (GABA) levels. Also, elevated glutamate levels in the primary motor cortex of rats with absence epilepsy (but not in normal animals) are reduced by ethosuximide.
Wiley - Tập 13 Số 2 - Trang 224-239 - 2007
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