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Zoolog Sci. 2008 May; 25(5): 526-32
Mota NR, Robe LJ, Valente VL, Budnik M, Loreto EL
The mesophragmatica group of Drosophila belongs to the virilis-repleta radiation of the Drosophila subgenus. This group comprises 13 Neotropical species that are endemic to the South-American continent and seem to be fundamentally Andean in their distribution. The mesophragmatica-group phylogeny has been inferred previously by other authors based on morphological, cytological, and isozyme analyses. However, the relationships within the group have not yet been completely resolved, although its monophyletic origin has already been confirmed by molecular data. This work attempts to enhance the molecular approach to the relationships among the species of the mesophragmatica group, using both nuclear and mitochondrial markers. Phylogenetic analyses were performed using fragments of the nuclear alcohol dehydrogenase (Adh; 631 bp), alpha-methyldopa (Amd; 1211 bp), dopa-decarboxylase (Ddc; 1105 bp), and hunchback (Hb; 687 bp) genes and the mitochondrial cytochrome oxidase subunit II (COII; 672 bp) gene, and included a total of 4306 bp. The sequences obtained for eight representatives of the mesophragmatica group were analyzed both individually and in combination by distance methods, maximum parsimony, and maximum likelihood. Our results support subdivision of the mesophragmatica group into three main lineages: the first is composed of D. viracochi; the second comprises a clade grouping the sibling species D. pavani and D. gaucha; and the third encompasses D. gasici, D. brncici, and D. mesophragmatica. The best supported scenario suggests that D. viracochi is an early offshoot in the mesophragmatica group, with this and other early branchings occuring in the Pliocene/Pleistocene Epochs, possibly associated with Andean glacial refuges. Also based on the phylogenies obtained, we present a genealogical view of the evolution of previously described characters within the group.
J Chromatogr A. 2008 May 24;
Borst C, Holzgrabe U
A chiral microemulsion electrokinetic chromatography method has been developed for the enantiomeric separation of 3,4-dihydroxyphenylalanine (dopa), its precursors phenylalanine and tyrosine, and the structurally related substance methyldopa. The separations were achieved using an oil-in-water microemulsion, which consisted of the oil-compound ethyl acetate, the surfactant sodium dodecylsulfate (SDS), the co-surfactant 1-butanol, the organic modifier propan-2-ol and 20mM phosphate buffer pH 2.5 or 2.0 as aqueous phase. For enantioseparation sulfated beta-cyclodextrin was added. The resolution of each racemate was optimized by varying the concentration of the buffer and all components of the microemulsion. Enantioseparation could be achieved for dl-dopa, dl-phenylalanine and dl-tyrosine within 13min with a resolution of 4.3, 3.1 and 3.3, respectively, and for methyldopa in 17min (Rs: 1.4). The established methods allowed the detection of dopa, phenylalanine, tyrosine and methyldopa with a limit at 0.5, 1.0, 0.2 and 2.0mug/ml.
Clin Neuropharmacol. 2008 May-Jun; 31(3): 134-40
Müller T, Kolf K, Ander L, Woitalla D, Muhlack S
A matter of debate is the impact of levodopa (LD) application in patients with Parkinson disease (PD) on altered force development and coordination, which are also influenced by the strength of muscles used. The objectives were to compare the motor response, the development of grip strength, and the pharmacokinetic behavior of LD and its main peripheral metabolite 3-O-methyldopa (3-OMD) after intake of 200-mg retarded-release levodopa/carbidopa (LD/CD) and of 150-mg LD/CD/entacapone (LD/CD/EN). Twelve patients with PD received both LD formulations within a standardized setting under double-blind conditions with a crossover design 1 day after the other. Motor symptoms significantly improved, LD plasma concentrations went up, and grip strength increased after both LD/CD and LD/CD/EN administration. There were no significant differences between both conditions with regard to motor response and LD pharmacokinetics. The 3-OMD levels were significantly lower during catechol-O-methyltransferase (COMT) inhibition with entacapone. The LD/CD/EN compound was superior over the retarded-release LD formulation, indicating the impact of LD on grip force. This may be caused by the interference of 3-OMD with the blood-brain barrier transport of LD; therefore, LD delivery is greater during the LD/CD/EN condition. Because the rating scale used does not consider the grip strength, this effect of better blood barrier transport of LD was not reflected. Another hypothesis may be that more acidic metabolites appear during peripheral LD metabolism by means of COMT, whereas COMT inhibition is accompanied by more basic LD metabolites (ie, the tyrosine aminotransferase-dependent substrates dihydroxyphenylpyruvate acetate and trihydroxyphenylacetate). This antiacid scenario may support a better muscle function with a positive impact on muscle excitability and contractibility.
Use of antihypertensive drugs during pregnancy and lactation.
Cardiovasc Ther. 2008; 26(1): 38-49
Ghanem FA, Movahed A
The decision to treat elevated arterial pressure in pregnancy depends on the risk and benefits imposed on the mother and the fetus. Treatment for mild-to-moderate hypertension during pregnancy may not reduce maternal or fetal risk. Severe hypertension, on the other hand, should be treated to decrease maternal risk. Methyldopa and beta-adrenoceptor antagonists have been used most extensively. In acute severe hypertension, intravenous labetalol or oral nifedipine are reasonable choices.
Clin Auton Res. 2008 Mar; 18 Suppl 1: 19-24
Kaufmann H
Neurogenic orthostatic hypotension results from failure to release norepinephrine, the neurotransmitter of sympathetic postganglionic neurons, appropriately upon standing. In double blind, cross over, placebo controlled trials, administration of droxidopa, a synthetic amino acid that is decarboxylated to norepinephrine by the enzyme L: -aromatic amino acid decarboxylase increases standing blood pressure, ameliorates symptoms of orthostatic hypotension and improves standing ability in patients with neurogenic orthostatic hypotension due to degenerative autonomic disorders. The pressor effect results from conversion of droxidopa to norepinephrine outside the central nervous system both in neural and non-neural tissue. This mechanism of action makes droxidopa effective in patients with central and peripheral autonomic disorders.
Clin Ther. 2008 Mar; 30(3): 482-98
Esnault VL, Brown EA, Apetrei E, Bagon J, Calvo C, DeChatel R, Holdaas H, Krcmery S, Kobalava Z,
BACKGROUND: Placebo-controlled trials have found that angiotensin-converting enzyme inhibitors (ACEIs) decrease proteinuria and slow the progression of nondiabetic nephropathies. However, head-to-head comparisons of ACEIs and calcium channel blockers (CCBs) have shown conflicting results. Indeed, a recent metaanalysis concluded that there is still uncertainty about the greater renoprotection seen with ACEIs or angiotensin II receptor blockers in nondiabetic patients with renal disease, particularly when using true glomerular filtration rate (GFR) as the primary outcome. OBJECTIVE: The objective of this 3-year, randomized, multicenter, double-blind, placebo-controlled study was to compare true GFR decline (measured by yearly 51Cr-EDTA blood clearance) in nondiabetic, nonnephrotic adult hypertensive patients with estimated creatinine clearance of 20 to 60 mL/min.1.73 m(2), when randomized to a CCB (amlodipine, 5-10 mg/d) or an ACEI (enalapril, 5-20 mg/d). METHODS: Patients (aged 18-80 years) entered a 4-week placebo run-in washout period and previous antihypertensive drugs were tapered off over 2 weeks. Add-on treatments were atenolol (50-100 mg/d), loop diuretics (furosemide, 20-500 mg/d or torsemide, 5-200 mg/d), alpha-blockers (prazosin, 2.5-5 mg/d or doxazosin, 1-16 mg/d), and centrally acting drugs (rilmenidine, 1-2 mg/d or methyldopa, 250-500 mg/d). The primary end point was true GFR measured by yearly (51)Cr-EDTA blood clearance. Secondary end points included a clinical composite of renal events and tolerability collected by a full clinical and laboratory evaluation at each study visit. Post hoc analyses for the change in GFR, proteinuria, and time to clinical events were also planned on baseline proteinuria subgroups (or=1 g/d) before unblinding the database. RESULTS: Three hundred eighteen patients entered the run-in period and 263 patients (156 men/107 women; mean age, 58 years) were randomized to receive either amlodipine (5 mg/d, n=132) or enalapril (5 mg/d, n=131). Blood pressure declined from 165/102 mm Hg to 138/84 mm Hg and 138/85 mm Hg with amlodipine and enalapril, respectively (no between-group significance). Only 20.8% of the patients randomized to ACEI treatment received diuretics at the last observation. No statistically significant difference was found between amlodipine and enalapril in GFR decline (-4.92 and -3.98 mL/min.1.73 m(2), respectively, at last observation) and composite secondary end point after a median follow-up of 2.9 years, including in the subgroup of patients with proteinuria >1 g/d at baseline. Protein excretion rate decreased significantly from baseline in patients taking enalapril plus diuretics (median -270 mg/d; P1 g/d.
Enteral levodopa/carbidopa infusion in advanced Parkinson disease: long-term exposure.
Clin Neuropharmacol. 2008 Mar-Apr; 31(2): 63-73
Nyholm D, Lewander T, Johansson A, Lewitt PA, Lundqvist C, Aquilonius SM
OBJECTIVES: In patients with advanced Parkinson disease, levodopa/carbidopa formulated as a gel suspension (Duodopa) permits continuous delivery into the small intestine using a portable pump, resulting in less variability in levodopa concentrations and fewer motor fluctuations and dyskinesias than with oral levodopa administration. This is a retrospective analysis of the long-term clinical experience with this agent. METHODS: All but 1 of the patients who had received enteral levodopa infusion treatment between January 1, 1991, and June 30, 2002, consented to a review of their hospital charts. RESULTS: Of the 65 patients with initial testing of the treatment, 86% opted for continued treatment via percutaneous endoscopic gastrostomy or gastrojejunostomy. Total exposure to levodopa infusion was 216 patient-years (mean, 3.7 years). Maximum treatment duration was 10.7 years. Fifty-two patients were treated for 1 year or longer. The adverse effect profile of levodopa/carbidopa infusion was similar to that observed with oral administration of levodopa. Seven deaths occurred, all considered unrelated to the treatment. Intestinal tube problems, including dislocation of the intestinal tube to the stomach, were the most common technical problem, occurring in 69% of the patients during the first year. The optimal daily dose of levodopa decreased by an average of 5% during follow-up. CONCLUSIONS: The safety of enteral infusion of levodopa/carbidopa formulated as a gel suspension was found acceptable. For most patients, the technical challenges posed by the enteral infusion system were offset by the improvement in motor fluctuations and dyskinesias offered by this technique.
Ideggyogy Sz. 2008 Jan 30; 61(1-2): 42-8
Klivényi P, Vécsei L
The triple combination of levodopa, DDCI and entacapone (Stalevo) is used to treat motor complication in Parkinsonian patients with fluctuation. An observational investigation has been conducted in Hungary to study the effects of Stalevo on the "wearing off" phenomenon and on the quality of life in patients, who are to be treated with. The introduction of Stalevo to the treatment resulted in no changes in the number of patients taking selegiline, amantadine and dopamine agonists, while the number of patients taking anticholinergic drugs were slightly increased. This treatment significantly decreased the average Hoehn-Yahr stadium, as well as the non-motor symptoms, without any remarkable side effect. Stalevo also improved the quality of life, detected by the EQ-5D questionnaire and the visual analogue scale.
Acute overdose with controlled-release levodopa-carbidopa.
Clin Toxicol (Phila). 2008 Mar; 46(3): 274-7
Delmas G, Rothmann C, Flesch F
INTRODUCTION: Reports of acute levodopa-carbidopa overdose are rare and no case of an acute overdose with a controlled-release formulation has been described. We describe such a case in which serial concentrations of catecholamines were measured. CASE REPORT: A 55-year-old man ingested 89 tablets of Sinemet 50/200 (17.8 g of levodopa, 4.45 g of carbidopa). Clinical effects and plasma concentrations of dopamine, noradrenaline and adrenalin were assessed over 66 hours. On admission 2.5 hours after the ingestion, his physical examination was normal except for mydriasis and urine retention. Five hours post-ingestion he had psychomotor agitation, delirium with logorrhea, joviality, visual hallucinations, regular sinus tachycardia and xerostomia. The clinical course included two episodes hypotension and four of transient tachycardia. Treatment was symptomatic and supportive. Clinical toxicity reappeared 48 hours after the intoxication. The patient was discharged at the end of the fourth day with amnesia for the event. DISCUSSION: Dopamine showed an initial plasma concentration peak 14 hours after the toxic ingestion, followed by a second peak 38 hours after the ingestion. The initial peak of noradrenaline occurred 20 hours post-ingestion with a second lower peak at 38 hours. There were no elevations in adrenalin concentrations. CONCLUSION: There appeared to be no correlation between the intensity of the clinical signs and the blood concentrations of dopamine and noradrenaline, although the resolution of the clinical signs did correspond to these catecholamines return to normal values. Patients who ingest controlled-release formulations need to be observed until after the second catecholamine peak.
Clin Neuropharmacol. 2008 Jan-Feb; 31(1): 2-18
Ferreira JJ, Almeida L, Cunha L, Ticmeanu M, Rosa MM, Januário C, Mitu CE, Coelho M, Correia-Guedes L, Morgadinho A, Nunes T, Wright LC, Falcão A, Sampaio C, Soares-da-Silva P
OBJECTIVE: To investigate the effects of nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor, on levodopa pharmacokinetics, COMT activity, and motor fluctuations in Parkinson disease in comparison to placebo and entacapone. METHODS: Randomized, double-blind, placebo-controlled, 4-way crossover study consisting of 4 treatment periods (6-9 days duration each) in 19 patients (65.3 +/- 8.5 years) treated with carbidopa/levodopa 3 to 7 times per day. Nebicapone/entacapone/placebo and carbidopa/levodopa doses were administered concomitantly. At the end of each period, a levodopa test was performed, and levodopa and 3-O-methyldopa levels and COMT activity were assayed. RESULTS: After 75 mg nebicapone, 150 mg nebicapone, and 200 mg entacapone, levodopa area under the plasma concentration time curve significantly increased 28.1, 48.4, and 33.3%, and 3-O-methyldopa area under the plasma concentration time curve significantly decreased 59.2, 70.8, and 59.1%, respectively. Peak COMT inhibition was similar between active treatments, but extent of COMT inhibition was more sustained with 75 and 150 mg nebicapone than with 200 mg entacapone. After the levodopa test doses, ON time significantly increased 29 minutes with 75 mg nebicapone, 45 minutes with 150 mg nebicapone, and 16 minutes with 200 mg entacapone. Patients' diaries showed a decrease in daily OFF time of 109 minutes with 75 mg nebicapone, 103 minutes with 150 mg nebicapone, and 71 minutes with 200 mg entacapone, and an increase in daily ON time of 74, 101, and 74 minutes, respectively. Treatments were generally well tolerated and safe; no relevant changes in liver function tests were reported. CONCLUSIONS: Nebicapone, a new COMT inhibitor, significantly decreased COMT activity, increased systemic exposure to levodopa, and improved motor response. Nebicapone deserves further evaluation in larger samples of patients.