Dopaminergic agonists in Parkinson's disease.

BACKGROUND: Non-ergoline dopamine agonists (DA) are effective treatments for Parkinson's disease (PD). This review presents the pharmacology, evidence of efficacy and safety profile of pramipexole, ropinirole, and rotigotine, and practical recommendations are given regarding their use in clinical practice. RESULTS: Extended-release formulations of pramipexole and ropinirole and transdermal continuous delivery rotigotine patches are currently available; these may contribute to stabilising of plasma levels. In early PD, the three drugs significantly improve disability scales, delay time to dyskinesia and allow a later introduction of levodopa. In late PD they reduced total 'off'-time, improved Unified Parkinson's Disease Rating Scale (UPDRS) in both 'on' and 'off' state and allowed a reduction in total levodopa dosage. A significant improvement in quality of life scales has also been demonstrated. Extended-release formulations have proved to be non-inferior to the immediate release formulations and are better tolerated (ropinirole). Despite a generally good safety profile, serious adverse events, such as impulse control disorder and sleep attacks, need to be routinely monitored. Although combination therapy has not been addressed in scientific literature, certain combinations, such as apomorphine and another DA, may be helpful. Switching from one DA to another is feasible and safe, although in the first days an overlap of dopaminergic side effects may occur. When treatment with DA is stopped abruptly, dopamine withdrawal syndrome may present. Suspending any DA, especially pramipexole, has been linked to onset of apathy, which may be severe. CONCLUSIONS: New non-ergotine DAs are a valuable option for the treatment of both early and late PD. Despite their good safety profile, serious adverse effects may appear; these effects may have a pathoplastic effect on the course of PD and need to be monitored.

Advanced Parkinson's disease: clinical characteristics and treatment. Part II.

INTRODUCTION: Many patients who have had Parkinson's disease (PD) for several years will present severe motor fluctuations and dyskinesias which require more aggressive therapies. The different approaches which are now available include deep brain stimulation of the subthalamic nucleus or medial globus pallidus, subcutaneous infusion of apomorphine, and intestinal infusion of levodopa-carbidopa. OBJECTIVE: To define the indications and results for the 3 available therapies for advanced PD. DEVELOPMENT: Exhaustive review of the literature concerning the indications and results of deep brain stimulation, subcutaneous apomorphine infusion and duodenal infusion of levodopa/carbidopa gel to treat patients with advanced Parkinson disease. CONCLUSIONS: Although numerous studies have confirmed the efficacy of the 3 different therapies in advanced PD, there are no comparative studies that would allow us to define the best candidate for each technique.

[Advanced Parkinson's disease: clinical characteristics and treatment (part 1)]. / Enfermedad de Parkinson avanzada. Características clínicas y tratamiento (parte I).

INTRODUCTION: A large percentage of patients with Parkinson's disease (PD) develop motor fluctuations, dyskinesias, and severe non-motor symptoms within 3 to 5 years of starting dopaminergic therapy, and these motor complications are refractory to treatment. Several authors refer to this stage of the disease as advanced Parkinson's disease. OBJECTIVE: To define the clinical manifestations of advanced PD and the risk factors for reaching this stage of the disease. DEVELOPMENT: This consensus document has been prepared by using an exhaustive literature search and by discussion of the contents by an expert group on movement disorders of the Sociedad Española de Neurología (Spanish Neurology Society), coordinated by two of the authors (JK and MRL). CONCLUSIONS: Severe motor fluctuations and dyskinesias, axial motor symptoms resistant to levodopa, and cognitive decline are the main signs in the clinical phenotype of advanced PD.

Efficacy and safety of pallidal stimulation in primary dystonia: results of the Spanish multicentric study.

BACKGROUND: Dystonia is a complex clinical syndrome originated by a wide range of aetiologies. The diagnosis of dystonia is made after the evaluation of aetiological, phenomenological and genetic factors. Medications, except in patients with dopa-responsive dystonia, are of limited efficacy. Botulinum toxin injections are not applicable to patients with generalised dystonia, since many muscular groups contribute to disability. Clinical studies in children and adults with primary generalised dystonia (PGD) have reported beneficial effects of bilateral GPi deep brain stimulation (DBS) in both motor symptoms and disability produced by dystonia as well as a favourable impact of DBS in the health-related quality of life (HRQoL). Some clinical aspects of GPi stimulation in primary dystonia still remain controversial such as the influence of disease duration or age at onset in determining the postoperative clinical outcome. RESULTS: The authors report the results of a multicentric study designed to assess the tolerability and clinical effects of bilateral pallidal DBS on motor impairment, functional disability, quality of life, pain and mood in patients with medically refractory primary generalised or segmental dystonia.

[Quality of life in Alzheimer's disease]. / Calidad de vida en la enfermedad de Alzheimer.

INTRODUCTION: Quality of life is a concept that is receiving increasing amounts of attention; its assessment complements the traditional clinical evaluation, which is of special interest in areas related with healthcare organisation. Here, we present a study on quality of life in Alzheimer's disease and its relationship with cognitive and functional measures. PATIENTS AND METHODS: Quality of life was evaluated by means of the EQ-5D scale in a sample of cases of Alzheimer's disease (diagnosed according to criteria established by the National Institute of Neurologic, Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) that donated blood samples for the National DNA Bank. The status of the global deterioration scale was determined and a verbal fluency test and the Folstein minimental test were also carried out. A classic analysis, variable contrast by means of chi-square for proportions and Student's t test for measurements were conducted, as well as estimation of r for the regression models in the quantitative variables. The social rate was determined using the software application SPSS v. 11. RESULTS: Altogether 141 cases were analysed, with a male to female ratio of 2:1, and a mean age of 76.2 years. Aspects such as personal hygiene, activity and, to a lesser extent, motility are affected in Alzheimer's disease, but pain and anxiety aspects do not seem to be affected. There is a relationship between quality of life, functional scales and cognitive scales. Functional aspects correlate with quality of life better than cognitive ones. CONCLUSIONS: Quality of life is evaluated in Alzheimer's disease using general scales, such as EQ-5D. Cognitive aspects do not appear to provide relevant information about quality of life that is not already provided by the functional aspects.

[Neuroprotection in Parkinson's disease: analysis though group of experts' methodology]. / Neuroprotección en la enfermedad de Parkinson: análisis a través de la metodología de informadores clave.

INTRODUCTION: Currently used antiparkinsonian drugs neither stop nor slow-down the progressive nature of the disease. The final phase of PD is characterized by the presence of symptoms and signs resistant to dopaminergic agents, such as depression, dementia, freezing and falls. Therefore, it is urgent to develop therapies able to positively modify this outcome. Despite neuroprotection is a research priority in PD, no effective strategies have been found so far. METHOD: A key informants study was conducted. A group of experts in PD fulfilled a questionnaire of 10 questions to explore the most important topics related to neuroprotection. Afterwards a consensus about the current situation of neuroprotection in PD was established and future directions of development were suggested. RESULTS: Most of the answers emphasized the need of new concepts, the limitations of animal models and the difficulties in the difficulties in demonstrating a neuroprotective effects in humans owing to a lack of biomarkers. Some of the experts believe that we are already exerting a disease modifying effect. CONCLUSIONS: The concept of neuroprotection should be widened. Animal models should be improved. A reliable biomarker to start neuroprotective therapies long before the appearance of motor symptoms and to evaluate the neuroprotective effect of any therapy should be urgently developed.

[Diagnosis of vascular parkinsonism: correlation of the symptoms with neuroimaging and utility of SPECT with 123I-ioflupane]. / Diagnóstico del parkinsonismo vascular: correlación de la clínica con la neuroimagen y la utilidad de la SPECT con 123I-ioflupano.

INTRODUCTION: The concept of vascular parkinsonism (VP) has evolved since it was introduced by Critchley. The relationships between the clinical manifestations and neuroimagining of patients with VP to determine the utility of SPECT in its diagnosis have been established. MATERIAL AND METHODS: Retrospective study of patients with suspicion of VP according to Ziljmans 2004 criteria. RESULTS: A total of 22 patients were included. The most frequent risk factor was AHT. The most frequent manifestations were: bradykinesis, followed by gait disorder. Response to L-dopa was related with symptoms in lower limbs (p=0.014). The most frequent alterations on the magnetic resonance imaging were: atrophy with ventricular dilation followed by white matter lesions. The Hachinski scale was related with acute onset (p=0.022) and territorial infarction (p=0.039), and the Winikates with subcortical- paraventricular white matter lesions (p=0.036), and both with gender (male) (p=0.031), and stroke background (p=0.022). Alteration in gait was associated with paraventricular white matter lesions (p = 0.043), and other manifestations with lesions in the medulla (p=0,020). Tremor was associated with bilateral involvement of putamens in SPECT (p=0.039), strategic lesion with putamen involvement (p = 0.028) and lesions of periventricular white matter lesions with SPECT type 1 and 2 (p=0.045). There were no significant relationships of the SPECT with response to L-dopa or with the scales. Discussion. The different relationships between symptoms, scales and neuroimagin show the complexity of the subject and the need to use all of them in the diagnosis of VP.

Efecto de la suplementación oral con sobre en el perfíl lipídico de pacientes venezolanos hiperlipémicos / Effect of copper suplementation in lipid profile of Venezuelan hiperlipemic patients

Se considera que la mayoría de las dietas occidentales satisfacen los requerimientos diarios de cobre debido a su presencia ubicua en los alimentos. Estudios recientes han demostrado que el cobre alimentario se encuentra a menudo por debajo de sus requerimientos diarios, lo que puede determinar una carencia de este elemento. Esta carencia está asociada con hipercolesterolemia e hipertrigliceridemia, tanto en humanos como en animales experimentales. En el presente estudio de intervención se examonó el efecto de la administración de 5mg de Cu/día, en 73 pacientes (grupo tratado), de ambos géneros, con edades entre 26y 48 años, con niveles séricos elevados de colesterol total y triglicéridos sin tratamiento con drogas hipolipémicas y se comparó con 73 pacientes hiperlipémicos no sometidos a tratamiento con Cu (grupo control), quienes fueron agrupados por género, edad, peso corporal, consumo de cigarrillos, ingesta de calorías y grasas y actividad física. Antes de administrar el cobre, se extrajo una muestra de sangre para las determinaciones de cobre, cinc y lípidos séricos. Al final del período experimental (45 días), se obtuvo una muestra de sangre para las determinaciones correspondientes. Los resultados sufieren la existencia de una cerencia marginal del elemento traza en el 38 por ciento de los sujetos y demuestran que el cobre disminuye significativamente (p<0.05) los nivles séricos del colesterol total (r=-0.976), de triglicéricos (r=-0.972), de LDL-colesterol (r=-0.961) y de cinc (r=-0.980) con un ligero incremento (r=-0.984) del HDL- colesterol. Estos hallazgos demuestran que el cobre se puede emplear en el tratamiento de los pacientes con hipercolesterolemia e hipertrigliceridemia; aunque los mecanismos, que explican como el cobre determina estos cambios, no se conocen exactamente

[Effect of copper supplementation on lipid profile of Venezuelan hyperlipemic patients]. / Efecto de la suplementación oral con cobre en el perfil lipídico de pacientes Venezolanos hiperlipémicos.

It has been assumed that most Western diets satisfy the requirement of copper/day because of ubiquitous presence of this element in most foods. Recent studies have shown that dietary copper (Cu) may often fall below the estimated daily requirements, what could determine a deficiency of this trace element. This deficiency is associated with hypercholesterolemia and hypertrigliceridemia, both in human and experimental animals. In the present intervention study was examined the effect of the administration of 5 mg of Cu/day in 73 patients (treated group), of both genders, with ages between 26 and 48 years, with high serum levels of total cholesterol and triglycerides without pharmacological treatment and compared with 73 hyperlipemic subjects non-treated with copper (control group) who were matched by gender, age, body weight, smoking habits, calories and fat intake, and physical activity. Before copper administration, a sample of blood was obtained for serum determinations of copper, zinc and lipids. At the end of the experimental period (45 days), a new sample of blood was taken for the corresponding determinations. The results suggest the existence of a marginal deficiency of the trace element in 38% of the subjects and demonstrate that copper supplementation decreases (p < 0.05) serum levels of total cholesterol (r = -0.976), triglycerides (r = -0.972), LDL-cholesterol (r = -0.961) and zinc (r = -0.980) with a slight increment (r = 0.894) of HDL-cholesterol. These findings demonstrate that copper can be used in the treatment of the patients with hypercholesterolemia and hypertriglyceridemia. The mechanisms by which Cu determines these changes are not known.

HPLC determination of Vitamin D(3) and its metabolite in human plasma with on-line sample cleanup.

A HPLC method with automated column switching and UV-diode array detection is described for the simultaneous determination of Vitamin D(3) and 25-hydroxyvitamin D(3) (25-OH-D(3)) in a sample of human plasma. The system uses a BioTrap precolumn for the on-line sample cleanup. A sample of 1ml of human plasma was treated with 2ml of a mixture of ethanol-acetonitrile (2:1 (v/v)). Following centrifugation, the supernatant was evaporated to dryness under a stream of dry and pure nitrogen. The residue was reconstituted in 250muL of a solution of methanol 5mmoll(-1) phosphate buffer, pH 6.5 (4:1 (v/v)), and a 200mul aliquot of this solution was injected onto the BioTrap precolumn. After washing during 5min with a mobile phase constituted by a solution of 6% acetonitrile in 5mmoll(-1) phosphate buffer, pH 6.5 (extraction mobile phase), the retained analytes were then transferred to the analytical column in the backflush mode. The analytical separation was then performed by reverse-phase chromatography in the gradient elution mode with the solvents A and B (Solvent A: acetonitrile-phosphate buffer 5mmoll(-1), pH 6.5; 20:80 (v/v); solvent B: methanol-acetonitrile-tetrahydrofuran, 65:20:15 (v/v)). The compounds of interest were detected at 265nm. The method was linear in the range 3.0-32.0ngml(-1) with a limit of quantification of 3.0ngml(-1). Quantitative recoveries from spiked plasma samples were between 91.0 and 98.0%. In all cases, the coefficient of variation (CV) of the intra-day and inter-day-assay precision was

[Effect of cooper supplementation on blood pressure values in patients with stable moderate hypertension]. / Efecto de la suplementación con cobre sobre los valores de presión arterial en pacientes con hipertensión moderada estable.

Copper (Cu) deficiency is associated with changes in arterial pressure. The effect depends of the age of initiation of the copper-deficient diet. Copper deficiency started at a young age causes hypotension. When initiated in older or adult animals, copper deficiency can cause hypertension. A case-control study was carried out to investigate the effect of administrating 5 mg Cu/d in 60 subjects, both genders, with mild stable hypertension, pharmacologically untreated (treated group) and compared with 60 hypertensives (control group) who were matched by gender, age, body weight, smoking habits, calories, fat and salt intake (NaCl), and physical activity. Hypertension was diagnosed when the blood pressure was > 150/95 mm Hg. Mean age, mean corporal weight and risk factors were similar in both groups. The results suggested the existence of a marginal deficiency of the trace element in 62% of subjects and demonstrated that Cu decreases systolic (r = -0.963) and diastolic (r = -0.981) blood pressures in treated group (p < 0.05). Control patients did not show significant changes in their arterial pressures. These findings indicate a functional alteration in human blood pressure regulation during mild copper depletion and suggest that Cu could be used in the treatment of stable moderate arterial hypertension. Further investigation is needed to determine the extent of this influence.

Efecto de la suplementación con cobre sobre los valores de presión arterial en pacientes con hipertensión moderada estable / Effect of cooper supplementation on blood pressure values in patients with stable moderate hypertension

Copper (Cu) deficiency is associated with changes in arterial pressure. The effect depends of the age of initiation of the copper-deficient diet. Copper deficiency started at a young age causes hypotension. When initiated in older or adult animals, copper deficiency can cause hypertension. A case-control study was carried out to investigate the effect of administrating 5 mg Cu/d in 60 subjects, both genders, with mild stable hypertension, pharmacologically untreated (treated group) and compared with 60 hypertensives (control group) who were matched by gender, age, body weight, smoking habits, calories, fat and salt intake (NaCl), and physical activity. Hypertension was diagnosed when the blood pressure was > 150/95 mm Hg. Mean age, mean corporal weight and risk factors were similar in both groups. The results suggested the existence of a marginal deficiency of the trace element in 62 per cent of subjects and demonstrated that Cu decreases systolic (r = -0.963) and diastolic (r = -0.981) blood pressures in treated group (p < 0.05). Control patients did not show significant changes in their arterial pressures. These findings indicate a functional alteration in human blood pressure regulation during mild copper depletion and suggest that Cu could be used in the treatment of stable moderate arterial hypertension. Further investigation is needed to determine the extent of this influence.

Unique origin and low penetrance of the 946delGAG mutation in Valencian DYT1 families.

Mutations in the DYT1 gene cause idiopathic torsion dystonia (ITD) transmitted in families as an autosomal dominant trait with incomplete penetrance. The most common mutation, 946delGAG, has been observed in populations with different ethnic and geographic origins. We have investigated 40 individuals from 22 unrelated families with ITD originating from the Land of Valencia, Spain, for the presence of this mutation and we found 5 patients and 6 unaffected subjects from 4 families who were carriers of the mutation. This finding indicates that 18% of families may be diagnosed as DYT1 and that penetrance is reduced. We detected two different geographic and linguistic origins of the Valencian families. However, by haplotype analysis using D9S1260, D9S1261, D9S63 and D9S1262 as flanking markers, we demonstrated that all affected and unaffected carriers shared a common chromosome confirming identical origin of the mutation in the four families. We postulate a unique origin for the 946delGAG mutation in the Land of Valencia and, based on linguistic criterion, we propose that the mutation might have occurred at the beginning of the second millennium. Genetic analysis of another family from Castilla-La Mancha showed a different haplotype segregating with the disease, suggesting that at least two distinct mutational events for the 946delGAG mutation have occurred in Spain.

Determination of paraquat in human blood plasma using reversed-phase ion-pair high-performance liquid chromatography with direct sample injection.

This report describes the determination of paraquat (PQ) in human blood plasma samples by a direct-injection reversed-phase ion-pair chromatographic method. Blood plasma filtrate was injected directly into the LiChrospher(R) RP-18 alkyl-diol silica (ADS) precolumn integrated in a column switching system using a mixture of 3% 2-propanol and 10 mM sodium octane sulfonate (SOS) in a 0.05 M phosphate buffer (pH 2.8). After washing with this phase, the ADS precolumn was back-flushed with the analytical mobile phase consisting of 40% of methanol and 10 mM SOS in a 0.05 M phosphate buffer (pH 2.8) at a flow rate of 1.0 ml min(-1), in order to carry the analyte to a conventional reversed-phase analytical column, where the separation of PQ was achieved and finally detected by UV at 258 nm. The recoveries of PQ from human blood plasma samples ranged between 95.0 and 99.5% at nine different concentrations (from 0.05 to 3.00 microg of PQ ml(-1)) with coefficients of variation <2.5% (n=3). The precision expressed as relative standard deviation was below 3.5% for between-day and below 4.3% for within-day measurements (n=5). The detection limit (signal-to-noise ratio, S/N>3) was 0.005 microg ml(-1) with an injection volume of 200 microl. The proposed method is promising for the identification and quantification of PQ at low concentration levels and is suitable for its analysis in human blood plasma samples from intentional or accidental poisonings cases with a sample throughput of 5 samples per hour.

Flow analysis-hydride generation-Fourier transform infrared spectrometric determination of antimony in pharmaceuticals.

In this work, a flow analysis system with hydride generation and Fourier transform infrared (FTIR) spectrometric detection has been developed for the determination of antimony in pharmaceuticals. The method is based on the on-line mineralization/oxidation of the organic antimonials present in the sample and pre-reduction of Sb(V) to Sb(III) with K(2)S(2)O(8) and KI, respectively; prior to the stibine generation. The gaseous SbH(3) is separated from the solution in a gas phase separator, and transported by means of a nitrogen carrier into a short pathway (10 cm) IR gas cell, where the corresponding FTIR spectrum is acquired by accumulating 3 scans in a continuous mode. The 1893 cm(-1) band was used for the quantification of the antimony. The procedure is carried out in a closed system, which reduces sample handling and makes possible the complete automation of the antimony determination. The figures of merit of the proposed method (linear range: 0-600 mg l(-1), limit of detection (3sigma)=0.9 mg l(-1), limit of quantification (10sigma)=3 mg Sb l(-1), precision (R.S.D.) less than 1% and sample frequency=28 h(-1)), are appropriate for the designed application. Furthermore, precise and accurate results were found for the analysis of different antimonial pharmaceutical samples, indicating that the methodology developed represents a valid alternative for the determination of antimony in pharmaceuticals, which could be suitable for the routine control analysis.

Column-switching high-performance liquid chromatographic analysis of carbamazepine and its principal metabolite in human plasma with direct sample injection using an alkyl-diol silica (ADS) precolumn.

In this paper, the on-line coupling of solid-phase extraction, based on a restricted-access support with high-performance reverse phase chromatography for the analysis of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) in human plasma samples is described. A precolumn packed with 25 mum C(18) alkyl-diol support is used for direct plasma injection. Using column-switching techniques, the analytes were enriched on the precolumn by a 5 mM phosphate buffer (pH 7) with 2% of methanol solution at a flow-rate of 0.8 ml min(-1), while proteins and endogenous hydrophilic substances in plasma were washed off to waste. The enriched analytes were then back-flushed onto the analytical C(18) column, separated by a mixture of 10 mM phosphate buffer (pH 7) acetonitrile (70:30 v/v) solution at a flow-rate of 1.0 ml min(-1) and detected by the ultraviolet absorbance set at 212 and 285 nm and without transfer loss. Linear calibration graphs were obtained for sample injection volumes of 50 (0.2-4.0 of mug of CBZ ml(-1) and 0.1-5.0 mug of CBZ-E ml(-1), respectively), and 20 mul (5.0-20.0 mug of CBZ ml(-1)); in either case the r-value was >0.9963. Recoveries from spiked plasma samples were quantitative for both analytes and the coefficients of variation were below 3.83%. The lowest samples concentrations that can be quantified with acceptable accuracy and precision was 0.2 mug CBZ ml(-1) and 0.1 mug CBZ-E ml(-1) when a sample volume of 50 mul was injected. Concentrations of 0.08 and 0.05 mug ml(-1) of CBZ and CBZ-E were considered the limit of detection for a signal-to-noise ratio of 3. Furthermore, the developed column-switching method was successfully applied to the determination of CBZ and CBZ-E in plasma samples of patients submitted to CBZ therapy.

A flow injection-ETAAS system for the on-line determination of total and dissolved silica in waters.

In this work total (Si-tot) and 'soluble' or reactive (Si-sol) concentrations of silicon in natural and tap waters were sequentially determined by electrothermal atomic absorption spectrometry (ETAAS). First, samples were on-line diluted based on the merging-zone principle in order to allow the determination of Si-tot within the 300-1000 mugSil(-1) range. After the dilution process, a sub-sample was collected in the capillary of a sampling arm assembly (SAA). Thereafter, samples were subject to a precipitation/dissolution process in order to allow the determination of Si-sol within the 280-850 mugSil(-1). Si-sol was precipitated with ammonium chloride and collected on the walls of a knotted coil. The precipitate was dissolved with ammonium molybdate in an acidic medium (HNO(3)) and a sub-sample was then collected in the SAA. In both cases, 10 mul volumes of the sub-sample were injected into the atomizer with the previous introduction of 20 ng of Eu as chemical modifier (10 mul) by the spectrometer autosampler. The recovery values obtained with natural waters spiked samples were over 46% and the agreement between observed and certified samples values was good. The proportion of Si-sol in comparison with the Si-tot was high (85-95%) in most natural waters. The precision of the method was 2.4-3.5 and 4.5-6.2% (n=10) for the determination of Si-tot and Si-sol, respectively.