Mitochondrial abnormalities in migraine. Preliminary findings.
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Biomedical subjects
Publications and source records attributed to R Riva.
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Patients with problems of internal medicine presenting at first-aid units of city hospitals represent a considerable work load. 1667 patients of this type have been examined retrospectively. The most numerous group had cardiocirculatory (22%) and nervous system (21%) problems, 9% had problems linked to their mental state and 11% dermatology complaints in general. 1047 patients underwent further investigation and/or specialist examination (247 neurological and 166 cardiological). Patients with jaundice, diabetes mellitus and cardiac decompensation underwent the highest number of laboratory examinations. The highest percentage of X-rays was done on patients suffering from chronic bronchitis during an acute episode, the highest percentage of ECGs in patients with prethoracic pain or cardiopalmus. In first aid also, some tests seem to be carried out as routine or for legal medicine purposes while for problems where tests are less easy or harder to understand (e.g. loss of consciousness episodes), a specialist is frequently brought in. The work load on the first-aid out-patients structure can be reduced by promoting greater awareness of the problem on the part of the internist and by rerouting users to non-hospital structures.
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Metoclopramide extracted from plasma and urine has been analysed using reversed phase HPLC with acetic acid/acetonitrile/triethylamine as eluent and fluorescence detection. This method exploits the natural fluorescence of metoclopramide for its detection in patients on multiple drug therapies.
A rapid and specific method has been developed for the determination of orphenadrine concentration in plasma. It involves a one-step sample preparation using n-hexane/isopropyl alcohol (98:2) extraction, and analysis by gas chromatography on a wide bore capillary column using nitrogen/phosphorus detection. This procedure considerably simplifies previously reported assays and is specific and sensitive enough for the determination of orphenadrine in plasma of patients on chronic therapy.
The influence of meal ingestion time on rate and extent of oral levodopa absorption was evaluated in a group of 17 patients, after administration of their usual second daily dose of levodopa plus carbidopa (Sinemet 10:1) or benserazide (Madopar 4:1). Standard meals were consumed by the patients after they had fasted 15-17 h, on one occasion 30 min before ingestion of the levodopa "study dose" and, at another time, 2 h after ingestion of the same dose. This study dose, ranging from 50 to 250 mg levodopa, was given to the patients at 11 a.m., 4 h after their first morning dose. Time to peak plasma levodopa concentration increased threefold (from 45 +/- 23 to 134 +/- 76 min, p less than 0.001), when levodopa was administered after meals. Area under the 6-h plasma concentration-time curve for levodopa was decreased in 10 subjects, unchanged in three and higher in four after ingestion of meals, the latter finding probably resulting from an erratic absorption even at fasting. On the whole, levodopa absorption proved significantly lower (p less than 0.01), on the average 15%. Similarly, peak plasma levodopa concentrations were lower in 12 patients, unchanged in two, and higher in three, with an overall significant decrease (p less than 0.001) of 30% on the average. The data confirm the importance of meal ingestion time in relation to levodopa dose as a determinant of drug absorption.
Eight healthy volunteers were treated with a single dose of pyrazinamide 35 mg/kg. The aim of the study was to evaluate the pharmacokinetic profile of the product and of its metabolites. Urine and blood samples were collected till the 60th h. The kinetics of pyrazinamide could be characterized as follows: CPmax = 50.1 micrograms/ml, tmax less than 1 h, t1/2 alpha = 3.2 h, t1/2 beta = 23 h, U(0-60 h) = 1.6% of the dose administered. The kinetics of the main metabolite, the pyrazinoic acid, gave the following values: CPmax = 66.6 micrograms/ml, tmax = 4 h, t1/2 beta = 12.3 h, U(0-60 h) = 37.5%, of the administered dose.
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The protein binding of carbamazepine (CBZ) in vitro was assessed in sera from 47 patients with various diseases known to alter alpha 1-acid glycoprotein (AAG) concentration and from 20 drug-free normal control subjects. In the patient group, AAG and albumin (HSA) concentrations ranged from 6 to 74 mumol/l and from 377 to 652 mumol/l, respectively; in the controls, protein concentrations were less variable, ranging from 11 to 26 mumol/l for AAG and from 623 to 754 mumol/l for HSA. In both the patient and the combined patient and control groups, free CBZ fractions were inversely correlated with the serum AAG concentration (r = -0.62). No significant relationship could be found between the free CBZ fraction and the serum HSA concentration. The free CBZ fraction was moderately but significantly decreased in patients with AAG levels above 26 mumol/l (the highest value found in controls) as compared either to patients with a normal AAG concentration or to control subjects (19 +/- 5% vs 23 +/- 4% and 23 +/- 2%), despite the finding of a higher HSA concentration in the control group. The data confirm AAG as an important determinant of interindividual variability in serum CBZ binding.
The relationship between the serum protein binding of carbamazepine (CBZ) and carbamazepine-10,11 epoxide (CBZ-E) and the concentration of alpha 1-acid glycoprotein (AAG) and albumin (HSA) was examined in 39 CBZ-treated epileptic children aged 4 months to 12 years. A significant inverse correlation was found between the free fraction of both compounds and serum AAG, even though changes in AAG concentration explained only part of the variation in binding. No correlation was found between the free fraction of CBZ and CBZ-E and HSA, probably due to the small intersubject variation in HSA concentration. In vitro experiments showed that both CBZ and CBZ-E were bound to HSA and to a lesser extent to AAG. At equivalent HSA concentrations, the binding of CBZ and its metabolite increased proportionately with increasing AAG concentration within the range occurring clinically.
The performance of the enzyme multiplied immunoassay technique (EMIT) in the measurement of total and free plasma carbamazepine (CBZ) levels was assessed in 140 clinical specimens and compared with a reference high pressure liquid chromatography (HPLC) technique. Free drug was measured in plasma filtrates obtained by the Free Level system. Both total and free CBZ levels as determined by EMIT correlated strongly with corresponding HPLC values (r = 0.88 and 0.92, respectively). Plasma CBZ concentrations, however, were higher by EMIT than by HPLC. The degree of CBZ overestimation by EMIT was relatively small (about 14%) in whole plasma but quite considerable (35% on average) in the filtrates. As a result, estimated values of free CBZ fraction were also higher for EMIT than for HPLC. Separate experiments in vitro suggested that the discrepancies between the two methods were due to cross-reaction of the EMIT reagent with the 10,11-epoxide metabolite of CBZ. The greater degree of overestimation for the free drug can be explained by the higher proportion of less protein-bound metabolite in the filtrates. These results need to be taken into account in the interpretation of free CBZ level data from laboratories using different techniques.
The diurnal variation in total and free plasma phenytoin (PHT) concentration at steady state was examined in eight epileptic patients receiving combination therapy with tid valproic acid (VPA) as sodium salt. Eight patients treated with PHT, but not with VPA, were studied for comparison purposes. In the absence of VPA coadministration, total and free PHT concentrations did not change significantly during the day and showed only minor intrapatient fluctuations (14 and 13%, respectively). In patients receiving VPA, the mean total PHT did not change significantly, whereas the free PHT increased during the day (p less than 0.05). The fluctuations in total and free PHT in these patients were 16 and 17% on average. In the presence of VPA, the free PHT fraction was higher than in controls (13.9 +/- 2.3% versus 8.3 +/- 1.9%; p less than 0.01) and fluctuated to a greater extent (29 versus 14% in controls; p less than 0.01), mainly as a result of combined opposite swings in both total and free concentration. The diurnal changes in free PHT concentration and fraction correlated positively with the changes in plasma VPA. An inverse relationship between total PHT concentration and plasma VPA was found in some patients. These data demonstrate that the displacement interaction between PHT and VPA is subject to diurnal variation, probably as a result of the fluctuation in plasma VPA. The implications of these findings are discussed.
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Plasma protein binding of propranolol (PROP) was determined in 18 migraine patients chronically treated with different doses (from 60 to 240 mg/day) of the drug. In 9 patients serum lipids and PROP binding were determined before and during the therapy. Free fractions of PROP ranged from 4.7 to 13.3% and they were similar to those found in vitro in healthy volunteers. Total and free concentrations were highly correlated (r = 0.929; p less than 0.001); correlations between daily doses (in mg/kg) and free and total concentrations were very similar: r = 0.76 and r = 0.73 respectively. Changes in binding and serum lipids during the therapy were insignificant and unrelated.
The incidence of lateral gaze nystagmus and its correlation with free and total plasma concentrations of carbamazepine (CBZ) and carbamazepine-10, 11-epoxide (CBZ-E) were examined in 97 epileptic patients receiving chronic treatment with CBZ alone (n = 54) or in combination with phenobarbital (PB) (n = 43). All patients had plasma CBZ concentrations within the clinically optimal range (less than 50 mumol/L). Nystagmus was seen in 26% of patients receiving monotherapy and in 33% receiving combination therapy. Within each group, however, nystagmus was much more frequent among patients with higher CBZ concentrations. For patients receiving PB in combination the CBZ levels above which nystagmus was particularly frequent appeared to be lower than in the monotherapy patients--a finding that could not be attributed to differences in plasma PB concentrations. The correlation of CBZ-E levels (or the sum of CBZ + CBZ-E) with the occurrence of nystagmus was no better than that observed with CBZ levels alone. Free drug levels did not appear to be superior to total levels in discriminating between patients with or without nystagmus. These results indicate that the occurrence of nystagmus is concentration-dependent within the therapeutic plasma CBZ concentration range and suggest that the threshold at which this neurological sign appears is reduced in the presence of PB, possibly as a result of a pharmacodynamic interaction.
Combined pressure and pH measurement of distal esophagus is very important for an accurate diagnostic approach and a correct therapeutic course of gastro-esophageal reflux disease. Sixty-eight patients with suspected gastroesophageal reflux disease have been examined by combined pressure and pH-measurement. Collected data confirm the method worth, that allows to study gastro-esophageal reflux and the esophageal motor dysfunction related.
Intra-operative esophageal manometric evaluations are examined. The data refer to: extramucosal myotomy by thoracotomy; hiatal hernia repair by laparatomy; pharingo-crico-myotomy by cervicotomy. The utility of this intra-operative measurement clearly appears, especially in order to an immediate evaluation of surgical correction.