Increased kidney xanthine oxidoreductase activity in salt-induced experimental hypertension.

Clinical and experimental studies have established an association between high sodium intake and arterial hypertension. The renal mechanisms resulting in impaired sodium excretion in hypertension-prone subjects are not clear. In hypertension-prone rats, high blood pressure results in increased renal mass and hemodynamic changes, both of which may alter renal oxygen distribution. Xanthine oxidoreductase (XOR) oxidizes ATP metabolites hypoxanthine and xanthine to urate. Because XOR is induced by hypoxia, we assessed kidney XOR activity in 2 models of salt-sensitive hypertension, spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (Dahl S) rats. Increasing sodium intake from basal (0.08%) to high (2.56% wt/dry wt in the diet) increased renal XOR activity dose-dependently from 68+/-8 to 143+/-21 microU/mg protein in the Dahl S (P<0.05) but not in Dahl salt-resistant (Dahl R) rats. On basal and high sodium diets, SHR had higher renal XOR activity (101+/-10 and 134+/-26 microU/mg protein, respectively) than normotensive Wistar-Kyoto rats (55+/-2 and 58+/-6 microU/mg protein, P<0.05). Sodium restriction (0.02% wt/wt) downregulated kidney XOR activity in both Dahl S and R rats by nearly 40%. In SHR, allopurinol treatment totally inhibited renal XOR activity, but neither systolic blood pressure nor renal mass changed. The results suggest that renal XOR induction is a consequence of increased salt intake or the resulting hypertension. However, further studies on renal XOR activity during the development of hypertension are needed to assess the importance of XOR in the pathophysiology of arterial hypertension.

Beneficial effects of a potassium- and magnesium-enriched salt alternative.

The effects on blood pressure and the development of cardiac hypertrophy of sodium chloride (regular salt) and a novel potassium-, magnesium-, and l-lysine-enriched salt alternative, which in a previous study prolonged the life span of hypertensive rats nearly threefold as compared with the animals receiving regular salt, were compared both in spontaneously hypertensive rats and their hypertension-resistant genetic controls. In particular, the possible protective effect of increased intakes of potassium, magnesium, and l-lysine during a high intake of sodium chloride was examined. Therefore, the salt alternative was added at 1.75 times higher levels to produce the same dietary levels of sodium chloride in the regular salt and the salt alternative groups. Regular salt produced a remarkable left ventricular hypertrophy in both rat strains, but as compared with the respective control groups, it induced an increase of blood pressure only in the spontaneously hypertensive rats. The salt alternative did not induce a rise in blood pressure in either of the rat strains, nor did it produce left ventricular hypertrophy in the hypertension-resistant rats and, in the spontaneously hypertensive animals, significantly less hypertrophy than regular salt. The salt alternative appeared to prevent the sodium chloride-induced volume load since plasma levels of atrial natriuretic peptide were increased in the regular salt groups but remained normal in the salt alternative groups. Therefore, potassium, magnesium, and/or l-lysine of the salt alternative produced a powerful protection against the harmful effects of sodium chloride.

Placental transfer and maternal midazolam kinetics.

Midazolam was given in a single 15-mg oral dose as a sedative the evening before elective cesarean section. Twelve hours later, levels of this new benzodiazepine were measureable in the fetomaternal entity in only one of 13 cases. After 15 mg midazolam orally or 0.05 mg/kg midazolam intramuscularly 15 to 60 min before elective cesarean section, there was evident transfer of drug into the placenta, but transfer took place more slowly than with diazepam. On the basis of kinetics derived from maternal serum concentrations after oral, intramuscular, or intravenous dosing, midazolam appears to have a rapid onset and short duration of action, which was also evident from subjective assessments by the patients. There was wide interindividual variation in the gastrointestinal absorption of midazolam in full-term pregnant women. Clinically, midazolam nevertheless seemed to be very useful for nocturnal sedation before elective cesarean section; it ensures a mean duration of sleep of about 6 hr and there are virtually no detectable levels of drug in the fetomaternal entity the next morning.

Rapid normalization of antipyrine oxidation by heme in variegate porphyria.

Effects of heme on hepatic xenobiotic drug metabolism were investigated in eight subjects with variegate porphyria. A single infusion of heme arginate (3 mg/kg heme) reversed rapidly the prolonged mean elimination half-life of antipyrine from 27.2 to 12.7 hours (p less than 0.001) and increased total clearance from 0.23 to 0.44 ml/min/kg (p less than 0.001). Excretion of 6 beta-hydroxycortisol and D-glucaric acid increased significantly during heme infusion. Excretion of urinary porphyrin precursors increased during the antipyrine test but was normalized by heme. It is concluded that in variegate porphyria a partial block in heme biosynthesis results in subnormal capacity of P450-associated monooxygenases, but this is easily normalized by exogenous heme.

Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans.

Statins, which are commonly used drugs for hypercholesterolemia, inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. Important nonsterol compounds, such as ubiquinone, are also derived from the same synthetic pathway. Therefore it has been hypothesized that statin treatment causes ubiquinone deficiency in muscle cells, which could interfere with cellular respiration causing severe adverse effects. In this study we observed decreased serum levels but an enhancement in muscle tissue ubiquinone levels in patients with hypercholesterolemia after 4 weeks of simvastatin treatment. These results indicate that ubiquinone supply is not reduced during short-term statin treatment in the muscle tissue of subjects in whom myopathy did not develop.

A potentially hazardous interaction between erythromycin and midazolam.

Interaction between erythromycin and midazolam was investigated in two double-blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pretreatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration-time curve after oral intake more than four times (p < 0.001) and reduced clearance of intravenously administered midazolam by 54% (p < 0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p < 0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Valproate and clonazepam in the treatment of severe progressive myoclonus epilepsy.

Twenty-six adults with severe progressive myoclonus epilepsy (PME) were admitted to a long-term prospective clinical study; 19 were followed up for six years. The previous medication, phenytoin sodium and other antiepileptic drugs, was changed to valproate sodium (Deprakine [Finland]; Depakene Syrup, comparable US product), clonazepam (Clonopin), and phenobarbital, and the patients' conditions improved. After six years of follow-up, the favorable result continued. The mean plasma concentration in 26 patients after four months of follow-up was 27.8 +/- 6.9 mg/L for valproate, 0.053 +/- 0.025 mg/L for clonazepam, and 19.2 +/- 7.9 mg/L for phenobarbital. The clinical response was not in accordance with the plasma drug concentrations when the data of the whole population were statistically analyzed. The classification of disability of patients with PME into five degrees was useful. The longlasting favorable result suggests that the combination of valproate, clonazepam, and phenobarbital is the most effective therapy for severe PME.

The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle.

It has been hypothesized that treating hypercholesterolemic patients with statins will lead not only to a reduction in cholesterol, but also to inhibited synthesis of other compounds which derive from the synthetic pathway of cholesterol. In theory, this could further lead to ubiquinone deficiency in muscle cell mitochondria, disturbing normal cellular respiration and causing adverse effects such as rhabdomyolysis. Furthermore, ubiquinone is one of the lipophilic antioxidants in low-density lipoprotein (LDL), and therefore it has also been hypothesized that statin treatment will reduce the antioxidant capacity of LDL. We investigated the effect of 6 months of simvastatin treatment (20 mg/day) on skeletal muscle concentrations of high-energy phosphates and ubiquinone by performing biopsies in 19 hypercholesterolemic patients. Parallel assays were performed in untreated control subjects. The muscle high-energy phosphate and ubiquinone concentrations assayed after simvastatin treatment were similar to those observed at baseline and did not differ from the values obtained in control subjects at the beginning and end of follow-up. These results do not support the hypothesis of diminished isoprenoid synthesis or energy generation in muscle cells during simvastatin treatment. Furthermore, the results of analysis of antioxidant concentrations in LDL before and after simvastatin treatment indicate that the antioxidant capacity of LDL is maintained in simvastatin-treated patients.

The effects of anabolic androgenic steroids on serum ubiquinone and dolichol levels among steroid abusers.

We measured serum ubiquinone and dolichol concentrations in 13 men while they abused anabolic androgenic steroids (AAS) and during the following withdrawal period. Serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and triglycerides were also determined. AAS administration increased serum ubiquinone by 68% (P < .001) and decreased serum dolichol by 30% (P < .002). Both nonsterol isoprenoid levels in plasma correlated with the AAS dose, ubiquinone positively (P < .001) and dolichol negatively (P < .002). When the subjects were taking steroids, the ubiquinone to LDL ratio was 42% higher than during the withdrawal period. In conclusion, our study suggests that AAS have an influence on the by-products of the mevalonate pathway.

Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects.

To study the effects of cirrhosis of the liver on the pharmacokinetics of midazolam single IV (7.5 mg as base) and p.o. (15.0 mg as base) doses of midazolam were administered to seven patients with cirrhosis of the liver and to seven healthy control subjects. One cirrhotic patient did not receive the oral dose. The distribution of midazolam in both study groups was alike as indicated by similar values of t1/2 alpha, V1 and Vss. Also the plasma protein binding of midazolam was unchanged in the patients with cirrhosis. The elimination of midazolam was significantly retarded in the patients as indicated by its lower total clearance (3.34 vs. 5.63 ml/min/kg), lower total elimination rate constant (0.400 vs. 0.721 h-1), and longer elimination half-life (7.36 vs. 3.80 h). The bioavailability of oral midazolam was significantly (P less than 0.05) higher in patients than controls (76% vs. 38%). The antipyrine-half-life was 32.4 h in the patients and 11.8 h in the controls. There were statistically significant (P less than 0.01) correlations between the clearances of the two drugs (r = 0.680) and between their half-lives (r = 0.755). The hypnotic effects of midazolam were similar in both groups. However, on a pharmacokinetic basis a reduced dosage of midazolam to patients with advanced cirrhosis of the liver is recommended.

Correlation of hypotensive effect of plasma protein fraction with prekallikrein activator activity: a clinical study in patients having open-heart surgery.

We studied the hemodynamic responses to the administration of 20 ml of three protein solutions having different prekallikrein activator (PKA) activities in patients undergoing cardiac operation. PKA levels of the two plasma protein fraction (PPF) solutions studied were 193% and 60%, respectively, while that of the albumin solution was less than or equal to 3%. A significant correlation was found between the PKA activity of the test solutions and the decrease in systemic vascular resistance produced by the solutions during cardiopulmonary bypass and in the postoperative period. Vasodilatation was considerably more marked in the postoperative phase than during cardiopulmonary bypass. Since cardiac output increased simultaneously with the decrease in vascular resistance in the postoperative period, the hypotension observed did not fully reflect the degree of vasodilatation. In some patients, substantial vasodilatation was observed also after the administration of albumin solution with low PKA level. We conclude that although the PPF-induced vasodilatation correlates with the PKA activity of the solution, occasional hypotensive reactions are probably due to mechanisms other than those linked with increased PKA level.

Thrombocyte aggregation in hereditary spherocytosis.

Thrombocyte function was studied in seven splenectomized patients and one unsplenectomized patient with hereditary or congenital spherocytosis (HS). Adenosine diphosphate (ADP) concentrations, which trigger the aggregation of control thrombocytes, induced only a release reaction in thrombocytes from six of the HS patients. Collagen-induced thrombocyte aggregation was also diminished in two patients, and epinephrine-induced thrombocyte aggregation in one patient. Two patients whose thrombocytes responded normally to ADP, collagen and epinephrine, were identical twins with spherocytosis of equivocal hereditary. Ristocetin-induced aggregation was normal in all the patients studied. Xanthines (pentoxifylline, theophylline) had no effect on the aggregation of thrombocytes from HS patients or controls. Half-life of thrombocytes was normal in the two splenectomized patients studied. The results demonstrate that not only red cells but also thrombocytes are defective in HS.

Long-term tiapamil treatment of patients with angina pectoris.

The effects of a 12-week oral treatment with tiapamil (200 mg t.i.d.) were compared to those of placebo treatment in a group of 20 men with coronary heart disease. There was a slight reduction of anginal symptoms (p less than 0.05) and a tendency to less nitroglycerin consumption (p less than 0.07). There were no statistically significant differences between the treatments in blood pressure, exercise tolerance during repeated exercise tests, ECG conduction intervals, or routine laboratory tests. No adverse side-effects were encountered. It seems that tiapamil may be beneficial in preventing angina pectoris, but a higher oral dose must be used.

The use of low-resolution FT-IR spectrometry for the analysis of alcohols in breath.

Fast and reliable diagnostic methods are needed for detection or exclusion of industrial solvents as a cause of intoxication. Analyzing human breath reveals the presence of any volatile substance. A portable Fourier transform infrared (FT-IR) multicomponent point-of-care analyzer was developed for exhaled breath. The analyzer proved to be accurate and precise in laboratory tests for simultaneous measurement of methanol and ethanol in water. Ethanol, in addition to normal contents of breath, was simultaneously analyzed in human experiments, and the results correlated well with blood samples. FT-IR method has a traceable calibration to physical properties of the analyte. The measured spectra can also be saved and analyzed later. Breath analysis with FT-IR is fast and easy, and no preparation of the sample is needed.

FT-IR breath test in the diagnosis and control of treatment of methanol intoxications.

A portable Fourier transform infrared (FT-IR) multicomponent point-of-care analyzer was tested for the diagnosis of methanol intoxications. Breath analysis with FT-IR was fast and easy, and no sample preparation was needed. The analyzer was adequately sensitive and accurate in detecting and quantitating clinically relevant amounts of ethanol and methanol in the breath of seriously ill patients. FT-IR spectrometry was also suitable for nearly on-line monitoring of the exhaled ethanol and methanol during hemodialysis. The breath analysis results correlated well with blood samples. The FT-IR method used also has a traceable calibration to physical properties of the analyte, and the measured spectra can be saved for later analysis.

Midazolam kinetics before, during and after cardiopulmonary bypass surgery.

Gas-chromatographically determined serum concentrations of midazolam were recorded before, during and after cardiopulmonary bypass in patients scheduled for a coronary artery bypass grafting operation. Following single 0.075 mg/kg (n = 6) and 0.15 mg/kg (n = 6) intravenous injections of midazolam, a mean distribution phase half-life of 3.4 and 4.4 min respectively was calculated. At the establishment of the bypass, a rapid drop in the concentration of midazolam was observed followed by a significant increase in concentration during the postperfusion period. The apparent mean elimination phase half-life (281 min) of midazolam was longer than that (about 120 min) measured in earlier works in young, healthy subjects. Thus the metabolism of midazolam during the postperfusion period appears to be slower.

Precise quantification of fever in childhood bacterial meningitis.

Precise quantity of fever was determined in 191 cases of childhood bacterial meningitis by calculating the areas between the line indicating 37.8 degrees C or 39.5 degrees C temperature and the line connecting all individual temperature values. Temperature measurements were performed rectally one to four times a day throughout the hospitalization. The obtained areas under the curves (AUC), expressed as degree-hours, proved to be a sensitive index for delineating each individual fever pattern and reflected the magnitude of fever more precisely than the traditional fever curves. Children under five had significantly (p less than 0.05) greater AUC than those at five to 15 years; similarly, patients with Haemophilus influenzae meningitis showed greater AUC (i.e., had more fever) than those with meningococcal disease (p less than 0.05). The overall rates of secondary (14%), persistent (16%), and prolonged fever (8%) were virtually identical to previous reports; no drug fever was reported in this study. In cases with prolonged fever, a significantly higher rate (40%) of neurological complications was found compared to those who became afebrile earlier. This method is potentially utilizable in other diseases and conditions where precise measurement of fever is of clinical or scientific relevance.