Side effects of phenobarbital and phenytoin during long-term treatment of epilepsy

ABSTRACT Phenobarbital and phenytoin have good antiepileptic effect, but clinically significant untoward effects occur during their long-term use. Phenobarbital may cause hyperactivity, behavioral problems, sedation, and even dementia; these effects are dose related to some extent. Side effects of phenytoin include sedation, a cerebellar syndrome, phenytoin encephalopathy, psychosis, locomotor dysfunction, hyperkinesia, megaloblastic anemia, decreased serum folate level, decreased bone mineral content, liver disease, IgA deficiency, gingival hyperplasia, and a lupus-like hypersensitivity syndrome. Especially susceptible to the neurotoxic effects of phenytoin are epileptic children with severe brain damage who are on multiple drugs. In those children, balance disturbance may develop and be followed by gradual loss of locomotion. Among 131 mentally retarded epileptic patients, phenytoin intoxication occurred in 73 (56 %), of whom 18 experienced persistent loss of locomotion. There is experimental evidence that the toxic action of phenytoin lies at the cellular level, predominantly in the cerebellum. Many experts avoid the long-term use of phenytoin because of its insidious and potentially dangerous side effects.     

Nonlinear heart rate variability in CABG patients and the preconditioning effect.

OBJECTIVE: Heart rate variability (HRV) is the most frequently used noninvasive diagnostic method in the assessment of cardiac autonomic control. The clinical relevance of HRV, especially nonlinear HRV in CPB patients has not been well studied. Short brief myocardial ischemia has been reported to influence HRV. We therefore hypothesis that the protective mechanism of ischemic preconditioning (IP) may involve in cardiac autonomic regulation. METHODS: Eighty-six CABG patients were randomized into a control and an IP group. The IP patients received two periods of 2-min ischemia followed by 3-min reperfusion by aortic cross-clamped. Holter data were collected in 86 CABG patients before and after surgery. Arrhythmias, linear and nonlinear HRV measures were analyzed. RESULTS: All time and frequency domain HRV variables as well as nonlinear indexes of HRV, the short-term (4-11 beats) scaling exponent alpha1, were suppressed significantly after surgery in both study groups. The lower pre- and postoperative exponent alpha1 predict the higher incidence of postoperative AF and worse postoperative outcome. The suppressed exponent alpha1 was attenuated in the IP group as compared to controls (P = 0.008). No other differences were observed in the changes in linear HRV measures between the groups. IP significantly reduced the incidence of postoperative arrhythmias and improved postoperative outcome. CONCLUSIONS: The present findings show that cardiac autonomic regulation is impaired after CABG. Nonlinear HRV exponent alpha1 is a more sensitive measure to predict the postoperative outcome in CABG patients. IP alleviates the extreme autonomic reactions after surgery, suggesting that cardiac autonomic regulation is involved in the IP protective mechanism.     

Treatment of secondary hyperparathyroidism by high calcium diet is associated with enhanced resistance artery relaxation in experimental renal failure

Background. Vasorelaxation is impaired in renal failure (RF)and hypertension. A high calcium diet enhances vasodilatationand reduces blood pressure in experimental hypertension. Oralcalcium salts are used as phosphate binders in RF. However,the effect of increased calcium intake on arterial tone in RFis unknown. Methods. We investigated the influence of an 8-week high calciumdiet (0.3 vs 3.0%) on resistance artery tone in 5/6 nephrectomized(NTX) rats. Calcium was supplemented as carbonate salt, bloodpressure measured by tail-cuff, urine collected in metaboliccages, and samples taken for blood chemistry and parathyroidhormone (PTH). Functional studies of isolated third-order branchesof the mesenteric artery in vitro were performed using the Mulvanymultimyograph. Results. Plasma urea was elevated 1.6-fold and systolic bloodpressure by 10 mmHg after NTX, while increased calcium intakewas without effect on these variables. Plasma PTH and phosphatewere raised following NTX, and suppressed by high calcium diet.Vasorelaxations induced by K⁺ channel agonists 11,12-epoxyeicosatrienoicacid and levcromakalim were impaired after NTX. Vasorelaxationinduced by acetylcholine was also reduced following NTX, andexperiments with N^G-nitro-L-arginine methyl ester, diclofenacand charybdotoxin + apamin suggested that the K⁺ channel-mediatedcomponent of endothelium-dependent relaxation was deficientafter NTX. Increased calcium intake corrected all impairmentsof vasodilatation in NTX rats. Conclusions. Deficient vasorelaxation via K⁺ channels was normalizedby high calcium diet in experimental RF. This effect was independentof the degree of renal impairment and blood pressure, but wasassociated with improved calcium metabolism: plasma levels ofPTH and phosphate were decreased and ionized calcium was increased.     

Neuromuscular performance of lower limbs during voluntary and reflex activity in power- and endurance-trained athletes

Neural, mechanical and muscle factors influence muscle force production. This study was, therefore, designed to compare possible differences in the function of the neuromuscular system among differently adapted subjects. A group of 11 power-trained athletes and 10 endurance-trained athletes volunteered as subjects for this study. Maximal voluntary isometric force and the rate of force production of the knee extensor and the plantar flexor muscles were measured. In addition, basic reflex function was measured in the two experimental conditions. The power athletes produced higher voluntary forces (P<0.01-0.001) with higher rates for force production (P<0.001) by both muscle groups measured. Unexpectedly, however, no differences were noticed in the electromyogram time curves between the groups. During reflex activity, the endurance group demonstrated higher sensitivity to the mechanical stimuli, i.e. the higher reflex amplitude caused a higher rate of reflex force development, and the reflex amplitude correlated with the averaged angular velocity. The differences in the isometric conditions could be explained by obviously different muscle fibre distribution, by different amounts of muscle mass, by possible differences in the force transmission from individual myofibrils to the skeletal muscle and by specificity of training. In addition, differences in nervous system structure and muscle spindle properties could explain the observed differences in reflex activity between the two groups.     

Peripheral nerve injury and recovery after temporary ischemia

Summary Nerve (NCV) and motor (MNCV) conduction velocities of the rat sciatic nerve were examined between 1 and 90 days after ischemia for 1, 2, 3, 4 or 6 h. The results were compared to light and electron microscopy of the nerve.Slight diminution in the MNCV was observed 1 day after 1–2 h ischemia, whereas 3–6 h ischemia resulted in a complete conduction block. Diminution in the NCV occurred first after ischemia for 2 h and a complete block was seen after 4 and 6 h ischemia. Reduced NCV and MNCV were seen between 4 and 18 days only in the animals subjected to ischemia of longer duration of 3–6 h. Both the NCV and MNCV were nearly normalized at the 90th day. Ischemia of 4 and 6 h resulted in denervation of some of the muscle fibers, seen as spontaneous fibrillation at the 4th and 18th day.Electron microscopy and histometric studies showed degeneration of myelinated fibers increasingly after longer durations of ischemia; ischemia for 2 h caused a degeneration of about 5%, 3 h of about 35%, 4 h about 45%, and 6 h about 75% of the fibers. Myelinated fibers of different sizes were equally damaged. In the teased fiber preparations normal and myelin sheaths undergoing Wallerian-like degeneration was seen. Regeneration occurred, but even at the 90th day there was a tendency of the myelin/axon ratio towards values less than control values.     

The main neutral protease of rat skin is a mast cell enzyme. Immunohistochemical localization of the enzyme in rat skin with the peroxidase-antiperoxidase (PAP) complex method.

The highly sensitive PAP immunoperoxidase method was used to localize the main neutral protease of rat skin. The use of the neutral detergent, Triton X-100, in the reagent and washing solutions was observed to effectively decrease the nonspecific staining. The specific staining was localized to the mast cell granules.     

Cardioprotective effects of vasopeptidase inhibition vs. angiotensin type 1-receptor blockade in spontaneously hypertensive rats on a high salt diet.

The aim of our study was to compare the cardioprotective effects of vasopeptidase inhibition with those of angiotensin type 1 (AT1)-receptor blockade, a diuretic and the combination of AT1-receptor blockade and a diuretic in an experimental rat model of essential hypertension on a high salt diet. Spontaneously hypertensive rats (SHR) (n =73) were divided into 6 groups to receive the following diet and drug regimens for 8 weeks: 1) low salt controls (NaCl 0.5%); 2) high salt controls (NaCl 6%); 3) omapatrilat (40 mg/kg/d) on a high salt diet; 4) losartan (30 mg/kg/d) on a high salt diet; 5) hydrochlorothiazide (HCTZ; 10 mg/kg/d) on a high salt diet; and 6) losartan+HCTZ (30+10 mg/kg/d) on a high salt diet. Blood pressure was measured by tail-cuff plethysmography. The histological score of myocardial damage, myocardial collagen volume fraction (CVF), connective tissue growth factor (CTGF) expression and cardiomyocyte apoptosis were determined. As an antihypertensive, omapatrilat showed greater efficacy than monotherapy with losartan or HCTZ, and was equally effective as the combination of losartan+HCTZ. Assessed by myocardial damage score, omapatrilat and losartan protected cardiac morphology better than HCTZ or the drug combination. Omapatrilat decreased CVF to a greater extent than the other therapies, whereas losartan was most effective in decreasing CTGF expression. All drug treatments, except HCTZ, decreased cardiomyocyte apoptosis. Our findings provide evidence that both vasopeptidase inhibition and AT1-receptor blockade exert cardioprotective properties beyond their blood pressure-lowering effects. Cardioprotection was associated with prevention of cardiomyocyte apoptosis and inhibition of extracellular matrix formation.     

EMG,muscle fibre and force production characteristics during a 1 year training period in elite weight-lifters

Summary The effects of a 1 year training period on 13 elite weight-lifters were investigated by periodical tests of electromyographic, muscle fibre and force production characteristics. A statistically non-significant increase of 3.5% in maximal isometric strength of the leg extensors, from 4841±1104 to 5010±1012 N, occured over the year. Individual changes in the high force portions of the force-velocity curve correlated (p<0.05–0.01) with changes in weight-lifting performance. Training months 5–8 were characterized by the lowest average training intensity (77.1+2.0%), and this resulted in a significant (p<0.05) decrease in maximal neural activation (IEMG) of the muscles, while the last four month period, with only a slightly higher average training intensity (79.1±3.0%), led to a significant (p<0.01) increase in maximum IEMG. Individual increases in training intensity between these two training periods correlated with individual increases both in muscular strength (p<0.05) and in the weight lifted in the clean & jerk (p<0.05). A non-significant increase of 3.9% in total mean muscle fibre area occurred over the year. The present findings demonstrate the limited potential for strength development in elite strength athletes, and suggest that the magnitudes and time courses of neural and hypertrophic adaptations in the neuromuscular system during their training may differ from those reported for previously untrained subjects. The findings additionally indicate the importance of training intensity for modifying training responses in elite strength athletes.     

Moderate running exercise augments glycosaminoglycans and thickness of articular cartilage in the knee joint of young beagle dogs

The local influences of physical exercise on thickness and glycosaminoglycan (GAG) content of canine articular cartilage were measured by microspectrophotometry of Safranin O- and periodic acid-Schiff (PAS)-stained tissue sections. Female Beagle dogs were housed in individual cages (bottom 0.9 × 1.2 m) and divided into runner (n = 6) and control (n = 8) groups. The trainig program started at the age of 15 weeks. During the subsequent 10 weeks, the dogs were accustomed to running on a treadmill inclined 15° uphill. Thereafter, the dogs ran 1 h daily, 5 days a week, at a speed of 4 km/h for 15 weeks. At the age of 40 weeks, the dogs were killed, and the samples for histology were taken from 11 different anatomical locations of the right knee (stifle) joint. The thickness of the uncalcified cartilage increased 19–23% on the lateral condyle and patellar surface of the femur, whereas the enhancement was smaller in other parts of the trained cartilage. The calcified cartilage did not show thickness alterations. Total GAGs were augmented by 28% in the summits on the femoral condyles, more on the medial than lateral side. The increased GAGs appeared to be predominantly chondroitin sulphates and were localized in the intermediate, deep, and even in the calcified zones, whereas the superficial zone did not show changes. There was a concomitant increase of non-GAG oligosaccharides in the intermediate and deep zones, but not in the calcified cartilage. As judged from the enhanced GAG content and thickness, it is considered that moderate running exercise locally alters the biological properties of young articular cartilage at regions bearing the highest loading surplus.