Effect of non-steroidal anti-inflammatory drugs on the anticonvulsive activity of valproate and diphenylhydantoin against maximal electroshock-induced seizures in mice

OBJECTIVE: To collect the ratings of American rheumatologists regarding relative short-term and long-term effectiveness of disease-modifying antirheumatic drug (DMARD) therapy in the treatment of rheumatoid arthritis and to compare these data with results of a meta-analysis of randomized, controlled clinical trials (RCTs) of these drugs. METHODS: A survey was mailed to 3,200 United States rheumatologists who were members of the American College of Rheumatology during the summer of 1996. The survey was completed by 645 rheumatologists. RESULTS: Methotrexate (MTX) was rated as substantially more effective than any other DMARD after both 1 year and 4 years of therapy. At 1 year, more than 90% of rheumatologists rated MTX as "good or excellent," compared with 35% giving a similar rating to intramuscular (IM) gold, the second-ranked DMARD. At 4 years, MTX was rated as "good or excellent" by 65%, compared with 53% for combinations, 30% for prednisone, and 11% for hydroxychloroquine, the second-ranked single DMARD. These ratings reflect results of long-term observational studies, but differ considerably from a meta-analysis of results of short-term RCTs, in which the efficacy of MTX, sulfasalazine, penicillamine, and IM gold were indistinguishable. CONCLUSION: The ratings of US rheumatologists regarding effectiveness of DMARD therapies are in agreement with observational data, but differ substantially from results of RCTs. These findings suggest that observational studies may yield useful and important information about treatment results, which are complementary to, but not available from, the RCT model. Regulatory agencies should consider long-term observational studies as a part of the evaluation of drugs.     

Non-steroidal anti-inflammatory drugs and the protective activity of valproate and diphenylhydantoin against maximal electroshock-induced seizures in mice--an interaction

OBJECTIVE: To discuss the clinical implications of systemic lupus erythematosus (SLE) as a complication of a urological condition. METHODS: Herein we describe a patient who presented with acute pyelonephritis due to ureteropelvic juntion stenosis, and a superimposed activation of SLE that had not been previously detected. RESULTS: This form of presentation led to a delay in making the diagnosis since it was focused urologically. The diagnosis of SLE was based on the clinical features, determination of antinuclear antibodies (ANA) and a decrease in serum complement. CONCLUSION: When a patient consults with fever arising from a urological condition that is refractory to conventional therapy, it is mandatory to make the differential diagnosis from other disease entities, as shown in this case.     

Influence of a potential anti-asthmatic drug, CR 2039, upon the anticonvulsive activity of conventional antiepileptics against maximal electroshock-induced seizures in mice

CR 2039 [[4-(1H-tetrazol-5-yl)-N-(4-(1H-tetrazol-5-yl]phenylbenza m ide], in doses of 10, 50, and 100 mg/kg i.p., significantly elevated the threshold for electroconvulsions, increasing the CS50 (current strength 50% in mA) values from 6.3 to 7.2, 7.5, and 7.6 mA, respectively. When combined with carbamazepine, diphenylhydantoin, or valproate, CR 2039 (5 and 10 mg/kg) potentiated the anticonvulsive action of these antiepileptics against maximal electroshock-induced convulsions which was reflected by significant decreases in the respective ED50s (in mg/kg). The protective efficacy of phenobarbital was not affected by the phenylbenzamide derivative. The potentiation of the anticonvulsive activity of three antiepileptics was not accompanied by increased adverse effects, evaluated in the chimney test (motor coordination) and passive avoidance task (long-term memory). Finally, CR 2039 (10 mg/kg) did not alter the plasma levels of the antiepileptic drugs studied which speaks against a pharmacokinetic mechanism in the observed results. It is concluded that CR 2039 may prove a safer anti-asthmatic drug for the use in epileptic patients than aminophylline which, either acutely or chronically, considerably impaired the anticonvulsive activity of conventional antiepileptics.     

Influence of aminophylline and 8-(p-sulfophenyl)theophylline on the anticonvulsive action of diphenylhydantoin, phenobarbital, and valproate against maximal electroshock-induced convulsions in mice

Time variation of drinking is substantial and has an effect on aggregate estimates of consumption. In this article it is shown that because of a considerable seasonal variation in consumption (+/- 20%) a serious bias in annual consumption estimates can be expected in surveys with a limited time frame. The present study analyzes drinking data collected in the general population of the Netherlands from March 1985 through December 1985 (including Christmas and New Year's Eve). Since it was expected that sensitivity to temporal fluctuations might not be equal for different methods of measurement, several indices of consumption were compared. Although the assessed seasonal effect varies indeed across types of measurement, across male and female subsample and across types of alcoholic beverage, the general tendency is for consumption to be highest in the spring season and lowest in the autumn. Sales figures fluctuate accordingly. It is evident that the risk of biased estimates is larger the shorter the time frame of the survey. Seasonal variation was highest in the frequency domain. Furthermore, exclusion from the time frame of collective holidays, during which people drink more often and more per occasion (viz., Christmas), increases the risk of biased estimates. Even estimates of abstention, but also regular heavy drinking among women, appear to vary considerably over the three seasons in this study. The main conclusion is that results of comparisons of survey data on drinking, particularly those over time, are more or less invalid if the respective time frames of the surveys do not correspond.     

Effects of misoprostol on pentylenetetrazol-induced seizures in mice

The effects of prostaglandin E-analogue misoprostol on the susceptibility to pentilenetetrazol (PTZ)-induced seizures were examined in mice. Misoprostol (200-800 micrograms/kg), given subcutaneously 45 min before the subconvulsive dose of PTZ (30 mg/kg, i.p) provoked dose-dependent clonic-tonic seizures (30 to 100%) and mortality in mice. At 300 g/kg, s.c., misoprostol pretreatment significantly (p < 0.05) lowered the onset latency to first convulsion as well as the latency to mortality induced by a convulsive dose of PTZ (60 mg/kg, i.p.). At this dose misoprostol was found to lower the CD50 and Ld50 values for PTZ by 21% and 36% respectively. The results suggest that prostaglandins are likely to lower the threshold for convulsions.     

Propranolol-induced seizures in mice: the role of noradrenaline

The effects of some noradrenergic agents, phenobarbitone, diazepam and phenytoin on seizures produced by propranolol were investigated in mice. Isoprenaline and DL-threo-3,4-dihydroxyphenylserine (DOPS) effectively antagonized the seizures elicited by propranolol. Pargyline and imipramine significantly attenuated propranolol-induced seizures and also significantly potentiated the protecting effect of DOPS against the seizures. alpha-Methyl-p-tyrosine, disulfiram and reserpine significantly potentiated propranolol-elicited seizures. However, DOPS significantly antagonized the seizure-potentiating effects of alpha-methyl-p-tyrosine, disulfiram and reserpine. Phenylephrine, clonidine, prazosin, idazoxan, phenobarbitone, diazepam and phenytoin did not significantly alter propranolol-induced seizures. These results suggest that propranolol-induced seizures in mice may involve a noradrenergic mechanism mediated via central beta-adrenoceptors.     

Genomic imprinting and audiogenic seizures in mice

Audiogenic seizure (AGS) susceptibility in mice is a multifactorial behavioral disorder that involves severe generalized convulsions in response to loud, high-frequency sound. The inheritance of AGS susceptibility was examined in crosses between AGS-susceptible DBA/2J (D2) mice and epilepsy-prone (EP) mice. The EP mice were selected for high AGS susceptibility in a BALB/c-derived line. The AGS phenotype was similar in the EP and D2 mice at 30 days of age. The frequency of generalized clonic-tonic AGS was high in both the D2 and the EP mice (53 and 83%, respectively) but was low in the reciprocal EPD2F1 and D2EPF1 hybrids (14 and 19%, respectively). In the backcross to the EP parent, no significant associations were found between AGS susceptibility and microsatellite markers linked to Asp1 or Asp2, AGS genes located on Chromosomes 12 and 4, respectively. Significant associations were found for markers linked to Asp3, which is located in the proximal region of Chromosome 7. The influence of Asp3 on AGS susceptibility was seen in the EP x EPD2F1 backcross but not in the reciprocal EPD2F1 x EP backcross, suggesting that Asp3 expression is influenced by genomic imprinting. A model is proposed where genomic imprinting represses the maternal Asp3 allele, providing an influence largely from the paternal allele.     

Effects of 2-deoxy-D-glucose and 3 deazauridine individually and in combination on the replication of Japanese B encephalitis virus

We have tested the potencies of the competitors of glucose, 2-deoxy-d-glucose, and of uridine, 3-deazauridine, on the inhibition of Japanese B encephalitis virus multiplication in BHK-21 cell cultures. The relative effectiveness of the viral inhibitors were evaluated individually and in combination in relation to cytotoxicity as a measure of the selectivity of inhibition. When the drugs were administered individually, the antiviral activity was masked by the cytotoxic effect on the host. By combining the two drugs, it was possible to inhibit Japanese encephalitis virus production at noncytotoxic concentrations. The effects of 2-deoxy-d-glucose and 3-deazauridine on the growth inhibition of BHK-21 cells in cultures were only additive, while they were clearly synergistic on the inhibition of Japanese encephalitis virus production. Thus, it was possible to achieve an increased antiviral effect without a significant increase in cytotoxicity. Although the precise biochemical mechanism of the antiviral activity of these antimetabolites in combination is not known, our results indicate the potential value of this approach in viral chemotherapy.     

Comparison of fluid and flunixin meglumine therapy in combination and individually in the treatment of toxic mastitis

During a three-year study, 54 cows with toxic mastitis were allocated randomly to one of three treatment groups (A, B and C). Each cow was re-examined within 24 hours of the initial examination, and, during this time, group A received fluid therapy (45 liters of intravenous isotonic electrolyte solution) and flunixin meglumine (2000 mg), group B received fluid therapy only, and group C received flunixin meglumine only. In addition all the cases were treated with parenteral and intramammary tetracyclines, oxytocin and calcium boroglucoanate. There was no significant difference in the rate of survival between the treatment groups and 29 of the cows (53.7 per cent, 95 per cent confidence interval of 39 to 67 per cent) survived.     

Effect of nifedipine and verapamil on hypotensive action of clonidine in rabbits

Infections associated with central venous catheters continue to be a major source of sepsis, particularly in hospitalized patients. In developing a strategy for the prevention of these infections, the source and route of invasion of the causative micro-organisms need to be considered. The main source of micro-organisms is the patient's skin. They can gain access to a catheter at the time of insertion, as well as via the external or internal catheter surfaces. Attempts to reduce the incidence of infections range from the type of skin preparation selected, to care of the insertion site post-catheterization. Improvements in catheter design have also reduced the likelihood of infection and include the development of non-leachable smooth catheters with anti-adhesive coatings. More recently, catheters containing antimicrobial agents have become available and preliminary studies have demonstrated a reduction in microbial colonization and associated sepsis. Future preventative strategies may include the application of low voltage electric current in combination with antimicrobials.     

Recruitment deafness: Functional effect of priming-induced audiogenic seizures in mice.

Investigated the absolute threshold of the auditory evoked potential (AEP) at the level of the inferior colliculus in 30 C57BL/6J mice. In Exp I, acoustic priming at 16 days of age, which induces susceptibility to audiogenic seizures, elevated this threshold for individual frequencies from 5 kHz to 25 kHz in 21-day-old mice by 5-11 db. In Exp II, the amplitude of the AEP was examined in response to a flat 10-20 kHz noise band. At low intensities, the AEP amplitude was considerably higher for nonprimed Ss, but at high sound levels this relationship reversed. Results indicate that primed mice show recruitment deafness and offer a method of investigating recruitment deafness in humans. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of nifedipine on electrical activity of the brain in rat

The anxiolytic effect of the calcium channel blockers nifedipine and verapamil was tested in mice using two test: the conditioned suppression of the motility test and the black and white box test. The nifedipine but not the verapamil, in low doses (0.1 mg/kg b.w), proved anxiolytic effect and both nifedipine and verapamil in high dose (1.6-2.5 mg/kg b.w) had anxiogenic properties. The anxiogenic effect was correlated with the capacity of the drugs to block the calcium channels and the anxiolytic effect of low doses of the nifedipine was considered to be produced by opening these structures. These data were considered important for a new future aboard of the treatment and pathophysiology of the anxiety.     

Superovulation in llamas (Lama glama) with pFSH and equine chorionic gonadotrophin used individually or in combination

The purpose of this experiment was to evaluate the efficacy of pFSH and/or equine chorionic gonadotrophin (eCG) for inducing superovulation in llamas. Sixteen adult llamas weighing on average 130 kg (range 110-140) and which had been showing signs of oestrus for 5 days were randomly allocated to three treatment groups and one control group (n = 4). Llamas in Group A received eCG (500 IU, i.m.) once daily for 3 days, those in Group B received pFSH i.m., in decreasing doses every 12 h for 5 days for a total of 220 mg, while those in Group C received eCG (500 IU, i.m.) once, and pFSH (total of 156 mg, i.m.) in decreasing doses for the next 4 days. Llamas in Group D (control) received saline (5 ml, i.m.) every 12 h for 5 days. All llamas were allowed to be mated on the evening of Day 5 and were given hCG (750 IU, i.m.) at that time; a second mating was carried out 12 h later. A non-surgical ova/embryo collection technique was performed 7 days after the first mating and then the ovarian response was evaluated by way of laparoscopy. All 16 llamas were mated successfully. The mean (SEM) number of ovulations (7.3 +/- 3.1) in Group B was significantly higher (P < 0.05) than in the other groups (1.5 +/- 0.5, 2.0 +/- 0.7, and 0.3 +/- 0.3 for groups A, C and D, respectively). The number of follicles > 10 mm at the time of ova/embryo collection was significantly higher (P < 0.05) in the groups treated with eCG. A total of 21 ova/embryos was recovered from the all flushed llamas, corresponding to 47.7% of corpora lutea observed. Of the 21 ova, 15 were fertilised; 13 of those were classified as excellent blastocysts and the remaining 2 were classified as dead or degenerating. Results demonstrate that llamas can be successfully ovarian superstimulated while expressing behavioural oestrus and suggest that pFSH is more effective than eCG to induce superovulation.     

Blockade of morphine-induced hindlimb myoclonic seizures in mice by ketamine

Morphine administration can lead to a variety of side-effects, including myoclonus. In an animal model, high morphine doses given intrathecally elicit hindlimb myoclonic seizures which are not influenced by traditional opioid receptor antagonists, such as naloxone. Ketamine prevents this seizure-like activity in a dose-dependent manner. The response is stereoselective, with S-ketamine far more potent than R-ketamine. A competitive NMDA antagonist, NPC17742, also prevents the seizures, although less potently than ketamine. Dextromethorphan has limited activity in this model, while haloperidol and pentothal are without any effect.     

Electroencephalographic correlates of audiogenic seizures during ethanol withdrawal in mice

C57BL/6Bg mice had silver bead electrodes chronically implanted on the surface of the cortex and had their cortical EEG recorded during audiogenic seizures following ethanol withdrawal. For 7 days, the experimental groups were fed a liquid diet containing 6% v/v ethanol ad lib as the only source of food and water. The control group was fed a similar diet containing an isocaloric amount of sucrose. The cortical EEG's of experimental and control groups before, during, and after treatment were virtually identical. Only the experimental group was susceptible to audiogenic seizures. During audiogenic seizures, the cortical EEG showed no sign of spike waves or paroxysmal activity. This is in contrast to picrotoxin convulsions with these same mice as well as to spontaneous convulsions in animals following ethanol withdrawal. Similar EEG observations have been reported on audiogenic seizures from genetic and acoustically primed susceptibilities. Consequently, we suggest that all audiogenic seizure responses, including those during ethanol withdrawal, are a type of subcortical epilepsy.     

Additive anticonvulsant effect of flunarizine and sodium valproate on electroshock and chemoshock induced seizures in mice

Calcium influx through the TRP and TRPL light-activated channels triggers a complex regulatory hierarchy resulting in positive and negative feedback regulation of the phototransduction cascade. Recent studies have begun to elucidate the function of TRP and TRPL in vivo, and to examine their relationship to intracellular calcium changes during the light response.     

Tramadol, a centrally acting opioid: anticonvulsant effect against maximal electroshock seizure in mice

A survey was undertaken to analyze osseointegrated implants placed in irradiated maxillae and mandibles. It was found that nine centers in Japan and two centers in the United States had placed 228 implants in 44 patients. Of 228 implants, 59 were placed in the maxilla, 169 in the mandible. Three of 169 implants placed in irradiated mandibles were removed; 17 of 59 were removed from maxillae. One hundred nineteen implants were placed in the mandible without adjunctive hyperbaric oxygen treatment, of which only 2 were removed. From these results, it is suggested that osseointegrated implants can be placed in the irradiated mandibles of selected patients without hyperbaric oxygen treatment.