Epilepsy management in older people: Lessons from National Audit of Seizure management in Hospitals (NASH).

PURPOSE: Epilepsy is the third most common diagnosis in older people, however management in this group remains variable. National Audit of Seizure management in Hospitals (NASH) set out to assess care provided to patients attending hospitals in England following a seizure. METHOD: 154 Emergency Departments (EDs) across the UK took part. 1256 patients aged 60 years or over were included for analysis (median age 74 years, 54% men). 51% were known to have epilepsy, 17% had history of previous seizure or blackout and 32% presented with a suspected first seizure. RESULTS: 14% of older patients with epilepsy were not on treatment, 59% were on monotherapy. Sodium valproate was the most commonly used antiepileptic, 28%. 35% of patients with epilepsy, aged 60 and over, had a CT during admission compared to only 17% of those under 60. 80% of patients aged 60 and over presenting with a likely first seizure were admitted to hospital, compared to 65% of those under 60. 34% of those with suspected first seizure were referred to a neurologist on discharge compared to 68% of patients under the age of 60. 52% of 60-69year olds with a suspected first seizure were referred to neurology compared to 25% of patients aged 80-89. CONCLUSIONS: Older patients presenting with seizures are more likely to be admitted to hospital and have imaging. They are less likely to be referred to specialist services on discharge. There appears to be significant disparity in patient age and rate of referral.

Relationship between plasma and saliva quinine levels in humans.

The relationship between saliva and plasma levels of quinine was studied in four healthy volunteers. After a single oral dose of quinine sulfate (600 mg) to the volunteers, quinine was determined in both saliva and plasma simultaneously over a 48-h period by an ion pair reverse-phase high performance liquid chromatography method. The tmax (4.3 +/- 0.5 h) and elimination half-life (11.8 +/- 2.9 h) of quinine derived from saliva levels were comparable with those obtained from plasma levels (tmax = 2.8 +/- 0.2 h, t1/2 = 12.9 +/- 2.3 h). A significant correlation existed between the plasma and saliva concentrations of the drug (r = 0.93, n = 20, p < 0.001). The mean saliva/plasma quinine concentration ratio was 0.24 +/- 0.02. The results suggest that quinine is passively secreted into saliva and that saliva level determination may be useful as a noninvasive method in the evaluation of pharmacokinetic parameters and therapeutic drug monitoring of quinine.

Column liquid chromatographic analysis of quinine in human plasma, saliva and urine.

A new simple, selective and reproducible high-performance liquid chromatographic method for the determination of quinine in plasma, saliva and urine is described. The ion-pair method was carried out on a reversed-phase C18 column, using perchlorate ion as the counter ion and ultraviolet detection at 254 nm. Quinine was well resolved from its major metabolite, 3-hydroxyquinine, and the internal standard, primaquine. The limit of detection was 10 ng/ml and the recovery was greater than 90% from the three biological fluids.

Disposition of quinine in rats with induced renal failure.

Aetiologically different models of experimental acute renal failure were induced in rats by the administration of glycerol, mercuric chloride and gentamicin, respectively, to different groups. Quinine levels in plasma and urine of the rats with induced renal failure were determined and pharmacokinetic parameters (elimination t1/2, CLp, V, CLR AUC0-infinity) of the drug were derived and compared with values obtained from control rats following intraperitoneal administration of a 10 mg/kg body-weight dose of quinine. Results showed that each of the three compounds caused an up to 25-fold increase in the plasma levels of the drug and a marked decrease in the levels of the metabolite 3-hydroxyquinine. All the pharmacokinetic parameters determined for the rats with renal impairment were markedly different when compared to control. The high plasma quinine levels observed in the rats with renal failure could be largely due to the marked decrease in V and reduced metabolism. Also, in the rats with renal impairment, no correlation was observed between the increased plasma urea levels and plasma quinine levels or disposition of the drug. The results of the study suggest that quinine should be used with caution in patients with renal impairment. The plasma urea levels, as a measure of renal function, might not provide a suitable index for determining quinine dosage.

An in-vitro study of chloroquine transport in the rat submaxillary gland.

The uptake and efflux of chloroquine by the rat submaxillary gland in-vitro were studied under various incubation conditions. Variations in the extracellular pH significantly affected both the uptake and efflux of the drug. Increasing chloroquine concentration significantly decreased the uptake. Uptake was also decreased significantly (P less than 0.05) when compared with control conditions (pH 7.40, 37.5 degrees C, O2 aeration, 6 x 10(-6) M chloroquine) by the following experimental variations: aeration of the incubation medium with N2 instead of O2; decrease of bath temperature from 37.5 to 4 degrees C; addition of metabolic inhibitors, cyanide (10(-3) M), iodoacetic acid (10(-3) M) and o-nitrophenol (10(-3) M). Cimetidine (10(-3) M), a known organic cationic inhibitor, had no significant effect on chloroquine uptake when compared with control values. These results show that the uptake of chloroquine by the rat submaxillary gland in-vitro is concentration-dependent and this is indicative of possible saturable binding sites for the drug in the gland. These results suggest that the transfer of chloroquine across the submaxillary gland may be mediated by an active transport process. On the other hand, it is possible that the apparent active transport process implicated in this study could be a consequence of chloroquine ion trapping in the acidic interior of lysosomes.

Characterization of the principal metabolite of quinine in human urine by 1H-n.m.r. spectroscopy.

1. The major metabolite of quinine in human urine, which is also the sole metabolite in human plasma and saliva, has been identified and characterized by chemical ionization mass spectrometry and 1H-n.m.r. spectrometry. 2. The mass spectrum showed that an oxygen atom is incorporated in the quinuclidine nucleus, and the exact position of the oxidation was established from the n.m.r. spectrum to be at the C-3 position.

Excretion of proguanil in human saliva.

After a single oral administration of a 300 mg dose of proguanil to six volunteers, the presence of the drug in saliva was established by chromatographic and spectrophotometric methods. The tmax and elimination half-life of proguanil derived from salivary levels were 4.0 +/- 1.26 h and 15.1 +/- 1.8 h, respectively. These results are in agreement with values previously reported for the drug using plasma level data. The mean saliva: plasma proguanil concentration ratio was 0.41 +/- 0.17 and this was not time dependent. There was a correlation (r = 0.82) between the saliva and simultaneous plasma proguanil concentration. The results suggest that proguanil is passively secreted into saliva and that saliva levels may be useful in the determination of pharmacokinetic parameters and the therapeutic monitoring of the drug.

Effects of antimalarial agents on plasma levels of chlorpromazine and its metabolites in schizophrenic patients.

The plasma content of chlorpromazine (CPZ) and its two metabolites 7-OH-chlorpromazine (CPZ-OH) and chlorpromazine sulphoxide (CPZ-SO) were measured in the blood of schizophrenic patients established on chlorpromazine therapy. Administration of the commonly used antimalarial agents chloroquine sulphate, amodiaquine hydrochloride and Fansidar one hour before the first dose of chlorpromazine for the day led to marked increases in CPZ and CPZ-OH over control levels. There were no consistent changes in CPZ-SO levels. The implications of these findings are discussed, first with regard to possible therapeutic relevance for the management of schizophrenia and more particularly, with regard to the possible toxic effects of concurrent administration of antimalarial agents and chlorpromazine.

The effect of some hepatotoxins on the sulphoxidation of cimetidine in rat.

Sulphoxidation of cimetidine was investigated in male and female rats after pretreatment with the hepatotoxins allyl alcohol, dl-ethionine, thioacetamide and carbon tetrachloride. There was a marked sex difference in cimetidine sulphoxidation in response to the hepatotoxin pretreatment. All the hepatotoxins enhanced cimetidine sulphoxidation in the male rat (P less than 0.01). Carbon tetrachloride and thioacetamide inhibited cimetidine sulphoxidation in the female rat (P less than 0.01) but dl-ethionine and allyl alcohol had no effect on this metabolic pathway.

Influence of species, sex and drug pretreatment on the metabolism of metyrapone.

The metabolism of metyrapone was investigated in three mammalian and four non-mammalian species, and keto reduction was found to be the major metabolic route (except in the cat). Toad, lizard and tortoise did not form metyrapone N-oxides. Rat and cat formed both isomeric N-oxides of metyrapone, whereas rabbit and pigeon have a limited capacity to form only the N-oxide II and N-oxide I, respectively. There were marked sex differences in both keto reduction and N-oxidation in the rat. Anthracene did not affect metyrapone N-oxides formation in the male rat; however phenobarbitone and pregnenolone significantly induced N-oxide II formation, whereas ethanol induced both isomeric N-oxides formation. Cimetidine, a known cytochrome P-450 inhibitor, inhibited the N-oxide II formation but with an enhanced N-oxide I formation.

A possible cytochrome P-450-mediated N-oxidation of diethylcarbamazine.

There was a marked sex difference in the N-oxidation of diethylcarbamazine (DEC) in the rat. In 72 h, 41 and 20% of the administered DEC was excreted in urine as the N-oxide in male and female rats respectively. Safrole, metyrapone and ethanol inhibited this N-oxide formation in male rats by 71, 37 and 44% whereas in female rats the values were 20, 25 and 0% respectively. Phenobarbitone and anthracene enhanced N-oxide formation in male rats by 17 and 20% and in female rats by 50 and 90% respectively, but the amount of the N-oxide formed was more in the males. The result suggests a possible involvement of a sub-population of cytochrome P-450 isozyme (which is more in male rats) in the N-oxidation of DEC.

Possible prostaglandin-mediated effect of diethylcarbamazine on rat uterine contractility.

The effect of diethylcarbamazine pretreatment on uterine contractility was investigated in both pregnant and nonpregnant rats. The pretreatment potentiated the uterine responses to oxytocin and acetylcholine, and enhanced the spontaneous uterine contraction of rats in oestrus or 17-20 days pregnant. This enhanced contraction was antagonized both in-vivo and in-vitro by indomethacin, suggesting the involvement of prostaglandins.

Evolutionary trend in the metabolic oxidation of chlorpromazine.

The metabolism of the widely used antipsychotic drug chlorpromazine has been investigated in man, five mammalian and four non-mammalian species, and 7-hydroxylation was found to be the major metabolic route. All of the previously reported major oxidized metabolites were excreted by man, rhesus monkey and capuchin monkey, while sulfoxidation was extensive in rat and N-demethylation in rabbit. Lizard and tortoise did not form sulfoxides, and tortoise was unable to N-demethylate the drug. Toad, pigeon and cat had limited capability for these two metabolic pathways.

Learned helplessness in the gerbil?

Evidence of learned helplessness was demonstrated in Mongolian gerbils. Two consecutive days of jump-up escape were followed 24 hr later by testing in a bar-press escape task. Reliable differences occurred between escapable and inescapable animals and between inescapable and control animals.

Effect of drug pretreatment on the metabolic oxidation of chlorpromazine in rat.

The metabolic oxidation of chlorpromazine (CPZ) was investigated after pretreatment of rats with some drugs and chemicals for 6 days. Pentobarbitone, gamma-collidine, ethanol, and anthracene induced a significant increase in both S-oxidation and 7-hydroxylation, whereas CPZ pretreatment increased mainly 7-hydroxylation. Metyrapone and safrole preferentially inhibited 7-hydroxylation. Chloroquine and quinine pretreatment increased urinary excretion of CPZ and its metabolites, probably due to occupation of CPZ-binding sites rather than as a result of enzyme induction.

Predictive indices for chlorpromazine therapy in schizophrenics.

1 Response to chlorpromazine therapy was studied in 24 schizophrenics and 75% reduction in Brief Psychiatric Rating scale (BPRS) within 4 weeks of treatment was taken to indicate good response. 2 Test oral dose of CPZ (200 mg) was administered and serial blood samples and total urine excreted in 6 h were taken for analyses of CPZ and its metabolites. 3 Area under the plasma time curve (AUC) showed an inverted U-shaped relationship with % reduction in BPRS. 4 Three groups of patients were identified, responders, l- and h-group non-responders. 5 l- and h-groups respond on further treatment with haloperidol (30 mg daily) and ECT respectively. 6 Responders showed threshold metabolic molar fraction MMFHO-CPZ greater than or equal to 3.0 x 10(-5) and MMFHO-CPZ/MMFCPZ-SO greater than 1.

Analysis of in vivo results of cyclophosphamide-induced chromosomal damage in mammals from sensitivity and statistical aspects.

Metaphase analysis, the micronucleus test, and the dominant lethal assay were performed in rodents with cyclophosphamide. The variance in the results indicated that use of binomial statistics (or the Poisson or normal approximations of this distribution) would be inappropriate for determination of significance. This conclusion was reinforced by finding that negative binomial distributions best explained certain aspects of the data, as well as being theoretically more likely. Because there was no simple significance test based on negative binomial statistics and there was some doubt about the distributional form, a distribution-free significance test seemed most appropriated. Thus a one-sided Kolomogorov-Smirnov two-sample test was used. Although both the dominant lethal assay and metaphase analysis proved superior to the micronucleus test in terms of degree of response, this advantage was more than offset by the lesser difficulties and greater number of cells that could be analyzed in the micronucleus assay.

Mutagenicity of antibiotics in microbial assays. Problems of evaluation.

5 antibiotics, 4 of which inhibit protein synthesis in different ways, and 1 of which inhibits bacterial cell-wall synthesis, were tested in a battery of microbial assays for possible genetic effects. All the antibiotics, chloramphenicol, tetracycline, gentamicin, oleandomycin and phosphonomycin induced forward mutation to L-azetidine-2-carboxylic acid resistance in Escherichia coli WP2. This response was closely correlated with the toxic effects and was inferred to be deletion mutation. In addition, chloramphenicol was weakly active in reversion of the frame-shift mutation in Salmonella typhimurium TA98, gentamicin caused petite induction in S. cerevisiae at pH 4.4--4.7 and tetracycline gave a significant reponse with gene conversion and petite induction also in S. cerevisiae but at pH 7.2. The results, particularly those with E. coli, cast doubts on the validity of testing specifically designed antibacterial agents in bacteria, and raise serious problems in the evaluation of such data in terms to human populations.