Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.

https://science.sciencemag.org/content/sci/217/4558/408.full.pdf

The Cholinergic Hypothesis of Geriatric Memory Dysfunction

Well-being : the foundations of hedonic psychology

admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

https://cyberleninka.org/article/n/148766.pdf

Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation

Helicobacter pylori is the first formally recognized bacterial carcinogen and is one of the most successful human pathogens, as over half of the world's population is colonized with this gram-negative bacterium. Unless treated, colonization usually persists lifelong. H. pylori infection represents a key factor in the etiology of various gastrointestinal diseases, ranging from chronic active gastritis without clinical symptoms to peptic ulceration, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma. Disease outcome is the result of the complex interplay between the host and the bacterium. Host immune gene polymorphisms and gastric acid secretion largely determine the bacterium's ability to colonize a specific gastric niche. Bacterial virulence factors such as the cytotoxin-associated gene pathogenicity island-encoded protein CagA and the vacuolating cytotoxin VacA aid in this colonization of the gastric mucosa and subsequently seem to modulate the host's immune system. This review focuses on the microbiological, clinical, immunological, and biochemical aspects of the pathogenesis of H. pylori.

Pathogenesis of Helicobacter pylori Infection

Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications

Objective

To investigate the CYP2C19 polymorphism in Tanzanians because this enzyme shows large interindividual differences in activity and metabolizes several drugs of importance in Africa, especially the antimalarial agent chloroguanide (INN, proguanil)



Methods

Two hundred fifty-one Tanzanian healthy volunteers were phenotyped with respect to CYP2C19 with use of a single oral dose of mephenytoin (n = 106), a single oral dose of omeprazole (n = 207), or both Sixty-two were phenotyped with both probe drugs The urinary 0- to 8-hour S/R-mephenytoin ratio and the plasma omeprazole metabolic ratio (MR) (omeprazole/hydroxyomeprazole) 3 hours after drug intake were determined The genotype was determined by analysis for CYP2C19*1 (wt), CYP2C19*2 (m1), and CYP2C19*3 (m2) Ten subjects with high omeprazole MR were screened for new mutations in the CYP2C19 gene by searching for single-strand conformation polymorphisms (SSCP)



Results

Eight subjects were classified as mephenytoin poor metabolizers (75%) Only 5 of these were homozygous for mutated alleles The S/R ratio was skewed to the right (lower CYP2C19 activity) compared with other ethnic groups studied previously No new mutations were found with polymerase chain reaction (PCR)-SSCP We found 30 volunteers (145%) with an MR >7, which is the antimode found previously in white subjects and Asian subjects Of the 251 volunteers genotyped, 32% were homozygous for mutated alleles and 661% were homozygous for the wild-type allele The allele frequencies of CYP2C19*1, *2, and *3 were 815%, 179%, and 06%, respectively The correlation between the S/R-mephenytoin ratio and the omeprazole MR was significant (Spearman r = 059; P < 01)



Conclusion

Tanzanians have a decreased capacity to metabolize both omeprazole and mephenytoin when their genotype is compared with metabolic capacity and genotype in other previously studied populations We identified a low frequency of the Asian allele (CYP2C19*3) Although we did not find any new mutations, our results may be consistent with the presence of yet-unidentified mutations of CYP2C19 that causes decreased CYP2C19 activity in the Tanzanian population



Clinical Pharmacology & Therapeutics (1998) 64, 391–401; doi:

Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype

A large interindividual variability has previously been demonstrated in the bioavailability, steady-state plasma concentrations and clearance of clozapine, an atypical neuroleptic drug. To evaluate the importance of genetic factors in the metabolism of clozapine, its disposition after a single oral dose of 10 mg was studied in 15 healthy Caucasian volunteers. Five of the subjects were poor metabolisers (PM) of debrisoquine, five were PM of S-mephenytoin, and the remaining five were extensive metabolisers (EM) of both probe drugs. There was a 10-fold interindividual variation in Cmax and a 14-fold variation in AUC(0, 24) of clozapine among the 15 subjects studied. The mean (s.d.) Cmax was 117 (81) nmol l-1 and the mean AUC(0,24) value was 890 (711) nmol l-1 h. The value of t1/2,z varied 3-fold with a mean (s.d.) of 13.3 (5.0) h. There were no significant differences in the plasma concentrations or any of the pharmacokinetic parameters of clozapine between PM and EM of debrisoquine, or between the two S-mephenytoin hydroxylation phenotypes. We conclude that neither of the major genetic polymorphisms of oxidative drug metabolism contribute to the large interindividual variability in clozapine pharmacokinetics.

/pdf/disposition-of-clozapine-in-man-lack-of-association-with-1je6kdvclf.pdf

Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms.

Objective

This study investigated whether time-dependent artemisinin pharmacokinetics correlated to CYP3A4 or CYP2C19 activity in vivo.



Methods

Artemisinin (two oral doses per day of 250 mg) was given to nine healthy Vietnamese subjects for 7 days (day 1 to day 7). Single 20 mg doses of omeprazole were given orally on day −7, day 1, and day 7. Single doses of artemisinin and omeprazole were given in combination on day 14 after a 6-day washout period. The pharmacokinetics of artemisinin, omeprazole, hydroxyomeprazole, and omeprazole sulfone were evaluated on days −7, 1, 7, and 14. On the same days urine was collected for the determination of 6β-hydroxycortisol and cortisol excretion.



Results

Areas under plasma concentration-time curves (AUC) for artemisinin and omeprazole decreased on day 7 to 20% (95% confidence intervals, 13%, 28%) and 35% (25%, 46%), respectively, compared with values on day 1. AUC ratios for hydroxyomeprazole/omeprazole increased 2.2-fold (1.7, 2.7) on day 7 compared with values on day 1. All values were normalized at day 14. There were no significant changes in the omeprazole sulfone/omeprazole ratio or in the 6β-hydroxycortisol/cortisol ratio between the study days. In one subject found to have poor CYP2C19 metabolization, the elimination of omeprazole increased after artemisinin exposure, with no change in the hydroxyomeprazole/omeprazole AUC ratio.



Conclusion

Artemisinin did not alter CYP3A4 activity, whereas in increase in CYP2C19 activity was observed. The increased elimination of omeprazole in both poor and extensive CYP2C19 metabolizers suggests artemisinin induces both CYP2C19 and another enzyme.



Clinical Pharmacology & Therapeutics (1998) 64, 160–167; doi:

Artemisinin induces omeprazole metabolism in human beings

– Repeated lumbar punctures in 16 healthy volunteers showed reproducible concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF). In seven depressed patients, studied during two or three illness periods, the metabolite concentrations were also fairly stable. In 11 patients CSF concentrations of 5-HIAA, but not of HVA, were higher after recovery than during depression. This increase of 5-HIAA after recovery was confined to patients whose initial serotonin metabolite levels were low. The finding constitutes further evidence of a biochemical heterogeneity within the depressive disorders, and suggests that patients whose CSF 5-HIAA is low during a depressive episode may have a less stable serotonin system than other patients with depressive illness.

Leif Bertilsson

Papers

Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications

Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype

Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms.

Artemisinin induces omeprazole metabolism in human beings

CSF monoamine metabolites of depressed patients during illness and after recovery