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

Aging-induced Changes in Acetylcholine and Serotonin Content of Discrete Brain Nuclei

Mephenytoin (100 mg) and debrisoquin (10 mg) were administered orally, both separately and together, to 41 healthy subjects. The ratios between the S and R enantiomers of mephenytoin and between debrisoquin and 4-OH-debrisoquin in urine were determined by use of GC. These ratios were used as measures of drug hydroxylation. There was no change in the phenotypic trait values of the two drugs when they were coadministered. Mephenytoin and debrisoquin then were coadministered to 253 healthy Swedish subjects, before bedtime, and urine samples were collected at periods of 0 to 8, 8 to 24, and 24 to 32 hours after drug administration. In the first sample, seven of the 253 subjects (2.8%, 95% confidence interval 0.8% to 4.8%) had an S/R ratio of greater than 0.8; this indicated that they were poor hydroxylators of S-mephenytoin. In the two consecutive samples, the S/R ratios of mephenytoin did not change in these seven persons, whereas it decreased to less than 0.2 in the third sample in the extensive hydroxylators. As was reported before, there was no relationship between the mephenytoin S/R ratio and the debrisoquin metabolic ratio (rs = 0.01). Coadministration of debrisoquin and mephenytoin before bedtime and urine collection during two consecutive nights allow for an accurate determination of both phenotypes in the population.



Clinical Pharmacology and Therapeutics (1989) 45, 495–499; doi:10.1038/clpt.1989.63

S-mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquin.

Twenty-five healthy volunteers were given 100 mg caffeine orally and several estimates of cytochrome P450 1A2 (CYP1A2) activity were evaluated. The validation was performed by correlation of different parameters in plasma, saliva, and urine to two measures of caffeine clearance, CL on and CL 137X→17X that served as standards of reference. Two subjects were excluded because of noncompliance with a caffeine-free diet. In the remaining 23 subjects, both plasma and saliva total clearances of caffeine were highly correlated with each other (r s = 0.97, p < 0.0001). The ratio 17X/137X restricted to one sampling point taken 4 hours after dose, showed a high correlation (r s ) with CL oral and CL 137X→17X in plasma (0.84/0.83) and saliva (0.82 / 0.77) (p < 0.0001 for all the correlation values) where 17X is 1,7--dimethylxanthine (paraxanthine) and 137X is 1,3,7-trimethylxanthine (caffeine). Additionally, the ratio (AFMU + IU + IX + 17U + 17X)/137X in a 0-24 hours urine sampling showed the highest correlation with CL 137X→17X (r s = 0.85, p < 0.001) where AFMU is 5-acetylamino-6-formylamino-3-methyluracil, 1U is 1-methyluracil, 1X is 1-methylxanthine, and 17U is 1,7-dimethyluric acid. The major estimates of CYP1A2 activity were significantly less in nonsmoking females, and this probably was related to the use of oral contraceptives in this subpopulation. In summary, among caffeine-based approaches for CYPI A2, the authors recommend either plasma or saliva 17X/137X ratio and the urinary (AFMU + IU + IX + 17U + 17X)/137X ratio during a sampling interval of at least 8 hours, starting at time zero since caffeine intake. These indices are simple, reliable, and relatively inexpensive estimates of CYP1A2 activity to be used in the study of human populations.

Evaluation of caffeine as an in vivo probe for CYP1A2 using measurements in plasma, saliva, and urine.

Omeprazole (20 mg orally) was given to 103 healthy Korean subjects and blood was taken 3 h alter administration. The plasma concentration ratio of omeprazole and hydroxyomeprazole, used as an index of CYP2C19 activity, was bimodally distributed. Thirteen subjects (12.6%) were identified as poor meta

CYP2C19 genotype and phenotype determined by omeprazole in a Korean population.

Objective

To determine whether cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of tolterodine by investigating potential differences in pharmacokinetics and pharmacodynamics (heart rate, accommodation, and salivation) of tolterodine and its 5-hydroxymethyl metabolite between poor metabolizers and extensive metabolizers of debrisoquin (INN, debrisoquine).



Methods

Sixteen male subjects (eight extensive metabolizers and eight poor metabolizers) received 4 mg tolterodine by mouth twice a day for 8 days followed by a single intravenous infusion of 1.8 mg tolterodine for 30 minutes after a washout period. Doses were given as the tartrate salt. The pharmacokinetics of tolterodine and 5-hydroxymethyl metabolite were determined, and the pharmacodynamics were measured.



Results

The mean systemic clearance of tolterodine was significantly lower (p < 0.001) among poor metabolizers (9.0 ± 2.1 L/hr) compared with extensive metabolizers (44 ± 13 L/hr), resulting in a fourfold longer elimination half-life (p < 0.001). The terminal half-life of the 5-hydroxymethyl metabolite (2.9 ± 0.4 hours) was slightly longer than that of the parent compound (2.3 ± 0.6 hours) among extensive metabolizers, but the 5-hydroxymethyl metabolite was undetectable in the serum of poor metabolizers. Only minor differences in pharmacodynamic effects after tolterodine dosage were observed between the groups. Tolterodine caused a similar decrease in salivation in both panels. The decrease occurred when the concentration of unbound tolterodine and 5-hydroxymethyl metabolite among extensive metabolizers was comparable with that of tolterodine among poor metabolizers.



Conclusions

Tolterodine is extensively metabolized by CYP2D6 with high specificity. Despite the effect on pharmacokinetics, the CYP2D6 polymorphism does not appear to be of great importance in the antimuscarinic effect, probably because of the additive action of parent drug and active metabolite.



Clinical Pharmacology & Therapeutics (1998) 63, 529–539; doi:

Leif Bertilsson

Papers

Aging-induced Changes in Acetylcholine and Serotonin Content of Discrete Brain Nuclei

S-mephenytoin hydroxylation phenotypes in a Swedish population determined after coadministration with debrisoquin.

Evaluation of caffeine as an in vivo probe for CYP1A2 using measurements in plasma, saliva, and urine.

CYP2C19 genotype and phenotype determined by omeprazole in a Korean population.

Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of tolterodine