Pharmacological Cognitive Enhancement in Healthy Individuals: A Compensation for Cognitive Deficits or a Question of Personality?

The ongoing bioethical debate on pharmacological cognitive enhancement (PCE) in healthy individuals is often legitimated by the assumption that PCE will widely spread and become desirable for the general public in the near future. This assumption was questioned as PCE is not equally save and effective in everyone. Additionally, it was supposed that the willingness to use PCE is strongly personality-dependent likely preventing a broad PCE epidemic. Thus, we investigated whether the cognitive performance and personality of healthy individuals with regular nonmedical methylphenidate (MPH) use for PCE differ from stimulant-naïve controls. Twenty-five healthy individuals using MPH for PCE were compared with 39 age-, sex-, and education-matched healthy controls regarding cognitive performance and personality assessed by a comprehensive neuropsychological test battery including social cognition, prosocial behavior, decision-making, impulsivity, and personality questionnaires. Substance use was assessed through self-report in an interview and quantitative hair and urine analyses. Recently abstinent PCE users showed no cognitive impairment but superior strategic thinking and decision-making. Furthermore, PCE users displayed higher levels of trait impulsivity, novelty seeking, and Machiavellianism combined with lower levels of social reward dependence and cognitive empathy. Finally, PCE users reported a smaller social network and exhibited less prosocial behavior in social interaction tasks. In conclusion, the assumption that PCE use will soon become epidemic is not supported by the present findings as PCE users showed a highly specific personality profile that shares a number of features with illegal stimulant users. Lastly, regular MPH use for PCE is not necessarily associated with cognitive deficits.

[Experimental study of dicholine succinate pharmacokinetics].

We have conducted for the first time an experimental study of pharmacokinetics of dicholine succinate (DCS) for different ways of its administration in rats The quantitative evaluation of DCS and its metabolites was performed by the radioactive isotope technique. Various parameters of DCS pharmacokinetics were estimated, including the dose dependence of drug content in the blood plasma, total bioavailability, distribution kinetics, and the main ways of DCS excretion.

Studies on the metabolism and the toxicological analysis of the nootropic drug fipexide in rat urine using gas chromatography-mass spectrometry.

Qualitative studies are described on the metabolism and the toxicological analysis of the nootropic fipexide (FIP) in rat urine using gas chromatography-mass spectrometry (GC-MS). FIP was extensively metabolized to 1-(3,4-methylenedioxybenzyl)piperazine (MDBP), 4-chlorophenoxyacetic acid, 1-[2-(4-chlorophenoxy)acetyl]piperazine, N-(4-hydroxy-3-methoxy-benzyl)piperazine, piperazine, N-(3,4-methylenedioxybenzyl)ethylenediamine, and N-[2-(4-chlorophenoxy)acetyl]ethylenediamine. The authors' systematic toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis of one urine aliquot, liquid-liquid extraction and acetylation allowed the detection of FIP via its metabolites in rat urine after administration of a common FIP dose. Therefore, this qualitative procedure should also be suitable for detection of a FIP intake in human urine. Differentiation of an intake of FIP from that of other drugs which form common metabolites is discussed.

Plasma tacrine concentrations are significantly increased by concomitant hormone replacement therapy.

BACKGROUND: In vitro results suggest that the synthetic hormones used in postmenopausal hormone replacement therapy (HRT) may be significant inhibitors of oxidative drug metabolism. Moreover, HRT has been reported to enhance response to tacrine in postmenopausal patients with Alzheimer's disease, but the mechanism of this interaction remains unclear. OBJECTIVE: To examine the effect of HRT with 2 mg estradiol valerate and 0.25 mg levonorgestrel once daily on the pharmacokinetics of tacrine. METHODS: Ten healthy female volunteers received treatment for 10 days with once-daily HRT or placebo in a randomized, double-blind crossover study. One hour after the last HRT or placebo capsule on day 10, the subjects received a single 40-mg dose of tacrine. Plasma samples were collected for 30 hours and urine samples were collected for 24 hours after tacrine intake for the measurement of tacrine and 1-hydroxytacrine concentrations. RESULTS: HRT increased the mean plasma concentration-time curve calculated from zero to infinity (AUC) of tacrine by 60% (P = .009); the greatest individual increase in the AUC was about threefold. Similarly, the mean peak concentration in plasma of tacrine was 46% (P = .031) higher in the HRT phase compared with the placebo phase. HRT reduced the mean apparent oral clearance of tacrine by 31% (P = .014), but no significant difference was found in the elimination half-life or the renal clearance of tacrine between the HRT phase and the placebo phase. The metabolic ratio (1-hydroxytacrine AUC/tacrine AUC) was significantly (mean, 26%; P < .001) reduced in all 10 subjects. CONCLUSIONS: HRT with estradiol and levonorgestrel significantly increased plasma tacrine concentrations. This interaction between tacrine and HRT involves reduced metabolic conversion of tacrine to its main metabolite 1-hydroxytacrine by CYP1A2 during the first-pass phase. The interaction may be clinically important with regard to both enhanced efficacy and increased likelihood of concentration-dependent adverse effects of tacrine in the long-term treatment of patients with Alzheimer's disease. Accordingly, smaller doses of tacrine may be appropriate when coadministered with HRT.

Comparison of pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly and young subjects.

Pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly subjects were compared with those in younger subjects. Fourteen healthy male volunteers (7 elderly subjects aged 68-79 years and 7 young subjects aged 20-32 years) were included in the study. In a parallel group design, a tablet containing 100 mg NS-105 was administered orally after breakfast. One young subject was excluded from the pharmacokinetic analyses owing to an insufficient urine collection. The maximum plasma concentration (Cmax) was higher in the elderly (3.06 +/- 0.69 vs. 2.13 +/- 0.34 micrograms/ml, the elderly vs. the young, mean +/- SD, p = 0.0117) and area under the plasma concentration curve (AUC) was also higher in the elderly (24.6 +/- 4.4 vs. 14.4 +/- 3.1 micrograms.hr/ml, p = 0.0006). There is a tendency that time to reach Cmax was longer in the elderly (2.1 +/- 1.1 vs. 1.3 +/- 0.5 hr, p = 0.1199), and a tendency of prolongation of elimination half-life. Urinary recovery of NS-105 was less in the elderly up to 8 h after administration, while total recovery of the dose was not different in the two groups. Total clearance was reduced in the elderly (0.076 +/- 0.013 vs. 0.121 +/- 0.025l/kg/hr, p = 0.0013) and the decrease seemed to be mainly due to a decrement in renal clearance of the drug in the elderly. A significant correlation was found between renal clearance of NS-105 and creatinine clearance of each subject (r = 0.583, p = 0.0364). These observations indicate that the plasma concentration of NS-105 will increase in elderly subjects mainly due to a decrement in renal clearance of the drug. Careful observation is needed when prescribing the drug to an elderly patient.

Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: a preliminary report.

The administration of cytidine-5'-diphosphate choline (CDP-choline, citicoline) to animals increases the rate of membrane phospholipid synthesis and elevates brain dopamine levels. Because cocaine dependence has been associated with increases in brain phospholipid precursors, as well as depletion of dopamine within the central nervous system, the present outpatient study was conducted to assess the safety of citicoline (500 mg bid) and to determine if short-term treatment alters mood states and cocaine craving in subjects with a history of cocaine dependence. In addition, measures of drug craving and mood states after presentation of cocaine-related cues were collected on two occasions: before and after 14 days of double-blind treatment with either citicoline or placebo. Subjects did not experience any side effects and citicoline treatment was associated with decreases in self-reported mood states associated with cocaine craving. These preliminary data are encouraging and suggest that citicoline warrants further study as a promising potential treatment for cocaine abuse and dependence that is devoid of side effects.

The O-demethylation of the antidementia drug galanthamine is catalysed by cytochrome P450 2D6.

Galanthamine proved effective in symptomatic treatment of senile dementia of Alzheimer's type. The aim of this study was to elucidate the metabolism of galanthamine. Two novel metabolites of galanthamine have been isolated from the urine of eight young men after single doses of 10-15 mg. Some 19.8% of the doses were excreted as O-demethylgalanthamine glucuronide, 5% as N-demethylgalanthamine, 25.1% as galanthamine, and 0.8% as epigalanthamine. After coadministration of quinidine hydrogen sulfate, which inhibits cytochrome P450 2D6 (CYP2D6) selectively, O-demethylgalanthamine glucuronide was highly diminished in urine. In vitro, human liver microsomes metabolized galanthamine to O-demethylgalanthamine with Vmax 5.2 nmol/mg protein/h and Km 187 microM. Ki of quinidine to inhibit O-demethylation was 28 nM. To inhibit cholinesterases, O-demethylgalanthamine was 10-fold more selective for acetylcholinesterase (AChE) versus butyrylcholinesterase (BuChE) than galanthamine. After glucuronidation, O-demethylgalanthamine failed to inhibit AChE and BuChE. N-Demethylgalanthamine inhibited cholinesterases less potently than galanthamine.

Radioimmunoassay for a novel benzodiazepine inverse agonist, S-8510, in human plasma and urine.

A radioimmunoassay (RIA) was developed for a new benzodiazepine inverse agonist, 2-(isoxazol-3-yl)-3,6,7,9-tetrahydroimidazo [4,5-d] pyrano [4,3-b] pyridine monophosphate monohydrate (S-8510), in human plasma and urine. For competitive RIA, three amino derivatives of S-8510 were labelled by the Bolton and Hunter method and rabbit antisera were prepared using three immunogens, conjugates of three carboxyl derivatives of S-8510 with bovine serum albumin. All combinations of the labelled antigens and antisera were examined and homologous combinations were selected for the competitive RIA. One of the three homologous combinations had the best selectivity after investigations of cross-reactivity using 12 related compounds and was very sensitive for S-8510. Next, a pretreatment for biological samples was developed using mixed mode solid-phase extraction (SPE) column followed by the RIA (SPE/RIA). The assay recoveries for human plasma and urine were both excellent and the limits of quantitation were extremely low, 80 and 200 pg ml(-1), respectively. Human plasma samples and urine samples after administration of this drug were successfully measured by the SPE/RIA. No cross-reactive metabolites were detected in any fractions after RP-HPLC separation of the plasma samples. The RIA using carefully selected antiserum and labelled antigen was highly specific for unchanged S-8510. To simplify the RIA procedure, a scintillation proximity assay (SPA) using the same labelled antigen and antiserum was developed for analyzing S-8510 in human plasma and found to be very promising.

Pharmacokinetics of NS-105, a novel cognition enhancer. 2nd communication: distribution and transfer into fetus and milk after single administration, and effects of repeated administration on pharmacokinetics and hepatic drug-metabolizing enzyme activities in rats.

The tissue distribution and transfer into the fetus and milk of NS-105 ((+)-5-oxo-D-prolinepiperidinamide monohydrate, CAS 110958-19-5), a novel cognition enhancer, were investigated in rats after single oral administration of 14C-NS-105. The effects of repeated oral administration on the pharmacokinetics of NS-105 and hepatic drug-metabolizing enzyme activities also were investigated in rats. The radioactivity concentration in most tissues of male rats reached a maximum of 0.5 h after the single oral administration of 14C-NS-105, indicating rapid absorption and distribution, 0.5 h after the administration, the highest concentrations were present in the kidney and stomach, and the lowest in the white fat. The concentrations in the remaining tissues were moderately lower than the plasma value. The radioactivity concentrations in all the tissues tested decreased along with the plasma concentration, and were below or near the detection limit 24 h after the administration. Most of the radioactivity in the plasma, liver, kidney and cerebrum was due to unchanged NS-105. The tissue distribution patterns of radioactivity in female (non-pregnant) and pregnant rats after the oral administration of 14C-NS-105 did not differ from the pattern in male rats, revealing neither sex- nor pregnancy-related differences in NS-105 distribution. In pregnant rats, the maximum concentration in the fetus was 66% of that in the maternal plasma. In lactating rats, the radioactivity concentration in the milk was similar to that in the plasma. During and after the repeated oral administration of 14C-NS-105, the plasma concentrations and cumulative urinary and fecal excretions of radioactivity did not change with the number of administrations and were similar to the corresponding values after the single administration. The radioactivity concentrations in most tissues 8 h after the 7th, 14th and 21st administrations were about twice the corresponding values after the single administration, indicating that there is no marked accumulation of radioactivity in the tissues and that a steady state level was reached within 1 week. Repeated oral administration of NS-105 (10 mg/kg) to male rats did not affect hepatic drug-metabolizing enzyme activities.

Radioimmunoassay for TA-0910, a new stable thyrotropin releasing hormone analogue and its metabolite, TA-0910 acid-type, in human plasma and urine.

Radioimmunoassay (RIA) was investigated for the determination of TA-0910 and its main metabolite, TA-0910 acid-type, in human plasma and urine. TA-0910 is a new metabolically stable analogue of thyrotropin releasing hormone (TRH). Antiserum was raised in the rabbit against the 1-fluoro-2,4-dinitrophenyl derivative of TA-0910 or TA-0910 acid-type conjugated to keyhole limpet hemocyanin (KLH). The radioligand was prepared by iodination with 125I of the histidine imidazole ring of TA-0910 or TA-0910 acid-type. Cross-reactivities of anti-TA-0910 or TA-0910 acid-type antiserum for TA-0910, its metabolite and related compounds were low. The calibration range was 0.02-5 ng ml-1 using 100 microliters human plasma or urine. Inter-day variations of TA-0910 and TA-0910 acid-type assay in plasma were 3.5-15.5 and 1.8-9.4%, respectively. The variations of the assay in urine were the same as those in plasma. The recovery of TA-0910 and TA-0910 acid-type spiked in plasma or urine samples was approximately 100%. Furthermore, this method was applied to the determination of TA-0910 and TA-0910 acid-type in human plasma and urine samples, for the evaluation of the pharmacokinetics of TA-0910 in humans. From the results it was demonstrated that he developed RIA was useful for the determination of TA-0910 and TA-0910 acid-type in human plasma and urine, and was applicable to pharmacokinetic studies in humans.

[Fast thin-layer densitometric determination of the nootropic piracetam in biological material]. / Rasche dünnschicht-densitometrische Bestimmung des Nootropikums Piracetam in biologischem Material.

After oral doses of piracetam this drug is detectable in serum as well as in urine after formation of the red Fe(III)-hydroxamatecomplex by thin-layer densitometry. Detection in serum requires extraction with a mixture of dichloromethane/ methanol, while urine can be used directly after dilution. The limit of quantification in urine is 100 micrograms/ml and in serum 4.0 micrograms/ml. The new method was validated by HPLC. The coefficient of correlation was 0.9999% for determination in urine and 0.9986% for determination in serum.

Metabolic disposition of the cognition activator tacrine in rats, dogs, and humans. Species comparisons.

The metabolic fate of tacrine [1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate (THA)] was examined in rats, dogs, and humans. After administration of single oral doses of [14C]THA to rats, dogs, and humans, drug-derived material was well absorbed, with urinary excretion being the predominant route of radiolabel elimination. Metabolic profiling of plasma and urine from rats, dogs, and humans showed THA to be extensively metabolized with marked species differences in quantitative amounts of metabolites observed. Plasma profiles were similar to respective urinary profiles in all three species. Present in profiles of urine from rats were 1-hydroxy (OH)-THA (major), 2-OH-THA, and 4-OHA-THA, and unchanged THA. Also observed were trace amounts of more polar metabolites, presumably arising from sequential metabolism. Metabolic profiling of dog urine also showed 1-OH-THA to be the major metabolite, with trace amounts of the 2-OHA-THA and 4-OH-THA regioisomers and THA excreted. In dog urine, more of the radioactivity was associated with polar metabolites, including 1,3-dihydroxy-THA and a dihydrodiol metabolite. Human urinary metabolic profiles were more similar to that in dogs than in rats, with no single metabolite constituting > 10% of urinary radioactivity. Present in human urine were phenol glucuronide metabolites, of which 7-OH-THA was identified as an aglycone. Relevance of the marked quantitative differences in THA metabolism between rats, dogs, and humans to species differences in THA hepatotoxic potential remains to be established.