The effects of the glycine reuptake inhibitor R213129 on the central nervous system and on scopolamine-induced impairments in psychomotor and cognitive function in healthy subjects.

In this study the effects of R213129, a selective glycine transporter 1 inhibitor, on central nervous system function were investigated in healthy males in the absence and presence of scopolamine. This was a double-blind, placebo-controlled, 4-period crossover ascending dose study evaluating the following endpoints: body sway, saccadic and smooth pursuit eye movements, pupillometry, electroencephalography, visual analogue scales for alertness, mood, calmness and psychedelic effects, adaptive tracking, finger tapping, Visual and Verbal Learning Task, Stroop test, hormone levels and pharmacokinetics. R213129 dose levels were selected based on exposure levels that blocked the GlyT1 sites >50% in preclinical experiments. Forty-three of the 45 included subjects completed the study. Scopolamine significantly affected almost every central nervous system parameter measured in this study. R213129 alone compared with placebo did not elicit pharmacodynamic changes. R213129 had some small effects on scopolamine-induced central nervous system impairments. Scopolamine-induced finger tapping impairment was further enhanced by 3 mg R213129 with 2.0 taps/10 seconds (95% CI -4.0, -0.1), electroencephalography alpha power was increased by 10 mg R213129 with respectively 12.9% (0.7, 26.6%), scopolamine-induced impairment of the Stroop test was partly reversed by 10 mg R213129 with 59 milliseconds (-110, -7). Scopolamine produced robust and consistent effects in psychomotor and cognitive function in healthy volunteers. The most logical reason for the lack of R213129 effects seems to be that the central nervous system concentrations were too low. The effects of higher doses in healthy volunteers and the clinical efficacy in patients remain to be established.

Psychomotor and cognitive effects of a single oral dose of talnetant (SB223412) in healthy volunteers compared with placebo or haloperidol.

Central Nervous System (CNS) effects of talnetant, an NK-3 antagonist in development for schizophrenia, were compared to those of haloperidol and placebo. The study was randomised, double-blind, three-way crossover of talnetant 200 mg, haloperidol 3 mg or placebo. Twelve healthy males participated and EEG, saccadic and smooth pursuit eye movements, adaptive tracking, body sway, finger tapping, hormones, visual analogue scales (VAS) for alertness, mood and calmness and psychedelic effects, left/right distraction task, Tower of London and Visual and Verbal Learning Task were assessed. Haloperidol showed (difference to placebo; 95% CI; p-value) decreases in EEG alpha power (-0.87microV; -1.51/-0.22; p = 0.0110), saccadic inaccuracy (2.0%; 0.5/3.6; p = 0.0133), smooth pursuit eye movements (-7.5%; -12.0/-3.0; p = 0.0026), adaptive tracking (-3.5%; -5.4/-1.7; p = 0.0009), alertness (-6.8 mm; -11.1/-2.4; p = 0.0039), negative mood (-4.6 mm; -8.6/-0.6; p = 0.0266), the ability to control thoughts (1.2 mm; 0.2/2.3; p = 0.0214), and an increase of serum prolactin (ratio 4.1; 3.0/5.6; p < 0.0001). Talnetant showed decreased alpha power (-0.69 muV; -1.34/-0.04; p = 0.0390), improved adaptive tracking (1.9%; 0.1/3.7; p = 0.0370) and reduced calmness on VAS Bond and Lader (-4.5 mm; -8.0/-1.0; p = 0.0151). Haloperidol effects were predominantly CNS-depressant, while those of talnetant were slightly stimulatory. The results suggest that talnetant penetrates the brain, but it remains to be established whether this dose is sufficient and whether the observed effect profile is class-specific for NK3-antagonists.

The effects of a glycine reuptake inhibitor R231857 on the central nervous system and on scopolamine-induced impairments in cognitive and psychomotor function in healthy subjects.

The effects of the selective inhibitor of the glycine transporter 1, R231857, in development for schizophrenia, on the central nervous system (CNS) were investigated in healthy males in the absence and presence of scopolamine. This was a double-blind, placebo-controlled, four-period crossover ascending dose study. Pharmacokinetics, body sway, saccadic and smooth pursuit eye movements, pupillometry, pharmacoelectroencephalogram (EEG), Visual Analogue Scales (VAS) for alertness, mood, calmness and psychedelic effects, adaptive tracking, finger tapping, Stroop test, Visual and Verbal Learning Task (VVLT) and hormone levels were assessed. R231857 was administered alone and together with scopolamine to investigate the potential reversal of anticholinergic CNS impairment by the glycine reuptake inhibitor. Forty-two of the 45 included subjects completed the study. Scopolamine significantly affected almost every CNS parameter measured in this study. R231857 alone showed some pharmacodynamic changes compared with placebo. Although these effects might be an indication that R231857 penetrated the CNS, they were not consistent or dose-related. R231857 had some small effects on scopolamine-induced CNS-impairment, which were also not clearly dependent on dose. Scopolamine proved to be an accurate, reproducible and safe model to induce CNS impairment by an anticholinergic mechanism. R231857 lacked consistent dose-related effects in this study, probably because CNS concentrations were too low to produce significant/ reproducible CNS-effects or to affect the scopolamine challenge in healthy volunteers. The effects of higher doses in healthy volunteers and the clinical efficacy in patients remain to be established.

The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A alpha2,3 selective agonist, in comparison with lorazepam in healthy volunteers.

Benzodiazepines are effective short-term treatments for anxiety disorders, but their use is limited by undesirable side effects related to Central Nervous System impairment and tolerance development. SL65.1498 is a new compound that acts in vitro as a full agonist at the gamma-aminobutyric acid(A) 2 and 3 receptor and as a partial agonist at the 1 and 5 receptor subtypes. It is thought that the compound could be anxiolytic by its activation at the alpha2 and alpha3 receptor subtypes, without causing unfavourable side effects, which are believed to be mediated by the alpha1 and alpha5 subtypes. This study was a double-blind, five-way cross-over study to investigate the effects of three doses of SL65.1498 in comparison with placebo and lorazepam 2 mg in healthy volunteers. The objective was to select a dose level (expected to be therapeutically active), free of any significant deleterious effect. Psychomotor and cognitive effects were measured using a validated battery of measurements, including eye movements, body sway, memory tests, reaction-time assessments, and visual analogue scales. The highest dose of SL65.1498 showed slight effects on saccadic peak velocity and smooth pursuit performance, although to a much lesser extent than lorazepam. In contrast to lorazepam, none of the SL65.1498 doses affected body sway, visual analogue scale alertness, attention, or memory tests. This study showed that the three doses of SL65.1498 were well tolerated and induced no impairments on memory, sedation, psychomotor, and cognitive functions.

[Integration of training in pharmacology and pharmacotherapy in the medical curriculum in Leiden, the Netherlands]. / Integratie van onderwijs in farmacologie en farmacotherapie in het geneeskundecurriculum in Leiden.

In the new medical curriculum at Leiden University Medical Centre, the Netherlands, two aspects of the training in pharmacology and pharmacotherapy--the acquisition of knowledge and its application--have been integrated. On the basis of the approved subject matter and goals, four computer programmes were developed: the Teaching Resource Centre (TRC) Pharmacology database, the interactive TRC teaching programme, the Individual Therapy: Evaluation and Plan (ITEP), and the relational curriculum database. Together, these programmes provide the necessary knowledge in pharmacodynamics and pharmacokinetics, pharmacotherapy and the mechanisms of drug action, as well as possibilities for monitoring the educational process. The figures are created with the aid of a symbolic language, assuring a uniform presentation of all the information throughout the curriculum. Attention is also paid to the integration of these aspects with other subjects in the medical curriculum. Implementation of the teaching system in pharmacology was started at the beginning of 2001. Currently, the TRC database contains almost all the subject matter that is planned to be included. The next step in the process will be the assessment of both the knowledge and its application. TRC Pharmacology is a new method of integrating basic knowledge of pharmacology and pharmacotherapy in a medical school curriculum.

REM sleep effects as a biomarker for the effects of antidepressants in healthy volunteers.

The potential use of rapid eye movement (REM) sleep effects as a biomarker for the therapeutic effects of antidepressants in healthy volunteers is reviewed. A literature search was performed to select studies investigating the effects of antidepressants on REM sleep. To assess the specificity of REM sleep effects as a biomarker, the effects of other central nervous system drugs on REM sleep were also investigated. A significant REM sleep reduction was shown for 16 of 21 investigated antidepressants after single-dose (mean reduction 34.1%) and for 11/13 drugs after multiple-dose administration (mean reduction 29.2%). The median increase in REM latency was approximatety 60% after single- or multiple-dose administration. REM sleep effects were linearly normalized to therapeutic doses, by dividing the REM sleep effect by the investigated dose and multiplying by the therapeutic dose. Normalized REM sleep effects were highly variable (range -27.0% to 81.8% for REM sleep; range -17.0% to 266.3% for REM latency) and demonstrated no relationship with relevant pharmacological properties of the investigated drugs. No quantifiable dose-response relationship could be constructed after single and multiple dose administration. REM sleep effects were not specific for antidepressants. Benzodiazepines, for example, caused an average dose normalized REM sleep reduction of 8.7% and a median 8.6% increase of REM latency. This review demonstrates that although REM sleep effects occur with most of the antidepressants, it is by itself of limited value as a biomarker for antidepressant action. The specificity for antidepressants is limited, and it does not show a quantitative dose-response relationship to antidepressant agents. This is at least partly due to the complex relationships between drug pharmacokinetics and the variable time course of REM and other sleep stages throughout the night. Models that take these complex relationships into account may provide more comprehensive and quantifiable results.

Phosphate-binding capacities of calcium and aluminum formulations.

Calcium and aluminum phosphate binders are used to treat hyperphosphatemia which is responsible for the development of osteodystrophy commonly seen in patients with end-stage renal disease. The purpose of this study was to determine the phosphate binding capacities of several frequently used calcium and aluminum formulations. The effect of formulation types on phosphate binding was evaluated. Calcium and aluminum phosphate binders were administered to six healthy volunteers after phosphate load on separate study days. Total urine outflow was collected afterwards to determine the amount of phosphate recovered, which indicates the ability of the phosphate binder to reduce gastrointestinal phosphate absorption. The amounts of urinary phosphate recovered were different after administration of the phosphate binders. Calcium acetate resulted in the least amount of phosphate excreted. Calcium carbonate suspension, when compared with the tablet formulation, caused a smaller amount of phosphate excreted in the urine. Different phosphate binders formulations were found to have different phosphate binding capacities. Patients should therefore be closely monitored for efficacy after switching from one phosphate binder to another.

Psychotherapeutic agents in older adults. Compliance: problems and opportunities.

Many studies have demonstrated the problems patients have with medications. In these studies, the elderly and patients utilizing psychiatric medications are often cited as having the greatest noncompliance. This article reviews the extent of noncompliance in this population and the effect of noncompliance on disease management. Factors related to the health care provider, the patient, and the type of therapy that lead to noncompliance are reviewed. Opportunities and intervention techniques are provided to improve patient outcomes.

Treatment of depression in late life.

Depression is a common problem in older patients and a significant contributor to morbidity and mortality in this population. The identification and treatment of depression is more complex in older patients because of difficulty in diagnosis, coexisting illnesses, and concurrent drug therapy. In addition, a variety of medical conditions and drugs can cause depression. Treatment often has to be modified in consideration of other illnesses, medications, and the reduced ability of the elderly to metabolize drugs. Duration of treatment may be longer than with young patients because older adults may respond more slowly to antidepressants.

Update on the use of antidepressants in the elderly.

This chapter presents a review of the current status of depression treatment for the elderly. The authors describe currently available antidepressants and discuss special considerations when they are used to treat elderly patients.

Gender effect on diuretic response to hydrochlorothiazide and furosemide.

Gender has been shown to elicit differences in drug disposition and response to therapeutic agents. We measured the diuretic response to oral hydrochlorothiazide, oral and intravenous furosemide in 6 male and 6 female normal volunteers. After fasting overnight, each subject received single doses of the individual diuretics or no treatment on 4 separate days. Total urine output was collected over the next 24 hours for volume measurement and determination of sodium and potassium concentrations. There was no statistically significant difference found between male and female subjects with respect to urine flow rate, sodium, and potassium excretion rates among the treatments. However, when natriuretic response was adjusted for mg/kg of the intravenous furosemide dose received, male subjects had a higher peak sodium excretion rate than the female subjects. Results of this study reveal a gender-related difference on the natriuretic response to diuretics. Further studies are necessary to identify if this gender-related difference is caused by differences in drug metabolism, disposition, or intrinsic diuretic responsiveness at the site of action.

Drug-induced seizures in the elderly. Causative agents and optimal management.

We conducted a review of drugs that were most commonly associated with inducing seizures in the elderly population. The method for determining the risk of these agents includes evaluating the utilisation and the percentage of adverse events in previous studies and case reports. Classes of medications, such as anti-psychotics and antidepressants, are extensively reviewed to provide the clinician with treatment options in high risk patients. The risk of seizures secondary to the withdrawal of alcohol (ethanol) and benzodiazepines, and methods employed to minimise the risk are discussed. In addition, the management of patients with drug-induced seizures is delineated. Drug-induced seizures are a potentially serious adverse effect. It is important that clinicians are aware of which classes of medications and individual medications are associated with reducing seizure threshold.

Effect of diuretic drugs on creatinine clearance determination.

Diuretic drugs have been reported to alter the glomerular filtration rate and possibly the creatinine excretion by the kidneys. We evaluated the effects of single doses of diuretic drugs on creatinine clearance determination. Ten healthy volunteers were randomized to receive either oral hydrochlorothiazide, oral furosemide, intravenous furosemide, or no treatment in a cross-over fashion during four separate test days with 6-day washout periods. Urine and blood specimens were collected during 24 h after the treatments. Specimens were assayed for creatinine, and the creatinine clearance corresponding to the 4-, 6-, 12-, and 24-h urine collections were calculated. Analysis of variance did not show a statistically significant effect of the diuretic regimens on creatinine clearance over these periods. This study demonstrates that single doses of diuretic drugs do not have significant effect on creatinine clearance determination using urine collected during 4-24-h periods.

Kinetics of uptake and effects of topical indomethacin application on protein concentration in the aqueous humor of dogs.

The pharmacokinetic properties of indomethacin and its effects on aqueous protein values were studied in 15 clinically normal Beagles. The dogs were treated every 6 hours with 1% indomethacin suspension in 1 eye, with the other eye serving as a control. After 24 hours, the dogs were anesthetized and samples of aqueous humor (AH) were drawn by aqueocentesis at 0, 15, 30, 60, and 90 minutes after initial paracentesis. Additional samples were drawn at the time of euthanasia, 180 (6 dogs) and 360 minutes (9 dogs) minutes after initial paracentesis. Blood samples were obtained at each treatment and at each aqueocentesis. The eyes were enucleated after dogs were euthanatized. Aqueous protein concentrations and indomethacin concentrations in AH, plasma, and different ocular tissues were determined. Topical indomethacin administration had no effect on baseline protein concentrations of AH. It reduced protein concentrations in AH significantly at all times after initial aqueocentesis. This reduction was approximately 30%. Indomethacin in the AH is mostly protein-bound. Concentrations were 350 ng/ml in primary AH and 1,305 ng/ml in secondary AH, 90 minutes after initial aqueocentesis. Free-drug concentrations were relatively constant at about 220 ng/ml. Indomethacin administered topically is readily absorbed by the ocular adnexae, reaching a steady-state concentration of 25 ng/ml in blood plasma 18 hours after the start of treatment. Plasma concentrations were 50 times lower than therapeutically effective concentrations. High indomethacin concentrations were found in the cornea only. Low concentrations were found in the iris and ciliary body, the lens, and in the choroid.(ABSTRACT TRUNCATED AT 250 WORDS)

17 Beta-hydroxysteroid UDP-glucuronosyl transferase is expressed in bile ductular epithelial cells under physiological conditions.

Using an improved procedure to isolate pure bile ductular epithelial cells from rat liver, we were able to define UDP-glucuronosyl transferase (UDPGT) isozymes expressed in these cells under physiological conditions. The cells contained mRNA for a 17 beta-hydroxysteroid, a 3 alpha-hydroxysteroid and a phenol UDPGT. Concomitantly, a distinct pattern of UDPGT-immunoreactive proteins was expressed, including a putative 17 beta-hydroxysteroid UDPGT. The presence of this UDPGT isozyme was confirmed by a high level of testosterone glucuronidation activity. This is the first demonstration of a metabolic pathway in bile ductular epithelial cells that is primarily dedicated to the processing of endogenous compounds.