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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 a power (-0.87μV; -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 μV; -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. [ABSTRACT FROM AUTHOR]

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 γ-aminobutyric acidA α2 and α3 receptor and as a partial agonist at the α1 and α5 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. [ABSTRACT FROM AUTHOR]

Purpose: The prevalence of CYP21A2 gene variants and genotype-phenotype correlations are variable among populations. The aim of this study was to characterize CYP21A2 gene variants in adult patients with classical congenital adrenal hyperplasia (CCAH) from southern Poland and to analyze genotype-phenotype correlations., Materials/methods: A total of 48 patients (30 women and 18 men) with CCAH were included in the study. Patients were divided into two clinical subgroups, namely, salt-wasting (SW) - 38 patients and simple virilizing (SV) - 10 patients. A genetic analysis MLPA (multiplex ligation-dependent probe amplification) was performed in all of them. In dubious cases, the analysis was complemented by Sanger sequencing. Genotypes were classified into five groups (depending on the residual in vitro enzymatic activity), namely, null, A, B, C, and D, and correlated with the clinical picture., Results: Molecular defects were investigated and identified in 48 patients. The most common variant in the studied group was I2G, followed by whole or partial gene copy deletion, and I172N. One novel variant c.[878G>T] (p.Gly293Val) was found. In nine patients, a non-concordance between genotype and phenotype was observed. Genotype-phenotype correlations measured by positive predictive value (PPV) were as follows: 100% in group null, 90.5% in group A, and 66.7% in group B., Conclusions: CYP21A2 variants in the studied cohort were similar to values previously reported in other countries of the region. There was a good correlation between genotype and phenotype in the null and A groups, the correlation being considerably lower in group B., (© 2022. The Author(s).)

The 2019-2020 Academic Affairs Committee was charged with identifying promising practices in academic-practice partnerships and professional pharmacy organization initiatives that are accelerating the transformation of a workforce prepared to assume responsibility for society's medication use needs in 2030 and determining the role AACP can plan in supporting these partnerships and initiatives. The committee identified a set of ideal principles, characteristics, and design elements of a high-quality, large-scale workforce development program. The committee also categorized current mechanisms for professional workforce development, in addition to identifying their strengths and weaknesses, with the realization that novel approaches are needed to accomplish the goal of large-scale workforce transformation. This report also highlights two existing initiatives aligned with accelerating the transformation of the workforce (ie, the Community Pharmacy Enhanced Services Network (CPESN) ACT (Academia-CPESN Transformation) Pharmacy Collaborative and the American Pharmacists Association ADVANCE platform) and is proposing a policy statement affirming AACP's support. Furthermore, the committee is proposing another policy statement supporting colleges and schools of pharmacy taking an active role in implementing innovative and novel approaches for the development of the current workforce. In order to truly understand the many factors influencing large-scale workforce transformation, the committee is also proposing a stakeholder conference with a wide range of participants and a targeted set of questions focused on current and future needs., (© 2020 American Association of Colleges of Pharmacy.)

Background and Purpose: The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences (SSPPS) used the opportunity of curriculum renewal to integrate knowledge and skills learned from didactic courses into the introductory pharmacy practice experiences (IPPEs) occurring simultaneously. This paper describes and evaluates the meaningful application of course content into IPPEs, and evaluates the success using qualitative feedback., Educational Activity and Setting: Students entering the renewed curriculum starting in fall 2012 were provided a list of pharmacy skills and activities from didactic course directors that reinforced course content for that semester. The skills and activities were to be completed during the students' IPPE visits in the community or health systems settings, depending on the program year and semester., Findings: Students successfully completed course assignments during their IPPE course program. Not all activities could be completed as designed, and many required modification, including simulated experiences. Feedback from faculty and preceptor members of the school's experiential education committee demonstrated that these activities were valuable and improved learning of course material, but were challenging to implement., Discussion and Summary: A renewed curriculum that mapped course assignments for completion in experiential settings was successfully established, after some modifications. The program was modified at regular intervals to improve the ability of preceptors to complete these activities in their individual practice environment. A balance between the school providing guidance on what activities students should perform and allowing unstructured independent learning with the preceptor is needed for an optimal experience., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

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.

Background and Objective: Anaemia is a serious comorbidity that is common in patients with renal failure or cancer. CNTO 528 is the first Mimetibody developed to mimic the effects of erythropoietin (EPO), a hormone that stimulates the production of red blood cells (RBCs). The objective of this study was to develop a pharmacokinetic and pharmacodynamic model for CNTO 528 in healthy male subjects., Methods: A pharmacokinetic/pharmacodynamic model for CNTO 528 was developed to describe the serum concentration versus time profile and the pharmacological responses of percentage of reticulocytes, total RBC counts and haemoglobin concentration after a single intravenous administration of CNTO 528 at 0.03, 0.09, 0.3 and 0.9 mg/kg in 24 healthy subjects. An open, linear, two-compartment model was used to characterize the pharmacokinetic parameters of CNTO 528. A catenary cell production and lifespan loss model was used to fit the pharmacodynamic data, yielding estimates of drug potency (SC(50)), efficacy (S(max)) and other pharmacodynamic parameters. Bootstrap and posterior predictive checks (PPC) were used to evaluate the model., Results: Administration of CNTO 528 stimulated the production of reticulocytes, RBCs and haemoglobin. CNTO 528 exhibits a half-life of 141 hours, or approximately 5.9 days. The SC(50) was estimated to be 0.37 mg/L, indicating that low serum CNTO 528 concentration was sufficient to produce pharmacological effects. Compared with historical controls, CNTO 528 S(max) appears to be 2-fold higher than recombinant human EPO. Bootstrap analysis and PPCs confirmed the accuracy and precision in the parameter estimates and the adequacy of the model to describe the CNTO 528 pharmacokinetics and pharmacodynamics., Conclusion: The mechanistic population model was suitable to characterize the pharmacokinetics and pharmacodynamics of intravenously administered CNTO 528 in healthy subjects. This qualified model is deemed appropriate to conduct clinical trial simulations and to support the decision-making process for dose selection in studies of EPO-stimulating agents.

The erythropoietin mimetic antibody fusion protein CNTO 528 was developed as a novel antibody fusion protein by constructing an active hematopoietic peptide onto an IgG1-based scaffold. This resulted in a molecule with a long circulating half-life and a prolonged effect of stimulating reticulocyte production and hemoglobin (Hgb) synthesis. To assess the safety, pharmacokinetics, and pharmacodynamics of CNTO 528, the authors gave 44 adult healthy male subjects single or fractionated doses of intravenous CNTO 528 or placebo. CNTO 528 was generally well tolerated. The maximum observed concentration (Cmax) and the area under the concentration versus time curve (AUC) increased in an approximately dose-dependent manner between the 0.09-mg/kg and 0.9-mg/kg doses. The maximum effect on the reticulocyte response occurred approximately 8 to 9 days after administration. A median increase in Hgb (> or =1 g/dL above baseline) was achieved 9 to 10 days after administration, with a maximum effect between 19 and 26 days. Two subjects in the 0.9-mg/kg dose group had elevated Hgb concentrations requiring phlebotomy. In this first-in-human study, CNTO 528 was well tolerated and effective in elevating and maintaining Hgb by at least 1 g/dL following a single intravenous administration, which suggests that an erythropoietin mimetic molecule, such as CNTO 528, may be an effective therapy for patients with anemia.

Background: Due to curricular changes at Leiden University Medical School, students have been exposed to different amounts of pharmacology and pharmacotherapy education. Cohort 1999 received little training; whereas cohort 2000 was provided with self-study materials preclinically and extra attention to pharmacotherapy during rotations. This study compares the cohorts by performance in and perception of pharmacotherapeutic abilities during the internal medicine rotation., Results: Preclinically, both cohorts were unable to adequately complete therapeutic plans. While cohort 1999 did not improve during the rotation, cohort 2000 did. For both cohorts the percentage of students feeling confident about various pharmacotherapeutic abilities increased significantly during rotations, but only 25% felt secure about their overall ability., Conclusions: The extra education helped cohort 2000 perform better, but did not improve their confidence in their pharmacotherapeutic ability. Thorough preclinical training and compulsory practice with feedback and assessment are necessary for students to develop competence in pharmacotherapy.

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.

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.

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.

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.

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 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.

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.

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.

Ninety-two patients in long-term treatment for obesity completed a questionnaire on the weight development of their close family members. Of 47 such relatives, 37 had lost a mean of 6.1 kg and 10 increased a mean of 5.1 kg. Treatment of obesity will affect many more than those taking part in the actual program and generally result in weight loss. This effect on family members was mostly considered beneficial.

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.