Characteristics of children and adolescents first prescribed proton pump inhibitors or histamine-2-receptor antagonists: an observational cohort study

Objective: To describe the characteristics of pediatric patients prescribed proton pump inhibitors (PPIs) vs those of pediatric patients prescribed histamine-2-receptor antagonists (H₂RAs).

Methods: Observational studies were conducted using The Health Improvement Network (THIN) and the PHARMO Database Network. Patients aged 0–18 years who were first prescribed a PPI or H₂RA between October 1, 2009 and September 30, 2012 (THIN) or between September 1, 2008 and August 31, 2011 (PHARMO) were included. Patient characteristics were identified and compared between the PPI and H₂RA cohorts using odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age and sex.

Results: The mean age (years) was higher in the PPI than in the H₂RA cohorts (THIN 12.3 [n?=?8204] vs 5.4 [n?=?7937], PHARMO 11.0 [n?=?15 362] vs 7.1 [n?=?6168]). Previous respiratory disease was more common in the PPI than in the H₂RA cohort in THIN (OR?=?1.19, 95% CI?=?1.08–1.30), as were asthma and respiratory medication use in PHARMO (OR?=?1.27, 95% CI?=?1.12–1.45 and OR?=?1.23, 95% CI?=?1.10–1.38, respectively) and oral corticosteroid use in both databases (OR?=?1.45, 95% CI?=?1.10–1.92 [THIN]; OR?=?2.80, 95% CI?=?2.11–3.71 [PHARMO]). Non-steroidal anti-inflammatory drugs, antibiotics, and oral contraceptives were also more common in PPI than in H₂RA cohorts in both databases.

Conclusions: Pediatric patients receiving PPIs and those receiving H₂RAs may represent different patient populations. PPIs may be more commonly prescribed than H₂RAs among patients with respiratory diseases.     

Pharmacokinetics of the novel PAR-1 antagonist vorapaxar in patients with hepatic impairment

Purpose

To determine whether hepatic impairment has an effect on the pharmacokinetics (PK) of vorapaxar or M20, its main pharmacologically active metabolite.

Methods

This was an open-label study in which a single 40-mg oral dose of vorapaxar was administered to patients with mild (n?=?6), moderate (n?=?6), and severe (n?=?4) hepatic impairment and healthy controls (n?=?16) matched for age, gender, weight, and height. Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8?weeks postdose.

Results

Plasma vorapaxar and M20 PK profiles were similar between patients with impaired liver function and healthy controls. Group mean values for vorapaxar C_max and AUC_tf were 206–279?ng/mL and 14,200–18,200?ng·h/mL, respectively, with the lowest values observed in patients with severe impairment. Vorapaxar median T_max and mean t_1/2 values were 1.00–1.75?h and 298–366?h, respectively. There was no apparent correlation between vorapaxar or M20 exposure or t_1/2 values and disease severity. Vorapaxar was generally well tolerated; one serious adverse event (gastrointestinal bleeding secondary to ruptured esophageal varices) was reported in a patient with severe hepatic impairment.

Conclusions

Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20. No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment. Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment, administration of vorapaxar to such patients is not recommended given their bleeding diathesis.     

Risperidone, QTc interval prolongation, and torsade de pointes: a systematic review of case reports

Rationale

A recent publication asserted that even low-dose risperidone may induce corrected QT (QTc) interval prolongation up to 500 ms without drug-induced I_Kr blockade. We seek to better understand the complexity of any link between risperidone-induced/associated QTc interval prolongation and torsade de pointes (TdP).

Objectives

The objective of this study is to systematically analyze all available case reports of risperidone, QTc interval prolongation, and/or TdP.

Method

We identify case reports using PubMed, Medline, EMBASE, and Cochrane.

Results

Of the 15 cases found, nine were adult women (ages 31, 33, 34, 37, 47, “elderly”, 77, 84, and 87 years) and one was a teenager. There were four men (ages 28, 29, 29, and 46 years) and one preadolescent boy. Besides risperidone administration or overdose, traditional risk factors for QTc interval prolongation and TdP included female sex (n?=?10), older age (n?=?4), heart disease (n?=?3), hypokalemia (n?=?2), bradycardia (n?=?1), liver disease (n?=?1), QTc interval prolonging drugs other than risperidone (n?=?8), and metabolic inhibitors (n?=?2). TdP occurred in four cases. Six patients died, and three deaths were probably related to TdP.

Conclusion

Risperidone (when properly prescribed in patients free of other risk factors for QTc interval prolongation and TdP) is a relatively safe drug. Conventional statistics can neither predict the individual patient who will experience TdP nor determine the relationship of drug dose to QTc interval prolongation and TdP. Narrative medicine using a case report format appears to be an alternative and valuable additional approach to advance our understanding of this relationship and to reduce risks.     

Superstitious conditioning as a model of delusion formation following chronic but not acute ketamine in humans

Background

Ketamine has previously been shown to induce delusion-like or referential beliefs, both acutely in healthy volunteers and naturalistically among nonintoxicated users of the drug. Delusions are theoretically underpinned by increased superstitious conditioning or the erroneous reinforcement of random events.

Materials and methods

Using a novel and objectively measured superstitious conditioning task, experiment 1 assessed healthy volunteers before and during placebo (n?=?16), low-dose (n?=?15), and high-dose ketamine (n?=?16) under randomized and double-blind conditions. Experiment 2 used the same task to compare ketamine users (n?=?18), polydrug controls (n?=?19), and nondrug-using controls (n?=?17).

Results

In experiment 1, ketamine produced dose-dependent psychotomimetic effects but did not cause changes in superstitious conditioning. Experiment 2 found increased levels of superstitious conditioning among ketamine users compared to polydrug and nondrug-using controls, respectively, as evidenced by both objective task responses and subjective beliefs following the task.

Conclusions

Results indicate that chronic but not acute exposure to ketamine may increase the propensity to adopt superstitious conditioning. These findings are discussed in terms of acute and chronic ketamine models of delusion-like belief formation in schizophrenia.     

Drug-induced immune thrombocytopaenia: results from the Berlin Case–Control Surveillance Study

Purpose

Drug-induced immune thrombocytopaenia is a rare, serious condition that can be triggered by numerous medications. To characterize the spectrum of drugs associated with immune thrombocytopaenia (ITP) in the Berlin Case–Control Surveillance Study (FAKOS).

Methods

Adult hospitalized patients with new onset idiopathic, secondary or drug-induced acute ITP and hospital control patients were ascertained by active surveillance in 50 Berlin hospitals (>180 clinical departments) between 2000 and 2009. Drug exposures were obtained in a personal interview. Chronic cases were excluded in a follow-up after 6 or more months. A standardized causality assessment was conducted for each ITP patient to assess possible drug aetiology. Drug risks were quantified in a case–control design with unconditional logistic regression analysis.

Results

Ninety out of 169 validated cases of acute ITP were assessed as being at least possibly drug-related (n?=?85 different drugs overall, n?=?30 drugs with certain or probable causality). Drugs involved in ≥2 cases with a probable or certain relationship were tirofiban (n?=?10 cases), abciximab (n?=?4), trimethoprim/sulphamethoxazole (n?=?4), influenza vaccine (n?=?3), and citalopram (n?=?2). Pneumococcal and poliomyelitis vaccine were assessed as probably causing ITP in one case each. In the case–control analyses, significantly increased risks were observed for tirofiban, abciximab, trimethoprim/sulphamethoxazole, gentamicin, triamterene/hydrochlorothiazide, drospirenone/ethinylestradiol, and influenza vaccination.

Conclusions

Our study confirms known ITP risks for glycoprotein IIb/IIIa receptor antagonists and sulphonamides and generates signals for several other drugs and vaccines. New onset of ITP should not only direct attention to drugs as possible aetiological agents, but also to vaccines that are known to cause autoimmune phenomena.     

Effects of TNF inhibitor on innate inflammatory and Th17 cytokines in stimulated whole blood from rheumatoid arthritis patients

Background

Recent studies point to important roles for IL-17 and Th17 cells in sustaining chronic inflammation and articular destruction in rheumatoid arthritis (RA). We investigated the effects of TNF inhibitor on innate inflammatory and Th17 cytokines production by ex vivo lipopolysaccharide (LPS)-stimulated whole blood in patients with RA and the associations of cytokine levels in whole blood cultures with autoantibodies and markers of disease activity.

Materials and methods

Whole blood cultures from 18 healthy volunteers and 19 RA patients on etanercept therapy were stimulated with LPS and the production of IL-6, TNF-??, IL-23, IL-17A and IL-21 was measured by ELISA.

Results

After stimulation with LPS, the interleukin (IL)-17A (p?=?0.020) and IL-21 (p?=?0.0001) secretions were significantly higher in patients with RA than in controls, while the TNF-?? (p?=?0.002) was significantly lower at baseline. Etanercept significantly decreased IL-21 production (p?=?0.007), while IL-6 production (p?=?0.005) significantly increased after 6?months of therapy. IL-21 significantly correlated with RF (r?=?0.917, p?<?0.01) and antimutated citrullinated vimentin antibodies (r?=?0.770, p?<?0.01) at baseline. Logistic regression analysis revealed that baseline IL-21 levels (p?=?0.004) were significant predictors of DAS28-ESR at 6?months follow-up.

Discussion

Stimulation with LPS increased production of Th17 cytokines in whole blood cultures in patients with RA. Etanercept therapy decreased IL-21 secretion, while the capacity of whole blood cells to produce IL-6 increased. IL-21 production is strongly associated with the levels of autoantibodies. Our findings suggest that IL-21 production in LPS-stimulated whole blood cultures may be predictive of clinical response to etanercept treatment in patients with RA.     

Pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism

Objective

To study the impact of the 79A>C polymorphism in the cytidine deaminase (CDA) gene on the pharmacokinetics of gemcitabine and its metabolite 2′,2′-difluorodeoxyuridine (dFdU) in non-small-cell lung cancer (NSCLC) patients.

Patients and methods

Patients (n?=?20) received gemcitabine 1,125 mg/m² as a 30 min i.v. infusion as part of treatment for NSCLC. Plasma samples were collected during 0–6 h after gemcitabine administration. Gemcitabine and dFdU were quantified by high performance liquid chromatography with ultraviolet detection. The CDA 79A>C genotype was determined with PCR and DNA sequencing.

Results

Gemcitabine was rapidly cleared from plasma and undetectable after 3 h. The allele frequency of the 79A>C polymorphism was 0.40. Diplotypes were distributed as A/A n?=?8, A/C n?=?8 ,and C/C n?=?4. No significant differences were found between the different CDA genotypes and gemcitabine or dFdU AUC, clearance, or half-life.

Conclusion

The 79A>C polymorphism in the CDA gene does not have a major consistent and signficant impact on gemcitabine pharmacokinetics.     

The atypical antipsychotic risperidone reverses the recognition memory deficits induced by post-weaning social isolation in rats

Rationale

Rearing rats in isolation from weaning is an established preclinical neurodevelopmental model which induces behavioural deficits with apparent translational relevance to some core symptoms of schizophrenia.

Objective

This study evaluated the ability of the atypical antipsychotic risperidone to reverse behavioural deficits induced by post-weaning social isolation of rat pups and to further characterise the predictive validity of this model.

Method

Forty-five male Lister hooded rats were housed in groups of 3–4 (n?=?16) or singly (n?=?29) for 4 weeks immediately after weaning on postnatal day (PND) 22–24. On PND 51, novel cage-induced locomotor activity (LMA) was assessed to subdivide rats into groups balanced for behavioural response. On PNDs 58, 59, 65 and 72, rats received either vehicle (1 ml/kg; i.p.) or risperidone (0.2 or 0.5 mg/kg; i.p.) 30 min prior to testing in LMA, novel object discrimination (NOD), prepulse inhibition (PPI) of acoustic startle and conditioned emotional response (CER) learning paradigms, respectively.

Results

Isolation rearing had no effect on PPI, but produced LMA hyperactivity and impaired NOD and CER compared to group-housed controls. Risperidone caused a dose-dependent reduction in LMA, irrespective of rearing condition, but selectively reversed the NOD deficit in isolation-reared rats. Risperidone did not reverse the isolation rearing-induced CER deficit.

Conclusions

Similar to its clinical profile, risperidone only partially reverses the schizophrenic symptomology; since it reversed some, but not all, of the learning and memory deficits induced by post-weaning isolation, the isolation rearing model may be useful to predict antipsychotic activity of novel therapeutic agents.     

Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1

Purpose

We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1*15 haplotype in healthy volunteers.

Methods

In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n?=?6), with CYP2C19*1/*1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n?=?4), with CYP2C19 EM and homozygous (n?=?3) or heterozygous for SLCO1B1*15 (n?=?1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3–14 and twice-daily oral doses of 500 mg clarithromycin on study days 11–14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin).

Results

Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (C_max) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and C_max by 27 % (n?=?10, both p?<?0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed.

Conclusions

Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.     

Cigarette craving and withdrawal symptoms during temporary abstinence and the effect of nicotine gum

Rationale

It is widely believed that nicotine withdrawal symptoms appear within a few hours of stopping smoking, but few data exist documenting their emergence in naturalistic settings. In several countries, nicotine replacement products are licensed for relief of withdrawal symptoms during temporary abstinence, but again, there are no data supporting this from naturalistic settings.

Objectives

To examine the emergence of cigarette craving and withdrawal symptoms during temporary abstinence in a naturalistic setting while using either nicotine or placebo gum.

Methods

Double-blind, randomised, placebo-controlled study in which 132 dependent smokers abstained for 6 h with the assistance of either nicotine (2 mg, n?=?42 or 4 mg, n?=?24) or placebo (n?=?66) gum while travelling on a non-smoking train. Outcome measures were ratings of craving and mood withdrawal symptoms prior to treatment and at regular intervals during abstinence.

Results

In a multivariate analysis of all symptoms, there was no interaction between treatment and time [F(21,110)?=?1.28, p?=?0.20, $ \eta_{\mathrm{p}}^2 $ ?=?0.20] nor an effect of treatment [F(7,124)?=?0.45, p?=?0.87, $ \eta_{\mathrm{p}}^2 $ ?=?0.03]. There was an effect of time [F(21,110)?=?11.59, p?<?0.001, $ \eta_{\mathrm{p}}^2 $ ?=?0.69) and univariate analyses revealed that the majority of symptoms increased linearly throughout the period of abstinence with detectable onsets typically between the first 60 and 180 min of abstinence.

Conclusions

Smokers who temporarily abstain in naturalistic settings experience craving and withdrawal symptoms that emerge linearly over the first 6 h of abstinence. Changes in craving and several mood withdrawal symptoms can be detected within the first 3 h. Nicotine gum may not have an acute effect on the development of these symptoms.     

CYP2A6 genetic variation and dexmedetomidine disposition

Purpose

There is a large interindividual variability in dexmedetomidine dose requirements for sedation of patients in intensive care units (ICU). Cytochrome P450 2A6 (CYP2A6) mediates an important route of dexmedetomidine metabolism, and genetic variation in CYP2A6 affects the clearance of other substrate drugs. We examined whether CYP2A6 genotypes affect dexmedetomidine disposition.

Methods

In 43 critically ill ICU patients receiving dexmedetomidine infusions adjusted to achieve the desired level of sedation, we determined a median of five plasma dexmedetomidine concentrations each. Forty subjects were genotyped for five common CYP2A6 alleles and grouped into normal (n?=?33), intermediate (n?=?5), and slow metabolizers (n?=?2).

Results

Using a Bayesian hierarchical nonlinear mixture model, estimated dexmedetomidine clearance was 49.1?L/h (posterior mean; 95% credible interval 41.4–57.6?L/h). There were no significant differences in dexmedetomidine clearance among normal, intermediate, and slow CYP2A6 metabolizer groups.

Conclusion

Genetic variation in CYP2A6 does not appear to be an important determinant of dexmedetomidine clearance in ICU patients.     

Association between initial morphine intake and body weight change,acoustic startle reflex and drug seeking in rats

Rationale

Although chronic use of opiates can induce physical dependence and addiction, individual differences contributing to these symptoms are largely unknown.

Objectives

Using intravenous morphine self-administration (MSA), we investigated whether individual differences in drug intake are associated with weight change, acoustic startle reflex (ASR), pre-pulse inhibition (PPI), and drug seeking during spontaneous withdrawal.

Methods

Male Sprague-Dawley rats self-administered morphine (0.5 mg/kg/infusion) or saline for 3 weeks (4–6 h/day, 5 days/week) and drug intake and body weight were monitored daily. The ASR and the PPI (baseline, 1 day and 1 week) and drug seeking (1 week) were measured during spontaneous withdrawal.

Results

Morphine animals did not gain weight (101 %?±?0.69), while the control animals did (115 %?±?1.06) after 3 weeks of self-administration. The ASR and the PPI were not significantly different between morphine and saline animals in 1-day or 1-week withdrawal. However, individual differences in initial (first 10 min), but not total (4–6 h), morphine intake of the daily sessions were positively correlated with weight change (r?=?0.437, p?=?0.037) and drug seeking (r?=?0.424, p?=?0.035) while inversely correlated with the ASR (r?=??0.544, p?=?0.005) in 1-week withdrawal from chronic morphine.

Conclusions

A subgroup of animals that self-administered a larger amount of morphine at the beginning of the daily sessions exhibited subsequent weight gain, reduced ASR, and enhanced drug seeking in morphine withdrawal. Thus, individual differences in initial morphine intake may reveal a novel behavioral phenotype in opioid addiction.     

CYP2C9, KCNJ11 and ABCC8 polymorphisms and the response to sulphonylurea treatment in type 2 diabetes patients

Purpose

Sulphonylureas (SU) are widely used in the management of type 2 diabetes. We investigated the influence of CYP2C9, KCNJ11 and ABCC8 polymorphisms on the response to SU currently used in everyday clinical practice.

Methods

Patients treated for type 2 diabetes with sulphonylurea in monotherapy (n?=?21) or in combination with metformin (n?=?135) were provided with glucose-monitoring devices and instructed to measure fasting blood glucose levels once per week and additionally at any signs and symptoms suggesting low blood glucose for a period of three months. All patients were genotyped for CYP2C9 rs1799853 and rs1057910 (*2 and *3 allele, respectively), KCNJ11 rs5219 and rs5215, and ABCC8 rs757110.

Results

The average duration of diabetes in the study group was 10.6?±?7.1 years. Most of the patients achieved relatively good blood glucose control (HbA1c 7.0?±?0.9). In total, 76 hypoglycemia events were observed (mean 0.48?±?1.3). No severe hypoglycemia was reported; the lowest blood glucose was 2.1 mmol/l. Although 124 (79.5 %) patients never experienced hypoglycemia, 32 (20.5 %) patients experienced from one to eight events. None of the investigated polymorphisms influenced HbA1c levels or risk for hypoglycemia episodes in the whole group of patients. CYP2C9 genotype significantly influenced the occurrence of hypoglycemia events among the elderly patients (aged 60 years and over; n?=?103). Among them, carriers of two wild-type alleles suffered 0.36?±?0.98 events, while patients with one or two polymorphic alleles had 0.79?±?1.7 or 2.67?±?4.6 events, respectively (p?=?0.014).

Conclusions

Our results indicate that the CYP2C9 genotype may influence the risk for hypoglycemia events in elderly patients, but not in the overall population of type 2 diabetes patients.     

Utilization and safety of proton-pump inhibitors and histamine-2 receptor antagonists in children and adolescents: an observational cohort study

Background: Little is known about the use of acid-suppressing treatments and related safety events in children.

Objective: This study compared patient characteristics and safety outcomes among children prescribed acid-suppressing drugs for the first time.

Methods: The Health Improvement Network was used to determine the characteristics of children prescribed a proton pump inhibitor (PPI; esomeprazole or another PPI) or a histamine-2 receptor antagonist (H₂RA) by UK primary care physicians between October 2009 and September 2012. Pre-defined safety outcomes were compared among the treatment groups in up to 18 months of follow-up.

Results: The cohorts comprised 8,172 patients on PPIs (including 24 patients on esomeprazole) and 7,905 on H₂RAs. The baseline characteristics were similar between cohorts, although the children in the PPI cohorts tended to be older. No safety outcomes occurred in the esomeprazole cohort. In the other-PPIs cohort, 92 safety outcomes occurred, most commonly gastroenteritis (n?=?36; 39.1%). In the H₂RAs cohort, 193 safety outcomes occurred, most commonly gastroenteritis (n?=?62; 32.1%). The incidence of most safety outcomes was higher in the H₂RAs cohort than in the other-PPIs cohort, including failure to thrive (3.11 [95% confidence interval (CI)?=?2.25–4.28] vs 0.49 per 1,000 person-years [95% CI?=?0.22–1.07]) and gastroenteritis (5.27 [95% CI?=?4.11–6.75] vs 3.04 per 1,000 person-years [95% CI?=?2.20–4.20]).

Conclusion: Esomeprazole is rarely prescribed to children when they first require acid-suppressing medication, compared with other PPIs/H₂RAs. Overall, more safety outcomes occurred in the H₂RAs cohort than in the PPI cohorts.     

Influence of chronic hepatitis C infection on cytochrome P450 3a4 activity using midazolam as an in vivo probe substrate

Purpose

Inflammation-related changes in pharmacokinetics have been described for a number of disease-states including cancer, infection, and autoimmune disorders. This study examined the impact of chronic hepatitis C infection (CHC) on the pharmacokinetics of the cytochrome P450 3A probe midazolam in patients without significant liver disease who were either treatment naïve or prior interferon null-responders.

Methods

Data were pooled from three studies which compared the pharmacokinetics of oral midazolam in healthy volunteers (n?=?107) and in treatment-naive patients (n?=?35) and interferon-null responders (n?=?24) with CHC but without significant liver disease. Oral midazolam was administered as a single 2 mg oral dose, followed by frequent pharmacokinetic sampling and determination of the pharmacokinetics of midazolam and its α-hydroxy metabolite. CYP3A activity was determined by the metabolic ratio (MR) of the AUC metabolite/AUC parent and compared across groups as the mean effect ratio (test/reference).

Results

The midazolam MR was lower in treatment-naïve patients with CHC than in health volunteers with a mean effect ratio of 0.63 [90 % confidence interval (CI) 0.56–0.72]. The effect was more pronounced in null-responders, who demonstrated a mean MR effect ratio of 0.46 (90 % CI 0.39–0.53) compared to volunteers. The mean area under the concentration–time curve (AUC_inf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively.

Conclusions

The results of this study demonstrate a reduction in CYP3A4 activity between healthy volunteers and patients with CHC, with interferon null-responders demonstrating the most substantial difference. These results may have implications for the pharmacotherapy of patients infected with CHC.     

Synthesis and biological evaluation of novel condensed pyrimidinylmethylsulfinylbenzimidazoles as antiulcer agent

Current therapies to treat gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and other acid-related diseases either prevent stimulation of the parietal cell (H₂-receptor antagonists) or inhibit gastric H⁺/K⁺-ATPase (proton pump inhibitors). The inhibition of acid production by proton pump inhibitors (PPI’s) provides more effective relief of symptoms and healing. A series of novel 4-substituted-2-(1H-benzimidazol-2-yl)methylsulfinylpyrimidines were synthesized as target compounds and antiulcer activity was done using parameters like total acidity, pH, and total gastric acid volume by pylorus ligation method on Wistar rats. Three different dose levels were employed for testings. The target compounds 4-substituted-2-(1H-benzimidazol-2-yl)methylsulfinylpyrimidines were effective for ulcer treatment and among them compounds 10c, 10d, 8b, and 8c exhibited potent antisecretory activity. Overall, compounds 10c, 10d, 8b, and 8c can be looked upon as potential leads for further development and investigations.     

Brain RGS4 and RGS10 protein expression in schizophrenia and depression. Effect of drug treatment

Rationale

Regulator of G-protein signaling (RGS) proteins, RGS4 and RGS10, may be involved in the pathophysiology of schizophrenia. RGS4 has attracted special interest since the reports of genetic association between SNPs in RGS4 and schizophrenia. However, there is no information about the subcellular distribution of RGS4 and RGS10 proteins in psychiatric disorders.

Objectives

Plasma membrane RGS4 and cytosolic RGS10 protein immunoreactivity in prefrontal cortex from schizophrenic subjects (n?=?25), non-diagnosed suicides (n?=?13), and control subjects (n?=?35), matched by age, gender, and postmortem delay, was analyzed by western blot. A second group of depressed subjects (n?=?25) and control subjects (n?=?25) was evaluated. The effect of the antipsychotic or antidepressant treatments was also assessed.

Results

No significant differences in plasma membrane RGS4 and cytosolic RGS10 protein expression were observed between schizophrenic subjects, non-diagnosed suicides, and control subjects. However, RGS4 immunoreactivity was significantly higher (Δ?=?33?±?10 %, p?<?0.05) in the antipsychotic-treated subgroup (n?=?12) than in the antipsychotic-free subgroup (n?=?13). Immunodensities of plasma membrane RGS4 and cytosolic RGS10 proteins did not differ between depressed and matched control subjects.

Conclusions

Expression of RGS4 and RGS10 proteins at their predominant subcellular location was studied in the postmortem brain of subjects with psychiatric disorders. The results suggest unaltered membrane RGS4 and cytosolic RGS10 proteins levels in schizophrenia and major depression. Antipsychotic treatment seems to increase membrane RGS4 immunoreactivity. Further studies are needed to elucidate RGS4 and RGS10 functional status.     

The nicotinergic receptor as a target for cognitive enhancement in schizophrenia: Barking up the wrong tree?

Rationale

Cognitive symptoms have increasingly been recognized as an important target in the development of future treatment strategies in schizophrenia. The nicotinergic neurotransmission system has been suggested as a potentially interesting treatment target for these cognitive deficits. However, previous research yielded conflicting results, which may be explained by several methodological limitations, such as the failure to include both a group of smoking and non-smoking schizophrenic patients, the use of only a single nicotine dose, and the inclusion of a very limited cognitive battery.

Objectives

The present study aims at investigating the cognitive effects of nicotine in schizophrenia while addressing these methodological issues.

Methods

In a double-blind placebo-controlled randomized crossover design, cognitive effects are assessed in smoking (n?=?16) and non-smoking (n?=?16) schizophrenic patients after receiving active (1 or 2 mg) or placebo oromucosal nicotine spray.

Results

A modest improving effect of nicotine on attention in the smoking but not the non-smoking group was found. No enhancing effects were found on measures of visual memory, working memory, processing speed, psychomotor speed, or social cognitive functioning in either patient group.

Conclusions

These findings suggest that the nicotinic receptor only has limited value as a cognitive treatment target in schizophrenia.     

Dexamphetamine effects on prepulse inhibition (PPI) and startle in healthy volunteers

Rationale

Amphetamine challenge in rodent prepulse inhibition (PPI) studies has been used to model potential dopamine involvement in effects that may be relevant to schizophrenia, though similar studies in healthy humans have failed to report replicable or robust effects.

Objectives

The present study investigated dexamphetamine effects on PPI in healthy humans with an increased dose and a range of startling stimulus intensities to determine participants' sensitivity and range of responses to the stimuli.

Methods

A randomised, placebo-controlled dexamphetamine (0.45 mg/kg, per os.), double-blind, counterbalanced, within-subject design was used. PPI was measured in 64 participants across a range of startling stimulus intensities, during two attention set conditions (ATTEND and IGNORE). Startle magnitudes for pulse-alone and prepulse-pulse magnitudes were modelled using the startle reflex magnitude (sigmoid) function. Parameters were extracted from these fits, including the upper limit of the asymptote (maximum startle reflex capacity, R _MAX), intensity threshold, stimulus intensity that elicits a half-maximal response (ES₅₀) and the maximum rate of change of startle response magnitude to an increase in stimulus intensity.

Results

Dexamphetamine increased the threshold and ES₅₀ of the response to pulse-alone trials in both sexes and reduced R _MAX exclusively in females. Dexamphetamine modestly increased PPI of the R _MAX across both attention conditions. PPI of R _MAX was reduced during the ATTEND condition compared to the IGNORE condition.

Conclusions

Results indicate that sex differences exist in motor, but not sensory, components of the startle reflex. Findings also reveal that administration of 0.45 mg/kg dexamphetamine to healthy humans does not mimic PPI effects observed in schizophrenia.