Efficacy and Safety of a Lercanidipine/Enalapril Fixed-Dose Combination in Hypertensive Patients in Portugal

Background

Fixed-dose combinations of hypertensive drugs have been advocated as a suitable option for hypertensive patients who require two or more drugs to achieve blood pressure (BP) targets.

Objectives

Our objective was to assess the efficacy and safety of lercanidipine/enalapril in clinical practice.

Methods

This observational study collected data for patients with hypertension treated by 46 specialists at clinics across Portugal with lercanidipine/enalapril (10/20 mg). The primary outcome measure was the reduction from baseline in systolic BP (SBP) and diastolic BP (DBP).

Results

The registry enrolled 315 patients (59.1 % females; mean age 64.84 ± 12.18 years). Baseline SBP and DBP were 159.11 ± 16.93 and 88.32 ± 12.35 mmHg, respectively. At a mean 2.88 ± 1.75 months after starting lercanidipine/enalapril, the mean change from baseline in SBP and DBP were −18.08 ± 15.91 and −10.10 ± 11.46 mmHg, respectively (both p < 0.001). This corresponded to reductions of 11.4 and 11.3 % in SBP and DBP, respectively. SBP was reduced independently of sex and age, and DBP was reduced independently of sex. The BP control (<140/90 mmHg) rate significantly increased from 10.2 % at baseline to 51.0 % after a mean of 2.88 months of treatment with lercanidipine/enalapril (p < 0.001). Adverse effects were seen in only one patient (0.3 %), who developed a persistent dry cough.

Conclusions

Treatment with the fixed-dose combination lercanidipine/enalapril was associated with significant reductions in SBP and DBP, and a significant increase in the BP control rate. This fixed-dose combination has been shown to effectively reduce BP, generally independently of age and sex, and with an excellent safety profile.     

Risk of Falling and Hypnotic Drugs: Retrospective Study of Inpatients

Background

Falls and related injuries remain a concern for patient safety in many hospitals and nursing care facilities. In particular, reports examining the relationship between accidents and drugs with a sedative effect have been increasing; however, the analysis of correlation between the background factors of fall accidents and the detailed therapeutic category of drugs is insufficient.

Objectives

Our objective was to estimate fall risk following the administration of hypnotics in inpatients within an acute hospital. We assessed the relationship between falls and hypnotic drugs compared with other medicines.

Study Design and Setting

An inpatient population-based study was carried out at Gunma University Hospital, where all inpatients admitted between 1 October and 31 December 2007 were included. Over a 3-month follow-up period, all reports of falling accidents from ward medical staff were investigated.

Results and Discussion

Falls occurred in 1.8 % of males and 1.3 % of females in the study population (n = 3,683). The mean age of patients who experienced falls (64.7 ± 19.5 years) was significantly higher than that of patients who did not (56.2 ± 20.2 years). Multivariate analysis revealed the following drugs as high-risk factors for falling: hypnotics (odds ratio [OR] 2.17, 95 % CI 1.44–3.28), antiepileptics (OR 5.06, 95 % CI 2.70–9.46), opioids (OR 3.91, 95 % CI 2.16–7.10), anti-Alzheimer’s (OR 5.74, 95 % CI 1.62–20.3), anti-Parkinson’s (OR 5.06, 95 % CI 1.58–16.24), antidiabetics (OR 3.08, 95 % CI 1.63–5.84), antihypertensives (OR 2.24, 95 % CI 1.41–3.56), and antiarrhythmics (OR 2.82, 95 % CI 1.36–5.86). Multivariate logistic regression analysis of hypnotics, brotizolam, zopiclone, and estazolam revealed a significant association with an increased risk of inpatient falling accidents, while zolpidem, triazolam, flunitrazepam, and nitrazepam did not.

Conclusion

The present findings suggest that the risk of falling accidents in hospitals differs according to the type of hypnotic drug administered. The appropriate selection of hypnotic drugs, therefore, might be important for reducing the number of patient falls.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-013-0019-3) contains supplementary material, which is available to authorized users.     

An influence of adrenaline (1:80,000) containing local anesthesia (2% Xylocaine) on glycemic level of patients undergoing tooth extraction in Riyadh

Objective

Aim is to compare the glycemic level among patients before, and after local anesthesia containing adrenaline 1:80,000 among patients who need dental extraction.

Materials and methods

60 patients were randomly selected including 30 healthy and 30 with a diabetes history for this study in Riyadh city. First the blood glucose level was measured before administering local anesthesia containing adrenaline after taking their history with glucocheck according to instructions, then blood Sugar level was recorded after administering local anesthesia containing adrenaline 1:80,000 concentrations. Blood sugar level was also checked 5 min after the tooth extraction procedure.

Results

There were no significant results found after the administration of local anesthesia containing adrenaline in both healthy and diabetic patients (p > 0.05). However, change of significance (p < 0.05) was noticed in diabetic patients who had not taken their hypoglycemic medication; there was a rise in their blood glucose level after extraction.

Conclusion

The study concluded no significant effect on the glycemic level of patients after the administration of local anesthesia containing adrenaline 1:80,000 in healthy and diabetic patients whether hypoglycemic medication was taken or not but a rise in blood sugar level was found among diabetic patients who did not take their hypoglycemic medications undergoing tooth extraction.     

Correlation Between Trough Plasma Dabigatran Concentrations and Estimates of Glomerular Filtration Rate Based on Creatinine and Cystatin C

Aims

Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft–Gault (CG) equation to gauge renal function, instead of contemporary equations including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations employing creatinine (CKD-EPI_Cr), cystatin C (CKD-EPI_Cys) and both renal biomarkers (CKD-EPI_CrCys).

Methods

A linear regression model including the dabigatran etexilate maintenance dose rate, relevant interacting drugs and genetic polymorphisms (including CES1), was used to analyse the relationship between the values from each renal function equation and trough steady-state plasma dabigatran concentrations.

Results

The median dose-corrected trough steady-state plasma dabigatran concentration in 52 patients (38–94 years) taking dabigatran etexilate was 60 µg/L (range 9–279). The dose-corrected trough concentration in a patient on phenytoin and phenobarbitone was >3 standard deviations below the cohort mean. The CG, CKD-EPI_Cr, CKD-EPI_Cys and CKD-EPI_CrCys equations explained (R², 95 % CI) 32 % (9–55), 37 % (12–60), 41 % (16–64) and 47 % (20–69) of the variability in dabigatran concentrations between patients, respectively. One-way analysis of variance (ANOVA) comparing the R² values for each equation was not statistically significant (p = 0.74).

Discussion

Estimates of renal function using the four equations accounted for 32–47 % of the variability in dabigatran concentrations between patients. We are the first to provide evidence that co-administration of phenytoin/phenobarbitone with dabigatran etexilate is associated with significantly reduced dabigatran exposure.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-014-0045-9) contains supplementary material, which is available to authorized users.     

Effect of Rivastigmine on Mobility of Patients with Higher-Level Gait Disorder: A Pilot Exploratory Study

Background

Higher-level gait disorder (HLGD) in older adults is characterized by postural instability, stepping dysrhythmicity, recurrent falls and progressive immobility. Cognitive impairments are frequently associated with HLGD.

Objectives

The aim of this study was to compare gait and cognitive performance before and after the use of rivastigmine in patients with HLGD, free from cognitive impairment or Parkinsonism.

Methods

Fifteen non-demented patients with HLGD (age 79.2 ± 5.9 years; 11 women; Mini-Mental State Examination [MMSE] 28.3 ± 1.4) received escalating doses of rivastigmine for 12 weeks in an open-label, pilot study. They were assessed before and after treatment (week 0 and week 12), and after a 4-week washout period (week 16). Assessments included the Mindstreams computerized neuropsychological battery, Activities-specific Balance Confidence Scale, State-Trait Anxiety Inventory, Geriatric Depression Scale, Timed Up and Go (TUG) test, gait speed and stride time variability. One-way multiple analysis of variance tests for repeated measures were used, and Pillai’s trace test was considered as robust to investigate significant differences.

Results

The mean dose of rivastigmine during the 8–12 week period was 5.1 ± 2.3 mg/day. A positive effect was observed on the Mindstreams memory subscale and anxiety scores [Pillai’s trace: F(6,724) = 0.508, p = 0.010; and F(7,792) = 0.545, p = 0.006, respectively, over the course of the study] as well as on mobility (TUG test) [Pillai’s trace: F(4,863) = 0.448; p = 0.028], whereas gait speed and stride time variability did not change.

Conclusions

The use of relatively low-dose rivastigmine did not affect gait speed and stride time variability; however, the general mobility and anxiety were improved. These preliminary results warrant a larger, randomized, placebo-controlled study.     

Effectiveness of Golimumab in Clinical Management of Patients with Rheumatoid Arthritis

Background and Objectives

Limited data are available regarding the use of golimumab (100 mg) every 4 weeks, with or without methotrexate (MTX). The aim of this retrospective analysis was to evaluate the effectiveness and safety of golimumab following usual clinical practice in Japanese patients with rheumatoid arthritis (RA) according to the recommendations given in the Japanese package insert.

Patients and Methods

Japanese RA patients with moderate-to-high disease activity, according to the 28-joint disease activity score based on C-reactive protein (DAS28-CRP) criteria, despite treatment with MTX or another biological agent, were enrolled. Patients were assigned to 50 mg golimumab plus MTX or 100 mg golimumab monotherapy every 4 weeks for 24 weeks. All patients were given MTX if it was not contraindicated. The primary endpoint was the proportion of patients achieving clinical remission (defined as a DAS28-CRP <2.3 or a simplified disease activity index [SDAI] score <3.3) at 24 weeks.

Results

Most patients received combined 50 mg golimumab plus MTX (41/43). In these patients, the primary endpoint, clinical remission, was attained in 83 % of patients according to DAS28-CRP criteria (p < 0.001) and 69 % according to SDAI criteria (p < 0.001) by week 24. Adverse events were reported in 11.6 % of patients receiving golimumab.

Conclusions

Golimumab (50 mg) plus MTX effectively reduced the signs and symptoms of RA and was generally well tolerated in patients with an inadequate response to MTX and other biological agents.     

Efficacy and Safety of a Fixed Combination of Irbesartan/Hydrochlorothiazide in Chinese Patients with Moderate to Severe Hypertension

Background and Objectives

In a multi-center, single-arm, prospective study, we investigated the efficacy and safety of the fixed irbesartan/hydrochlorothiazide combination in Chinese patients with moderate to severe hypertension.

Methods

Eligible patients were aged 18–75 years, with a blood pressure of 160–199 mmHg systolic or 100–119 mmHg diastolic during a 1-week wash-out phase off antihypertensive medication. The enrolled patients started antihypertensive treatment with irbesartan/hydrochlorothiazide 150 mg/12.5 mg once daily, with the possible addition of irbesartan 150 mg once daily and up-titration to irbesartan/hydrochlorothiazide 300 mg/25 mg once daily at 4 and 8 weeks of follow-up, respectively. The primary efficacy variable was the goal blood pressure-attaining rate at 12 weeks of follow-up (<140/90 mmHg, or <130/80 mmHg in patients with diabetes mellitus).

Results

In the intention-to-treat analysis (n = 501) at 12 weeks of follow-up, the goal blood pressure-attaining rate was 57.3 %, and the mean change in blood pressure from baseline was 27.8 mmHg [95 % confidence interval (CI) 26.4–29.1 mmHg; p < 0.001] systolic and 13.5 mmHg (95 % CI 12.6–14.4 mmHg; p < 0.001) diastolic. Similar findings were observed in the per-protocol analysis (n = 449). The prevalence of microalbuminuria and left ventricular hypertrophy significantly (p ≤ 0.01) decreased from 33.4 % (150/449) and 50.4 % (215/427) at baseline to 23.4 % (105/447) and 41.3 % (176/427) at the end of follow-up, respectively. Four patients (2.0 %) reported a serious adverse event.

Conclusion

The fixed irbesartan/hydrochlorothiazide combination may control blood pressure to the target level in about 60 % of Chinese patients with moderate to severe hypertension, with an acceptable safety profile.     

Stability of Ertapenem 100 mg/mL in Manufacturer’s Glass Vials or Syringes at 4°C and 23°C

Background:

Prophylactic administration of ertapenem as a single 1-g IV dose has been shown to reduce sepsis after prostate biopsy.

Objective:

To evaluate the stability of ertapenem after reconstitution with 0.9% sodium chloride to a final concentration of 100 mg/mL and storage in the manufacturer’s original glass vials or polypropylene syringes.

Methods:

On study day 0, 100 mg/mL solutions of ertapenem were retained in the manufacturer’s glass vials or packaged in polypropylene syringes and stored at 4°C or 23°C without protection from fluorescent room light. Samples were assayed periodically over 18 days using a validated, stability-indicating liquid chromatographic method with ultra-violet detection. A beyond-use date was determined as the time for the concentration to decline to 90% of the initial (day 0) concentration, based on the fastest degradation rate, with 95% confidence.

Results:

Reconstituted solutions stored in the manufacturer’s glass vials or polypropylene syringes exhibited a first-order degradation rate, such that 10% of the initial concentration was lost in the first 2.5 days when stored at 4°C or within the first 6.75 h when stored at room temperature (23°C). Analysis of variance showed differences in the percentage remaining due to temperature (p < 0.001) and study day (p < 0.001) but not type of container (p = 0.98). When a 95% CI for the degradation rate was calculated and used to determine a beyond-use date, it was established that more than 90% of the initial concentration would remain for 2.35 days at 4°C and for 0.23 day (about 5 h, 30 min) at room temperature.

Conclusions:

A 100 mg/mL ertapenem solution stored in the manufacturer’s glass vial or a polypropylene syringe will retain more than 90.5% of the initial concentration when stored for 48 h at 4°C and for an additional 1 h at 23°C.     

Comparison of Two Forms of Loperamide–Simeticone and a Probiotic Yeast (Saccharomyces boulardii) in the Treatment of Acute Diarrhoea in Adults: A Randomised Non-Inferiority Clinical Trial

Background

Acute diarrhoea is a frequent health problem in both travellers and residents that has a social and economic impact. This study compared the efficacy and tolerability of two loperamide–simeticone formulations and a Saccharomyces boulardii capsule as symptomatic treatment.

Methods

This was a prospective, randomised, single (investigator)-blind, three-arm, parallel group, non-inferiority clinical trial in adult subjects with acute diarrhoea at clinics in Mexico and India, with allocation to a loperamide–simeticone 2/125 mg caplet or chewable tablet (maximum eight in 48 h) or S. boulardii (250 mg twice daily for 5 days).

Outcome Measures

The primary outcome measure was the number of unformed stools between 0 and 24 h following the initial dose of study medication (NUS 0–24). The secondary outcome measures were time to last unformed stool (TLUS), time to complete relief of diarrhoea (TCRD), time to complete relief of abdominal discomfort (TCRAD) and the subject’s evaluation of treatment effectiveness. Follow-up endpoints at 7 days were feeling of complete wellness; stool passed since final study visit; and continued or recurrent diarrhoea.

Subjects

In this study, 415 subjects were randomised to either a loperamide–simeticone caplet (n = 139), loperamide–simeticone chewable tablet (n = 139) or S. boulardii capsule (n = 137) and were included in the intention-to-treat analysis.

Results

With regards to mean NUS 0–24, the loperamide–simeticone caplet was non-inferior to loperamide–simeticone tablets (3.4 vs. 3.3; one-sided 97.5 % confidence interval ≤0.5), with both significantly lower than S. boulardii (4.3; p < 0.001). The loperamide–simeticone groups had a shorter median TLUS [14.9 and 14.0 vs. 28.5 h (loperamide–simeticone caplet and chewable tablet groups, respectively, vs. S. boulardii); p < 0.001], TCRD (26.0 and 26.0 vs. 45.8 h; p < 0.001) and TCRAD (12.2 and 12.0 vs. 23.9 h; p < 0.005) than S. boulardii. Treatment effectiveness for overall illness, diarrhoea and abdominal discomfort relief was greater (p < 0.001) in the loperamide–simeticone groups than with S. boulardii. At 7-day follow-up most subjects reported passing stool at least once since the final study visit (loperamide–simeticone caplet 94.1 %, loperamide–simeticone chewable tablet 94.8 %, S. boulardii 97.0 %), did not experience continued or recurrent diarrhoea [loperamide–simeticone caplet 3.7 % (p < 0.03 vs. S. boulardii), loperamide–simeticone chewable tablet 3.7 %, S. boulardii 5.7 %] and felt completely well [loperamide–simeticone caplet 96.3 % (p < 0.02 vs. S. boulardii), loperamide–simeticone chewable tablet 96.3 % (p < 0.02 vs. S. boulardii), S. boulardii 88.6 %]. All treatments were well-tolerated with few adverse events.

Conclusions

The loperamide–simeticone caplet was non-inferior to the original loperamide–simeticone chewable tablet formulation; both formulations can be expected to demonstrate similar clinical efficacy in the relief of symptoms of acute diarrhoea. Both loperamide–simeticone formulations were superior to the S. boulardii capsule in the primary and secondary endpoints.

Clinical Trial Registration

ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00807326","term_id":"NCT00807326"}}NCT00807326.     

Serum Concentration of Lignocaine After Pertubation: An Observational Study

Objective

The objective of this study was to report the serum concentration of lignocaine after pertubation in patients with endometriosis.

Design

Prospective observational study.

Setting

The study was carried out at a gynaecological outpatient unit in Stockholm, Sweden.

Population

Eligible patients had endometriosis with a dysmenorrhoic pain score of >50 mm on a visual analogue scale, and patent fallopian tubes.

Methods

Patients with endometriosis (n = 25) were included in the study. The patients received pre-ovulatory pertubations with lignocaine hydrochloride 10 mg (n = 16) or ringer acetate (placebo, n = 9). The procedure comprised passing the study solution through the uterus and the fallopian tubes via an intra-cervical balloon catheter. Serum samples were collected at 0, 5, 15 and 30 min after pertubation.

Main Outcome Measures

The serum samples were analysed for the concentration of lignocaine with an LCMS-SIM method.

Results

Low levels of lignocaine were detected in the serum samples following pertubation of 10 mg lignocaine hydrochloride. The highest observed concentration was seen after 30 min (mean 0.050 μg/ml), with an individual maximum of 0.124 μg/ml. Maximum concentration (C_max) and time to C_max (T_max) could not be calculated, since the highest values were observed in the 30-min samples, which was the last sample obtained. Lignocaine was not detected after pertubation with placebo.

Conclusions

The serum levels of lignocaine following pertubation of 10 mg lignocaine hydrochloride are detectable but low. Lignocaine pertubated through the fallopian tubes reaches the peritoneal cavity and diffuses through the peritoneum into the blood circulation. Pertubation with lignocaine is safe and has no lignocaine-related adverse events.     

α-Lipoic Acid and Superoxide Dismutase in the Management of Chronic Neck Pain: A Prospective Randomized Study

Background and Objective

Since oxidative stress plays a pathogenetic role in chronic neck pain (CNP), we investigated whether a combination of α-lipoic acid (ALA) and superoxide dismutase (SOD) might improve pain control and the efficacy of physiotherapy (“multimodal therapy”) in patients with CNP.

Setting

This study was conducted in the Rehabilitation Unit of the Department of Surgical and Oncological Sciences at the University Policlinic in Palermo, Italy.

Design and Patients

This was a prospective, randomized, open study in outpatients.

Intervention

Patients randomly received either physiotherapy alone (group 2; n = 45) or a combination of ALA 600 mg and SOD 140 IU daily in addition to physiotherapy (group 1; n = 51), for 60 days. Pain was assessed by a visual analogue scale (VAS) and a modified Neck Pain Questionnaire (mNPQ). Treatment compliance and safety were also evaluated.

Results

Both groups experienced a significant reduction in the VAS and mNPQ scores after 1 month; however, while no further improvement was observed in group 2 at 60 days, group 1 showed a further VAS reduction (p < 0.001). In addition, in the mNPQ at 60 days, more patients in group 1 than in group 2 reported that their neck pain was improved (p < 0.01), and they showed greater compliance with prescribed physiotherapy (p = 0.048). No drug reaction was observed.

Conclusion

Use of ALA/SOD in combination with physiotherapy may be a useful approach to CNP, being antioxidants that act on nerve inflammation and disease progression.

Clinical Rehabilitation Impact

These preliminary observations suggest that some interesting goals (better pain control and physical wellbeing) can be achieved by multimodal therapy in CNP patients.     

Study of Sustained Blood Pressure-Lowering Effect of Azelnidipine Guided by Self-Measured Morning and Evening Home Blood Pressure: Subgroup Analysis of the At-HOME Study

Background

Morning hypertension is a risk factor for cardiovascular and cerebrovascular events, and consequently diagnosis and control of morning hypertension are considered very important. We previously reported the results of the Azelnidipine Treatment for Hypertension Open-label Monitoring in the Early morning (At-HOME) Study, which indicated that azelnidipine effectively controlled morning hypertension.

Objectives

The objective of this At-HOME subgroup analysis was to evaluate the sustained blood pressure (BP)-lowering effect of azelnidipine, using mean morning and evening systolic BP [ME average] and morning systolic BP minus evening systolic BP (ME difference).

Methods

We analyzed the self-measured home BP data (measured in the morning and at bedtime) from this 16-week prospective observational study to clarify the effect of morning dosing of azelnidipine (mean [± standard deviation] maximum dose 14.3 ± 3.6 mg/day). A subgroup of patients from the At-HOME Study who had an evening home BP measurement within 28 days prior to the baseline date were used for efficacy analysis (n = 2,546; mean age, 65.1 years; female, 53.6 %).

Results

Home systolic BP/diastolic BP levels in the morning and evening were significantly lowered (p < 0.0001) by −19.4 ± 17.1/−10.3 ± 10.6 and −16.9 ± 17.0/−9.4 ± 10.6 mmHg, respectively. Home pulse rates in the morning and evening were also significantly lowered (p < 0.0001) by −3.5 ± 7.8 and −3.5 ± 7.3 beats/min, respectively. At baseline, patients whose ME average was ≥135 mmHg and whose ME difference was ≥15 mmHg (defined as morning-predominant hypertension) accounted for 20.4 % of the study population. However, at the end of the study, the number of such patients was significantly reduced to 7.9 % (p < 0.0001). Patients whose ME average was ≥135 mmHg and whose ME difference was <15 mmHg (defined as sustained hypertension) accounted for 71.1 % of the study population at baseline. This was reduced significantly to 42.8 % at the end of the study (p < 0.0001). ME average decreased significantly from 153.8 ± 15.5 mmHg to 135.6 ± 11.9 mmHg, and ME difference also decreased significantly from 6.7 ± 13.1 mmHg to 4.7 ± 10.8 mmHg (both p < 0.0001).

Conclusion

These results suggest that azelnidipine improved morning hypertension with its sustained BP-lowering effect.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-013-0007-7) contains supplementary material, which is available to authorized users.     

Role of Cognitive Enhancer Therapy in Alzheimer’s Disease with Concomitant Cerebral White Matter Disease: Findings from a Long-Term Naturalistic Study

Background

Evidence is lacking for cognitive enhancer therapy in patients with Alzheimer’s disease (AD) and concomitant cerebrovascular disease (mixed AD) as such patients would have been excluded from clinical trials. Earlier studies of mixed AD have focused on large vessel cerebrovascular disease. The influence of small vessel cerebrovascular disease (svCVD) in the form of white matter hyperintensity (WMH) on treatment outcomes in mixed AD has not been addressed.

Objective

In this long-term naturalistic study, we evaluated the effectiveness of cognitive enhancers in patients with mixed AD with svCVD.

Methods

We conducted a retrospective analysis of a prospective clinical database from a memory clinic of a tertiary hospital. Magnetic resonance imaging WMH was used as a marker of svCVD. Demographic, cognitive, and treatment data were analysed. Linear mixed models with patient-specific random effects were used to evaluate cognitive outcomes over time while adjusting for confounders.

Results

Patients with mixed AD (n = 137) or AD without svCVD (pure AD) (n = 28) were studied over a median duration of 28.7 months. Patients with mixed AD had a higher prevalence of hypertension (62.8 vs. 35.7 %, p = 0.011). The majority (75.2 %) of the study sample were managed with monotherapy. Mini Mental State Examination (MMSE) scores decreased over time (−0.04, p = 0.007), and the decrease was similar for both diagnosis groups (−0.03, p = 0.246). Annual estimated mean MMSE decline was 0.84 for pure AD and 0.48 for mixed AD. Similar trends were observed with Montreal Cognitive Assessment (MoCA) scores, with annual estimated mean reduction of 0.72 and 0.48 for pure AD and mixed AD, respectively.

Conclusion

Cognitive enhancers are effective in slowing the rate of cognitive decline in patients with AD with svCVD. These findings would need to be confirmed in randomized clinical trials.     

Very Short-Term Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin on the Secretion of Insulin,Glucagon, and Incretin Hormones in Japanese Patients with Type?2 Diabetes Mellitus: Analysis of Meal Tolerance Test Data

Background

Sitagliptin inhibits dipeptidyl peptidase-4, which inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. To assess its antidiabetic potency, we used meal tolerance tests (MTTs) to determine the very short-term effects of sitagliptin on plasma concentrations of insulin and glucagon.

Methods

On day 1, patients with newly diagnosed or uncontrolled type 2 diabetes mellitus started a calorie-restricted diet. On day 2, the first MTT was performed, before treatment with sitagliptin 50 mg/day started later the same day. On day 5, a second MTT was performed. Area under the concentration–time curves (AUCs) of relevant laboratory values were calculated [AUC from time zero to 2 h (AUC_0–2h) and from time zero to 4 h (AUC_0–4h)].

Results

Fifteen patients were enrolled. AUCs for postprandial plasma glucose were decreased after 3 days of sitagliptin treatment [AUC_0–2h 457 ± 115 mg/dL·h (25.4 ± 6.4 mmol/L·h) to 369 ± 108 mg/dL·h (20.5 ± 6.0 mmol/L·h); AUC_0–4h 896 ± 248 mg/dL·h (49.7 ± 13.8 mmol/L·h) to 701 ± 246 mg/dL·h (38.9 ± 13.7 mmol/L·h); both p < 0.001]. AUC_0–2h and AUC_0–4h for postprandial plasma glucagon also decreased: 195 ± 57 to 180 ± 57 pg/mL·h (p < 0.05) and 376 ± 105 to 349 ± 105 pg/mL·h (p < 0.01), respectively. The AUC_0–2h [median with quartile values (25 %, 75 %)] for active GLP-1 increased: 10.5 (8.5, 15.2) to 26.4 (16.7, 32.4) pmol/L·h (p = 0.03).

Conclusions

Very short-term (3-day) treatment with sitagliptin decreases postprandial plasma glucose significantly. This early reduction in glucose may result partly from suppression of excessive glucagon secretion, through a direct effect on active GLP-1. Improvement in postprandial plasma glucose, through suppression of glucagon secretion, is believed to be an advantage of sitagliptin for the treatment of patients with type 2 diabetes.     

Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit

Aims

The long-term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose-corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated in vivo.

Methods

Sixty-five tacrolimus- and 10 cyclosporine-treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8-h area under the concentration-time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes.

Results

Tacrolimus clearance decreased gradually throughout the entire first year but only in CYP3A5*3/*3 homozygous recipients (25.6 ± 11.1 l h^–1 at day 7; 17 ± 9.1 l h^–1 at month 12; P < 0.001). In mixed model analysis, decreasing CYP3A4 activity, measured by apparent oral MDZ clearance (924 ± 443 ml min^–1 at day 7 vs. 730 ± 344 ml min^–1 at month 1; P < 0.001), explained 55.4% of the decline in tacrolimus clearance in the first month. CYP3A4 activity decreased by 18.9 ml min^–1 for every milligram of methylprednisolone dose tapering within the first month; beyond this point it remained stable. A gradual rise in haematocrit throughout the entire first year explained 31.7% of the decrease in tacrolimus clearance in the first month and 23.6% of the decrease between months 1 and 12. Cyclosporine clearance did not change over time.

Conclusions

The maturation of tacrolimus disposition in the first year after renal transplantation observed in CYP3A5*3/*3 homozygous patients can partly be explained by a (steroid tapering-related) decline in CYP3A4 activity and a progressive increase in haematocrit.     

Periodic Rosuvastatin or Atorvastatin Dosing Arrays (PRADA): Patient-Centered Practice

Background

Non-adherence is a major obstacle with long-term daily statin therapy.

Objective

This retrospective study reviewed the medical records of patients with hyperlipidemia during an 8-year period in a private internal medicine practice. Periodic dosing was negotiated following several patients’ refusal of statin therapy because of muscle aches or cost.

Methods

The clinical impetus was patient adherence to statin therapy. Treatment was initiated by dispensing rosuvastatin or atorvastatin in a stepwise patient-directed approach (from two times/week to three times/week to every other day, up to five times/week). The primary endpoint was to assess the concentration of low-density lipoprotein cholesterol (LDL-C) and the total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio with patient-directed dosing intervals. The secondary endpoint was a head-to-head comparison of atorvastatin and rosuvastatin to evaluate the mean decrease in the LDL-C and TC/HDL-C ratio.

Results

Chart review identified 46 patients who had been treated. Two patients with persistent myalgia terminated treatment before 12 weeks. Among the remaining 44 patients, 20 received doses of rosuvastatin from 15 to 100 mg per week, and 24 received atorvastatin from 20 to 140 mg per week. There was a significant decrease from pre-treatment in the mean TC/HDL-C ratio of 1.72 (31.1 %, P < 0.0001) and mean LDL-C of 43.3 mg/dL (30.2 %, P < 0.0001). An independent samples t-test showed a non-significant reduction of the mean TC/HDL-C ratio and LDL-C with rosuvastatin versus atorvastatin.

Conclusion

Periodic dosing of rosuvastatin or atorvastatin using a gradual, patient-directed, stepwise approach guided by cholesterol levels is an effective method of lipid lowering and carried a favorable 95.6 % adherence rate.     

Students’ attitude toward use of over the counter medicines during exams in Saudi Arabia

Purpose

To explore the use of over the counter (OTC) medicines among students during exams in Riyadh City, Kingdom of Saudi Arabia.

Method

A cross-sectional study was designed; using a self-administered twenty-two item online questionnaire for the students’ convenience and easy response disclosure. Data were analyzed using Statistical Package for Social Science (SPSS) version 13®.

Results

A total of N = 1596 students participated in this survey, of whom 829 (51.9%) were university students and 767 (48.1%) were high school students. Overall, 80.0% of the respondents disclosed the use of OTC non-steroidal anti-inflammatory drugs for headache and pain relief. In addition, other substances used during the exams were Energy Drinks (5.0%), Flu Medication (5.0%), Vitamins (5.0%) and Antibiotics (5.0%). Female students were found to be more knowledgeable about safety issues concerning the use of OTC medicines (5.11 ± 1.27, p = <0.001) than male students. Ease in access to OTC medicine, availability of pharmacist consultation and advertisement in print and electronic media were the main factors disclosed by the respondents that may result in an increase in the use of OTC products. The use of OTC medicines was generally higher among female students (p = 0.001).

Conclusion

The use of OTC medication during exams was more among high school and university students. Gender, age and educational institution were found significantly affecting the use of OTC medicines during exams.     

Recombinant Activated Factor VII Significantly Reduces Transfusion Requirements in Cardiothoracic Surgery

Background

The off-label use of recombinant activated factor VII (rFVIIa) for intractable bleeding is associated with a risk of thrombotic events. The objective of this study was to evaluate the incidence and predictors of rFVIIa-related thrombotic events and its efficacy in the reduction of transfusion requirements during various surgeries.

Methods

Ninety-two cases received rFVIIa for uncontrollable bleeding despite medical and surgical hemostasis. The incidence and risk factors of thrombotic events were analyzed. Blood products transfused in the 24 h before and after rFVIIa injection were calculated. Subgroup analysis was performed to see which types of surgeries benefited most from rFVIIa.

Results

The main indication for rFVIIa administration was uncontrollable bleeding during cardiothoracic surgery followed by coagulopathy due to liver failure followed by neurosurgical procedures. Requirements of blood products after rFVIIa decreased significantly by 45 % (p = 0.012), 52 % (p = 0.0001), and 75 % (p = 0.0001) for red blood cells, plasma, and cryoprecipitate, respectively. Subgroup analysis showed that cardiothoracic surgery was the sole group that benefited from rFVIIa with a reduction in transfusion of red blood cells (p = 0.013), plasma (p = 0.0001), and cryoprecipitate (p = 0.0001). Thrombotic events occurred in 9.8 % of the cases mostly on the arterial side (89 %) and have not contributed to mortality.

Conclusion

rFVIIa can significantly reduce transfusion requirements when given for intractable bleeding during cardiothoracic surgery at the expense of thrombotic events in approximately one tenth of the cases. Further prospective studies are necessary to study if this effect of rFVIIa is translated to a favorable outcome.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-015-0093-9) contains supplementary material, which is available to authorized users.     

Pharmacists’ and physicians’ perception and exposure to drug promotion: A Saudi study

Introduction

Drug promotion has to contribute to a more rational use of drugs. Concerns arise if promotion negatively influences prescribing/dispensing pattern. It is warranted to assess exposure and attitudes to, and acceptance of, drug promotion among pharmacists and physicians.

Methodology

Adopting a randomized, multiple site and cross-sectional survey study, questionnaires (n = 250) were completed by physicians and pharmacists to investigate the exposure, acceptance or skepticism of Saudi physicians/pharmacists to drug promotion as well as their perception of the appropriateness of gifts and to check if they had any teaching/training about dealing with medical representatives (MRs) and Pharma promotion.

Results

Significantly more pharmacists than physicians (32% vs. 23%; p < 0.05) reported being taught or educated about the ethics of drug promotion. The experience level was significantly associated with the teaching or training that the physicians and pharmacists received. Conference registration fees and drug samples were the most appropriate promotional gift for the physicians (67% and 66%, respectively; p < 0.01) whereas for pharmacists, the drug sample was considered the most suitable donation (79%). More pharmacists perceived drug companies as a useful way to gain knowledge about drugs than physicians (75% vs. 65%; p < 0.01). A higher proportion of both groups were accepting drug promotion than those skeptical about it.

Conclusion

The majority of physicians or pharmacists participating in this study have received gifts from pharmaceutical companies. The drug samples and printed educational materials are the most widely accepted gifts. Recent graduates and those with few years of experience had higher teaching/training than experienced physicians and pharmacists in pharmaceutical promotion ethics and tactics to deal with MRs. On the other hand, experienced healthcare team were more approached and targeted by pharmaceutical companies and MRs. It is highly recommended to implement courses/discussion groups on the ethical interaction between healthcare professionals and pharmaceutical companies in the curriculum of both pharmacy and medicine. Updating the physicians and pharmacists after graduation, as part of continued medical/pharmacy education, will eventually improve the healthcare professionals’ capability to act to the patients’ welfare.