Clinical pharmacists´ interventions in the management of type 2 diabetes mellitus: a systematic review.

BACKGROUND: Type 2 diabetes mellitus is a chronic disease that is reaching epidemic proportions worldwide. It is imperative to adopt an integrated strategy, which involves a close collaboration between the patient and a multidisciplinary team of which pharmacists should be integral elements. OBJECTIVE: This work aims to identify and summarize the main effects of interventions carried out by clinical pharmacists in the management of patients with type 2 diabetes, considering clinical, humanistic and economic outcomes. METHODS: PubMed and Cochrane Central Register of Controlled Trials were searched for randomized controlled trials assessing the effectiveness of such interventions compared with usual care that took place in hospitals or outpatient facilities. RESULTS: This review included 39 studies, involving a total of 5,474 participants. Beneficial effects were observed on various clinical outcomes such as glycemia, blood pressure, lipid profile, body mass index and coronary heart disease risk. For the following parameters, the range for the difference in change from baseline to final follow-up between the intervention and control groups was: HbA1c, -0.05% to -2.1%; systolic blood pressure, +3.45 mmHg to -10.6 mmHg; total cholesterol, +10.06 mg/dL to -32.48 mg/dL; body mass index, +0.6 kg/m2 to -1.94 kg/m2; and coronary heart disease risk, -3.0% and -12.0% (among the studies that used Framinghan prediction method). The effect on medication adherence and health-related quality of life was also positive. In the studies that performed an economic evaluation, the interventions proved to be economically viable. CONCLUSIONS: These findings support and encourage the integration of clinical pharmacists into multidisciplinary teams, underlining their role in improving the management of type 2 diabetes.

Pre-Clinical Assessment of the Nose-to-Brain Delivery of Zonisamide After Intranasal Administration.

PURPOSE: Zonisamide clinical indications are expanding beyond the classic treatment of epileptic seizures to Parkinson's disease and other neurodegenerative diseases. However, the systemic safety profile of zonisamide may compromise its use as a first-line drug in any clinical condition. Since zonisamide is marketed as oral formulations, the present study aimed at exploring the potential of the intranasal route to centrally administer zonisamide, evaluating the systemic bioavailability of zonisamide and comparing its brain, lung and kidney pharmacokinetics after intranasal, oral and intravenous administrations. METHODS: In vitro cell studies demonstrated that zonisamide and proposed thermoreversible gels did not affect the viability of RPMI 2650 or Calu-3 cells. Thereafter, male CD-1 mice were randomly administered with zonisamide by oral (80 mg/kg), intranasal or intravenous (16.7 mg/kg) route. At predefined time points, animals were sacrificed and plasma and tissues were collected to quantify zonisamide and describe its pharmacokinetics. RESULTS: Intranasal route revealed a low absolute bioavailability (54.95%) but the highest value of the ratio between the area under the curve (AUC) between brain and plasma, suggesting lower systemic adverse events and non-inferior effects in central nervous system comparatively to intravenous and oral routes. Furthermore, drug targeting efficiency and direct transport percentage into the brain were 149.54% and 33.13%, respectively, corroborating that a significant fraction of zonisamide suffers direct nose-to-brain transport. Lung and kidney exposures obtained after intranasal administration were lower than those observed after intravenous injection. CONCLUSIONS: This pre-clinical investigation demonstrates a direct nose-to-brain delivery of zonisamide, which may be a promising strategy for the treatment of central diseases.

In vitro assessment of the interactions of dopamine ß-hydroxylase inhibitors with human P-glycoprotein and Breast Cancer Resistance Protein.

Inhibition of the biosynthesis of noradrenaline is a currently explored strategy for the treatment of hypertension, congestive heart failure and pulmonary arterial hypertension. While some dopamine ß-hydroxylase (DBH) inhibitors cross the blood-brain barrier (BBB) and cause central as well as peripheral effects (nepicastat), others have limited access to the brain (etamicastat, zamicastat). In this context, peripheral selectivity is clinically advantageous, in order to prevent alterations of noradrenaline levels in the CNS and the occurrence of adverse central effects. A limited brain exposure results from the combination of several factors, such as a reduced passive permeability or affinity for efflux transporters, but efflux liabilities may also lead to unwanted drug-drug interactions (DDIs) in the presence of co-administered substrates or inhibitors. Thus, the purpose of the study herein presented was to explore the interaction of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), the two major efflux transporters of the BBB that hamper the entry of several drugs to the brain, with the DBH inhibitors, etamicastat, nepicastat and zamicastat. Madin-Darby canine kidney cells (MDCK II) and transfected lines with human MDR1 (MDCK-MDR1) and ABCG2 (MDCK-BCRP) genes were used as a BBB surrogate model. P-gp and BCRP substrates and/or inhibitors were identified through intracellular accumulation and bidirectional permeability assays. The obtained data revealed that zamicastat is a concentration-dependent dual P-gp and BCRP inhibitor with IC50 values of 73.8 ±â€¯7.2 µM and 17.0 ±â€¯2.7 µM, while etamicastat and nepicastat inhibited BCRP to greater extent than P-gp, with IC50 values of 47.7 ±â€¯1.8 µM and 59.2 ±â€¯9.4 µM, respectively. Additionally, etamicastat was identified as P-gp and BCRP dual substrate, as demonstrated by net flux ratios of 5.84 and 3.87 and decreased >50% by verapamil and Ko143. Conversely, nepicastat revealed to be a P-gp-only substrate, with a net flux ratio of 2.01, reduced to 0.92 in the presence of verapamil. Furthermore, nepicastat displayed a consistently higher apparent permeability (>8.49 × 10-6 cm s-1) than etamicastat (<0.58 × 10-6 cm s-1). The identification of etamicastat as a dual efflux substrate suggests that P-gp and BCRP may be partially responsible for the limited central exposure of this compound, in association with its low passive permeability. Moreover, the weak efflux inhibitory potencies of etamicastat and nepicastat revealed a low DDI risk, while the dual P-gp/BCRP inhibition of zamicastat could be studied in the future with synergically effluxed compounds, for which BBB penetration is severely impaired.

Pharmacist Interventions in the Management of Type 2 Diabetes Mellitus: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: Diabetes mellitus is a major health problem that is growing rapidly worldwide. A collaborative and integrated team approach in which pharmacists can play a pivotal role should be sought when managing patients with diabetes. OBJECTIVE: To identify and summarize the main outcomes of pharmacist interventions in the management of type 2 diabetes. METHODS: PubMed, Cochrane Central Register of Controlled Trials, and Web of Science were searched for randomized controlled trials evaluating the effectiveness of any pharmacist intervention directed at patients with type 2 diabetes in comparison with usual care. Outcome measures of interest included glycosylated hemoglobin (Alc), blood glucose, blood pressure, lipid profile, body mass index (BMI), 10-year coronary heart disease (CHD) risk, medication adherence, health-related quality of life (HRQoL), and economic outcomes. The risk of bias in included studies was assessed using the Cochrane risk of bias tool. RESULTS: Thirty-six studies were included in this systematic review, involving 5,761 participants. The studies evaluated the effects of several pharmacist interventions carried out in various countries and in different health care facilities, such as community pharmacies, primary care clinics, and hospitals. The number of studies reporting each outcome of interest varied. Alc was evaluated in 26 studies, of which 24 reported a greater reduction in this outcome in the intervention group compared with the control group, with the difference in change between groups ranging from -0.18% to -2.1%. Eighteen studies assessed change in systolic blood pressure, of which 17 studies reported a greater improvement in this outcome in the intervention group, with the difference in change between groups varying between -3.3 mmHg and -23.05 mmHg. For diastolic blood pressure, a greater effect was also observed in the intervention group in 14 out of 15 studies, with the difference in change between groups varying between -0.21 mmHg and -9.1 mmHg. Thirteen studies described total cholesterol as an outcome measure, of which 10 reported a greater improvement in this outcome in the intervention group, with the difference in change between groups ranging from +18.95 mg dL(-1) to -32.48 mg dL(-1). With regard to low-density lipoprotein cholesterol, a greater reduction in this parameter in the intervention group was documented in 12 out of 15 studies, with the difference in change between groups varying between +7.35 mg dL(-1) and -30 mg dL(-1). Similarly, favorable data were reported on high-density lipoprotein cholesterol in the intervention group in 9 out of 12 studies that assessed this outcome, with the difference in change between groups ranging from -5.8 mg dL(-1) to +11 mg dL(-1). Data on triglycerides were also reported in 12 studies, of which 9 reported a greater reduction in triglycerides levels in the intervention group, with the difference in change between groups varying between +12 mg dL(-1) and -62 mg dL(-1). Overall, a beneficial effect on BMI was also described in the intervention group in 12 out of 14 studies. Of note, in all 6 studies that estimated the 10-year CHD risk among study patients, a greater improvement in the intervention group versus the control group was found. In addition, pharmacist interventions also had a positive impact on medication adherence and HRQoL in most studies that ascertained these outcomes. Finally, although only 3 studies conducted a cost-effectiveness analysis, pharmacist interventions proved to be cost-effective. CONCLUSIONS: The findings from this review clearly support the involvement of pharmacists as members of health care teams in the management of patients with type 2 diabetes. DISCLOSURES: This systematic review was not funded. The authors declare that they have no conflicts of interest. Concept and study design were created by Pousinho, Morgado, and Alves. Pousinho took the lead in data collection, along with Alves, and data interpretation was performed by Pousinho, Falcão, and Alves. The manuscript was primarily written by Pousinho, along with Alves, and revised by Alves, Morgado, and Falcão.

Assessment of the efficacy and safety of eslicarbazepine acetate in acute mania and prevention of recurrence: experience from multicentre, double-blind, randomised phase II clinical studies in patients with bipolar disorder I.

BACKGROUND: Eslicarbazepine acetate (ESL) is an anticonvulsant approved as an adjunctive therapy in adults with partial-onset seizures. OBJECTIVE: To evaluate the efficacy, safety and tolerability of ESL in the treatment of acute mania and prevention of recurrence in bipolar disorder I. METHODS: Two 3-week multicentre, double-blind, randomised, placebo-controlled studies in acute mania (study BIA-2093-203: dose titrated by response, ESL 600-1800mg or 800-2400mg, once-daily; study BIA-2093-204: fixed doses of 600, 1200 and 1800mg, once-daily) were followed by a recurrence prevention study consisting of a 2-week open-label period (900mg, once-daily) continued by a double-blind, parallel-group, fixed dose (300, 900 and 1800mg, once-daily) period for a minimum of 6 months. The primary endpoint was changed from baseline until the end of the 3-week treatment period in Young Mania Rating Scale (YMRS) in studies BIA-2093-203 and BIA-2093-204, and the proportion of patients showing no worsening according to the Clinical Global Impressions - Bipolar Version (CGI-BP) over Part II in study BIA-2093-205. RESULTS: In study BIA-2093-203 (n=160, ITT), neither dose group was statistically different from placebo in the primary endpoint, though the ESL 800-2400mg showed a greater reduction in YMRS score (p=0.0523). CGI-BP score changes for mania and overall bipolar illness indicate a significant improvement in patient symptomatology for the ESL 800-2400mg group (from preceding and worst phase) and for ESL 600-1800mg group (from worst phase only) when compared to placebo. Study BIA-2093-204 (n=38) results were inconclusive due to premature termination caused by recruitment difficulties. In study BIA-2093-205 (n=85, ITT), at least 50% of patients showed no worsening in all treatment groups (p=0.250). ESL adverse events were mostly of mild and moderate intensities and consistent with previously reported observations for ESL. CONCLUSION: ESL treatment was not significantly different from placebo in manic patients in the primary outcome, but secondary outcomes may be suggestive of efficacy. The recurrence prevention study provides preliminary support for efficacy of ESL in patients recovered from an acute manic episode.

Understanding physician antibiotic prescribing behaviour: a systematic review of qualitative studies.

Inappropriate prescription has been associated with mounting rates of antibiotic resistance worldwide, demanding more detailed studies into physicians' decision-making process. Accordingly, this study sought to explore physicians' perceptions of factors influencing antibiotic prescribing. A systematic search was performed for qualitative studies focused on understanding physicians' perceptions of the factors, attitudes and knowledge influencing antibiotic prescription. Of the total of 35 papers selected for review purposes, 18 solely included physicians and the remaining 17 also included patients and/or other healthcare providers. Data collection was based mainly on interviews, followed by questionnaires and focus groups, and the methodologies mainly used for data analysis were grounded theory and thematic analysis. Factors cited by physicians as having an impact on antibiotic prescribing were grouped into those that were intrinsic (group 1) and those that were extrinsic (group 2) to the healthcare professional. Among the former, physicians' attitudes, such as complacency or fear, were rated as being most influential on antibiotic prescribing, whilst patient-related factors (e.g. signs and symptoms) or healthcare system-related factors (e.g. time pressure and policies/guidelines implemented) were the most commonly reported extrinsic factors. These findings revealed that: (i) antibiotic prescribing is a complex process influenced by factors affecting all the actors involved, including physicians, other healthcare providers, healthcare system, patients and the general public; and (ii) such factors are mutually dependent. Hence, by shedding new light on the process, these findings will hopefully contribute to generating new and more effective strategies for improving antibiotic prescribing and allaying global concern about antibiotic resistance.