Bioequivalence between generic tacrolimus products marketed in Spain by adjusted indirect comparison

Purpose

The objective of the study was to investigate the relative bioavailability between the generic tacrolimus products that are presently authorized in Spain by adjusted indirect comparison. This was based on demonstration of bioequivalence with the reference product (Prograf, Astellas Pharma), which makes these generic tacrolimus products prescribable, switchable and therapeutically equivalent to the reference product; yet, according to Spanish legislation, only prescribers can switch tacrolimus-containing products.

Methods

Data from independent bioequivalence studies that compare each generic product with the reference product were combined by adjusted indirect comparisons to investigate the relative bioavailability between generic drug products, since there is no direct bioequivalence study comparing generics to each other.

Results

Eight generic tacrolimus products in the form of capsules are presently authorized in Spain, but only five are marketed. These eight products represent only three different generic product developments. One product is authorized with four different names/companies, while another is authorized under three different names/companies. The adjusted indirect comparisons between generic products show bioequivalence within the conventional 80–125 % confidence interval acceptance criteria for area under the curve (AUC) and maximum concentration (Cmax).

Conclusion

Not only are the generic products bioequivalent with the reference product, but also with each other.     

Independent prescribing by pharmacists: a study of the awareness, views and attitudes of Scottish community pharmacists

Aims

To investigate community pharmacists’ awareness, views and attitudes relating to independent prescribing by community pharmacists and their perceptions of competence and training needs for the management of some common conditions.

Setting

Community pharmacies in Scotland.

Method

A pre-piloted postal questionnaire was mailed to 500 randomly selected community pharmacies in Scotland for completion by the ‘main pharmacist’.

Main outcome measures

Scottish community pharmacists’ awareness, views and attitudes towards independent prescribing by community pharmacists; perceived competence and training needs in relation to diagnosis and treatment of conditions in four therapeutic areas; perceptions about patient accessibility to medicines and safety of independent prescribing by community pharmacists; and attitudes towards becoming an independent prescriber. The items regarding perceptions and attitudes were subjected to Principal Components Analysis (PCA) to identify the domains. Univariate analysis was performed on individual items in the questionnaire against total scores on the identified domains; significant variables in univariate analysis were further analysed in linear regression models.

Results

A response rate of 43.4% (217/500) was achieved. Despite expressing confidence in their abilities to become independent prescribers and feeling competent in diagnosing and treating those conditions listed in the questionnaire, clinical training prior to implementation of independent prescribing was regarded important by 211 (97.7%) respondents, while 191 (88.4%) regarded clinical training in drugs used for treating the conditions to be important. Gaining improved patient consultation skills and ability to communicate prescribing actions to GP practices were regarded to be important by 125 (57.9%) and 172 (80.0%), respectively. In PCA, three domains—confidence in independent prescribing, satisfaction with the?current methods of supply, and requirements for the process of independent prescribing were identified. Practising more hours per week as a pharmacist (p = 0.01), supplementary prescribing training (p = 0.02), and involvement in Scottish Executive pharmaceutical care model schemes (p = 0.02), were found to be associated with greater ‘confidence in independent prescribing’.

Conclusion

High awareness of independent prescribing and perceived competence in diagnosing and selecting appropriate drugs for treating many common conditions were identified. Prescribing training with emphasis on evidence-based medicine, generic issues of prescribing and diagnostic and consultation skills is warranted before independent prescribing is undertaken by community pharmacists.     

Reversine, a 2,6-disubstituted Purine, as an Anti-cancer Agent in Differentiated and Undifferentiated Thyroid Cancer Cells

Purpose

A novel and effective treatment is urgently needed to deal with the current treatment dilemma in incurable differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC). Reversine, a small synthetic purine analogue (2,6-disubstituted purine), has been shown to be effective in tumor suppression.

Methods

We performed in vitro evaluation of anti-tumor effects of reversine on proliferation, cell cycle, and apoptosis in human PDTC, ATC, and follicular thyroid cancer cell lines, respectively.

Results

Treatment of these three lines with reversine inhibited proliferation in a time- and dose-dependent manner. G2/M accumulation was demonstrated in cell cycle analysis. Reversine induced apoptosis in PDTC cells with caspase-3 and caspase-8 activation, but not caspase-9. Use of a pan-caspase inhibitor before treatment with reversine attenuated cell death. Reversine also showed in vivo growth inhibitory effects on ATC cells in a xenograft nude mice model.

Conclusions

Data demonstrated that reversine is effective in inhibiting the growth of thyroid cancer cells by cell cycle arrest or apoptosis, especially with the more aggressive ATC and PDTC. Apoptosis was induced by the mitochondria-independent pathway. Reversine is therefore worthy of further investigation in clinical therapeutics.     

Drug–Drug Coamorphous Systems: Characterization and Physicochemical Properties of Coamorphous Atorvastatin with Carvedilol and Glibenclamide

Purpose

In this study, coamorphous form of atorvastatin calcium (ATC) with two drugs, i.e., carvedilol (CVD) and glibenclamide (GLN) in 1:1 stoichiometry, were prepared from solvent evaporation method and they were characterized and their physicochemical properties determined.

Methods

The coamorphous forms were characterized using differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD). The kinetic solubility of coamorphous form of ATC with CVD (ATC–CVD) and GLN (ATC–GLN) were determined along with stability of supersaturated state of coamorphous forms using developed accurate and precise UV-net analyte signal standard addition method (chemometrics-based approach) and HPLC.

Results

The results of DSC and analysis of glass transition temperatures (T _g), PXRD, and FT-IR indicated that the crystalline studied drugs were converted to coamorphous forms, with unique thermal behaviors, revealing a molecular interaction between two components. The kinetic solubility data revealed that coamorphous forms have better metastable solubility than those of crystalline state. In addition, these systems showed greater solution stability than those for amorphous form of single components reported in the literature.

Conclusion

Coamorphous ATC–CVD and ATC–GLN were shown to have improved physicochemical and solution stability properties as compared to crystalline components.     

Glucose and memory: The influence of drink, expectancy, and beliefs

Rationale

An increasing number of studies suggest that glucose can enhance aspects of memory and the central methodology is the use of the glucose–placebo design. One critical issue therefore is separating the pharmacological effects of glucose from the expectancies created by consuming a drink that might contain glucose.

Objective

A modified balanced placebo design examined the role that expectancy and belief about the drink consumed has on the pharmacological changes observed following glucose consumption.

Method

Ninety-three participants, allocated according to a drink (glucose, placebo) × message (told glucose, told nothing, told placebo) unrelated design, were administered tasks assessing immediate and delayed verbal free recall, spatial recognition and semantic verification. Each task has some evidence for hippocampus involvement, and variations in task difficulty were used to assess the idea that glucose effects are sensitive to task difficulty.

Results

While the messages biased drink judgements in the expected direction, judgements of drink content were at chance and glucose only enhanced delayed free recall. The subtle effects of the messages did not modify the glucose enhancement. However, believing glucose had been consumed showed an independent improvement in delayed free recall. There was no evidence that task complexity enhanced the glucose effect.

Conclusions

The findings indicate that expectancy effects are unlikely to be confused with glucose enhancements, but beliefs about consuming glucose can augment performance on delayed free recall. The discussion considers the hippocampus and complexity hypotheses of glucose’s mode of action and proposes the routine collection of drink beliefs in future studies.     

Factors influencing community pharmacist decision to dispense generic or branded medicines; Eastern Province,Alahsa, Saudi Arabia

Background

Rising costs of medicines have increased the interest of policy makers in generic medicines. However, consumers’ and health care providers’ perception and attitude towards generic medicine act as a main barrier to the promotion of generic medicines.

Objective

To explore the factors community pharmacists consider while dispensing branded or generic medicines to consumers.

Method

A qualitative study was planned; twenty community pharmacists (ten hospital affiliated pharmacies and ten non-hospital affiliated pharmacies) were approached using a convenient sampling method. Interviews were recorded and later were coded into themes.

Result

Overall, it is seen that generic medicine stock was available for antibiotics, pain killers, cough syrups, antihistaminics and antacids. Pharmacists working in hospital affiliated pharmacies were more concerned about the quality of drug before dispensing it to the consumer and they believe that what is prescribed is best for them and substitution or switching is unnecessary while for pharmacists in the non-hospital affiliated pharmacies, appearance of the client was found to be the main factor influencing them to dispense generic (low cost) or branded (expensive) medicines.

Conclusion

Physical appearance of the consumer is revealed to be one of the main factors affecting the pharmacist decision to dispense generic or branded medicine. Pharmacists practising in hospital affiliated pharmacies were found to be influenced by physicians’ recommendation, and prefer to dispense good quality medicines.     

Influence of various preseason training in elite youth soccer players

Aim

Endurance capacity of each individual soccer player can notably influence a team’s success. The opinion about the necessity of generic endurance specific training in soccer, especially in adolescent athletes, still varies widely.

Methods

We examined n = 38 elite premier league youth soccer players from three different age groups and with a different amount of endurance specific training. Two identical graded incremental exercise tests were performed before and after a 5 weeks training intervention. Besides soccer specific training, the different groups absolved either 25–30% (U16 and U19) or < 5% (U17) of generic endurance specific training as well as soccer specific endurance training. After the training intervention the alterations of blood lactate concentration (La-), the individual anaerobic threshold (LT) as well as the 4 mmol/-1 threshold were determined.

Results

Running velocity of the U16 and U19 players at individual anaerobic threshold and at the 4 mmol/-1 threshold increased significantly. In contrast, no changes of the LT or 4 mmol/-1 threshold could be detected for the U17 players.

Conclusions

The individual endurance capacity of young elite soccer players can be improved significantly, even over a short preseason period, by performing an adequate amount of generic endurance specific training.     

Adherence to hospital drug formularies and cost of drugs in hospitals in Denmark

Purpose

To investigate adherence rates to hospital drug formularies (HDFs) and cost of drugs in hospitals.

Methods

Data on drugs used during 2010 were analyzed for ten hospitals (two hospitals from each of the five regions), constituting 30 % of hospitals and 45 % of hospital beds in Denmark. Drug use data from individual hospitals were retrieved from the hospital pharmacies. Adherence to the HDFs was analyzed for selected substances characterised by extensive use both in primary and secondary sectors (ATC codes A10, B03, C03, C07, C08, C09, C10, J01, N02, N05 and R03). Within each group, we also identified the drugs constituting 90 % of the volume (= DU90%) and the adherence to the HDF in this segment (Index of Adherence).

Results

Substances used by hospitals varied between 598 and 1,093. The proportion of used substances that were on the HDF varied between 14 % and 44 %. University hospitals used a significantly higher total number of substances (median 165 vs. 139, p = 0.019) and cost/DDD [(median 5 vs. 2 Euros, p = 0.033), p = 0.033] in the DU90% segment than the regional hospitals. Index of adherence varied between 43 % and 91 %. For the selected ATC codes, the index of adherence was between 76 % and 100 %.

Conclusions

Adherence to the selected ATC groups was high, which means that the most commonly used substances are included in the HDFs, even though a variation existed. A large variation existed between the hospitals in the number of substances at HDFs.     

Knowledge,attitudes and beliefs of patients and carers regarding medication adherence: a review of qualitative literature

Purpose

The aim of this review is to cohere evidence on the knowledge, attitudes and beliefs of patients and carers regarding medication adherence. Medication adherence refers to “the extent to which the patient’s action matches the agreed recommendations”. Medication adherence is vital in preventing, managing and curing illnesses and, hence, is linked with positive health outcomes.

Methods

A search was conducted using the following databases: CINAHL, Embase, PubMed and Web of Knowledge from inception to November 2013. Titles and abstracts were screened for inclusion in the review according to pre-defined inclusion and exclusion criteria. Studies were assessed for quality, and data were extracted into a data extraction form. Results were analysed thematically.

Results

The final results included 34 articles. Eight analytical themes were identified: (i) beliefs and experiences of medicines, (ii) family support and culture, (iii) role of and relationship with health-care practitioners, (iv) factors related to the disease, (v) self-regulation, (vi) communication, (vii) cost and (viii) access. The theme, “beliefs and experiences of medicines”, was present in 33 studies, with many discussing the influence that side effects have on medication adherence.

Conclusions

There are a number of variables that impact upon the knowledge, attitudes and beliefs of patients and carers regarding medication adherence. This review presents an overview of the analytical themes which offers the opportunity to examine interventions and their relative efficacies to increase medication adherence.     

A qualitative study to explore how patients identify and assess symptoms as adverse drug reactions

Purpose

To explore how Thai patients assess symptoms as adverse drug reactions (ADRs).

Methods

Out-patients at two hospitals in Thailand previously reporting suspected ADRs to statins were purposively selected to cover factors relevant to the accuracy of ADR reports. Semi-structured interviews explored the mechanisms participants used to work out whether their symptoms were related to their statin. All interviews were audio-recorded, transcribed and independently thematically analyzed by two researchers.

Results

One hundred interviews were suitable for analysis; 52 were male, age range was 36 to 77 years (mean?±?S.D.: 59.83?±?9.14) and most (92) were taking other medicines in addition to statins. Patient assessment of symptoms as ADRs fell into two major themes: medicine-related factors and external factors. Timing relationships were mentioned most frequently (74), followed by information received (55), seeing similar symptoms in others (7) and diagnosis through blood tests (4). Use of multiple medicines, consideration of the medicine versus diseases, symptoms occurring with more than one medicine or relieved through treatment reduced confidence in ADR attribution. Many participants proposed alternative explanations for symptoms, including old age. Lack of information and knowledge were obstacles to the assessment process.

Conclusions

Patients assessed possible ADRs most often by considering timing relationships. While they also used medicine information, Thai patients received inadequate information to help them assess their symptoms. Patients expressed uncertainty and difficulties in deciding attribution when concomitant medicines and diseases were involved. The findings could support the development of a patient-friendly systematic tool for identifying and assessing possible ADRs.     

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.     

Pharmacokinetics and pharmacodynamics of single-dose oral tolvaptan in fasted and non-fasted states in healthy Caucasian and Japanese male subjects

Purpose

To compare the pharmacokinetics and pharmacodynamics of tolvaptan in Caucasian and Japanese healthy male subjects under fasting and non-fasting conditions.

Methods

This was a single-center, parallel-group, randomized, open-label, three-period crossover trial of single oral doses of tolvaptan 30?mg under fasting and non-fasting [a high-fat, high-calorie meal (HFM) or Japanese standard meal] conditions in 25 healthy male Caucasian subjects and 24 healthy male Japanese subjects. Pharmacodynamic endpoints were urine volume and fluid balance for 0 to 24?h postdose.

Results

In the fasted state, the plasma tolvaptan C_max and AUC_∞ geometric mean ratios (90 % confidence interval) were 1.105 (0.845–1.444) and 1.145 (0.843–1.554) for Japanese compared to Caucasian subjects. A HFM increased the C_max and AUC_∞ values by about 1.15-fold in both Japanese and Caucasian subjects.. Twenty-four-hour urine volumes paralleled pharmacokinetic changes, but the increases were not clinically significant. Fluid balance in the Japanese men was 1.4- to 2.0-fold more negative than that in the Caucasian men.

Conclusion

Tolvaptan pharmacokinetics is not clinically significantly affected by race. Body weight is a factor that affects exposure. Tolvaptan can be administered with or without food.     

Modafinil improves rapid shifts of attention

Rationale

The majority of studies investigating the cognitive effects of modafinil, a wake-promoting compound, demonstrate some improvements in attention. The potential of the drug to selectively benefit distinct components of attention has yet to be fully explored in healthy adults.

Objective

The present study was conducted to investigate modafinil’s effect on specific cognitive tasks that tax components of attention switching. One required the rapid switching of attention between stimuli, and another contained an embedded working memory component on top of the attentional shift requirements. Additionally, prospective memory was examined, which requires the interruption of an ongoing activity to retrieve and act upon a previously formed intention.

Materials and methods

Healthy non-smoking volunteers, matched on age, intelligence, and baseline cognitive ability, received either a capsule that contained 200 mg modafinil or placebo. Subjective measures of mood and physiological response were taken throughout the experimental session, and the tasks were completed between 2 and 3 h post-dosing.

Results

Two hundred milligrams modafinil improved accuracy without a reaction time trade-off, in both conditions of the attention-shifting task, but only when resources were most challenged. In contrast, the drug afforded no improvement in prospective remembering or in the ongoing task that was interrupted.

Conclusion

Modafinil appears to promote rapid switching of attention in conditions that are most demanding, whilst it offers no benefits in a task that requires unpredictable and infrequent disengagement of attention from an ongoing task in order to act upon an alternative task.     

Changes to the Statin Prescribing Policy in Belgium

Background and Objective New policies in Belgium encourage prescribing of generic HMG-CoA reductase inhibitors (statins), but may lead to non-equivalent switching of patients from more potent second generation statins, as has occurred elsewhere. We sought to assess the potential health economic impact of the new policies. Design This was a cost-effectiveness analysis Methods A Markov model was constructed to simulate the onset of cardiovascular disease (CVD) and death among a representative cohort of 80 Belgian patients initially free of CVD and taking atorvastatin. Cardiovascular risks were estimated from calibrated Framingham equations, and utilities and costs from published data. Decision analysis assessed the potential impact of switching all 80 patients to simvastatin. Changes in lipid levels expected to arise from switching were based on a published meta-analysis. Results If the 80 patients remained on atorvastatin, the model predicted that 23 (29%) would develop CVD over 20 years. If they were switched to simvastatin, the predicted number was 25 (31%), equating to a ‘number needed to harm’ of 52. Switching would lead to a net cost saving of € 131 (2012) per subject, but also a loss of 0.03 quality-adjusted life-years (QALYs) per subject. These equated to a decremental cost-effectiveness ratio of €4777 per QALY lost. Sensitivity analyses indicated this result to be robust. Conclusion Recently introduced statin prescribing policies in Belgium are likely, as intended, to reduce statin costs, but also increase the burden of CVD due to non-equivalent switching. It would be cost effective to maintain patients on atorvastatin for primary prevention rather than switch them to simvastatin.     

Evaluating pharmacists’ views, knowledge, and perception regarding generic medicines in New Zealand

Background

Generic medicines are commonly used in New Zealand; however, Pharmaceutical Management Agency of New Zealand (PHARMAC) has indicated a need for better information to the public. Studies on consumers’ perceptions suggest that pharmacists play an important role in consumers’ choice; hence, “quality use of generic medicines” can be promoted with a better understanding of pharmacists’ views, knowledge, and perception.

Objectives

(1)To evaluate pharmacists’ perceptions, views, and knowledge of and willingness to recommend generic medicines. (2) To explore pharmacists perceptions of the safety, quality, and efficacy of generic medicines. (3) To assess pharmacists’ views on current policy with respect to substitution of generic medicines.

Methods

A cross-sectional survey using a postal questionnaire was conducted, and questionnaires were sent to 625 randomly selected pharmacists from a list of 1594 pharmacists who had agreed to release their details for research purposes.

Results

Three-hundred and sixty pharmacists responded to the questionnaire (a response rate of 58%). Seventy percent of pharmacists stated there is no difference in safety between original brand and generic medicines. However, 65% stated that original brand medicines were of higher quality than their generic counterparts, and half stated that generic medicines and original brand medicines are equally effective. A large number of pharmacists reported concerns regarding brand substitution and offered suggestions, such as the need for advertising campaigns, patient pamphlets, updating prescribers’ software, and distinct packaging for generic medicines. It was found that pharmacists’ perceptions of generic medicines are primarily driven by PHARMACs policies and their experiences with consumers.

Conclusions

About one-third of pharmacists correctly defined the term “generic medicines,” suggesting discrepancies in pharmacists’ knowledge and perceptions of generic medicines. Concerns were raised regarding: quality, safety, and effectiveness; however, most of the pharmacists acknowledged the economic benefits to the health care system.