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Background. Chimeric antigen receptor (CAR) T cell therapy, a "living drug" immunotherapy, harnesses the power of T-cells from a patient (autologous) or healthy donor (allogeneic) to target and kill cancer cells and has shown unprecedented outcomes in patients with relapsed and refractory malignancies. Treatment with CAR-T cells requires the application of unique skillsets in recognised specialist centres for successful outcomes and requires management by the multidisciplinary team incorporating the specialist pharmacist. Method. A multimodal research strategy was employed for this literature review whereby PubMed, Google Scholar, Embase, Stella Library Search, EMA website, and EBMT website were sources of information. The search was limited from 2020 onwards with key terms referring to CAR-T cell therapy. Results and Discussion. There are six CAR-T cell products currently approved by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) which target haematological malignancies with abundant clinical trials underway exploring new and improved CAR designs and antigen targets. As CAR-T cell therapy is an advanced therapy medicinal product (ATMP), there is need for an extensive regulatory framework underpinning its safety and efficacy. The clinical pharmacist plays an integral role in the provision of safe and effective CAR-T cell therapy including governance, operational and clinical aspects of treatment. Pharmacists may also be involved through provision of "Qualified Person" (QP) expertise in clinical trials and for release within hospitals under certain circumstances. There is a need for harmonised and accessible guidance on the clinical delivery of ATMPs such as CAR-T cells, with fully delineated responsibilities of pharmacists involving the oversight and supervision of CAR-T cell treatment. Conclusion. There is an unmet need to provide suitable and applicable literature for clinical pharmacists who are involved in the delivery of CAR-T cells. We have provided an overview of T-cell biology and an explanation of CAR-T cell design and the biomanufacturing process. We reviewed the complex and multifaceted treatment cycle requiring considerable logistics, and described the involvement of the clinical pharmacist in each part of this cycle from patient selection to postinfusion care. Finally, we look to the challenges and future opportunities that will require the involvement of the clinical pharmacist. [ABSTRACT FROM AUTHOR]

This article focuses on the new Veterinary Medicines Regulation, which is applicable across all Member States of the European Union, including Ireland, from 28 January 2022. From this date, prophylactic use of antimicrobials (AMs) in groups of animals is banned, metaphylactic use in groups of animals is restricted, and certain AMs are reserved for humans only. In the Irish dairy industry, as elsewhere, successful implementation of the Regulation will require a high level of mastitis control across all herds, and measures to support high standards in antibiotic stewardship. National actions will be critical, to support optimal mastitis control throughout the national herd. For private veterinary practitioners (PVPs), the Regulation will lead to specific prescribing changes, including the requirement to shift from blanket to selective dry cow therapy. Further, prescribing choices will need to be guided by the categorisation for AMs developed by the European Medicines Agency (EMA). More broadly, the Regulation requires a fundamental shift in thinking both in terms of AM usage and of the role of the PVP. Given the close association between mastitis control and intramammary AM stewardship, it is imperative that prescribing and mastitis control decisions are made concurrently. A herd health approach will be critical, within a Client-Patient-Practice Relationship as outlined by the Veterinary Council of Ireland. On those farms with sub-optimal mastitis control, mastitis issues need to be sustainably resolved. A detailed farm investigation by the PVP, in partnership with the farmer and other milk quality professionals, is essential, to understand the epidemiology and on-farm drivers of mastitis, to develop farm-specific action plans, and to facilitate ongoing monitoring of progress. It is vital that PVPs provide leadership, with the provision of a holistic, herd health approach to inform both prescribing and mastitis control decisions in herds under their care. [ABSTRACT FROM AUTHOR]

Valproate is a known antiepileptic responsible for the valproate syndrome (FVS) in children whose mothers have used it during pregnancy (1). In 2014 The European Medicines Agency warned against the use of valproate in treating epilepsy but also some other illnesses such as e.g. the migraine (2). A recent study has described 29 cases of FVS diagnosed in Ireland from 1995-2016. Among malformations were those of the neural tube, heart, limbs, craniofacial etc. (2). However, all effects are still not completely explained at the molecular level (3,4). Today it is clear that anomalies of development of specific organs are induced at the specific time-windows or critical phases that correlate with the phases of organ development (5). On the basis of his experiments with various teratogenic agents, the founder of the Zagreb School of Mammalian Embryology academician N. Škreb (5) has proposed an "all or none" hypothesis regarding the early postimplantation development at the Pallanza conference already in 1960 (6). Before the formation of the mesoderm, the young mammalian embryo is either destroyed by the teratogen or recovers completely, and therefore these early stages are not susceptible to teratogens (5). The formation of the mesoderm and the three definitive germ-layers takes place at gastrulation. Therefore, gastrulation is the first and the most critical phase of mammalian development where the early embryo loses its plasticity. At that stage the „all or none rule” is lost and the influence of a teratogenic agent may be visible after birth (5,6,7). In this study we aimed to investigate the direct effect of valproate on the development of the gastrulating rat embryo (embryo proper) devoid of its extraembryonic parts and outside of the maternal environment. Fischer rat embryos were microsurgically isolated and grown in the original organ-culture model with the Eagle's Minimum Essential Medium and 50% rat serum (controls). Valproate (2mM or 1mM) was added to the culture medium and cultures were grown for 3 days or 2 weeks with 5% CO2 in ahumidified incubator. We used immunohistochemistry to detect cleaved caspase 3 as the marker of apoptosis and the Proliferating Cell Nuclear Antigen as the marker of proliferation. Stereology was used to calculate the volume density (Vv) of the apoptotic marker and proliferation index was calculated. Growth was measured by an ocular micrometer. Acetylated histone expression was detected by the Western blot. By measuring overall growth, from the third day onwards, a significantly lower growth was discovered in cultures with valproate that was also lower in embryos treated with the higher dose. After three days of culture, in embryos treated with the higher dose of valproate, a significantly higher apoptotic activity (Vv of cleaved caspase-3) was discovered than in controls and in embryos treated with the lower dose of valproate (Figure 1). After two weeks in culture, the proliferation index (PCNA index) was significantly lower in embryos treated with a higher dose of valproate. Higher dose also inhibited differentiation, especially of the nervous tissue. Higher expression of the acetylated histone H3 was discovered in embryos treated with valproate. It can be concluded that valproate negatively affects developmental processes already at the gastrulation stage, and its impact is dose-dependent. Apoptosis enhanced by the higher dose (2mM) may be connected to the enhanced histone acetylation caused by valproate that is an epigenetic drug and inhibitor of the histone deacetylase (3). [ABSTRACT FROM AUTHOR]

This section offers news briefs related to pharmaceutical medicine as of April 2014. The European Medicines Agency (EMA) is planning to publish full clinical trial data submitted by companies starting January 1, 2014. Adverse drug reaction (ADR) reporting guidance was included by Accreditation Canada in its latest Medication Management Standards. A decision was made by the Irish Medicines Board (IMB) to regulate Ireland's herbal medicines market.

This study aims to investigate the barriers that exist when implementing continuous improvement methodologies, such as Lean Six Sigma (LSS), within the Irish Pharma industry. The main finding of this study is that 45% of participants perceived that a highly regulated environment could be a barrier to continuous improvement implementation, while 97% of respondents utilised Continuous improvement (CI) methods, such as Lean, Six Sigma, and LSS, within their organisations. While the International Conference of Harmonisation integrates CI into its Pharmaceutical Quality Systems (PQS) regulations, the highest motivation for CI implementation amongst the Irish Pharma industry is to improve Productivity and Quality. The main obstacles highlighted for CI implementation in Pharma attributed to stringent regulatory regimes were fear of extra validation activity, a compliance versus quality culture, and a regulatory culture of being "safe". Another relevant finding presented in this paper is that participants CI LSS tools are very strongly integrated into the pharma industries corrective and preventative action system, deviations, and internal audit systems. Limitations of the research are that all the data collected in the survey came from professionals working for multinational Pharmaceutical companies based in Ireland. The authors understand that this is the first research focused on the barriers and status of CI initiatives in the pharmaceutical industry. The results of this study represent an important step towards understanding the enablers and obstacles for the use of continuous improvement methodologies in pharmaceutical manufacturing industries on a global scale. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to examine trends in valproate use among women of childbearing potential (WCBP) aged 16-44 years in Ireland following two European-directed regulatory interventions in December 2014 and April 2018., Methods: This was a repeated cross-sectional study using monthly national pharmacy claims data, to examine trend changes in the prevalence of valproate use among WCBP pre and post two separate regulatory events in December 2014 and April 2018. Annual population estimates from the Central Statistics Office were used to calculate the prevalence rate per 1000 eligible women. Segmented regression analysis of interrupted time series with negative binomial regression was used to examine rates for WCBP aged 16-44 years, and by 10-year age groups. Prevalence ratios (PR) are presented with 95% confidence intervals (CIs)., Results: Among WCBP aged 16-44 years, there was no statistically significant change in the month-to-month prevalence ratio in the post- compared to pre-December 2014 intervention period. A significant decline was, however, observed in the post-, compared to pre-April 2018 intervention period (PR = 0.998, [95% CIs: 0.996, 1.000]; p = 0.029). Among those aged 16-24 years, a significant decreasing trend in the month-to-month prevalence ratio was found in the post- compared to pre-December 2014 intervention period (PR = 0.991, [95% CIs: 0.984, 0.998];p <0.01). A marginal effect was observed in the post- compared to pre-April 2018 intervention period for those aged 25-34 years (PR = 0.996, [95% CIs: 0.992, 1.000]; p = 0.048)., Conclusion: Although no evidence of change was observed following the December 2014 intervention period, a significant decline in the prevalence ratio of valproate use was observed after the 2018 intervention, which may reflect the introduction of the most recent contraindication measures., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vyxeos, intended for the treatment of acute myeloid leukemia (AML). Vyxeos was designated as an orphan medicinal product on January 11, 2012. The applicant for this medicinal product was Jazz Pharmaceuticals Ireland Limited. Vyxeos is a liposomal formulation of a fixed combination of daunorubicin and cytarabine, antineoplastic agents that inhibit topoisomerase II activity and also cause DNA damage. The strength of Vyxeos is 5 units/mL, where 1 unit equals 1.0 mg cytarabine plus 0.44 mg daunorubicin. The marketing authorization holder Jazz Pharmaceuticals had found that this was an optimal ratio for the efficacy of the product. Study CLTR0310-301, a phase III, multicenter, randomized, trial of Vyxeos (daunorubicin-cytarabine) liposome injection versus standard 3+7 daunorubicin and cytarabine in patients aged 60-75 years with untreated high-risk (secondary) AML, showed a statistically significant difference between the two groups in overall survival (OS) with a median OS of 9.56 months in the daunorubicin-cytarabine arm compared with 5.95 months for standard chemotherapy (hazard ratio, 0.69; 95% confidence interval, 0.52-0.90; one-sided p = .003). The most common side effects were hypersensitivity including rash, febrile neutropenia, edema, diarrhea/colitis, mucositis, fatigue, musculoskeletal pain, abdominal pain, decreased appetite, cough, headache, chills, arrhythmia, pyrexia, sleep disorders, and hypotension. IMPLICATIONS FOR PRACTICE: Vyxeos has demonstrated a clinically significant improvement in overall survival compared with the standard of care 7+3 in the proposed population of patients with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia-related changes and therapy-related AML. This is remarkable given the very poor prognosis of these patients and their unmet medical need. Secondary endpoints support the primary outcome, in particular an increased rate of hematopoietic stem cell transplantation, which is potentially the only curative treatment in AML., (© AlphaMed Press 2020.)

The article focuses on antimicrobial resistance (AMR) and risk management measures on the veterinary use of antimicrobials (AMs). It mentions the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC), a programme initiated by the European Medicines Agency to provide information on the AMs veterinary usage in all European Member States (MSs). It discusses the impact of regulating veterinary prescription of AMs to veterinarians in Ireland.