Ethical challenges during critical phases of the COVID-19 pandemic: An interpretive synthesis.

BACKGROUND: During the most critical phases of COVID-19 pandemic, dramatic situations were experienced in hospitals and care centers that nurses could hardly verbalize. Especially relevant were deep challenges related to terminal illness, situations of extreme sacrifice, as well as reflections on protective measures mixed with beliefs. We intend to analyze which problems had the greatest impact on professionals. AIM: The aim is to explore the ultimate basis for action when making decisions and the orientation of their behavior in the face of moral conflicts. METHOD: The methodological strategy is an interpretive synthesis. Narrative review of academic articles that analyzed ethical dilemmas during the pandemic was carried out by searching five databases (Pubmed, Scopus, Psycinfo, CINHAL, and WOS) between January 2020 and December 2022. Finally, 43 articles were selected. ETHICAL CONSIDERATIONS: Ethical requirements were respected in all study phases. RESULTS: The reading and review of the 43 articles initiated the first phase of inductive coding which resulted in 14 initial sub-themes. Based on this structure, a second phase of coding was carried out, giving rise to six categories or emerging themes. To facilitate the process of identifying the central category, the authors agreed to carry out a phase of synthesis, grouping the six themes into three meta-themes: the identification and acceptance of human vulnerability; the discovery of positive paradigms in traumatic situations in society; the prevalence of the common good over the particular interest, as the core structure of any society. CONCLUSION: The study has shown the need to consider healthcare benevolence as a new dimension of health care upon global vulnerability. Responsibility is required to ensure the well-being of a global society, prioritizing the common good over particular interests and building solutions on solid moral structures. A new ethical landscape is essential, starting with a humanistic curricular training of all healthcare professionals.

Analysis in the ethical decision-making of dental, nurse and physiotherapist students, through case-based learning.

INTRODUCTION: Training in ethical competencies is perceived with special interest among the objectives of health education. The dimensions of the person such as integrity, autonomy and dignity influence the choice of interventions, but the different specialties of the health sciences conceive these dimensions with different perspectives depending on the clinical setting. These divergences can be detected during the first years of undergraduate studies, and it is important to know the professional bias and its possible causes. MATERIALS AND METHODS: A procedure was developed through case-based learning (CBL) to assess various characteristics of decision-making during the early stages of student training. A semi-quantitative method was designed based on the narrative responses of a case with ethical implications in the field of gender violence. The method was applied to 294 undergraduate students in nursing (95), physiotherapy (109) and dentistry (90) from the Faculty of Health Sciences of a Spanish university. A frequency analysis of the narrative responses of the students to the proposed case was carried out, using the chi-square test to determine any association between the variables studied: gender, specialty and ethical knowledge. RESULTS: Four types of response categories were detected, as a result of combining the personal conversation, report to legal authority or require assistance of other teams. The most common option in dentists is conversation only, while physical therapists include the assistance of other teams. In nursing, a balance is observed between both possibilities. The results show that student responses differ significantly among specialties and also differ significantly according to test scores on ethical knowledge. However, no significant differences were found between the responses provided by men and women. CONCLUSION: Most of the health sciences students highly valued their own capacity for dialogue and reflection to approach situations with complex ethical dimensions. We consider that case-based learning (CBL), in combination with narrative analysis is a valid means of evaluating the professional ethical competencies of students in health sciences careers applied to a common goal.

Moral dilemmas involving anthropological and ethical dimensions in healthcare curriculum.

BACKGROUND: Currently a variety of novel scenarios have appeared within nursing practice such as confidentiality of a patient victim of abuse, justice in insolvent patients, poorly informed consent delivery, non-satisfactory medicine outputs, or the possibility to reject a recommended treatment. These scenarios presuppose skills that are not usually acquired during the degree. Thus, the implementation of teaching approaches that promote the acquisition of these skills in the nursing curriculum is increasingly relevant. OBJECTIVE: The article analyzes an academic model which integrates in the curriculum a series of specific theoretical concepts together with practical skills to acquire the basic ethic assessment competency. RESEARCH DESIGN: The project includes designing two subjects, General Anthropology and Ethics-Bioethics, with an applied approach in the nursing curriculum. The sequential structure of the curriculum in both subjects is constituted by three learning domains (theoretical, practical, and communicative) with different educational strategies. ETHICAL CONSIDERATIONS: No significant ethical considerations as this is a discussion paper. FINDINGS: The model was structured from the anthropology's concepts and decision-making process, applied to real situations. The structure of the three domains theoretical-practical-communicative is present in each session. DISCUSSION: It is observed that theoretical domain fosters the capacity for critical analysis and subsequent ability to judge diverse situations. The practical domain reflected two significant difficulties: students' resistance to internalizing moral problems and the tendency to superficial criticism. The communicative domain has frequently shown that the conflicting points are in the principles to be applied. CONCLUSION: We conclude that this design achieves its objectives and may provide future nursing professionals with ethical competences especially useful in healthcare practice. The three domains of the presented scheme are associated with the same process used in decision making at individual levels, where the exercise of clinical prudence acquires particular relevance.

Moral enhancement, at the peak of pharmacology and at the limit of ethics.

The debate over the improvement of moral capacity or moral enhancement through pharmacology has gained momentum in the last decade as a result of advances in neuroscience. These advances have led to the discovery and allowed the alteration of patterns of human behavior, and have permitted direct interventions on the neuronal structure of behavior. In recent years, this analysis has deepened regarding the anthropological foundations of morality and the reasons that would justify the acceptance or rejection of such technology. We present a review of proposals for pharmacological interventions directed directly towards moral enhancement. In addition, we identify the ethical dilemmas that such interventions may generate, as well as the moral assessment of the authors of these studies. There is a moderate consensus on the risks of any intervention on the intimate structure of the human condition, its autonomy and identity, but there are large differences in explaining the reasons for this concern and especially in justifying such interventions. These findings show that it is necessary to investigate the moral assessment of authors and the ethical dimension within the field of pharmacology in order to identify future trends.

Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice.

Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC0→∞ 38% in plasma (p < 0.05) and 24% in liver (p < 0.001) and 23% in kidney (p < 0.001). However, AUC0→∞ remained unchanged in plasma and increased 41% in kidney (p < 0.001) of female mice. In brain, sunitinib exposure decreased 46% (p < 0.001) and 32% (p < 0.001) in male and female brain respectively. Mechanistically, diclofenac increased the liver uptake efficiency in male (27%, p < 0.05) and female (48%, p < 0.001) mice and 30% in kidney (p < 0.05) of male mice, probably owing to effects on efflux transporters. Sunitinib displayed sex-divergent DDI with diclofenac with probable clinical translatability due to potential different effects in male and female patients requiring careful selection of the NSAID and advanced TDM to implement a personalized treatment.

Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug-drug interaction in mice.

The sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60 mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC0→∞, 31% and 27% lower liver and kidney AUC0→∞ and 2.2-fold higher AUC0→∞ in brain (all p < 0.001) and had lower liver- and kidney-to-plasma AUC0→∞ ratios (p < 0.001) than male control mice. Paracetamol decreased 29% plasma AUC0→∞ (p < 0.05) in male mice and remained unchanged in female mice. In male and female mice, it decreased liver (15%, 9%), kidney (15%, 20%) and brain (47%, 50%) AUC0→∞ (p < 0.001) respectively owing to 52% brain uptake efficiency reduction in female mice (p < 0.01). Sunitinib displayed sex-divergent pharmacokinetics, tissue distribution and DDI with potential clinical translatability for the treatment of brain tumor and RCC patients.

Women's health, hormonal balance, and personal autonomy.

Hormone-based contraception disrupts hormonal balance, creating artificial states of anovulation and threatening women's health. We reviewed its main adverse effects and mechanisms on accelerated ovarian aging, mental health (emotional disruptions, depression, and suicide), sexuality (reduced libido), cardiovascular (brain stroke, myocardial infarction, hypertension, and thrombosis), and oncological (breast, cervical, and endometrial cancers). Other "collateral damage" includes negative effects on communication, scientific mistrust, poor physician-patient relationships, increased patient burden, economic drain on the healthcare system, and environmental pollution. Hormone-sensitive tumors present a dilemma owing to their potential dual effects: preventing some cancers vs. higher risk for others remains controversial, with denial or dismissal as non-relevant adverse effects, information avoidance, and modification of scientific criteria. This lack of clinical assessment poses challenges to women's health and their right to autonomy. Overcoming these challenges requires an anthropological integration of sexuality, as the focus on genital bodily union alone fails to encompass the intimate relational expression of individuals, complete sexual satisfaction, and the intertwined feelings of trust, safety, tenderness, and endorsement of women's femininity.

Significant reduction of brain cysts caused by Toxoplasma gondii after treatment with spiramycin coadministered with metronidazole in a mouse model of chronic toxoplasmosis.

Toxoplasma gondii is a parasite that generates latent cysts in the brain; reactivation of these cysts may lead to fatal toxoplasmic encephalitis, for which treatment remains unsuccessful. We assessed spiramycin pharmacokinetics coadministered with metronidazole, the eradication of brain cysts and the in vitro reactivation. Male BALB/c mice were fed 1,000 tachyzoites orally to develop chronic toxoplasmosis. Four weeks later, infected mice underwent different treatments: (i) infected untreated mice (n = 9), which received vehicle only; (ii) a spiramycin-only group (n = 9), 400 mg/kg daily for 7 days; (iii) a metronidazole-only group (n = 9), 500 mg/kg daily for 7 days; and (iv) a combination group (n = 9), which received both spiramycin (400 mg/kg) and metronidazole (500 mg/kg) daily for 7 days. An uninfected control group (n = 10) was administered vehicle only. After treatment, the brain cysts were counted, brain homogenates were cultured in confluent Vero cells, and cysts and tachyzoites were counted after 1 week. Separately, pharmacokinetic profiles (plasma and brain) were assessed after a single dose of spiramycin (400 mg/kg), metronidazole (500 mg/kg), or both. Metronidazole treatment increased the brain spiramycin area under the concentration-time curve from 0 h to ∞ (AUC(0-∞)) by 67% without affecting its plasma disposition. Metronidazole plasma and brain AUC(0-∞) values were reduced 9 and 62%, respectively, after spiramycin coadministration. Enhanced spiramycin brain exposure after coadministration reduced brain cysts 15-fold (79 ± 23 for the combination treatment versus 1,198 ± 153 for the untreated control group [P < 0.05]) and 10-fold versus the spiramycin-only group (768 ± 125). Metronidazole alone showed no effect (1,028 ± 149). Tachyzoites were absent in the brain. Spiramycin reduced in vitro reactivation. Metronidazole increased spiramycin brain penetration, causing a significant reduction of T. gondii brain cysts, with potential clinical translatability for chronic toxoplasmosis treatment.

Toxoplasma gondii: determination of the onset of chronic infection in mice and the in vitro reactivation of brain cysts.

Toxoplasma gondii is an intra-cellular parasite that infects humans through vertical and horizontal transmission. The cysts remain dormant in the brain of infected humans and can reactivate in immunocompromised hosts resulting in acute toxoplasmic encephalitis which may be fatal. We determined the onset and progression of brain cysts generation in a mouse model following acute toxoplasmosis as well as the ability of brain cysts to reactivate in vitro. Male Balb/c mice, (uninfected control group, n = 10) were infected orally (study group, n = 50) with 1000 tachyzoites of T. gondii (ME49 strain) and euthanized at 1, 2, 4, 8 and 16 weeks post infection. Brain tissue was harvested, homogenized, stained and the number of brain cysts counted. Aliquots of brain homogenate with cysts were cultured in vitro with confluent Vero cells and the number of cysts and tachyzoites counted after 1 week. Brain cysts but not tachyzoites were detected at week 2 post infection and reached a plateau by week 4. In vitro Vero cells culture showed similar pattern for cysts and tachyzoites and reactivation of cyst in vitro was not influenced by the age of the brain cysts.

Role of caregivers on medication adherence management in polymedicated patients with Alzheimer's disease or other types of dementia.

Background: Alzheimer's disease (AD) and other dementia patients may have severe difficulties to ensure medication adherence due to their generally advanced age, polymedicated and multi-pathological situations as well as certain degree of cognitive impairment. Thus, the role of patient caregivers becomes crucial to warrantee treatment compliance. Purpose: To assess the factors associated to patients and caregivers on medication adherence of patients with AD and other types of dementia as well as the degree of caregiver satisfaction with respect to treatment. Methods: An observational, descriptive, cross-sectional study among the caregivers of 100 patients with AD and other types of dementia of the "Cartagena and Region Association of Relatives of Patients with Alzheimer's Disease and other Neurodegenerative Diseases" was conducted to assess patient and caregiver factors that influence medication adherence evaluated with the Morisky-Green-Levine test. Results: Overall, adherence to treatment was 71%, with similar proportions between male and female patients. Greater adherence was found in married or widowed patients (49.3%), first degree (85.9%) or female (81.7%) caregivers but lower in AD patients (75.9%). Multivariate analysis showed a statistically significant positive association between non-adherence and male sex of the caregiver (OR 3.512 [95%IC 1.124-10.973]), dementia (OR 3.065 [95%IC 1.019-9.219]), type of caregiver (non-first-degree relative) (OR 0.325 [95%IC 0.054-0.672]) and civil status of the patient (OR 2.011 [95%IC 1.155-3.501]) favorable for married or widowed patients. No or week association was found with gender, age, education level, number of drugs used or polymedicated status of the patient. Caregivers considered the use (90%) and administration (91%) of the treatment easy or very easy and rarely interfered with their daily life, especially for female caregivers (p = 0.016). Finally, 71% indicated that they were satisfied or very satisfied with the treatment received by the patient. Conclusions: Caregivers influence therapeutic management with predictors for improved adherence including female gender and first-degree kinship, together with patient's marital status. Thus, training caregivers about the disease and the importance of medication adherence in AD patients may ensure optimal treatment.

Microwave-assisted Preparation of Cross-linked Gelatin-Paracetamol Matrices: Optimization Using the D-optimal Design

Objectives: This study was conducted to assess the effect of microwave heating on the preparation of paracetamol cross-linked gelatin matrices by using the design of experiment (DoE) approach and explore the influence of the duration of microwave irradiation, the concentrations of crosslinker, and the amount of sodium bicarbonate (salt) on paracetamol release. These parameters were also compared with those of the matrices prepared via conventional heating. Materials and Methods: Twenty gel matrices were prepared with different durations of microwave irradiation, amounts of maize, and concentrations of sodium bicarbonate as suggested by Design Expert (DX®). The percentage drug release, the coefficient of variance (CV) in release, and the mean dissolution time (MDT) were the properties explored in the designed experimentation. Results: Target responses were dependent on microwave irradiation time, cross-linker amount, and salt concentration. Classical and microwave heating did not demonstrate statistically significant difference in modifying the percentage of drug released from the matrices. However, the CVs of microwave-assisted formulations were lower than those of the gel matrices prepared via classical heating. Thus, microwave heating produced lesser variations in drug release. The optimized gel matrices demonstrated that the observed percentage of drug release, CV, and MDT were within the prediction interval generated by DX®. The release mechanism of the matrix formulations followed the Peppas-Korsmeyer anomalous transport model. Conclusion: The DoE-supported microwave-assisted approach could be applied to optimize the critical factors of drug release with less variation.

Increased Bioavailability of ß-Alanine by a Novel Controlled-Release Powder Blend Compared to a Slow-Release Tablet.

BACKGROUND: ß-Alanine is a sport supplement with increasing popularity due to its consistent ability to improve physical performance, with the downside of requiring several weeks of supplementation as imposed to the maximum daily and single dose tolerated without side effects (i.e., paresthesia). To date, the only alternative to overcome this problem has been use of a sustained-release tablet, while powders are the most commonly used format to deliver several grams of amino acids in a single dose. In this study we assessed the bioavailability, pharmacokinetics and paresthesia effect of ß-alanine after administration in a novel controlled-released powder blend (test) versus a sustained-release tablet (reference). METHODS: Twelve subjects (25.6 ± 3.2 y, 50% female) participated in a randomized, single-blind, crossover study. Each participant was administered orally the test (ß-alanine 8 g, l-histidine 300 mg, carnosine 100 mg) or the reference product (10 tablets to reach ß-alanine 8 g, Zinc 20 mg) with a 1-week washout period. ß-Alanine plasma concentrations (0-8 h) were determined by LC-MS/MS and model-independent pharmacokinetic analysis was carried out. Paresthesia intensity was evaluated using a Visual Analog Score (VAS) and the categorical Intensity Sensory Score (ISS). RESULTS: The CMAX and AUC0→∞ increased 1.6- and 2.1-fold (both p < 0.001) in the test product, respectively, which yielded 2.1-fold higher bioavailability; Ka decreased in the test (0.0199 ± 0.0107 min-1) versus the reference (0.0299 ± 0.0121 min-1) product (p = 0.0834) as well as V/F and Cl/F (both p < 0.001); MRT0→last increased in the test (143 ± 19 min) versus reference (128 ± 16 min) formulation (p = 0.0449); t1/2 remained similar (test: 63.5 ± 8.7 min, reference: 68.9 ± 9.8 min). Paresthesia EMAX increased 1.7-fold using the VAS (p = 0.086) and the ISS (p = 0.009). AUEC increased 1.9-fold with the VAS (p = 0.107) and the ISS (p = 0.019) reflecting scale intrinsic differences. Pharmacokinetic-pharmacodynamic analysis showed a clockwise hysteresis loop without prediction ability between CMAX, AUC0→∞ and EMAX or AUEC. No side effects were reported (except paresthesia). CONCLUSIONS: The novel controlled-release powder blend shows 100% higher bioavailability of ß-alanine, opening a new paradigm that shifts from chronic to short or mid-term supplementation strategies to increase carnosine stores in sports nutrition.

Differential effects of ketoconazole and primaquine on the pharmacokinetics and tissue distribution of imatinib in mice.

Imatinib, a selective inhibitor of c-KIT and Bcr-Abl tyrosine kinases, approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors, shows further therapeutic potential for gliomas, glioblastoma, renal cell carcinoma, autoimmune nephritis and other neoplasms. It is metabolized by CYP3A4, is highly bound to alpha-1-acid glycoprotein and is a P-glycoprotein substrate limiting its brain distribution. We assess imatinib's protein binding interaction with primaquine, which also binds to alpha-1-acid glycoprotein, and its metabolic interaction with ketoconazole, which is a CYP3A4 inhibitor, on its pharmacokinetics and biodistribution. Male ICR mice, 9-12 weeks old were given imatinib PO (50 mg/kg) alone or co-administered with primaquine (12.5 mg/kg), ketoconazole (50 mg/kg) or both, and imatinib concentration in the plasma, kidney, liver and brain was measured at prescheduled time points by HPLC. Noncompartmental pharmacokinetic parameters were estimated. Primaquine increased 1.6-fold plasma AUC(0)--> infinity, C(Max) decreased 24%, T(Max) halved and t(1/2) and mean residence time were longer. Ketoconazole increased plasma AUC(0)-->infinity 64% and doubled the C(Max), but this dose did not affect t(1/2) or mean residence time. When ketoconazole and primaquine were co-administered, imatinib AUC(0)-->infinity and C(Max) increased 32 and 35%, respectively. Ketoconazole did not change imatinib's distribution efficiency in the liver and kidney, primaquine increased it two-fold and it was larger when both the drugs were co-administered with imatinib. Ketoconazole did not change brain penetration but primaquine increased it approximately three-fold. Ketoconazole and primaquine affect imatinib clearance, bioavailability and distribution pattern, which could improve the treatment of renal and brain tumors, but also increase toxicity. This would warrant hepatic and renal functions monitoring.

Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice.

BACKGROUND: Sunitinib, a tyrosine kinase inhibitor to treat GIST and mRCC may interact with paracetamol as both undergo P450 mediated biotransformation and P-glycoprotein transport. This study evaluates the effects of sunitinib-paracetamol coadministration on liver and renal function biomarkers and liver, kidney, brain, heart and spleen histopathology. ICR male mice (n = 6 per group/dose) were administered saline (group-A) or paracetamol 500 mg/kg IP (group-B), or sunitinib at 25, 50, 80, 100, 140 mg/kg PO (group-C) or coadministered sunitinib at 25, 50, 80, 100, 140 mg/kg PO and paracetamol IP at fixed dose 500 mg/kg (group-D). Paracetamol was administered 15 min before sunitinib. Mice were sacrificed 4 h post sunitinib administration. RESULTS: Group-A serum ALT and AST levels were 14.29 ± 2.31 U/L and 160.37 ± 24.74 U/L respectively and increased to 249.6 ± 222.7 U/L and 377.1 ± 173.6 U/L respectively in group-B; group-C ALT and AST ranged 36.75-75.02 U/L and 204.4-290.3 U/L respectively. After paracetamol coadministration with low sunitinib doses (group-D), ALT and AST concentrations ranged 182.79-221.03 U/L and 259.7-264.4 U/L respectively, lower than group-B. Paracetamol coadministration with high sunitinib doses showed higher ALT and AST values (range 269.6-349.2 U/L and 430.2-540.3 U/L respectively), p < 0.05. Hepatic histopathology showed vascular congestion in group-B; mild congestion in group-C (but lesser than in group-B and D). In group-D, at low doses of sunitinib, lesser damage than in group-B occurred but larger changes including congestion were observed at high sunitinib doses. BUN levels were higher (p < 0.05) for group-B (33.81 ± 5.68 mg/dL) and group-D (range 35.01 ± 6.95 U/L to 52.85 ± 12.53 U/L) compared to group-A (15.60 ± 2.17 mg/dL) and group-C (range 17.50 ± 1.25 U/L to 26.68 ± 6.05 U/L). Creatinine remained unchanged. Renal congestion and necrosis was lower in group-C than group-B but was higher in group-D (p > 0.05). Mild cardiotoxicity occurred in groups B, C and D. Brain vascular congestion occurred at high doses of sunitinib administered alone or with paracetamol. Hepatic and renal biomarkers correlated with histopathology signs. CONCLUSIONS: Paracetamol and sunitinib coadministration may lead to dose dependent outcomes exhibiting mild hepatoprotective effect or increased hepatotoxicity. Sunitinib at high doses show renal, cardiac and brain toxicity. Liver and renal function monitoring is recommended.

Disposition and tissue distribution of imatinib in a liposome formulation after intravenous bolus dose to mice.

Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest. We assess the pharmacokinetic and tissue distribution profile of imatinib in a liposome formulation. Its single dose (6.25 mg x kg(-1)) in a liposome formulation was administered iv to male mice. Imatinib concentration was measured in plasma, spleen, liver, kidney and brain using a HPLC assay. Non-compartmental pharmacokinetic approach was used to assess the disposition parameters. The plasma disposition profile was biphasic with a plateau-like second phase. The AUC(0-->infinity) was 11.24 microg x h x mL(-1), the elimination rate constant (k(el)) was 0.348 h(-1) and the elimination half life (t(1/2)) was 2.0 h. The mean residence time (MRT) was 2.59 h, V(SS) was 1.44 L x kg(-1) and clearance was 0.56 L x h x kg(-1). Liver achieved the highest tissue exposure: CMAX = 18.72 microg x mL(-1); AUC(0-->infinity)= 58.18 microg x h x mL(-1) and longest t(1/2) (4.29 h) and MRT (5.31 h). Kidney and spleen AUC(0-->infinity) were 47.98 microg x h x mL(-1) and 23.46 microg x h x mL(-1), respectively. Half-life was 1.83 h for the kidney and 3.37 h for the spleen. Imatinib penetrated into the brain reaching approximately 1 microg x g(-1). Upon correction by organ blood flow the spleen showed the largest uptake efficiency. Liposomal imatinib presented extensive biodistribution. The drug uptake kinetics showed mechanism differences amongst the tissues. These findings encourage the development of novel imatinib formulations to treat other cancers.

Histopathological study of the hepatic and renal toxicity associated with the co-administration of imatinib and acetaminophen in a preclinical mouse model.

Imatinib, a selective tyrosine kinase inhibitor, is the first line treatment against chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumors (GIST). Several fatal cases have been associated with imatinib hepatotoxicity. Acetaminophen, an over-the-counter analgesic, anti-pyretic drug, which can cause hepatotoxicity, is commonly used in cancer pain management. We assessed renal and hepatic toxicity after imatinib and acetaminophen co-administration in a preclinical model. Four groups of male ICR mice (30-35 g) were fasted overnight and administered either saline solution orally (baseline control), imatinib 100 mg/kg orally (control), acetaminophen 700 mg/kg intraperitoneally (positive control) or co-administered imatinib 100 mg/kg orally and acetaminophen 700 mg/kg intraperitoneally (study group), and sacrificed at 15 min, 30 min, 1 h, 2 h, 4 h and 6 h post-administration (n = 4 per time point). The liver and kidneys were harvested for histopathology assessment. The liver showed reversible cell damage like feathery degeneration, microvesicular fatty change, sinusoidal congestion and pyknosis, when imatinib or acetaminophen were administered separately. The damage increased gradually with time, peaked at 2 h but resolved by 4 h. When both drugs were administered concurrently, the liver showed irreversible damage (cytolysis, karyolysis and karyorrhexis) which did not resolve by 6 h. Very minor renal changes were observed. Acetaminophen and imatinib co-administration increased hepatoxicity which become irreversible, probably due to shared P450 biotransformation pathways and transporters in the liver.

Ethical Challenges of Germline Genetic Enhancement.

The new reproductive technologies have opened the door to different processes of germline genetic enhancement by which the characteristics of an individual according to the interests of the agents involved could be selected during its gestation. Although the initiative is apparently oriented towards developing individuals that would excel in society, critical voices raise the concerns about that this approach would generate and need for a reflection on the ethical, social and legal implications of these techniques and their implementation in society. We reviewed the literature about these issues throughout their historical records to date, focusing on the moral arguments and non-clinical aspects that affect the legal and social environment. We have observed various trends of thought with divergent positions (proactive, preventive, and regulatory) as well as a large number of articles that try to reconcile the different approaches. This review illustrates a series of concepts from the ethics and philosophy fields which are frequently used in studies that evaluate the ethical implications of germline genetic enhancement, such as dignity, benefit, autonomy, and identity. In addition, amongst the many unresolved controversies surrounding genetic enhancement, we identify procreative beneficence, genetic disassociation, gender selection, the value of disability, embryo chimerization, and the psychosocial inequality of potentially enhanced individuals as crucial. We also develop possible scenarios for future debate. We consider especially important the definition and specification of three aspects which are essential for the deployment of new reproductive technologies: the moral status of the embryo undergoing enhancement, the legal status of the enhanced individual, and the responsibility of the agents executing the enhancement. Finally, we propose the precautionary principle as a means to navigate ethical uncertainties.

Sex-Divergent Clinical Outcomes and Precision Medicine: An Important New Role for Institutional Review Boards and Research Ethics Committees.

The efforts toward individualized medicine have constantly increased in an attempt to improve treatment options. These efforts have led to the development of small molecules which target specific molecular pathways involved in cancer progression. We have reviewed preclinical studies of sunitinib that incorporate sex as a covariate to explore possible sex-based differences in pharmacokinetics and drug-drug interactions (DDI) to attempt a relationship with published clinical outputs. We observed that covariate sex is lacking in most clinical outcome reports and suggest a series of ethic-based proposals to improve research activities and identify relevant different sex outcomes. We propose a deeper integration of preclinical, clinical, and translational research addressing statistical and clinical significance jointly; to embed specific sex-divergent endpoints to evaluate possible gender differences objectively during all stages of research; to pay greater attention to sex-divergent outcomes in polypharmacy scenarios, DDI and bioequivalence studies; the clear reporting of preclinical and clinical findings regarding sex-divergent outcomes; as well as to encourage the active role of scientists and the pharmaceutical industry to foster a new scientific culture through their research programs, practice, and participation in editorial boards and Institutional Ethics Review Boards (IRBs) and Research Ethics Committees (RECs). We establish the IRB/REC as the centerpiece for the implementation of these proposals. We suggest the expansion of its competence to follow up clinical trials to ensure that sex differences are addressed and recognized; to engage in data monitoring committees to improve clinical research cooperation and ethically address those potential clinical outcome differences between male and female patients to analyze their social and clinical implications in research and healthcare policies.

Sunitinib Possible Sex-Divergent Therapeutic Outcomes.

Sunitinib is a tyrosine kinase inhibitor used for the treatment of renal cell carcinoma and metastatic brain tumors. Preclinical pharmacokinetic studies have shown higher sunitinib hepatic and brain exposure in female mice and higher sunitinib kidney concentrations in male mice. We explored whether sex-divergent tissue pharmacokinetics may anticipate sex-divergent therapeutic and toxicology responses in male and female patients. The review of the available scientific literature identified case reports, case series reports, clinical trials, and other studies associating sex with sunitinib outcomes. The results suggest male patients may respond better to renal cell carcinoma treatment and female patients may have better brain tumor treatment outcomes but a higher incidence of adverse events. Although more high-quality evidence is needed, these results, as anticipated by the preclinical data, may indicate possible sunitinib sex-divergent therapeutic outcomes in patients. In addition, we propose the systematic analysis of sex-based outcomes in clinical trial reports and their inclusion and review in the ethics committees and review boards to prevent, amongst others, patient burden in upcoming clinical trials.