Until the last quarter of the 20th century, sex was not recognized as a variable in health research, nor was it believed to be a factor that could affect health and illness. Researchers preferred studying male models for a variety of reasons, such as simplicity, lower costs, hormone confounding effects, and fear of liability from perinatal exposure in case of pregnancy. Equitable representation is imperative for determining the safety, effectiveness, and tolerance of therapeutic agents for all consumers. Decades of female models’ underrepresentation in preclinical studies has resulted in inequality in the understanding, diagnosis, and treatment of disease between the sexes. Sex bias has been highlighted as one of the contributing factors to the poor translation and replicability of preclinical research. There have been multiple calls for action, and the inclusion of sex as a biological variable is increasingly supported. However, although there has been substantial progress in the efforts to include more female models in preclinical studies, disparities today remain. In the present review, we consider the current standard practice of the preclinical research setting, why the sex bias exists, why there is the need to include female models, and what risks may arise from continuing this exclusion from experimental design.

Background: Hydroxyurea (HU), also known as hydroxycarbamide, is an oral ribonucleotide reductase inhibitor. In 1999, the United States Food and Drug Administration (FDA) approved HU for the treatment of sickle cell disease (SCD). Since then, it has become the cornerstone in the management of SCD patients, helping to reduce vaso-occlusive crises, acute chest syndrome, the need for blood transfusions, hospitalizations and mortality. There is considerable variability among individuals in HU pharmacokinetic (Pk) parameters that can influence treatment efficacy and toxicity. The objective of this work is part of a clinical study aimed at investigating HU Pk and determining the optimal sampling time to estimate the Area Under the Curve (AUC) in SCD patients. Methods: HU plasma concentration in 80 patients at various time points (2, 4, 6, 24 h) following a 48-h drug washout was quantified using High-Pressure Liquid Chromatography (HPLC) coupled with an ultraviolet (UV) detection method previously described in the literature and adapted to new conditions with partial modifications. Results: The mean HU administered dose was 19.5 ± 5.1 mg/kg (range: 7.7–37.5 mg/kg). The median AUC quantified in plasma patients was 101.3 mg/L/h (Interquartile Range (IQR): 72.5–355.9) and it was not influenced by the weight-based dose. However, there was a strong positive correlation between AUC and Body Mass Index (BMI) as well as dose per Body Surface Area (BSA). Along with a three-point approach for AUC determination present in the literature, we show results obtained from a four-point sampling strategy, which is more useful and effective for better optimizing dose escalation to the maximum tolerated dose (MTD). Moreover, we observed that most patients achieved the maximum HU plasma concentration two hours after drug administration, regardless of age differences. Conclusions: HU treatment, which represents a milestone in the treatment of SCD due to its ability to reduce disease complications and improve patients’ quality of life, requires careful monitoring to optimize the individual dose for saving potential side effects and/or adverse events.

Background: Hydroxyurea is approved for the treatment of paediatric and adult sickle cell disease patients. It causes the synthesis of foetal haemoglobin and decreases platelets and granulocytes, but with a high interindividual variability, requiring higher dosages and escalating toxicity. Hereditary variables should be investigated to personalise treatment. We evaluated the possible influences of OCT1 and MAP3K5 gene polymorphisms on hydroxyurea pharmacokinetics. Methods: We conducted a retrospective analysis on 79 treated patients. The polymorphisms of OCT1 (rs683369 G > C) and MAP3K5 (rs9376230 C > A and rs9483947 C > T) were genotyped. Results: Sub-Saharan patients with the OCT1 rs683369 GG genotype showed a lower drug half-life, compared to those with the GC genotype. In sub-Saharan paediatric female patients, the OCT1 rs683369 GG genotype was associated with a lower t1/2 than the GC genotype. Conclusions: The findings demonstrate for the first time how crucial it is to assess the pharmacogenetics of hydroxyurea by taking into account the two sexes in different groups. Additionally, the data were evaluated with consideration for ethnic groups and individually for adults and children. Pharmacogenetic studies could improve the clinical management of hydroxyurea.

Phytotherapy has been used since ancient times for the treatment of many diseases, one of the fields of greatest use is oncology. Thus, patients use herbal medicines to counteract the side effects of chemotherapy, however these remedies, although natural, can lead to interactions if taken simultaneously with other medicines. The aim of the study was to identify interactions that may arise in the intake of oral chemotherapy in conjunction with phytotherapeutic substances This was a retrospective and descriptive study conducted among lung cancer patients actively undergoing chemotherapy. Data collection was conducted through the distribution to patients of a self-compiled and closed-ended questionnaires during chemotherapy treatment. Data relating to 35 patients were collected and interviews were collected for a total of 66 accesses to the facility. It was found that 69% take at least one phytotherapeutic substance. Among the most used substances we found green tea, 26% of accesses, and ginger, 30% of accesses. Some statistically significant comparisons were between chamomile and mucositis intake, turmeric and epigastric pain and sex differences considering diarrhea and headache. Obtained data confirmed that phytotherapics can increase the toxicities caused by chemotherapy.

Sickle Cell Disease is among the top 20 causes of mortality worldwide. Hydroxyurea is one of the most readily available and economical solutions approved for the treatment of Sickle Cell Disease patients: it induces the synthesis of foetal haemoglobin and decreases the inflammatory phenotype. Hydroxyurea shows high interindividual variability, re-quiring individualized dosing to balance therapeutic efficacy against escalating toxicity. In addition to non-genetic factors, hereditary variables can also be investigated to adopt a more tailored dosing regimen according to each patient's demographic, pharmacokinetic and pharmacogenetic profile. This study evaluated the possible influence of different genetic variants on hydroxyurea pharmacokinetics, by conducting a retrospective analysis on 79 treated patients, stratified by ethnicity, age and sex. SLC22A3*698 C>G variant was found to be the most significantly associated with an en-hanced function of the encoded transporter, improving the drug elimination process. ABCB1 1236 C>T, ABCB1 2677 G>A, ABCB1 3435 C>T, CYP2B6 516 G>T, CYP2C19*2 G>A, CYP2C9*3A A>C, CYP2D6*10 A>G, MAP3K5 13257 C>T, MAP3K5 6292 C>A and OCT1 480 C>G gene variants were instead found linked to a general loss-of-function phenotype, reflecting slower and less efficient drug metabolism. These findings demonstrate the importance of assessing hydroxyurea pharmacogenetics while taking into account different ethnic and demographic variables, in order to support a more personalized and effective therapeutic approach for sickle cell disease patients.

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