Forensic Toxicological and Medico-Legal Evaluation in a Case of Incongruous Drug Administration in Terminal Cancer Patients

Background: In most cases, palliative care is prescribed to adults diagnosed with cancer. The definition of the most suitable therapy for an effective sedation in terminal cancer patients still represents one of the most challenging goals in medical practice. Due to their poor health, the correct dosing of drugs used for deep palliative sedation in terminal cancer patients, often already on polypharmacological therapy, can be extremely complicated, also considering possible drug-to-drug interactions that could lead to an increased risk of overdose and/or incongruous administration with fatal outcomes. The case of a terminal cancer patient is presented, focusing on the “adequacy” of administered therapy. Materials and Methods: A young male, affected by Ewing sarcoma, attending a palliative care at his own home, died soon after midazolam administration. Toxicological and histological analyses were performed on body fluids and organ fragments. Results and Discussion: Morphological reliefs evidenced a neoplastic mass, composed of lobulated tissue with a lardy, pinkish-gray consistency, extending from the pleural surface to the lung parenchyma, also present at the sacrum region (S1–S5), at the anterior mediastinum level, occupying the entire left pleural cavity, and infiltrating the ipsilateral lung. Metastatic lesions diffused to rachis and lumbar structures. The brain presented edema and congestion. Toxicological analyses evidenced blood midazolam concentrations in the range of 0.931–1.690 µg/mL, while morphine was between 0.266 and 0.909 µg/mL. Death was attributed to cardiorespiratory depression because of a synergic action between morphine and midazolam. The pharmacological interaction between midazolam and morphine is discussed considering the clinical situation of the patient. The opportunity to proceed with midazolam administration is discussed starting from guidelines recommendation. Finally, professional liability outlines are highlighted.

Synergistic Herb-Herb Interaction of the Antinociceptive and Anti-Inflammatory Effects of Syzygium aromaticum and Rosmarinus officinalis Combination

The use of alternative medicine to treat pain has been increased, and the combination of several medicinal plants for its relief is a common practice in traditional medicine. The present study is aimed at determining whether a combination of Syzygium aromaticum (S. aromaticum) and Rosmarinus officinalis L. (R. officinalis) potentiates their antinociceptive and anti-inflammatory effects. These effects were explored using the formalin and carrageenan assays in rats, respectively. Animals received local pretreatment with S. aromaticum oil or R. officinalis ethanolic extract (0.1–100 μg/paw) alone or combined in a 1 : 1 rate. Concentration-response curves were built to compare pharmacological responses after an individual administration of S. aromaticum, R. officinalis, or their combination. The pharmacological interaction was investigated by an isobolographic study using the EC50 of each component in a fixed 1 : 1 ratio. S. aromaticum and R. officinalis administered alone showed significant and concentration-dependent antinociceptive and anti-inflammatory effects, but R. officinalis was more potent than S. aromaticum in both the antinociceptive and anti-inflammatory effects (EC50 = 7.96 ± 0.6 μg/paw vs. EC50 = 41.6 ± 1.7 μg/paw; EC50 = 1.97 ± 0.3 μg/paw vs. EC50 = 26.9 ± 2.5 μg/paw, respectively). The isobolographic analysis of the combination of these species in a 1 : 1 ratio showed a synergistic interaction between S. aromaticum and R. officinalis since Zmix (experimental value) was lower than Zadd (theoretical value) for both the antinociceptive effect (Zmix = 0.45 ± 0.1 < Zadd = 24.8 ± 1.3) and the anti-inflammatory effect (Zmix = 5.2 ± 0.6 < Zadd = 14.4 ± 2.2), suggesting a potentiation for both pharmacological effects. These results prove evidence of the efficacy of mixture herb-herb used in folk medicine for pain therapy. It also emphasizes the requirement of pharmacological studies to explore the efficacy and safety of herb interactions.

mTOR-Inhibition and COVID-19 in Kidney Transplant Recipients: Focus on Pulmonary Fibrosis

Kidney transplant recipients are at high risk of developing severe COVID-19 due to the coexistence of several transplant-related comorbidities (e.g., cardiovascular disease, diabetes) and chronic immunosuppression. As a consequence, a large part of SARS-CoV-2 infected patients have been managed with a reduction of immunosuppression. The mTOR-I, together with antimetabolites, have been often discontinued in order to minimize the risk of pulmonary toxicity and to antagonize pharmacological interaction with antiviral/anti-inflammatory drugs. However, at our opinion, this therapeutic strategy, although justified in kidney transplant recipients with severe COVID-19, should be carefully evaluated in asymptomatic/paucisymptomatic patients in order to avoid the onset of acute allograft rejections, to potentially exploit the mTOR-I antiviral properties, to reduce proliferation of conventional T lymphocytes (which could mitigate the cytokine storm) and to preserve Treg growth/activity which could reduce the risk of progression to severe disease. In this review, we discuss the current literature regarding the therapeutic potential of mTOR-Is in kidney transplant recipients with COVID-19 with a focus on pulmonary fibrosis.

Antagonistic Interaction between Histone Deacetylase Inhibitor: Cambinol and Cisplatin—An Isobolographic Analysis in Breast Cancer In Vitro Models

Breast cancer (BC) is the leading cause of death in women all over the world. Currently, combined chemotherapy with two or more agents is considered a promising anti-cancer tool to achieve better therapeutic response and to reduce therapy-related side effects. In our study, we demonstrated an antagonistic effect of cytostatic agent-cisplatin (CDDP) and histone deacetylase inhibitor: cambinol (CAM) for breast cancer cell lines with different phenotypes: estrogen receptor positive (MCF7, T47D) and triple negative (MDA-MB-231, MDA-MB-468). The type of pharmacological interaction was assessed by an isobolographic analysis. Our results showed that both agents used separately induced cell apoptosis; however, applying them in combination ameliorated antiproliferative effect for all BC cell lines indicating antagonistic interaction. Cell cycle analysis showed that CAM abolished cell cycle arrest in S phase, which was induced by CDDP. Additionally, CAM increased cell proliferation compared to CDDP used alone. Our data indicate that CAM and CDDP used in combination produce antagonistic interaction, which could inhibit anti-cancer treatment efficacy, showing importance of preclinical testing.

Increasing the Effectiveness of Pharmacotherapy in Psychiatry by Using a Pharmacological Interaction Database

Recent studies have shown that the knowledge of pharmacological interaction databases in global psychiatry is negligible. The frequency of hospitalizations in the case of patients taking new psychoactive substances along with other drugs continues to increase, very often resulting in the need for polypharmacotherapy. The aim of our research was to make members of the worldwide psychiatric community aware of the need to use a pharmacological interaction database in their daily work. The study involved 2146 psychiatrists from around the world. Participants were primarily contacted through the LinkedIn Recruiter website. The surveyed psychiatrists answered 5 questions concerning case reports of patients taking new psychoactive substances along with other drugs. The questions were answered twice, i.e., before and after using the Medscape drug interaction database. The mean percentage of correct answers given by the group of psychiatrists who were studied separately in six individual continents turned out to be statistically significantly higher after using the pharmacological interaction database (p < 0.001). This also applies to providing correct answers separately, i.e., to each of the five questions asked concerning individual case reports (p < 0.001). Before using the drug interaction database, only 14.1% of psychiatrists stated that they knew and used this type of database (p < 0.001). In the second stage of the study, a statistically significant majority of subjects stated that they were interested in using the pharmacological interaction database from that moment on (p < 0.001) and expressed the opinion that it could be effective in everyday work (p < 0.001). Using a pharmacological interaction database in psychiatry can contribute to the effectiveness of pharmacotherapy.

Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together

Histone deacetylase inhibitors (HDIs) are promising anti-cancer agents that inhibit proliferation of many types of cancer cells including breast carcinoma (BC) cells. In the present study, we investigated the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two HDIs, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), in luminal-like BC cells. The type of drug–drug interaction between CDDP and HDIs was determined by isobolographic analysis. MCF7 cells were genetically modified to express differential levels of Notch1 activity. The cytotoxic effect of SAHA or VPA was higher on cells with decreased Notch1 activity and lower for cells with increased Notch1 activity than native BC cells. The isobolographic analysis demonstrated that combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive or additive with tendency toward synergism interactions. Therefore, treatment of CDDP with HDIs could be used to optimize a combined therapy based on CDDP against Notch1-altered luminal BC. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of luminal-type BC with altered Notch1 activity.

Evaluation of the Expression Profile of Irinotecan-Induced Diarrhea in Patients with Colorectal Cancer

Irinotecan (CPT-11) is widely used for the treatment of unresectable colorectal cancer in combination with fluoropyrimidines, such as 5-fluorouracil and S-1. Diarrhea is one of the adverse effects associated with CPT-11 and frequently reported by patients treated with CPT-11-containing regimens combined with oral fluoropyrimidines. However, the mechanisms involved in this process, as well as whether fluctuations in the frequency and differences in the onset time of diarrhea with each CPT-11-containing regimen are caused by drug interactions remain unclear. Therefore, we examined the incidence of diarrhea caused by each CPT-11-containing regimen in patients with colorectal cancer using data from the large voluntary reporting Japanese Adverse Drug Event Report (JADER) database. Firstly, we searched for suspected drugs related to the occurrence of diarrhea using reported odds ratio and calculated the signal score to assess drug–drug interactions. Subsequently, we conducted a time-to-onset analysis using Weibull distribution. The results showed that the combination of CPT-11 with S-1 increased the frequency of diarrhea due to a pharmacological interaction but delayed its onset. The present results may contribute to the appropriate management of drug-induced adverse effects by healthcare professionals.

Analgesic Interaction Between Morphine with Fentanyl In Experimental Murine Pain

Opioids are among the most effective pain relievers available, however multimodal antinociception between opioids, has not been extensively studied in diverse animal pain models.In this study the pharmacological interaction of morphine with fentanyl was evaluated in different murine pain models by means of isobolographic analysis. In control animals, morphine and fentanyl produced a dose-related antinociceptive action in the murine assays and the rank of potency was: formalin hind paw phase I > formalin phase II > tail flick. Coadministration of morphine with fentanyl, in a fixed relation 1:1 of their ED50, produces a dose response in all tests and the isobologram resulted in synergism. Fentanyl was more effective than morphine which could be explained according the suggestion that opioids could be acting through other targets, with different binding capacity thru the regulation or activation of non-opioid receptors. Co-administration of morphine with fentanyl induces synergism in all murine trials, confirming the antinociceptive capacity of both opioids which would constitute a promisory idea to multimodal treatment of pain.