Effects of Concurrent Administration of Spironolactone in Veterans with Metastatic Prostate Cancer Receiving Abiraterone: A Real-World Retrospective Study.

INTRODUCTION: Prostate cancer is the most common cancer in men in the United States with low survival rates once metastasized. Abiraterone is approved for use in castrate-sensitive and castrate-resistant prostate cancer and is used extensively in the Veterans Affairs (VA) healthcare system. Spironolactone, a diuretic used to treat heart failure, edema, ascites, and hypertension, may increase androgen levels and reduce effectiveness of abiraterone when used concurrently to treat prostate cancer patients. While previous case studies support this, no large epidemiology studies have been conducted. The current study utilizes the large, VA prostate cancer data core and evaluates the effect of concomitant spironolactone on efficacy of abiraterone treatment in metastatic prostate cancer patients. PATIENTS AND METHODS: The study selected 18,943 veterans with metastatic prostate cancer on abiraterone treatment. Of these, 581 patients (3.1%) were also on concomitant spironolactone. The concomitant treatment group, abiraterone + spironolactone, significantly differed from the abiraterone-only group in body mass index, prevalence rates of heart failure and liver disease, and being previously treated with docetaxel. A 1:1 propensity score matching method was used to balance sample sizes and baseline traits between the two treatment groups, abiraterone versus abiraterone + spironolactone. Kaplan-Meier curves and Cox proportional hazard model were used to compare 5-year overall survival and all-cause mortality outcomes, respectively, between the two groups. RESULTS: After propensity score matched, the abiraterone + spironolactone group was treated with abiraterone significantly longer than the abiraterone-only group (mean ± standard deviation days 549.0 ± 552.3 vs. 435.5 ± 474.1; p = 0.0002) and had a higher 5-year overall survival rate (44% vs. 37%; p = 0.0116). Veterans with metastatic prostate cancer treated with abiraterone + spironolactone also had a lower 5-year all-cause mortality compared to those only on abiraterone (hazard ratio 0.80, 95% confidence intervals 0.61-0.96; p = 0.012). CONCLUSION: This large VA observational study suggests that concomitant use of spironolactone does not compromise cancer control or survival of metastatic prostate cancer patients treated with abiraterone.

Buprenorphine deaths confirmed by toxicology reveal a low proportion of opioid agonist treatment before death in Finland.

We studied opioid agonist treatment (OAT) status before buprenorphine-related death in Finland, where buprenorphine is the principal OAT medicine and also the most misused opioid, through a retrospective population-based study using medico-legal cause-of-death investigation and OAT patient records. The study included all death cases (N = 570) between 2018 and 2020 with a buprenorphine or norbuprenorphine finding in post-mortem toxicology and with known drug misuse history or concomitant findings of illicit drugs. Of the deceased, 10% had received OAT in the year before death. Less than 1% of individuals < 25 years had received OAT, whereas the proportion in individuals ≥ 25 years was 13% (p < 0.001). There were significantly more females and more fatal poisonings (p < 0.001) among those < 25 years than among those ≥ 25 years. OAT medication at the time of death was sublingual buprenorphine-naloxone in 74% and subcutaneous buprenorphine in 23%. Except for significantly fewer benzodiazepine findings among those receiving OAT, minimal differences were found in terms of age, gender, cause and manner of death, or concomitant substance use between the deceased in and outside of OAT. Concomitant misuse of benzodiazepines, psychostimulants, alcohol, and gabapentinoids was frequent both in and outside of OAT and likely contributed to the death. These results suggest that access to OAT especially for young people and treatment of multiple addictions should be improved. Comprehensive information from medico-legal cause-of-death investigation as a starting point, combined with subsequent ante-mortem patient records, proved to be a successful approach to shed light on the Finnish scene of buprenorphine mortality.

POR overexpression induces tamoxifen-resistance in breast cancer through the STAT1/c-Myc pathway.

Breast cancer is the most common cancer in women worldwide. Although tamoxifen (TAM), a selective estrogen receptor (ER) modulator, is widely used to treat ER-positive breast cancers, resistance to TAM remains a major clinical problem. NADPH-dependent cytochrome P450 reductase (POR) is known to participate in drug metabolism and steroid metabolism. Recent studies showed that high POR expression was correlated with poor outcomes in triple-negative breast cancer (TNBC), and POR might be a prognostic biomarker in TNBC. However, the role of POR in TAM resistance is still elusive. In this study, we found that high POR expression was associated with poor prognosis of ER-positive and TAM-treated breast cancer patients. In addition, COX analysis showed that POR expression was an independent prognostic biomarker for ER-positive as well as TAM-treated breast cancer patients. Furthermore, our results suggested that POR overexpression promoted TAM resistance by activating the STAT1/c-Myc pathway in ER-positive breast cancer cells. Immunohistochemical analysis showed that high POR/STAT1 expression was correlated with poor prognosis in TAM-treated breast cancer patients. Notably, combined treatment with TAM and a specific STAT1 inhibitor Fludarabine was more effective for inhibiting TAM-resistant breast cancer cells. Altogether, our findings suggested that POR overexpression induced TAM resistance through STAT1/c-Myc pathway and might serve as an independent prognostic biomarker in TAM-treated breast cancer patients. Combining TAM and STAT1 inhibitors might be an effective strategy for treating POR-induced TAM-resistant breast cancer.

Risk Factors for Poor Pain Control after Opioid Switching from Oxycodone Tablet to Fentanyl Patch.

Pain control becomes poor in some cases after opioid switching from oxycodone tablet (OXC) to fentanyl patch (FP). However, fewer studies on risk factors have been reported. In this study, we surveyed the states of pain control (PC) and opioid administration, patient background, laboratory test values, and concomitant drugs retrospectively in 86 patients switching from OXC to FP between June 2010 and April 2018 in Mazda Hospital and Hiroshima Prefectural Hospital. The subjects were divided into 2 groups based on the median number of days to the initial dose increase after switching to FP. Between the early (<7.5 d) and late (≥7.5 d) increase groups, a significant difference was noted in the presence or absence of liver metastasis (LM), concomitant drugs with a high protein binding rate (CDHPBR), and the state of PC before and after switching to FP (p < 0.05). Binary logistic regression analysis showed the presence of CDHPBR, absence of LM, and poor PC after switching were risk factors for early dose increase (presence of CDHPBR: odds ratios (OR), 3.30, 95% confidence interval (CI), 1.09-9.98; presence of LM: OR, 0.31, 95% CI, 0.10-0.93; good PC: OR, 0.23, 95% CI, 0.07-0.79, respectively). The initial dose increase after switching to FP was earlier in patients with CDHPBR and/or without LM than those without CDHPBR and with LM (p < 0.05, log-rank test). It was suggested that the analgesic effect of FP after switching from OXC is likely to be insufficient in patients treated with CDHPBR and patients without LM.

Drug metabolism and drug interactions: potential application to antituberculosis drugs.

Drug-drug interaction is an important element of modern drug development. In the case of antituberculosis drugs, which are frequently administered as combinations of multiple therapeutic agents, the potential for interactions between coadministered drugs and between new and existing drugs should be considered during the development of new antituberculosis drugs and combination regimens. The current understanding of drug-drug interactions involving the first-line antituberculosis drugs is reviewed in this article, along with the approaches that are used to prospectively delineate potential interactions during development of new therapies. In addition, current knowledge gaps are identified, and future directions for enhancing the understanding of drug-drug interactions that will further facilitate the development of novel antituberculosis therapies are discussed.

Immuno-oncological effects of standard anticancer agents and commonly used concomitant drugs: an in vitro assessment.

BACKGROUND: It has become evident in the field of oncology that the outcome of medical treatment is influenced by the combined effect exerted on both cancer- and immune cells. Therefore, we evaluated potential immunological effects of 46 standard anticancer agents and 22 commonly administered concomitant non-cancer drugs. METHODS: We utilized a miniaturized in vitro model system comprised of fluorescently labeled human colon and lung cancer cell lines grown as monocultures and co-cultured with activated peripheral blood mononuclear cells (PBMCs). The Bliss Independence Model was then applied to detect antagonism and synergy between the drugs and activated immune cells. RESULTS: Among the standard anticancer agents, tyrosine kinase inhibitors (TKIs) stood out as the top inducers of both antagonism and synergy. Ruxolitinib and dasatinib emerged as the most notably antagonistic substances, exhibiting the lowest Bliss scores, whereas sorafenib was shown to synergize with activated PBMCs. Most concomitant drugs did not induce neither antagonism nor synergy. However, the statins mevastatin and simvastatin were uniquely shown to synergize with activated PBMC at all tested drug concentrations in the colon cancer model. CONCLUSION: We utilized a miniaturized tumor-immune model to enable time and cost-effective evaluation of a broad panel of drugs in an immuno-oncology setting in vitro. Using this approach, immunomodulatory effects exerted by TKIs and statins were identified.

Immune Checkpoint Inhibitors and Opioids in Patients with Solid Tumours: Is Their Association Safe? A Systematic Literature Review.

BACKGROUND: Immune checkpoint inhibitors (ICIs) represent one of the most effective treatments for patients with cancer. As their activity relies on host immune system reactivity, the role of concomitant medications such as corticosteroids and antibiotics has been extensively evaluated. Preclinical data suggest that opioids may influence the immune system. METHODS: a systematic literature revision was performed using specific keywords on the major search engines. Two authors analysed all the studies and provided a selection of the following inclusion and exclusion criteria, respectively: 1. data collection of patients older than 18 years old affected by solid tumours; 2. description of ICIs efficacy in terms of PFS, OS, TTF, and ORR; 3. concomitant ICIs-opioids treatment and 1. language different from English; 2. not pertinent analyses. RESULTS: 523 studies were analysed, and 13 were selected and included in our series. A possible negative interaction between oral opioids and ICIs efficacy was observed. Most evidence was retrospective, and studies were heterogeneous. CONCLUSIONS: Even if oral opioids seem to impact negatively on ICIs efficacy in cancer patients, to date there is not sufficient evidence to avoid their prescription in this population.

Incidence of Delirium With Different Oral Opioids in Previously Opioid-Naive Patients.

BACKGROUND: Opioids are known to induce delirium, but few studies have closely investigated differences in incidence of delirium among different opioids. OBJECTIVES: To determine whether there is a clinically significant difference in the incidence of delirium between oral opioids in previously opioid-naive patients. METHODS: Subjects were 259 opioid-naive in-patients with cancer who were started on morphine sulfate, oxycodone hydrochloride, or tapentadol hydrochloride extended-release tablets at our hospital between August 1, 2014, and September 30, 2018. The incidence of delirium during the first week of treatment was compared between the drugs. RESULTS: The incidence of delirium was 4.8% (n = 83) for morphine sulfate, 6.9% (n = 131) for oxycodone hydrochloride, and 6.7% (n = 45) for tapentadol hydrochloride. The incidence did not significantly differ between oxycodone hydrochloride (OR = .69, 95% CI = .20-2.30, P [Fisher's exact test] = .77) or tapentadol hydrochloride (OR = .71, 95% CI = .15-3.32, P [Fisher's exact test] = .70) and morphine sulfate (reference group). Moreover, the incidence did not significantly differ between tapentadol hydrochloride (OR = 1.03, 95% CI = .27-3.00, P [Fisher's exact test] = 1.00) and oxycodone hydrochloride (reference group). CONCLUSION: The incidence of delirium in previously opioid-naive patients did not differ significantly among morphine sulfate, oxycodone hydrochloride, and tapentadol hydrochloride extended-release tablets, suggesting similar risk of delirium in opioid-naive patients among these oral opioids.

Pneumatosis Intestinalis Induced by Alpha-Glucosidase Inhibitors in Patients with Diabetes Mellitus.

Alpha-glucosidase inhibitor (αGIs)-induced pneumatosis intestinalis (PI) has been narrated in case reports but never systematically investigated. This study aimed to investigate the concurrency of PI and αGIs. A literature search was performed in PubMed, Google Scholar, WorldCat, and the Directory of Open-Access Journals (DOAJ) by using the keywords "pneumatosis intestinalis", "alpha-glucosidase inhibitors", and "diabetes". In total, 29 cases of αGIs-induced PI in 28 articles were included. There were 11 men, 17 women, and one undefined sex, with a median age of 67. The most used αGI was voglibose (44.8%), followed by acarbose (41.4%) and miglitol (6.8%). Nine (31%) patients reported concomitant use of prednisone/prednisolone with or without immunosuppressants. The main symptoms were abdominal pain (54.5%) and distention (50%). The ascending colon (55.2%) and the ileum (34.5%) were the most affected. Nineteen (65.5%) patients had comorbidities. Patients with comorbidities had higher rates of air in body cavities, the portal vein, extraintestinal tissues, and the wall of the small intestine. Only one patient was found to have non-occlusive mesenteric ischemia. Twenty-five patients were treated with conservative therapy alone, and two patients received surgical intervention. All patients recovered. In conclusion, comorbidities, glucocorticoids, and immunosuppressants aggravate αGIs-induced PI. Conservative therapy is recommended when treating αGIs-induced PI.

Use of natural medicine and dietary supplements concomitant with conventional medicine among people with Multiple Sclerosis.

BACKGROUND: The use of complementary and alternative medicine (CAM) are widespread among people with Multiple Sclerosis (PwMS) and are often used concomitant with conventional treatment. Natural medicine and dietary supplements (NADS) are the most frequently used CAM modality and among other patient groups use of NADS concomitant with conventional medicine has been reported as a potential risk to patients' safety due to risk of drug interactions. The use of NADS concomitant with conventional medicine has, however, not been investigated among PwMS. This study's aim was to investigate the prevalence of NADS and conventional MS-related medicine use among PwMS, specific types of NADS and conventional MS-related medicine used, the prevalence of NADS used concomitant with conventional MS-related medicine, and to characterize PwMS who use NADS and PwMS who use NADS concomitant with conventional MS-related medicine in a Danish context. METHODS: The study was a cross-sectional study conducted as an interviewer-administered survey via phone in April 2019. The questionnaire includes questions about the use of NADS and conventional MS medicine as well as sociodemographic and health-related factors. In total 384 PwMS answered the questionnaire. Both descriptive and logistic analyses were used to analyze the data. RESULTS: The results show that the majority of PwMS use conventional MS-related medicine. In total, 85 % (n=322) had used at least one NADS within the last 12 months including vitamin D. When excluding vitamin D, the use of NADS within the last 12 months was 78.4% (n=298). Beside vitamin D the most reported types of NADS used were fatty acids (37%), Multivitamins (37%), and Calcium (35%). A total of 75.8% (n=288) reported using NADS concomitant with conventional MS medicine, and the products most often combined with conventional MS medicine were Vitamin D, Multivitamin, Calcium, Magnesium, and fatty acids. The results suggest that PwMS using NADS concomitant with conventional MS-related medicine are characterized by a high prevalence of young and newly diagnosed patients with a high education level. CONCLUSION: The study contributes to a better understanding of NADS used among PwMS. The study shows that the majority of PwMS use NADS and that they use it concomitant with conventional MS-medicine. Furthermore, the detailed mapping of the specific types of NADS used gives a nuanced insight into the specific products of NADS used among PwMS, including different kinds of vitamins, minerals, and herbal remedies.

Polypharmacy in patients with multiple sclerosis: a gender-specific analysis.

BACKGROUND: Multiple sclerosis (MS) affects about three times more women than men. Due to variable MS courses, multiple therapies are necessary in clinical practice. OBJECTIVE: We aimed at conducting sex-specific analyses of MS patients regarding polypharmacy (≥ 5 drugs) and at identifying differences in the medication spectrum. METHODS: Clinico-demographic data were gathered from 306 patients using clinical examinations, structured patient interviews, and patient records. Statistical data analyses were performed to evaluate whether the same or different factors are associated with polypharmacy in both genders. RESULTS: Women (N = 218) and men (N = 88) showed similar polypharmacy rates (56.0% vs. 58.0%; p = 0.799). For both genders, higher age, severe disability degrees, comorbidities, and inpatient treatment were significantly associated with a higher polypharmacy risk. Low educational levels were predictors of polypharmacy only in women. Fampridine (p < 0.021) and antispasmodics (p < 0.010) were used more often by men, while women took more frequently thyroid medications (p < 0.001) and contraceptives (p < 0.001). The age-related increase in medication use was much stronger in women (p < 0.001). CONCLUSION: Male and female MS patients with older age, comorbidities, higher disability degree, and inpatient treatment are at greater risk of polypharmacy. Future studies should examine the occurrence of clinically relevant drug interactions in MS patients stratified by sex.

Influence of CYP2D6, CYP3A5, ABCB1, APOE polymorphisms and nongenetic factors on donepezil treatment in patients with Alzheimer's disease and vascular dementia.

PURPOSE: This study aims to evaluate the influence of genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and APOE genes and nongenetic factors on steady-state plasma concentrations (Cpss) of donepezil and therapeutic outcomes in Thai patients with Alzheimer's disease (AD) and vascular dementia (VAD). PATIENTS AND METHODS: Eighty-five dementia patients who received donepezil for at least six months were recruited. CYP2D6, CYP3A5, ABCB1, and APOE polymorphisms were genotyped. Cpss of donepezil was measured. Association of genetic and non-genetic factors with Cpss and clinical outcomes of donepezil (cognitive function as measured by the Thai Mental State Examination score; TMSE) were determined by using univariate and multivariate analysis. RESULTS: Both univariate and multiple linear regression analysis indicated that only CYP2D6*10 allele was associated with higher Cpss (p-value =0.029 and B =0.478, p-value =0.032, respectively) that might influence the clinical outcomes of donepezil. ie, TMSE (p-value =0.010 and B =4.527, p-value =0.001) and ΔTMSE (p-value =0.023 and B =4.107, p-value =0.002), especially in patients with AD. Interestingly, concomitant use of memantine was found to be associated with increased Cpss of donepezil (p-value =0.007 and B =0.511, p-value =0.014). Whereas, co-medication with antidepressant drugs attenuated clinical responses in patients with AD (TMSE: B =-2.719, p-value =0.013 and ΔTMSE: B =-2.348, p-value =0.028). Age was a significant predictor of donepezil response in VAD patients. No significant association of CYP3A5*3, ABCB1 3435C>T or ABCB1 1236C>T, and APOE ε4 genotypes with Cpss or clinical outcomes of donepezil was found in this study. CONCLUSION: Our results suggests that CYP2D6*10 strongly influences Cpss and there is a trend toward better outcomes of donepezil in patients with AD. Nongenetic factors including concomitant drugs treatment might alter Cpss of donepezil or clinical outcomes.

Practice Patterns of Medications for Patients With Malignant Bowel Obstruction Using a Nationwide Claims Database and the Association Between Treatment Outcomes and Concomitant Use of H2-Blockers/Proton Pump Inhibitors and Corticosteroids With Octreotide.

CONTEXT: Malignant bowel obstruction impairs the quality of life in patients with advanced cancer. Octreotide, acid-suppressing medications such as H2-receptor antagonists (H2-blockers) and proton pump inhibitors (PPIs), and corticosteroids are often used in combination for symptom control. OBJECTIVES: We evaluated the practice patterns of medications for patients hospitalized with malignant bowel obstruction using a large claims database in Japan. In addition, we explored the association of adding H2-blockers/PPIs or corticosteroids to octreotide on treatment outcomes. METHODS: We analyzed data from a nationwide medical claims database from April 2010 to March 2015 containing 975,000 patients. We included all adult inpatients with cancer who used octreotide 300 µg/day or more and summarized each patient's medication use. We also assessed whether concomitant use of H2-blockers/PPIs or corticosteroids was associated with the number of days of nasogastric tube (NGT) insertion; logistic regression was used to adjust the patients' baseline factors. RESULTS: We included 3090 patients; octreotide alone was used in 1649 (53%) cases. A combination of octreotide and H2-blockers or PPIs was used in 419 and 337 cases (14% and 11%), respectively; a combination of octreotide and corticosteroids was used in 374 cases (12%). Of the 1595 patients who underwent NGT insertion, those using corticosteroids with octreotide had a higher odds ratio of NGT removal within four days of insertion (adjusted odds ratio = 1.16; 95% CI = 1.08-1.23). CONCLUSION: Octreotide alone was used in the majority of patients, and the concomitant use of corticosteroids was more likely to be associated with early NGT removal.

Potential drug-drug interactions in inpatients treated at the Internal Medicine ward of Tikur Anbessa Specialized Hospital.

PURPOSE: Although the concomitant use of multiple drugs often increases therapeutic effectiveness, certain combinations result in unwanted drug-drug interactions (DDIs). Most interactions go unnoticed by physicians due to the absence of new clinical signs and symptoms, and because they often produce a worsening of already existing symptoms. Quantification of the occurrence of the potential DDIs is essential to prevent the harmful effects associated with interactions. This study was launched to assess the prevalence of potential DDIs in the Internal Medicine ward of Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. PATIENTS AND METHODS: Cross-sectional data were gathered from the medical charts of 252 randomly selected patients who were admitted to the Internal Medicine ward during August 23 to October 23, 2013, and exposed to at least two concomitant drugs. Potential DDIs were identified using Medscape Drug Interaction Checker. The data were analyzed using SPSS software. Logistic regression analysis was used to determine the presence of association between variables and p-value <0.05 was considered statistically significant. RESULTS: At least one potential DDI was found in 78.2% of the patients. The mean number of potential interactions per patient was 3.7±3.4. Out of the 719 potential interactions identified, 49.8% were pharmacokinetic type, 44.6% were pharmacodynamic and the remaining 5.6% were unknown mechanisms. Major potential DDIs accounted for 13.1% of the whole interactions; 53.5% were moderate interactions; and the remaining 33.4% were minor interactions. Ceftriaxone, cimetidine and heparin were the three most involved drugs in major potential interactions. Prescription of five or more concomitant drugs was associated with high risk of encountering potential DDIs. CONCLUSION: The findings of this study showed that the prevalence of potential DDIs among inpatients was high. Pharmacists should closely review drugs prescribed for patients and avoid dispensing combinations of drugs that may have serious DDIs.

Effects of concomitant drugs on sitagliptin-mediated improvement in glycemic control in Japanese patients with type 2 diabetes.

AIMS: We investigated to clarify factors associated with the efficacy of sitagliptin, a dipeptidyl peptidase (DPP)-IV inhibitor, for glycemic control including the confounding effect of concomitant drugs in patients with type 2 diabetes. METHODS: We included type 2 diabetes patients with HbA1c levels of ≥7% who were not under insulin treatment and were administered sitagliptin (50mg/day for 6 months). Reduction or discontinuation of insulin sensitizers was not permitted during the study period. Outcomes included HbA1c level variations and attaining a target HbA1c level of <7%. Associated factors with each outcome were examined using multivariate analysis. RESULTS: Of the 313 patients enrolled in this study, 147 (47.0%) attained HbA1c levels of <7%. High baseline HbA1c levels were associated with HbA1c level variations but inversely associated with attaining the target HbA1c level of <7%. Concomitant use of an insulin sensitizer and a α-glucosidase inhibitor and maintenance of the baseline dose of concomitant drugs were significantly associated with each outcome. CONCLUSIONS: Our results suggest that concomitant sitagliptin administration (50mg/day) will improve glycemic control if treatment is initiated before HbA1c levels deteriorate. Other medication should be continued at initiation of sitagliptin administration.