Inn Med (Heidelb). 2023 Dec 18. doi: 10.1007/s00108-023-01634-7. Online ahead of print.

ABSTRACT

The prevalence for chronic kidney disease (CKD) has steadily increased over the past decades. It is a gradually progressive disease that is associated with several comorbidities including cardiovascular diseases, hypertension, anemia, disorders of bone and mineral metabolism, electrolyte imbalance and acid-base abnormalities. All these comorbidities require adequate medication. Therefore, patients with CKD have a high risk for polypharmacy, which is defined as five or more medications daily. Polypharmacy causes a greatly increased risk for adverse drug effects and severe drug-drug interactions, which if not closely controlled and the individual doses adapted to the decreased renal function during the progression of the CKD, can result in increased morbidity and mortality. Therefore, several aspects of the medication need to be considered and constantly addressed. This article summarizes the problems arising from inadequate polypharmacy in CKD patients, including undesired adverse drug effects, drug interactions, the complexity of medication plans, treatment burden and nonadherence to the treatment. Furthermore, the most important steps to identify patients with inadequate polypharmacy are discussed, whereby complications can also be avoided and the benefits of the medication can be increased. Finally, the polypharmacy in acute kidney injury is dealt with.

PMID:38110759 | DOI:10.1007/s00108-023-01634-7

Indian J Tuberc. 2023;70 Suppl 1:S76-S81. doi: 10.1016/j.ijtb.2023.07.004. Epub 2023 Jul 7.

ABSTRACT

OBJECTIVES: Subsequent to introduction of daily fixed dose combination (FDC) regimen with increased dosages and inclusion of ethambutol in continuation phase of antitubercular therapy (ATT) in India, this study was done to evaluate adverse drug reactions (ADRs) in children and adolescents.

METHODS: Longitudinal observational study conducted in tertiary teaching hospital. Children (1 month-18 year), with newly diagnosed drug sensitive tuberculosis, started on daily FDC regimen of ATT, were included. Participants were followed up at 2 weeks, 8 weeks and 6 months. Division of AIDS (DAIDS) severity grading and World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality assessment was done.

RESULTS: In 99 participants, 29 experienced ADRs. Most commonly ADRs involved hepatobiliary (11.1%) and gastrointestinal (8.1%) systems. Grade 3 severity noted in 35.5% ADRs. Certain causality classified in 19.3%. Presence of ADRs was significantly higher in participants with vs without malnutrition [40.5% vs 21.1% (p = 0.036)]. Tendency for more severe ADRs noted in participants with vs without malnutrition [Grade 3 ADRs out of all ADRs: 64.7% vs 0% (p < 0.001)].

CONCLUSION: Incidence and severity of ADRs has increased after introduction of daily FDC of ATT. Most common ADR observed were hepatobiliary. Malnutrition and less weight for age were risk factors for occurrence and severity of ADRs.

PMID:38110265 | DOI:10.1016/j.ijtb.2023.07.004

JAMA Netw Open. 2023 Dec 1;6(12):e2348057. doi: 10.1001/jamanetworkopen.2023.48057.

ABSTRACT

IMPORTANCE: Recent data suggest that local treatment with radical prostatectomy or radiation may improve survival outcomes in men with advanced prostate cancer. However, evidence is lacking on treatment-related adverse effects among men with advanced prostate cancer.

OBJECTIVE: To assess the association of local treatment on treatment-related adverse effects among men diagnosed with advanced prostate cancer.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study assessed men diagnosed with advanced prostate cancer (defined as T4, N1, and/or M1 prostate cancer) between January 1, 1999, and December 31, 2013, with follow-up through December 31, 2021, who were treated at Veterans Health Administration medical centers.

EXPOSURE: Local treatment with radical prostatectomy or radiation.

MAIN OUTCOMES AND MEASURES: Main outcomes were treatment-related adverse effects, including constitutional, gastrointestinal, pain, sexual function, and urinary function conditions, at 3 intervals after initial treatment (≤1 year, >1 to ≤2 years, and >2 to ≤5 years) after initial treatment.

RESULTS: This cohort study consisted of 5502 men (mean [SD] age, 68.7 [10.3] years) diagnosed with advanced prostate cancer. Of the cohort, 1705 men (31.0%) received local treatment. There was a high prevalence of adverse conditions in men receiving both local and nonlocal treatment, and these adverse conditions persisted for more than 2 years to 5 years or less after initial treatment. A total of 916 men (75.2%) with initial local treatment and 897 men (67.1%) with initial nonlocal treatment reported the presence of at least 1 adverse condition for more than 2 years to 5 years or less after initial treatment. In the first year, local treatment (vs nonlocal) was associated with adverse gastrointestinal (multivariable-adjusted odds ratio [AOR], 4.08; 95% CI, 3.06-5.45), pain (AOR, 1.57; 95% CI, 1.35-1.83), sexual (AOR, 2.96; 95% CI, 2.42-3.62), and urinary (AOR, 2.25; 95% CI, 1.90-2.66) conditions. Local treatment (without secondary treatment) remained significantly associated with adverse gastrointestinal (AOR, 2.39; 95% CI, 1.52-3.77), sexual (AOR, 3.36; 95% CI, 2.56-4.41), and urinary (AOR, 1.39; 95% CI, 1.09-1.78) conditions at more than 2 years to 5 years or less after treatment.

CONCLUSIONS AND RELEVANCE: In this cohort study of men with advanced prostate cancer, local treatment was associated with persistent treatment-related adverse effects across multiple domains. These results suggest that patients and clinicians should consider the adverse effects of local treatment when making treatment decisions in the setting of advanced prostate cancer.

PMID:38109113 | DOI:10.1001/jamanetworkopen.2023.48057

Acta Psychiatr Scand. 2023 Dec 18. doi: 10.1111/acps.13643. Online ahead of print.

ABSTRACT

OBJECTIVE: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals.

METHOD: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events.

RESULTS: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes.

CONCLUSION: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy.

PMID:38110225 | DOI:10.1111/acps.13643

Clin Gastroenterol Hepatol. 2023 Dec 16:S1542-3565(23)01037-6. doi: 10.1016/j.cgh.2023.12.008. Online ahead of print.

NO ABSTRACT

PMID:38110061 | DOI:10.1016/j.cgh.2023.12.008

Small. 2023 Dec 18:e2306482. doi: 10.1002/smll.202306482. Online ahead of print.

ABSTRACT

Inflammatory bowel disease (IBD) has become a globally prevalent chronic disease with no causal therapeutic options. Targeted drug delivery systems with selectivity for inflamed areas in the gastrointestinal tract promise to reduce severe drug-related side effects. By creating three distinct nanostructures (vesicles, spherical, and wormlike micelles) from the same amphiphilic block copolymer poly(butyl acrylate)-block-poly(ethylene oxide) (PBA-b-PEO), the effect of nanoparticle shape on human mucosal penetration is systematically identified. An Ussing chamber technique is established to perform the ex vivo experiments on human colonic biopsies, demonstrating that the shape of polymeric nanostructures represents a rarely addressed key to tissue selectivity required for efficient IBD treatment. Wormlike micelles specifically enter inflamed mucosa from patients with IBD, but no significant uptake is observed in healthy tissue. Spheres (≈25 nm) and vesicles (≈120 nm) enter either both normal and inflamed tissue types or do not penetrate any tissue. According to quantitative image analysis, the wormlike nanoparticles localize mainly within immune cells, facilitating specific targeting, which is crucial for further increasing the efficacy of IBD treatment. These findings therefore demonstrate the untapped potential of wormlike nanoparticles not only to selectively target the inflamed human mucosa, but also to target key pro-inflammatory cells.

PMID:38109123 | DOI:10.1002/smll.202306482

J Med Life. 2023 Sep;16(9):1415-1420. doi: 10.25122/jml-2023-0101.

ABSTRACT

Polypharmacy, often defined as the concurrent use of five or more medications, has become increasingly common due to various factors, including shifts in lifestyle and a rise in health-related issues among individuals. However, using multiple medications could bring more issues to the patient, as it is linked to poor health outcomes, including medication nonadherence, adverse pharmacological effects, and decreased quality of life (QoL). This study aimed to determine the prevalence of polypharmacy and identify drug-related problems among adult patients in Al-Ahsa. A cross-sectional study was conducted among adult patients living in Al-Ahsa, Saudi Arabia, taking five or more medications. A self-administered questionnaire was distributed among the target population using an online survey. The questionnaire included sociodemographic data (i.e., age, sex, education, etc.), a questionnaire to assess behaviors regarding the use of polypharmacy, and a 10-item questionnaire to measure medication-related quality of life (MRQoL). In total, 196 of the 1,088 patients surveyed took five or more medications, indicating an 18% prevalence of polypharmacy. Among the 196 patients, 26.5% reported poor medication-related QoL. In univariate analysis, sex, occupational status, average monthly income, hypertension, asthma, difficulty managing medications, and side effects experienced were significantly associated with MRQoL. Independent significant predictors of poor MRQoL were having asthma and difficulty managing medications. The prevalence of poor medication-related quality of life among adult patients in our region was 26.5%, lower than that in previous studies. Poor MRQoL was associated with lower monthly income, hypertension, asthma, side effects, and difficulty managing medications.

PMID:38107723 | PMC:PMC10719800 | DOI:10.25122/jml-2023-0101

Chem Biol Interact. 2023 Dec 15:110838. doi: 10.1016/j.cbi.2023.110838. Online ahead of print.

ABSTRACT

Drug-induced nephrotoxicity is still a significant obstacle in pharmacotherapy of various diseases and it accounts for around 25 % of serious side-effects reported after drug administration. Furthermore, some groups of drugs such as nonsteroidal anti-inflammatory drugs, antibiotics, antiviral drugs, antifungal drugs, immunosuppressants, and chemotherapeutic drugs have the "preference" for damaging the kidney and are often referred to as the kidney's "silent killer". Clinically, the onset of acute kidney injury associated with drug administration is registered in approximately 20 % of patients and many of them develop chronic kidney disease vulnerability. However, current knowledge about the mechanisms underlying this dangerous phenomenon is still insufficient with many unknowns. Hence, the valuable use of these drugs in clinical practice is significantly limited. The main aim of this study is to draw attention to commonly prescribed nephrotoxic drugs by clinicians or drugs bought over the counter. In addition, the complex relationship between immunological, vascular and inflammatory events that promote kidney damage is discussed. The practical use of this knowledge could be implemented in the engineering of novel biomarkers for early detection of drug-associated kidney damage such as Kidney Injury Molecule (KIM-1), lipocalin associated with neutrophil gelatinase (NGAL) and various microRNAs. In addition, the utilization of artificial intelligence (AI) for the development of computer algorithms that could detect kidney damage at an early stage should be further explored. Therefore, this comprehensive review provides a new outlook on drug nephrotoxicity that opens the door for further clinical research of novel potential drugs or natural products for the prevention of drug-induced nephrotoxicity and accessible education.

PMID:38104745 | DOI:10.1016/j.cbi.2023.110838

BMC Cancer. 2023 Dec 15;23(1):1239. doi: 10.1186/s12885-023-11735-z.

ABSTRACT

BACKGROUND: Novel ADC drugs provide a new therapeutic strategy for gastric cancer.The present study aimed to analyze the clinical efficacy and drug toxicities of disitamab vedotin (RC48) plus immune checkpoint inhibitors(ICIs) and RC48 as third-line therapies and beyond for advanced and metastatic gastric cancer patients.

METHODS: This was an observational multicenter real-world study.From August 2021 to January 2022,patients with HER2-positive or HER2-low advanced and metastatic gastric cancer and failed from two or more lines of prior therapy were enrolled and treated with RC48 plus ICIs or RC48. In this study, progression free survival(PFS) was the primary end point. Other evaluation indicators were objective response rate(ORR),disease control rate(DCR),overall survival(OS) and drug toxicities.

RESULTS: 45 patients were enrolled,of which 25 patients received RC48 plus ICIs,20 patients received RC48.Patients who received RC48 plus ICIs obtained better ORR (36.0% vs. 10.0%, P = 0.044) and DCR (80.0% vs. 50.0%, P = 0.034) compared with RC48,and simultaneously,the median PFS in RC48 plus ICIs group were superior to RC48 group(6.2 m vs. 3.9 m).The median OS was not reached.No statistically differences were found between HER2-positive and HER2-low group with respect to ORR (27.3% vs. 16.7%, P = 0.464),DCR (66.7% vs. 66.7%, P = 1.000),median PFS(5.7 m vs. 4.3 m, P = 0.299).The most common adverse events (AEs) were decreased white blood count,decreased neutrophil count,fatigue,hypoaesthesia and alopecia.Grade 3-4 AEs occurred in 7(35.0%) patients of RC48 group and 10(40.0%) patients of RC48 plus ICIs group,respectively.

CONCLUSION: Compared with RC48 monotherapy, ICIs plus RC48 demonstrated superior third-line and beyond therapeutic efficacy for HER2-positive or HER2-low advanced and metastatic gastric cancer patients with manageable safety.

PMID:38102538 | PMC:PMC10724908 | DOI:10.1186/s12885-023-11735-z

PLoS One. 2023 Dec 15;18(12):e0291650. doi: 10.1371/journal.pone.0291650. eCollection 2023.

ABSTRACT

BACKGROUND: Healthcare workers (HCWs) are at high risk of experiencing work-related stress, burnout syndrome, and depression, especially during infectious disease outbreaks like COVID-19. Contributing factors include increased workload, lack of personal protective equipment, and inadequate support from the healthcare administration. Longitudinal studies have shown that the mental health status of HCWs has deteriorated over time. Social support and compassion satisfaction (CS) are protective factors that can mitigate adverse mental health effects. The present longitudinal study examined the mental health status of HCWs during the COVID-19 outbreak and aimed to identify potential predictors and protective factors.

METHODS: The study comprised 386 healthcare workers in Hungary and was conducted in two waves (T1 and T2) from January 2021 to January 2022. Participants completed an online survey including the Professional Quality of Life Scale, Maslach Burnout Inventory, demographic and work-related background factors. Statistical analyses included descriptive statistics, and a cross-lagged panel model (CLPM).

RESULTS: Frontline HCWs had higher levels of secondary traumatic stress (STS) and emotional exhaustion (EE) than non-frontline healthcare workers. Both groups experienced significant increases in these measures between T1 and T2. The CLPM indicated that EE had a significant lagged effect on STS among frontline workers, while STS had a significant lagged effect on EE among non-frontline workers. CS had a significant protective effect on both STS and EE in both groups.

CONCLUSIONS: The findings suggest that CS protects EE and STS, particularly among frontline HCWs. The study also showed that different causative relationships exist between these factors among frontline and non-frontline HCWs, which underlines the possible cyclical relationship between the two depending on the circumstances. The results provide insights into the protective role of positive work experiences and the importance of considering the needs of both frontline and non-frontline HCWs in preventive intervention programs.

PMID:38100495 | PMC:PMC10723657 | DOI:10.1371/journal.pone.0291650

Front Endocrinol (Lausanne). 2023 Nov 30;14:1267338. doi: 10.3389/fendo.2023.1267338. eCollection 2023.

ABSTRACT

BACKGROUND: Gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP) are the predominant pregnancy complications among singleton and twin pregnancies worldwide. Our primary objective was to explore the adverse effect of GDM and HDP on maternal-perinatal outcomes compared with non-GDM and non-HDP in singleton and twin pregnancies. The secondary objective was to find the risk of adverse maternal-perinatal outcomes in twin pregnancies compared with singleton pregnancies complicated with GDM and HDP in Hubei, China.

METHODS: A tertiary hospital-based retrospective study was conducted at Wuhan University Renmin Hospital, Hubei Province, China, from 2011 to 2019. A chi-square test was used to determine the difference in adverse maternal-perinatal outcomes between singleton and twin pregnancies. A multiple binary logistic regression model and a joinpoint regression model were used to determine the association of GDM and HDP with adverse maternal-perinatal outcomes and GDM and HDP temporal trend among singleton and twin pregnancies.

RESULTS: The trend of HDP [average annual percentage change (AAPC) 15.1% (95% confidence interval (95%CI): 5.3, 25.7)] among singleton pregnancies and GDM [AAPC 50.4% (95%CI: 19.9, 88.7)] among twin pregnancies significantly increased from 2011 to 2019. After adjusting for confounding factors, GDM is associated with an increased risk of C-section (adjusted odds ratio (aOR), 1.5; 95%CI: 1.3, 1.6) and macrosomia (aOR, 1.3; 95%CI: 1.1, 1.6) in singleton and preterm birth (PTB) (aOR, 2.1; 95%CI: 1.2, 3.3) in twin pregnancies compared with non-GDM. HDP was associated with a higher risk of C-section, PTB, perinatal mortality, and low birth weight (LBW) in both singleton and twin pregnancies compared with the non-HDP. Compared with singleton pregnancies complicated with GDM and HDP, twin pregnancies showed higher odds of C-section [(aOR, 1.7; 95%CI: 1.1, 2.7), (aOR, 4.6; 95%CI: 2.5, 8.7), respectively], PTB [(aOR, 22.9; 95%CI: 14.1, 37.3), (aOR, 8.1; 95%CI: 5.3, 12.3), respectively], LBW [(aOR, 12.1; 95%CI: 8.2, 18.1), (aOR, 5.1; 95%CI: 3.6, 7.4), respectively], and low Apgar score [(aOR, 8.2; 95%CI: 4.4, 15.1), (aOR, 3.8; 95%CI: 2.4, 5.8), respectively] complicated with GDM and HDP.

CONCLUSION: In conclusion, GDM showed an increased risk of a few adverse maternal-perinatal outcomes and HDP is associated with a higher risk of several adverse maternal-perinatal outcomes in singleton and twin pregnancies compared to non-GDM and non-HDP. Moreover, twin pregnancies complicated with GDM and HDP showed higher odds of adverse maternal-neonatal outcomes compared with singleton pregnancies complicated with GDM and HDP.

PMID:38098860 | PMC:PMC10720659 | DOI:10.3389/fendo.2023.1267338

Semin Liver Dis. 2023 Nov;43(4):402-417. doi: 10.1055/s-0043-1776761. Epub 2023 Dec 15.

ABSTRACT

In recent years cancer treatment has been revolutionized by the development and wide application of checkpoint inhibitor (CPI) drugs, which are a form of immunotherapy. CPI treatment is associated with immune-related adverse events, off-target tissue destructive inflammatory complications, which may affect a range of organs, with liver inflammation (hepatitis) being one of the more commonly noted events. This is a novel form of drug-induced liver injury and a rapidly evolving field, as our understanding of both the basic immunopathology of CPI hepatitis (CPI-H) and optimal clinical management, races to catch up with the increasing application of this form of immunotherapy in clinical practice. In this review, we summarize current evidence and understanding of CPI-H, from fundamental immunology to practical patient management.

PMID:38101418 | DOI:10.1055/s-0043-1776761

Georgian Med News. 2023 Oct;(343):172-178.

ABSTRACT

Drug-induced Nitrosogenesis/Carcinogenesis turns out to be a ubiquitous, pervasive, large-scale, poorly controllable concept for the academic community, which underlies the long-term, permanent modification of the human genome by contact with nitrosamines/NDSRIs, which ultimately leads to the generation of diverse cancers, but also melanoma in particular. The discovery of a (currently) unclassifiable number of nitroso derivatives/genome modifiers in the most commonly distributed drugs worldwide (in about 300 preparations according to the FDA/includes beta blockers/bisoprolol/nebivolol and ACE inhibitors/perindopril), their forced tolerability, attributed as a necessity or lack of alternative also to the present (but also to future periods), and their proven carcinogenicity (already 70 years ago), suggest a kind of creepy form of experiment to which public health is subjected worldwide. The creation of a universal nitroso-comfort of pharmaceutical companies and the regulation of a permanent intake of carcinogens in drugs for years to come, but also decades back, suggest possible cartel agreements between the regulation/distribution unit and that of production cycles. These "agreements" are becoming increasingly evident and in all likelihood position nitrosogenesis from a until recently unknown element, to a pathogenetic factor of paramount importance. Melanoma could be viewed precisely as the controlled end gene-modified product of drug-mediated nitrosogenesis/carcinogenesis, proven to be a locoregional (but not only) phenomenon hundreds if not thousands of times. The dilemma stays: Are the nitrosamines in drugs genetic weapons, ethnic bioweapons for silent war ? The nitrosogenesis concerning melanoma leads to the logical conclusion that cancer is in fact a largely controlled set event or, according to others, a forced necessity of evolutionary globalization processes to purge the population in certain regions. In favor of this statement indicative are namely: 1) lack of regulatory control/results of such conducted, 2) complete information veil for the end user regarding contamination with carcinogens/nitrosamines in certain batches or all batches of drugs, 3) misinformation and lack of transparency regarding the concept of nitrosogenesis also for the academic community, as well as 4) the impunity to pharmaceutical conglomerates after criminal negligence/controlled criminogenicity proven thousands of times by the FDA/EMA leading to regulatory controlled drug mediated genocide of the human population in certain areas on a daily basis. And most important of all: 5) the lack of refusal to eliminate these drugs, i.e. - the imposition of forced tolerance at any cost. It is extremely unfortunate that the mentioned and identified grotesque/situation, its tolerance on a global scale, lead to a misjudgement of the significance of real tumor inducers within the global health map//statistics as well as melanoma. The focus of prevention is being displaced, while the incidence of cancer in general and that of melanoma is skyrocketing. Nitrosamines could be defined as the newest, modern, until recently invisible and unknown, but -controllable form of genetic weapon to modify the human genome. Because of these very facts, the likelihood that clinicians and the academic community are in the frozen and permanent state of the Dunning-Kruger effect is very real. Certain globalization regulatory elements create problems and assignments that must be solved ˝competently˝ by incompetent, fully regulatable compartments. As their state of competence depends again and entirely on ˝their incompetence˝. Until now. After the formalization of the concept of Nitrosogenesis (as a form of genetic weapon) and melanoma for example, but not only, it remains to be seen whether universal incompetence will become a guarantee of competence and the survival. Or- will it remain again at the level of globalized, criminally conditioned, appointed and regulated from above "competent incompetence". The dilemmas to regulators and manufacturers remain open : Is it competent to take drugs that contain carcinogens/nitrosamines? Is it competent for this issue to continue for decades with impunity? Is it competent for regulators not to inform consumers about the presence of carcinogens/genome modifiers in medicines for decades? Is it competent for certain regions to be affected by nitrosamine contamination and not others? Is it competent not to reflect this in regional and global health bulletins on side effects? Is it competent to make thousands of times the profits from the modified genetic map business, regulated and legally initiated through the intake of carcinogens? Is it competent to have the concentration of carcinogens within polymedication exceeding many times the daily allowable doses of carcinogens and have no solution for this? Is it competent, when the intake of nitrosamines in medicines is associated with the generation of melanomas and heterogeneous cancers- to have no alternative to this or when one is available- to conceal it skillfully? Is it competent to determine carcinogenic activity based on mutagenic tests? Is it competent to be polyincompetent within a framework of mass (in)competence? We report systemically administered drugs for the treatment of high blood pressure from the group of beta blockers (bisoprolol/nebivolol) and ACE inhibitors (perindopril) that have been identified by regulators in the face of FDA as hypothetically contaminated with nitrosamines/NDSRIs with a carcinogenic potency between 4 and 5, respectively. Within this cumulative intake, (which according to the regulators was not at risk of developing cancerous forms), similar to other cases in the world literature, the patient developed a relatively short-term, metastatic nevus spilus-based nodular melanoma. The paper analyses not only the role of nitrosogenesis, but also that of two pregnancies and painful sunburns as potential cofactors for melanoma genesis. Academic attention is drawn to the potential impact of drug-mediated nitrosogenesis/carcinogenesis. Nitrosamines in the framework of polycontamination and polymedication could also be identified as one of the most effective, until recently unknown, modern generation genetic weapons for modifying the human genome and controlling cancer. Moreover, they could be controllably applied and skillfully targeted. At least until now. The officialization of carcinogens in more than 250 of the most common drugs and the clinico-pathological correlations concerning the development of cancer/melanoma in poorly controlled geographical regions represent a kind of in vivo prospective study to determine precisely the real carcinogenic role of nitrosamines to date.

PMID:38096536

BMC Geriatr. 2023 Dec 13;23(1):849. doi: 10.1186/s12877-023-04557-y.

ABSTRACT

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk of drug-related problems (DRPs) because of extensive comorbidities and pharmacokinetic changes. This study aimed to identify DRPs and possible contributing factors in hospitalized patients with CKD, and evaluate the efficacy of the clinical pharmacist services in detection and intervention of DRPs in a large general hospital in Zhejiang Province, eastern China.

METHODS: With the approval of the Ethics Committee, patients with CKD admitted to the nephrology ward from January to December 2020 were enrolled in this prospective study. The clinical pharmacist identified and intervened the DRPs during hospitalization. The DRPs were classified using the Pharmaceutical Care Network Europe (PCNE) DRP classification system, and all data were statistically analyzed using Statistical Package for Social Science (SPSS) version 26.0.

RESULTS: A total of 914 patients with CKD were included, with 463 DRPs observed among 420 (45.95%) participants; the average DRP per patient was 0.51 (standard deviation [SD], 0.60) before pharmacist intervention. Treatment safety accounted for the highest proportion of problems (43.84%), followed by treatment efficacy, accounting for 43.20%. Drug selection was the most common cause of DRPs (60.26%), and antibiotics and cardiovascular agents were the most common drugs associated with DRPs (32.84% and 28.66%, respectively). A total of 85.53% of pharmaceutical intervention recommendations were followed, and 84.23% of DRPs were completely resolved after intervention by the clinical pharmacist. The proportion of patients who experienced DRPs decreased to 7.77%, with an average of 0.08 (SD 0.28) DRPs during hospitalization after pharmacist's intervention. Significant contributing factors for DRPs were CKD stage 4, number of comorbid diseases, number of prescribed medications, and hospitalization days in both the univariate and multivariate logistic regression models.

CONCLUSION: DRPs are common among hospitalized patients with CKD in China. CKD stage 4, the number of comorbidities, use of multiple prescription drugs, and extended length of hospital stay are contributing factors for DRPs. Even only one clinical nephrology pharmacist in the nephrology ward, clinical pharmacist can play an important role in facilitating the identification of DRPs in patients with CKD and assisting physicians resolve DRPs in this single center study in China.

PMID:38093184 | PMC:PMC10717358 | DOI:10.1186/s12877-023-04557-y

Ann Oncol. 2023 Dec 11:S0923-7534(23)05108-6. doi: 10.1016/j.annonc.2023.12.001. Online ahead of print.

ABSTRACT

BACKGROUND: Primary analysis of the multicenter, open-label, single-arm, phase 2 DESTINY-Breast01 trial (median follow-up, 11.1 months) demonstrated durable antitumor activity with trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab emtansine (T-DM1). We report updated cumulative survival outcomes with median follow-up of 26.5 months (data cutoff, March 26, 2021).

PATIENTS AND METHODS: Patients with HER2-positive mBC resistant or refractory to T-DM1 received T-DXd 5.4 mg/kg intravenously every 3 weeks until disease progression, unacceptable adverse events, or withdrawal of consent. The primary end point was confirmed objective response rate by independent central review. Secondary end points included overall survival, duration of response, progression-free survival, and safety.

RESULTS: The objective response rate by independent central review was 62.0% (95% CI, 54.5-69.0) in patients who received T-DXd 5.4 mg/kg every 3 weeks (n = 184). Median overall survival was 29.1 months (95% CI, 24.6-36.1). Median progression-free survival and duration of response were 19.4 months (95% CI, 14.1-25.0) and 18.2 months (95% CI, 15.0 months-not evaluable), respectively. Drug-related treatment-emergent adverse events (TEAEs) were observed in 183 patients (99.5%), and 99 patients (53.8%) had 1 or more grade ≥ 3 TEAEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 15.8% of patients (n = 29), of which 2.7% (n = 5) were grade 5.

CONCLUSIONS: These updated results provide further evidence of sustained antitumor activity of T-DXd with a consistent safety profile in heavily pretreated patients with HER2-positive mBC.

CLINICALTRIALS: GOV: NCT03248492.

PMID:38092229 | DOI:10.1016/j.annonc.2023.12.001

Lancet Oncol. 2023 Dec 7:S1470-2045(23)00589-2. doi: 10.1016/S1470-2045(23)00589-2. Online ahead of print.

ABSTRACT

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients.

METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing.

FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state.

INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population.

FUNDING: Dizal Pharmaceutical.

PMID:38092009 | DOI:10.1016/S1470-2045(23)00589-2

JAAD Case Rep. 2023 Oct 14;42:91-94. doi: 10.1016/j.jdcr.2023.09.027. eCollection 2023 Dec.

NO ABSTRACT

PMID:38090663 | PMC:PMC10711113 | DOI:10.1016/j.jdcr.2023.09.027

Bull Cancer. 2023 Dec 11:S0007-4551(23)00441-1. doi: 10.1016/j.bulcan.2023.10.010. Online ahead of print.

ABSTRACT

The treatment of chronic myeloid leukemia relies on orally available tyrosine kinase inhibitors targeting the BCR::ABL1 oncoprotein. Bosutinib is a second generation adenosine triphosphate-competitive inhibitor approved for use in frontline adult chronic phase-chronic myeloid leukemia and all phases-chronic myeloid leukemia in the second line setting or beyond. Its efficacy was demonstrated in several pivotal clinical trials at 400mg once daily in the first line context and at 500mg once daily beyond first line. Bosutinib-related adverse events frequently occur early after treatment initiation and include gastro-intestinal symptoms and cytolytic hepatitis. These drug-related adverse events must be properly managed in order to preserve safety, efficacy and treatment acceptability. The French chronic myeloid leukemia study group gathered a panel of experts in hematology, pharmacology and hepatology in order to elaborate practical recommendations on the management of bosutinib treatment. These recommendations aim at optimizing the short and long-term tolerance and benefit/risk balance of bosutinib, mainly focusing at gastro-intestinal and liver toxicities.

PMID:38087729 | DOI:10.1016/j.bulcan.2023.10.010

Sci Rep. 2023 Dec 12;13(1):22013. doi: 10.1038/s41598-023-49443-0.

ABSTRACT

Adverse drug reactions (ADRs) are considered an inherent risk of medication use, and some ADRs have been associated with off-target drug interactions with mitochondria. Metabolites that reflect mitochondrial function may help identify patients at risk of mitochondrial toxicity. We employed a database strategy to identify candidate mitochondrial metabolites that could be clinically useful to identify individuals at increased risk of mitochondrial-related ADRs. This led to L-carnitine being identified as the candidate mitochondrial metabolite. L-carnitine, its acetylated metabolite, acetylcarnitine and other acylcarnitines are mitochondrial biomarkers used to detect inborn errors of metabolism. We hypothesized that changes in L-carnitine disposition, induced by a "challenge test" of intravenous L-carnitine, could identify mitochondrial-related ADRs by provoking variation in L-carnitine and/or acetylcarnitine blood levels. To test this hypothesis, we induced mitochondrial drug toxicity with clofazimine (CFZ) in a mouse model. Following CFZ treatment, mice received an L-carnitine "challenge test". CFZ-induced changes in weight were consistent with previous work and reflect CFZ-induced catabolism. L-carnitine induced differences in whole blood acetylcarnitine concentrations in a manner that was dependent on CFZ treatment. This supports the usefulness of a database strategy for the discovery of candidate metabolite biomarkers of drug toxicity and substantiates the potential of the L-carnitine "challenge test" as a "probe" to identify drug-related toxicological manifestations.

PMID:38086883 | PMC:PMC10716408 | DOI:10.1038/s41598-023-49443-0

J Pak Med Assoc. 2023 Dec;73(12):2524-2525. doi: 10.47391/JPMA.9763.

NO ABSTRACT

PMID:38083958 | DOI:10.47391/JPMA.9763