Front Psychiatry. 2023 Nov 23;14:1271152. doi: 10.3389/fpsyt.2023.1271152. eCollection 2023.

ABSTRACT

Psychedelic therapy is, arguably, the next frontier in psychiatry. It offers a radical alternative to longstanding, mainstays of treatment, while exciting a paradigm shift in translational science and drug discovery. There is particular interest in 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)-a serotonergic psychedelic-as a novel, fast-acting therapeutic. Yet, few studies have directly examined 5-MeO-DMT for trauma- or stress-related psychopathology, including post-traumatic stress disorder (PTSD). Herein, we present the first longitudinal case study on 5-MeO-DMT for chronic refractory PTSD, in a 23-year-old female. A single dose of vaporized bufotoxin of the Sonoran Desert Toad (Incilius alvarius), containing an estimated 10-15 mg of 5-MeO-DMT, led to clinically significant improvements in PTSD, with next-day effects. This was accompanied by marked reductions in hopelessness and related suicide risk. Improvements, across all constructs, were sustained at 1-, 3-, 6-, and 12-months follow-up, as monitored by a supporting clinician. The subject further endorsed a complete mystical experience, hypothesized to underly 5-MeO-DMT's therapeutic activity. No drug-related, serious adverse events occurred. Together, results showed that 5-MeO-DMT was generally tolerable, safe to administer, and effective for PTSD; however, this was not without risk. The subject reported acute nausea, overwhelming subjective effects, and late onset of night terrors. Further research is warranted to replicate and extend these findings, which are inherently limited, non-generalizable, and rely on methods not clinically accepted.

PMID:38076677 | PMC:PMC10710141 | DOI:10.3389/fpsyt.2023.1271152

Lancet Reg Health Am. 2023 Nov 24;28:100641. doi: 10.1016/j.lana.2023.100641. eCollection 2023 Dec.

ABSTRACT

BACKGROUND: Hypoglycaemia from diabetes treatment causes morbidity and lower quality of life, and prevention should be routinely addressed in clinical visits.

METHODS: This mixed methods study evaluated how primary care providers (PCPs) assess for and prevent hypoglycaemia by analyzing audio-recorded visits from five Veterans Affairs medical centres in the US. Two investigators independently coded visit dialogue to classify discussions of hypoglycaemia history, anticipatory guidance, and adjustments to hypoglycaemia-causing medications according to diabetes guidelines.

FINDINGS: There were 242 patients (one PCP visit per patient) and 49 PCPs. Two thirds of patients were treated with insulin and 40% with sulfonylureas. Hypoglycaemia history was discussed in 78/242 visits (32%). PCPs provided hypoglycaemia anticipatory guidance in 50 visits (21%) that focused on holding diabetes medications while fasting and carrying glucose tabs; avoiding driving and glucagon were not discussed. Hypoglycaemia-causing medications were de-intensified or adjusted more often (p < 0.001) when the patient reported a history of hypoglycaemia (15/51 visits, 29%) than when the patient reported no hypoglycaemia or it was not discussed (6/191 visits, 3%). Haemoglobin A1c (HbA1c) was not associated with diabetes medication adjustment, and only 5/12 patients (42%) who reported hypoglycaemia with HbA1c <7.0% had medications de-intensified or adjusted.

INTERPRETATION: PCPs discussed hypoglycaemia in one-third of visits for at-risk patients and provided limited hypoglycaemia anticipatory guidance. De-intensifying or adjusting hypoglycaemia-causing medications did not occur routinely after reported hypoglycaemia with HbA1c <7.0%. Routine hypoglycaemia assessment and provision of diabetes self-management education are needed to achieve guideline-concordant hypoglycaemia prevention.

FUNDING: U.S. Department of Veterans Affairs and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

PMID:38076413 | PMC:PMC10701452 | DOI:10.1016/j.lana.2023.100641

JHEP Rep. 2023 Aug 12;5(12):100880. doi: 10.1016/j.jhepr.2023.100880. eCollection 2023 Dec.

ABSTRACT

BACKGROUND & AIMS: There is concern about the burden of liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs).

METHODS: In a retrospective cohort study, we evaluated the likelihood of grade 3/4 liver injury, of grade 3/4 cholestatic liver injury, and of liver failure, as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5, following treatment with ICIs. We compared these occurrences with a group of cancer patients who were propensity-matched and treated with conventional chemotherapy. For all ICI patients experiencing grade 3/4 liver injury, we conducted a causality assessment using the RUCAM method and examined patient outcomes.

RESULTS: Among 952 patients (median [IQR] age 66 [57-73] years, 64% males) who were treated with ICI between January 1, 2015, and December 31, 2019, a total of 86 (9%) progressed to grade 3/4 liver injury, and liver failure was not observed. Anti-PD-(L)1/anti-CTLA-4 antibodies combinations (adjusted hazard ratio 3.36 [95% CI: 1.67-6.79]; p <0.001), and chronic hepatitis B (adjusted hazard ratio 5.48 [95% CI: 1.62-18.5]; p = 0.006], were independent risk factors. Liver injury was attributed to ICI treatment in 19 (2.0%) patients. Patients with ICI toxicity typically presented with granulomatous hepatitis or cholangiocyte inflammation. ICI withdrawal was associated with cancer progression and mortality. Re-introduction of ICI was not associated with recurrent grade 3/4 liver injury. Compared with matched patients treated with conventional, non-ICI-based chemotherapy, anti-PD-(L)1/anti-CTLA-4 combinations (p <0.001) and anti-PD-(L)1 monotherapies (p = 0.053) increased the risk of grade 3/4 liver injury and of grade 3/4 cholestatic liver injury, respectively.

CONCLUSIONS: An increased risk of grade 3/4 liver injury under anti-PD-(L)1/anti-CTLA-4 antibodies was observed, whereas no substantial increase in the likelihood of liver failure occurred even after treatment reintroduction.

IMPACT AND IMPLICATIONS: There is concern about liver injury in patients with cancer exposed to immune checkpoints inhibitors (ICIs). We investigated the burden of grade 3/4 liver injury after treatment with ICIs in a multicentric cohort of patients with cancer. Overall, a 9% incidence of grade 3/4 liver injury was detected after ICIs, and direct ICI hepatotoxicity was demonstrated in 2% of patients. Anti-PD-(L)1/Anti-CTLA-4 antibody combinations, and chronic HBV infection were independent risk factors. ICI withdrawal for grade 3/4 liver injury was associated with cancer progression. Re-introduction of ICI treatment was not associated with recurrent grade 3/4 liver injury.

PMID:38074948 | PMC:PMC10701119 | DOI:10.1016/j.jhepr.2023.100880

Cureus. 2023 Nov 7;15(11):e48453. doi: 10.7759/cureus.48453. eCollection 2023 Nov.

ABSTRACT

Durvalumab is an immune checkpoint inhibitor (ICI) belonging to the anti-programmed death-ligand 1 (PD-L1) class, and it is used in the treatment of various end-stage malignancies. Immune checkpoint inhibitors are associated with various systemic and cutaneous adverse events. Psoriasiform drug eruptions have been clinically observed in patients who have a personal history of psoriasis being treated with ICIs. We present a unique case of de novo psoriasis in a patient being treated for poorly differentiated adenocarcinoma of the lung. The patient responded well to topical treatment and did not require discontinuation of durvalumab. Our case highlights the importance of clinician familiarity with psoriasis presentation, its association with durvalumab therapy, and treatment options for durvalumab-induced psoriasis.

PMID:38074037 | PMC:PMC10702810 | DOI:10.7759/cureus.48453

Cureus. 2023 Nov 8;15(11):e48500. doi: 10.7759/cureus.48500. eCollection 2023 Nov.

ABSTRACT

AIMS: The aims were to evaluate rheumatic disorder patients' knowledge of the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs), dosage (from where the knowledge is acquired), contraindications (in pregnancy), and drug interactions (such as drug-related disorders), to improve their knowledge about taking NSAIDs in Saudi Arabia.

STUDY DESIGN: It is a descriptive cross-sectional study.

PLACE AND DURATION OF STUDY: The study was conducted among patients with rheumatic disorder (RD) in Saudi Arabia who were invited to join by completing an online questionnaire, from August to November 2022.

METHODOLOGY: Patients with RD who were 16 years and older, received oral NSAIDs, and agreed to participate were included in the study. The data was collected using an Internet-based questionnaire. The Internet-based questionnaire was designed using the Google Forms (Google LLC, Mountain View, California, United States) online survey platform. A consent form accompanied the questionnaire in a cover letter briefly describing the investigation.

RESULTS: A total of 756 participants answered the questionnaire and participated in the final analysis. Most of the participants (75.93%) were female. The type of NSAID used by the participants was Ibuprofen. The majority (83.41%) reported that they responded to the medication. When asked about the primary source of information about the correct dose of these medications, more than two-thirds (69.32%) reported that physicians are the main source of information. The majority of the participants (83.39%) denied using NSAIDs during pregnancy. Half of the participants (49.22%) said they had discussed these medications' harmful effects with their doctors or pharmacists. The female participants were more knowledgeable about NSAIDs and their side effects than the males.

CONCLUSION: The patient's knowledge related to the use of oral NSAIDs was not that satisfactory. There is an urgent need to educate the public regarding the appropriate use of NSAIDs by healthcare providers, particularly in relation to their proper use, potential side effects, and risks associated with long-term use.

PMID:38073919 | PMC:PMC10704060 | DOI:10.7759/cureus.48500

Eur J Hosp Pharm. 2023 Dec 9:ejhpharm-2023-003937. doi: 10.1136/ejhpharm-2023-003937. Online ahead of print.

ABSTRACT

BACKGROUND: Inhaled antibiotics have achieved or stabilised the clinical condition of patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa infection. We aimed to determine the effectiveness of aztreonam lysine inhaled solution (AZLI) in patients with CF and chronic P. aeruginosa infection.

METHODS: A retrospective observational study was conducted on patients with CF and chronic P. aeruginosa infection who received AZLI between July 2012 and September 2018 inclusive in three Spanish hospitals in a routine clinical practice setting. The primary endpoint was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) compared with the previous 12 months, at the start of AZLI treatment and 12 months after starting the drug. Other variables analysed were exacerbations, hospitalisations, type and route of antibiotics prescribed, weight and body mass index (BMI) and adverse drug reactions.

RESULTS: In a cohort of 52 patients, AZLI treatment led to stabilisation of FEV1, changing from a mean (SD) value of 55.60 (21.3)% at the start of treatment to 56.8 (20.4)% after 12 months of treatment (p=0.5296) in patients who had not previously received the drug. In addition, it significantly reduced exacerbations from a median (P25; P75) of 2.0 (1.0; 3.0) in the 12 months prior to AZLI to 1.0 (1.0; 2.0) in the 12 months after treatment initiation (p=0.0350). AZLI also reduced the need for other antibiotics and prevented a decrease in BMI, with an adequate safety profile.

CONCLUSIONS: AZLI achieved stabilisation of lung function measured by FEV1 in patients with CF and chronic P. aeruginosa infection, along with an adequate safety profile.

PMID:38071521 | DOI:10.1136/ejhpharm-2023-003937

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2023 Dec;31(6):1647-1656. doi: 10.19746/j.cnki.issn.1009-2137.2023.06.008.

ABSTRACT

OBJECTIVE: To establish a new digital polymerase chain reaction (dPCR) system for the detection of BCR-ABL fusion gene in patients with chronic myeloid leukemia (CML), and explore its analytical performance and clinical applicability in the detection of BCR-ABLp190/210/230.

METHODS: A new dPCR system for detecting BCR-ABLp190/210/230 was successfully developed, and its sensitivity difference with qPCR and improvement of drug side effects in patients with CML during drug reduction or withdrawal were compared.

RESULTS: Among 176 samples, qPCR and dPCR showed high consistency in the sensitivity of detecting BCR-ABL (82.39%), and the positive rate of dPCR was about 5 times higher that of qPCR (20.45% vs 3.98%). During follow-up, blood routine (25% vs 10%), kidney/liver/stomach (25% vs 20%) and cardiac function (10% vs 0) were significantly improved after drug reduction or withdrawal in patients with initial dPCR negative compared with before drug reduction or withdrawal.

CONCLUSIONS: This new dPCR detection system can be applied to the detection of BCR-ABLp190/210/230. It has better consistency and higher positive detection rate than qPCR. Drug withdrawal or dose reduction guided by dPCR has a certain effect on improving drug side effects.

PMID:38071041 | DOI:10.19746/j.cnki.issn.1009-2137.2023.06.008

Int J Mol Sci. 2023 Nov 28;24(23):16843. doi: 10.3390/ijms242316843.

ABSTRACT

Glucocorticoids (GCs) are widely used to treat inflammatory disorders such as acute lung injury (ALI). Here, we explored inorganic-organic hybrid nanoparticles (IOH-NPs) as a new delivery vehicle for GCs in a mouse model of ALI. Betamethasone (BMZ) encapsulated into IOH-NPs (BNPs) ameliorated the massive infiltration of neutrophils into the airways with a similar efficacy as the free drug. This was accompanied by a potent inhibition of pulmonary gene expression and secretion of pro-inflammatory mediators, whereas the alveolar-capillary barrier integrity was only restored by BMZ in its traditional form. Experiments with genetically engineered mice identified myeloid cells and alveolar type II (AT II) cells as essential targets of BNPs in ALI therapy, confirming their high cell-type specificity. Consequently, adverse effects were reduced when using IOH-NPs for GC delivery. BNPs did not alter T and B cell numbers in the blood and also prevented the induction of muscle atrophy after three days of treatment. Collectively, our data suggest that IOH-NPs target GCs to myeloid and AT II cells, resulting in full therapeutic efficacy in the treatment of ALI while being associated with reduced adverse effects.

PMID:38069173 | PMC:PMC10705980 | DOI:10.3390/ijms242316843

Prague Med Rep. 2023;124(4):392-412. doi: 10.14712/23362936.2023.30.

ABSTRACT

The COVID-19 pandemic generated a great impact on health systems. We compared evolution, polypharmacy, and potential drug-drug interactions (P-DDIs) in COVID-19 and non-COVID-19 hospitalizations during first wave of pandemic. Prescriptions for hospitalized patients ≥ 18 years (COVID-19 and non-COVID-19 rooms) between April and September 2020 were included. The computerized medical decision support system SIMDA and the physician order entry system Hdc.DrApp.la were used. Patients in COVID-19 rooms were divided into detectable and non-detectable, according to real-time reverse transcription polymerase chain reaction (RT-PCR). Number of drugs, prescribed on day 1, after day 1, and total; polypharmacy, excessive polypharmacy, and P-DDIs were compared. 1,623 admissions were evaluated: 881 COVID-19, 538 detectable and 343 non-detectable, and 742 non-COVID-19. Mortality was 15% in COVID-19 and 13% in non-COVID-19 (RR [non-COVID-19 vs. COVID-19]: 0.84 [95% CI] [0.66-1.07]). In COVID-19, mortality was 19% in detectable and 9% in non-detectable (RR: 2.07 [1.42-3.00]). Average number of drugs was 4.54/patient (SD ± 3.06) in COVID-19 and 5.92/patient (±3.24) in non-COVID-19 (p&lt;0.001) on day 1 and 5.57/patient (±3.93) in COVID-19 and 9.17/patient (±5.27) in non-COVID-19 (p&lt;0.001) throughout the hospitalization. 45% received polypharmacy in COVID-19 and 62% in non-COVID-19 (RR: 1.38 [1.25-1.51]) and excessive polypharmacy 7% in COVID-19 and 14% in non-COVID-19 (RR: 2.09 [1.54-2.83]). The frequency of total P-DDIs was 0.31/patient (±0.67) in COVID-19 and 0.40/patient (±0.94) in non-COVID-19 (p=0.022). Hospitalizations in the COVID-19 setting are associated with less use of drugs, less polypharmacy and less P-DDIs. Detectable patients had higher mortality.

PMID:38069645 | DOI:10.14712/23362936.2023.30

Ann Med. 2023;55(2):2288309. doi: 10.1080/07853890.2023.2288309. Epub 2023 Dec 8.

ABSTRACT

Objective: Evaluate the profiles of post-exposure prophylaxis (PEP) adherence, adverse drug reactions (ADRs), and discontinuation associated with ADRs to provide information for further PEP program improvement and increase adherence to PEP.Methods: The Web of Science, PubMed, Embase, and the Cochrane Library were searched for cohort studies reporting data related to PEP adherence or ADRs (PROSPERO, CRD42022385073). Pooled estimates of adherence, the incidence of ADRs and discontinuation associated with ADRs, and their 95% confidence intervals (CI) were calculated separately for the included literature using random effects models. For substantial heterogeneity, meta-regression and subgroup analyses were conducted to explore sources of heterogeneity.Results: Overall adherence was 58.4% (95% CI: 50.9%-65.8%), with subgroup analysis showing differences in adherence across samples, with the highest adherence among men who had sex with men (MSM) (72.4%, 95% CI: 63.4%-81.3%) and the lowest adherence among survivors of sexual assault (SAs) (41.7%, 95% CI: 28.0%-55.3%). The incidence of ADRs was 60.3% (95% CI: 50.3%-70.3%), and the prevalence of PEP discontinuation associated with ADRs was 32.7% (95% CI: 23.7%-41.7%), with subgroup analyses revealing disparities in the prevalence of discontinuation associated with ADRs among samples with different drug regimens. Time trend analysis showed a slight downward trend in the incidence of ADRs and PEP discontinuation associated with ADRs.Conclusion: Adherence to PEP was less than 60% across samples, however, there was significant heterogeneity depending on the samples. SAs had the lowest adherence and the highest incidence of PEP discontinuation. Ongoing adherence education for participants, timely monitoring, and management of ADRs may improve adherence.

PMID:38065681 | DOI:10.1080/07853890.2023.2288309

J Infect Dev Ctries. 2023 Nov 30;17(11):1549-1555. doi: 10.3855/jidc.18041.

ABSTRACT

INTRODUCTION: Favipiravir (FVP) is an antiviral and used to treat COVID-19. We aimed to document the safety and adverse events associated with FVP on the outcome of COVID-19 treatment.

METHODOLOGY: The study included 225 adult patients with moderate COVID-19 infection (World Health Organization scale-5). The adverse events (AEs) were evaluated using a grading scale supported by the Food and Drug Administration. Safety was assessed by the frequency of serious AEs.

RESULTS: The AEs associated with FVP treatment were hepatotoxicity (87/225, 38.7%), weakness (32/225, 14.2%), nephrotoxicity (26/225, 11.6%), nausea (18/225, 8.0%), diarrhea (8/225, 3.6%), vomiting (5/225, 2.2%), and insomnia (4/225, 1.8%); rash was not detected. Hepatotoxicity was observed more frequently in patients who also developed nephrotoxicity (57.7% vs 36.2%, p = 0.03). The deceased patients were significantly older and had higher prevalence of hypertension, congestive heart failure (CHF), coronary artery disease, cancer, nephrotoxicity. and angiotensin- converting enzyme inhibitors/angiotensin receptor blocker use. While male gender (OR: 5.38 CI: 1.64-17.67) and CHF (OR: 6.8 CI: 1.92-24.74) were significantly associated with nephrotoxicity, age (OR: 1.06 CI: 1.02-1.10), cancer (OR: 3.9 CI: 1.10-14.22) and nephrotoxicity (OR: 5.5 CI: 1.74-17.74) were associated with mortality.

CONCLUSIONS: Serious AEs were detected at very low levels that would not require discontinuation of treatment or any AE-related death. Since SARS-CoV-2 itself and drug interactions may differ, FVP-related AEs might vary in COVID-19 patients. Our study shows that FVP can be used safely with a low AE profile. More extensive evidence is required to evaluate the long-term AEs of FVP.

PMID:38064405 | DOI:10.3855/jidc.18041

BMC Pharmacol Toxicol. 2023 Dec 7;24(1):74. doi: 10.1186/s40360-023-00715-5.

ABSTRACT

BACKGROUND: Integrase strand transfer inhibitor (INSTIs)-based combination antiretroviral treatment in people living with HIV (PLWH) has been reportedly correlated with several adverse effects, such as weight gain, fetal defects or psychiatric disorders.

METHODS: To comprehensively understand the adverse effect of INSTIs, our study utilized Caenorhabditis Elegans (C. elegans) as a model to investigate how dolutegravir (DTG) affected its life cycle, growth, reproduction and lifespan.

RESULTS: Our results indicated that DTG enhanced body growth at the early stage of treatment, but no change was detected for long-term treatment. The treatment also influenced the reproductive system, decreased egg-hatching but had no effect on egg-laying. Besides, DTG resulted in lifespan reduction, which is dependent on increased levels of reactive oxidative species (ROS) accumulation. Treatment with N-acetyl-cysteine (NAC) in worms restrained intracellular ROS accumulation and improved DTG-induced lifespan reduction.

CONCLUSIONS: Our study demonstrates for the first time the effect of DTG treatment on life cycle. DTG-induced adverse effects are potentially associated with intracellular ROS accumulation. Quenching ROS accumulation might provide a novel strategy for dealing with the adverse effects of INSTIs.

PMID:38062506 | PMC:PMC10702061 | DOI:10.1186/s40360-023-00715-5

Medicine (Baltimore). 2023 Dec 8;102(49):e35926. doi: 10.1097/MD.0000000000035926.

ABSTRACT

BACKGROUND: Despite the availability of numerous treatment options, many patients with gastritis experience only partial symptom relief. CKD-495, a newly developed product with the active ingredient extracted from Cinnamomum cassia Presl., has demonstrated anti-inflammatory and antioxidant activity in vitro and an in vivo protective effect against gastric damage by stimulating mucus secretion. This study compared the efficacy and safety of CKD-495 with Artemisiae argyi folium (AAF) for the treatment of acute and chronic gastritis. AAF, a gastric mucosa protective agent that promotes gastric mucosa regeneration, has been used clinically for about 20 years.

METHODS: This phase III multicenter, randomized, double-blind, parallel-group trial (ClinicalTrials.gov; NCT04255589) assigned 242 patients with endoscopically-proven gastric mucosal erosions to receive CKD-495 75 mg (n = 122) or AAF 60 mg (n = 120), respectively, with placebo (for double-blind purposes) 3 times a day for 2 weeks. The primary efficacy endpoint was the erosion improvement rate. Secondary endpoints included erosion cure rates, and improvement rates for edema, redness, hemorrhage, and gastrointestinal (GI) symptoms. Drug-related adverse events were evaluated.

RESULTS: The erosion improvement rate was significantly higher in the CKD-495 group than in the AAF group for both the full analysis set (55.9% vs 39.4%, P = .0063) and per-protocol set (54.6% vs 38.2%, P = .0084). In addition, the erosion improvement rate in patients with acute or chronic gastritis showed that the CKD-495 group had better improvement of erosion than the AAF group, especially in patients with chronic gastritis. Analysis of secondary endpoints, which included erosion cure rate and the improvement rates of edema, redness, hemorrhage, and GI symptoms, showed that the CKD-495 group was more effective than the AAF group. There were no significant between-group differences in safety profiles. No serious adverse events or adverse drug reactions occurred.

CONCLUSIONS: These results demonstrate that CKD-495 75 mg is superior to AAF 60 mg in terms of the endoscopic improvement rate of erosions in patients with acute or chronic gastritis. This new mucoprotective agent, CKD-495, can be considered the therapy of choice for symptomatic relief and healing of gastritis.

PMID:38065906 | DOI:10.1097/MD.0000000000035926

Am J Hematol. 2023 Dec 8. doi: 10.1002/ajh.27080. Online ahead of print.

ABSTRACT

Avatrombopag is a newer thrombopoietin receptor agonist (TPO-RA) currently approved to treat chronic ITP (duration >12 months). No studies have yet evaluated the safety and effectiveness of avatrombopag in newly diagnosed ITP (duration <3 months) or persistent ITP (duration 3-12 months), and so its use in these populations is presently off-label worldwide. We hypothesize that avatrombopag has similar safety and effectiveness irrespective of ITP disease phase. To evaluate this, we performed a multicenter observational cohort study of adults with ITP treated with avatrombopag, comparing patient outcomes by disease phase (newly diagnosed/persistent versus chronic). Seventy-five patients were included, 23 with newly diagnosed/persistent ITP (17.7 patient-years of avatrombopag treatment) and 52 with chronic ITP (65.3 patient-years of avatrombopag treatment). On avatrombopag, 91% of newly diagnosed/persistent patients versus 96% of chronic patients (p = .58) achieved a platelet response (≥50 × 109 /L) and 86% versus 81% of patients (p = .78) achieved a complete response (≥100 × 109 /L). Median platelet counts on avatrombopag were similar between the two groups (165 × 109 /L vs. 129 × 109 /L, p = .57). Response durability was high and similar in both groups. No patients in the newly diagnosed/persistent group had a major bleeding event, thromboembolic event or avatrombopag discontinuation for adverse events, compared with 4, 1, and 2, respectively, in the chronic group. Thrombocytosis (platelets ≥400 × 109 /L) incidence was similar in the two groups. No other drug-related adverse events occurred in either group. Avatrombopag was safe and effective in patients with newly diagnosed and persistent ITP, with outcomes numerically, statistically, and clinically similar to patients receiving avatrombopag for chronic ITP.

PMID:38063420 | DOI:10.1002/ajh.27080

Cancer Med. 2023 Dec 8. doi: 10.1002/cam4.6786. Online ahead of print.

ABSTRACT

BACKGROUND: Fruquintinib has demonstrated significant improvement in overall survival (OS) among previously treated metastatic colorectal cancer (mCRC) patients. However, the utilization of fruquintinib has been constrained by various toxicities, such as hand-foot skin reaction (HFSR) and hypertension, particularly in elderly patients with reduced tolerance to the standard dosage. This study aims to investigate the efficacy and safety of fruquintinib dose-escalation strategy for elderly refractory mCRC patients.

PATIENTS AND METHODS: This open-label, single-arm, phase II trial included patients aged 65 years or over with mCRC who had progressed after two or more lines of chemotherapy. Fruquintinib was administered for 21 consecutive days of a 28-day treatment cycle. The starting dose of fruquintinib was 3 mg/day and escalated to 4 mg/day in Week 2 and 5 mg/day in Week 3 if no significant drug-related toxicity was observed. The highest tolerated dose from Cycle 1 would be administered in Cycle 2 and all subsequent cycles. Before commencing treatment, all enrolled patients underwent a G8 questionnaire and comprehensive geriatric assessments. The primary endpoint of the study was progression-free survival (PFS).

RESULTS: A total of 29 patients were enrolled and all started fruquintinib at 3 mg/day. Fifteen patients (51.7%) were subsequently escalated to 4 mg/day and 4 (13.8%) to 5 mg/day. Only four (13.8%) patients discontinued treatment due to adverse events (AEs). The median PFS was 3.8 months (95% CI, 2.7-4.9), and the median OS was 7.6 months (95% CI, 6.5-8.7). Treatment-related adverse events (TRAEs) were observed in all 29 patients (100%). The most frequently occurring (>10%) TRAEs greater than Grade 3 were HFSR (20.7%), hypertension (20.7%), and diarrhea (10.3%).

CONCLUSION: Our study indicated that a dose of 4 mg/day was well tolerated by most elderly patients, suggesting that fruquintinib dose-escalation strategy during the first cycle could serve as a viable alternative to the standard 5 mg/day dosing.

PMID:38063405 | DOI:10.1002/cam4.6786

Inn Med (Heidelb). 2023 Dec 7. doi: 10.1007/s00108-023-01630-x. Online ahead of print.

ABSTRACT

If the individual diagnoses of older people with multimorbidity are treated according to guidelines and by different specialists, confusing medication plans are sometimes the consequence. Therefore, a regular and structured drug evaluation is essential. As the life goals of patients can be very different, especially in older age, certain preliminary considerations should be made when starting, prescribing or discontinuing medication, taking into account the individual situation, including geriatric aspects. Updated so-called positive and negative lists provide assistance as to which medications are suitable or unsuitable for older people. Discontinuing certain medications when the life expectancy is reduced certainly makes sense but undertreatment of symptoms that cause distress to people, such as pain, should definitely be avoided.

PMID:38059997 | DOI:10.1007/s00108-023-01630-x

Eur J Clin Pharmacol. 2023 Dec 7. doi: 10.1007/s00228-023-03592-3. Online ahead of print.

ABSTRACT

PURPOSE: Selective androgen receptor modulators (SARMs) have demonstrated agonist activity on the androgen receptor in various tissues, stimulating muscle mass growth and improving bone reconstruction. Despite being in clinical trials, none has been approved by the Food and Drug Administration (FDA) or European Medicines Agency for pharmacotherapy. Still, SARMs are very popular as performance-enhancing drugs. The FDA has issued warnings about the health risks associated with SARMs, but the long-term exposure and possible adverse events still need to be fully understood. This review aims to evaluate the adverse events associated with using SARMs by humans.

METHODS: PubMed database was searched from September 16, 2022, to October 2, 2023. In total, 20 records were included in the final review. Data from preclinical and clinical studies supported the review.

RESULTS: Since 2020, 20 reports of adverse events, most described as drug-induced liver injury associated with the use of SARM agonists, have been published. The main symptoms mentioned were cholestatic or hepatocellular liver injury and jaundice. Limited data are related to the dosages and purity of SARM supplements.

CONCLUSION: Promoting SARMs as an anabolic agent in combination with other performance-enhancing drugs poses a risk to users not only due to doping controls but also to health safety. The lack of quality control of consumed supplements makes it very difficult to assess the direct impact of SARMs on the liver and their potential hepatotoxic effects. Therefore, more detailed analyses are needed to determine the safety of using SARMs.

PMID:38059982 | DOI:10.1007/s00228-023-03592-3

Bioessays. 2023 Dec 7:e2300117. doi: 10.1002/bies.202300117. Online ahead of print.

ABSTRACT

Bisphosphonates are a class of drugs which have shown good efficacy in the treatment of post-menopausal osteoporosis, as well as a good safety profile. However, side-effects such as risk for atypical femoral fractures (AFF) have appeared, leading to a decline in use of the drugs by many patients who would benefit from the treatment. While patient characteristics have contributed to improved understanding of risk factors, the mechanisms involved that explain AFF risk have not appeared. Recently, the possibility that the mechanism(s) involved drug-induced modification of cells of the nutrient canals of the femur and subsequent compromise in the bone matrix has been published. The present Hypothesis article builds on the concept presented earlier and expands into biomechanical considerations. An analogy of the mechanisms involved to a real-life scenario is also presented. While this analogy has limitations, consideration of the biomechanical implications of progressive alterations to defects presented by compromised nutrient canal-bone matrix also presents potential relationships with AFF risk.

PMID:38059881 | DOI:10.1002/bies.202300117

ANZ J Surg. 2023 Dec 7. doi: 10.1111/ans.18812. Online ahead of print.

ABSTRACT

BACKGROUND: In recent years, certain body composition measures, assessed by computed tomography (CT), have been found to be associated with chemotherapy toxicities. This review aims to explore available data on the relationship between skeletal muscle and adiposity, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intramuscular and intermuscular adipose tissue and their association with chemotherapy toxicity in non-metastatic colorectal cancer (CRC) patients.

METHODS: A systematic literature search following PRISMA guidelines was conducted in Medline, Embase, Cochrane and Web of Science, for papers published between 2011 and 2023. The search strategy combined keywords and MESH terms relevant to 'body composition', 'chemotherapy toxicities', and 'non-metastatic colorectal cancer'.

RESULTS: Out of 3868 studies identified, six retrospective studies fulfilled the inclusion criteria with 1024 eligible patients. Low skeletal muscle mass was strongly associated with increased incidence of both chemotherapy toxicities and dose-limiting toxicity (DLT). The association of VAT, intramuscular and intermuscular adiposity was heterogeneous and inconclusive. There was no association between SAT and chemotherapy intolerance. No universal definitions or cut-offs for sarcopenia and obesity were noted. All studies utilized 2-dimensional (2D) CT slices for CT body composition assessment with varied selection on the vertebral landmark and inconsistent reporting of tissue-defining Hounsfield unit (HU) measurements.

CONCLUSION: Low skeletal muscle is associated with chemotherapy toxicities in non-metastatic CRC. However, quality evidence on the role of adiposity is limited and heterogeneous. More studies are needed to confirm these associations with an emphasis on a more coherent body composition definition and an approach to its assessment, especially regarding sarcopenia.

PMID:38059530 | DOI:10.1111/ans.18812

Case Rep Ophthalmol. 2023 Dec 5;14(1):673-678. doi: 10.1159/000535077. eCollection 2023 Jan-Dec.

ABSTRACT

INTRODUCTION: With the increasing use of immune checkpoint inhibitors, ocular adverse events have gained attention. We describe a case of atypical keratitis presumably induced by atezolizumab, a programmed cell death ligand 1 inhibitor.

CASE PRESENTATION: A 73-year-old Japanese woman developed ring-shaped marginal infiltrations with epithelial breakdown of the corneas in both eyes. The patient had advanced small cell lung cancer and had received intravenous carboplatin, etoposide, and atezolizumab. She was treated with topical administration of 0.1% sodium phosphate betamethasone and 0.5% moxifloxacin six times daily. On day 14 following initial presentation, marked reduction of bilateral corneal infiltration was observed. During the succeeding cycles of chemotherapy, marginal keratitis did not recur, and then, the topical steroid was gradually tapered.

CONCLUSIONS: Cancer immunotherapy, including atezolizumab, may lead to active T-cell recruitment into the cornea, which result in autoimmune corneal keratitis. We believe that this report is informative to both ophthalmologists and oncologists involved in the treatment of patients receiving cancer immunotherapy.

PMID:38058358 | PMC:PMC10697742 | DOI:10.1159/000535077