BMC Med. 2023 Oct 9;21(1):388. doi: 10.1186/s12916-023-03089-x.

ABSTRACT

BACKGROUND: Dipeptidyl peptidase-4 inhibitors (DPP-4i) have become firmly established in treatment algorithms and national guidelines for improving glycemic control in type 2 diabetes mellitus (T2DM).To report the findings from a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial, which was designed to assess the efficacy and safety of a novel DPP-4 inhibitor fotagliptin in treatment-naive patients with T2DM.

METHODS: Patients with T2DM were randomized to receive fotagliptin (n = 230), alogliptin (n = 113) or placebo (n = 115) at a 2:1:1 ratio for 24 weeks of double-blind treatment period, followed by an open-label treatment period, making up a total of 52 weeks. The primary efficacy endpoint was to determine the superiority of fotagliptin over placebo in the change of HbA1c from baseline to Week 24. All serious or significant adverse events were recorded.

RESULTS: After 24 weeks, mean decreases in HbA1c from baseline were -0.70% for fotagliptin, -0.72% for alogliptin and -0.26% for placebo. Estimated mean treatment differences in HbA1c were -0.44% (95% confidence interval [CI]: -0.62% to -0.27%) for fotagliptin versus placebo, and -0.46% (95% CI: -0.67% to -0.26%) for alogliptin versus placebo, and 0.02% (95%CI: -0.16% to 0.19%; upper limit of 95%CI < margin of 0.4%) for fotagliptin versus alogliptin. So fotagliptin was non-inferior to alogliptin. Compared with subjects with placebo (15.5%), significantly more patients with fotagliptin (37.0%) and alogliptin (35.5%) achieved HbA1c < 7.0% after 24 weeks of treatment. During the whole 52 weeks of treatment, the overall incidence of hypoglycemia was low for both of the fotagliptin and alogliptin groups (1.0% each). No drug-related serious adverse events were observed in any treatment group.

CONCLUSIONS: In summary, the study demonstrated improvement in glycemic control and a favorable safety profile for fotagliptin in treatment-naive patients with T2DM.

TRIAL REGISTRATION: ClinicalTrail.gov NCT05782192.

PMID:37814306 | DOI:10.1186/s12916-023-03089-x

Am J Nephrol. 2023 Oct 9. doi: 10.1159/000534484. Online ahead of print.

ABSTRACT

BACKGROUND: Hyperphosphatemia in CKD patients is positively associated with mortality. Ferric citrate is a potent phosphorus binder that lowers serum phosphorus level and improves iron metabolism. We compared its efficacy and safety with active drugs in Chinese CKD patients with hemodialysis.

TRIAL DESIGN: This is an open-label active-drug-controlled multicenter randomized study.

METHODS: Chinese patients undergoing hemodialysis were randomized into two treatment groups in a 1:1 ratio receiving either ferric citrate or sevelamer carbonate respectively for 12 weeks. Serum phosphorus levels, calcium concentration, and iron metabolism parameters were evaluated at every two weeks. Frequency and severity of adverse events were recorded.

RESULTS: 217 (90.4%) patients completed the study, with balanced demographic and baseline characteristics between two groups. Ferric citrate decreased the serum phosphorus level to 0.59±0.54mmol/L, comparable to 0.56 ± 0.62 mmol/L by sevelamer carbonate. There was no significant difference between two groups (P>0.05) in the proportion of patients with serum phosphorus levels reaching the target range, the response rate to the study drug, and the changes of corrected serum calcium concentrations, and intact-PTH levels at the end of treatment. The change of iron metabolism indicators in the ferric citrate group were significantly higher than those in the sevelamer carbonate group. There are 47 (40.5%) patients in the ferric citrate group, and 26 (21.3%) in the sevelamer carbonate group experienced drug-related TEAEs, most were mild and tolerable. Common drug-related TEAEs were "gastrointestinal disorders", including diarrhea (12.9% vs. 2.5%), feacal discoloration (14.7% vs. 0%), and constipation (1.7% vs. 7.4%) in ferric citrate and sevelamer carbonate group respectively.

CONCLUSION: Ferric citrate capsules have good efficacy and safety in the control of hyperphosphatemia in adult patients with CKD undergoing hemodialysis. Efficacy is not inferior to sevelamer carbonate. The TEAEs were mostly mild and tolerated by the patients.

PMID:37812931 | DOI:10.1159/000534484

Clin Exp Rheumatol. 2023 Oct 5. doi: 10.55563/clinexprheumatol/rq4k3u. Online ahead of print.

ABSTRACT

OBJECTIVES: The approval of TNF-a inhibitors (TNFi) was a breakthrough in the treatment of ankylosing spondylitis (AS). Although also effective in psoriasis, drug-related adverse events of onset of psoriasiform skin lesions - paradoxical psoriasis (PP) under TNFi have been reported.

METHODS: We performed an electronic data search in MEDLINE via Pubmed and Cochrane library scientific databases from inception to January 2023, following the PRISMA guidelines. We assessed the distinct characteristics and frequency of risks for PP appearance in AS patients treated with different TNFi.

RESULTS: PP was found in 0.5-1% of TNFi-treated AS patients and the latency period was 2-11 months. The safest TNFi in terms of PP induction was certolizumab, whereas the one most commonly associated with PP was infliximab.

CONCLUSIONS: PP is an uncommon adverse reaction to TNFi treatment in AS patients and responds well to drug withdrawal. More large data studies need to be conducted though, to shed light on PP nature and management.

PMID:37812484 | DOI:10.55563/clinexprheumatol/rq4k3u

Crit Care Explor. 2023 Oct 5;5(10):e0986. doi: 10.1097/CCE.0000000000000986. eCollection 2023 Oct.

ABSTRACT

OBJECTIVES: To evaluate the study design and feasibility of drug administration and safety in a randomized clinical trial of recombinant human annexin A5 (SY-005), a constitutively expressed protein with anti-inflammatory, antiapoptotic, and anticoagulant properties, in patients with severe coronavirus disease 2019 (COVID-19).

DESIGN: Double-blind, randomized clinical trial.

SETTING: Two ICUs at an academic medical center.

PATIENTS/SUBJECTS: Adults admitted to the ICU with a confirmed diagnosis of COVID-19 and requiring ventilatory or vasopressor support.

INTERVENTIONS: SY-005, a recombinant human annexin A5, at 50 or 100 µg/kg IV every 12 hours for 7 days.

MEASUREMENTS AND MAIN RESULTS: We enrolled 18 of the 55 eligible patients (33%) between April 21, 2021, and February 3, 2022. We administered 82% (196/238) of the anticipated doses of study medication and 86% (169/196) were given within 1 hour of the scheduled time. There were no drug-related serious adverse events. We captured 100% of the data that would be required for measuring clinical outcomes in a phase 2 or 3 trial.

LIMITATIONS: The small sample size was a result of decreasing admissions of patients with COVID-19, which triggered a stopping rule for the trial.

CONCLUSIONS: Although enrollment was low, administration of SY-005 to critically ill patients with COVID-19 every 12 hours for up to 7 days was feasible and safe. Further clinical trials of annexin A5 for the treatment of COVID-19 are warranted. Given reduction of severe COVID-19 disease, future studies should explore the safety and effectiveness of SY-005 use in non-COVID-related sepsis.

PMID:37811130 | PMC:PMC10558223 | DOI:10.1097/CCE.0000000000000986

Ann Med Surg (Lond). 2023 Sep 1;85(10):5232-5234. doi: 10.1097/MS9.0000000000001231. eCollection 2023 Oct.

ABSTRACT

INTRODUCTION: Rhabdomyolysis may arise due to traumatic or non-traumatic causes leading to muscle injury. However, increased statin use has raised drug-related side effects like statin-related muscle damage.

CASE REPORT: A 74-year-old male with liver cirrhosis secondary to alcohol was prescribed atorvastatin for hyperlipidemia. He developed muscle tenderness and decreased muscle power 2 weeks following statin therapy, evident with a creatine phosphokinase level of more than 22 000 IU/l. The urinalysis also revealed positive for blood. Hence, atorvastatin was ceased. The patient's laboratory parameters improved significantly, implying atorvastatin is the causative agent for rhabdomyolysis.

DISCUSSION: Statins are usually safe and well-tolerated drugs; however, skeletal muscle symptoms occur in ~5-10% of patients. The risk factor for statin-induced muscle injury includes advanced age, drug-altering statin plasma level, liver disease, or chronic kidney disease. Moreover, the hepatic level of CYP450 and its CYP3A4 isoform are altered in chronic liver diseases. CYP3A4 isoenzyme and its activity declines in hepatic cirrhosis patients.

CONCLUSION: Statins are generally prescribed for hyperlipidemia and primary and secondary prevention in high-risk cardiovascular diseases. However, several risk factors alter statin metabolism, causing statin-induced muscle injury. Thus, despite several studies suggesting otherwise, special precautions should be taken in patients with chronic liver disease.

PMID:37811121 | PMC:PMC10553173 | DOI:10.1097/MS9.0000000000001231

Brain Behav Immun Health. 2023 Sep 23;33:100687. doi: 10.1016/j.bbih.2023.100687. eCollection 2023 Nov.

ABSTRACT

The term extrapyramidal disorders is most often used for conditions such as Parkinson's disease or Huntington's disease, but also refers to a group of extrapyramidal side effects of antipsychotics (EPS), such as tardive dyskinesia (TD). After a brief description of some clinical features of TD, this article summarizes the relatively scarce results of research on a possible link between mainly cytokine levels and TD. This data was found by systematically searching Pubmed and Embase. The limitations of these types of studies are a major obstacle to interpretation. After describing relevant aspects of the neuroinflammatory response and the neuroanatomical backgrounds of EPS, a new hypothesis for the origin of TD is presented with emphasis on dysfunctions in the striosomal compartment of the striatum and the dorsal diencephalic connection system (DDCS). It is postulated that (partly immunologically-induced) increase in oxidative stress and the dopamine-dependent immune response in classic TD proceed primarily via the DDCS, which itself is activated from evolutionarily older parts of the forebrain. Neuroinflammatory responses in the choroid plexus of the third ventricle may contribute due to its proximity to the habenula. It is concluded that direct evidence for a possible role of inflammatory processes in the mechanism of TD is still lacking because research on this is still too much of a niche, but there are indications that warrant further investigation.

PMID:37810262 | PMC:PMC10550815 | DOI:10.1016/j.bbih.2023.100687

Front Cardiovasc Med. 2023 Sep 21;10:1236547. doi: 10.3389/fcvm.2023.1236547. eCollection 2023.

ABSTRACT

BACKGROUND: Statin therapy in multimorbid older individuals with polypharmacy is controversial, particularly in primary prevention of cardiovascular disease. Thereby, physicians must weigh potential benefits against potential side effects, drug-drug interactions, and limited life expectancy.

AIM: To assess the prevalence and determinants of potentially inappropriate statin therapy in multimorbid older patients.

METHODS: We conducted a cross-sectional analysis of patients aged ≥70 years with multimorbidity and polypharmacy in the Swiss study center of OPERAM, a cluster-randomized trial on pharmacotherapy optimization to reduce drug-related hospital admissions. We assessed potential underuse (no statin but formal indication) and potential overuse (statin but no formal indication, including predicted >60% one-year mortality based on the Walter Score) based on current guidelines for patients in secondary and primary cardiovascular prevention. We assessed the association of potential statin overuse and underuse with six patient characteristics (age, gender, number of diagnoses, number of medications, mental impairment, being housebound) in LASSO-selection analyses.

RESULTS: Of 715 multimorbid older adults (79.7 ± 6.5 years, 39.9% women), 337 (47%) were on statin. Statin therapy was appropriate in 474 (66.3%), underused in 130 (18.2%), and overused in 111 (15.5%) patients. In participants in secondary cardiovascular prevention (n = 437), being female (odds ratio [OR] 2.65, 95% confidence interval [CI] 1.67-4.22) was significantly associated with potential underuse while being housebound (OR 3.53, 95%CI 1.32-9.46) and taking ≥10 medications (OR 1.95,95%CI 1.05-3.67) were associated with potential overuse. In participants in primary cardiovascular prevention (n = 278), 28.1% were potentially under- (9%) or overusing (19%) a statin, with no identified risk factor.

CONCLUSION: A third of hospitalized multimorbid older patients with polypharmacy potentially (either) overused or underused statin therapy. Among patients in secondary cardiovascular prevention, women were at risk for potential statin underuse. Housebound patients and those taking ≥10 medications were at risk for potential overuse of a statin. Physicians should carefully evaluate the indication for statin prescription in multimorbid older patients with polypharmacy.

PMID:37808883 | PMC:PMC10551156 | DOI:10.3389/fcvm.2023.1236547

Int Psychogeriatr. 2023 Oct 9:1-4. doi: 10.1017/S1041610223000807. Online ahead of print.

NO ABSTRACT

PMID:37807932 | DOI:10.1017/S1041610223000807

Ophthalmology. 2023 Oct 4:S0161-6420(23)00710-8. doi: 10.1016/j.ophtha.2023.09.031. Online ahead of print.

ABSTRACT

OBJECTIVES: To compare topical PHMB (polihexanide) 0.02% (0.2 mg/ml) + propamidine 0.1% (1 mg/ml) [PHMB 0.02%+propamidine] to PHMB 0.08% (0.8 mg/ml) with placebo [PHMB 0.08%] for Acanthamoeba keratitis (AK) treatment.

DESIGN: Prospective randomized, double-masked, active-controlled, multicentre, Phase3 study (ClinicalTrials.gov NCT03274895).

PARTICIPANTS: 135 at six European centres between 08/17/2017 to 06/18/2021.

METHODS: Principal inclusion criteria: ≥12 years old; in vivo confocal microscopy (IVCM) with clinical findings consistent with AK. Also included were participants with concurrent bacterial keratitis, using topical steroids, antiviral and antifungal drugs before randomisation. Principal exclusions: concurrent herpes or fungal keratitis, use of anti-amoebic therapy (AAT).

RANDOMISATION: 1:1 computer-generated, block size 4. This was a superiority trial having a predefined non-inferiority margin. The sample size of 130 participants gave approximately 80% power to detect 20 percentage point superiority for PHMB 0.08% for the primary outcome of the medical cure rate (without surgery or change of AAT) within 12 months (MCR_12), cure defined by clinical criteria 90 days after discontinuing anti-inflammatories and AAT. A prespecified multivariable analysis adjusted for baseline imbalances in risk factors affecting outcomes.

MAIN OUTCOME MEASURES: The MCR_12. Secondary outcomes included best-corrected visual acuity (BCVA) and treatment failure rates. Safety outcomes included adverse event rates.

RESULTS: 135 participants were randomised providing 127 in the full analysis subset (61 on PHMB 0.02%+propamidine and 66 on PHMB 0.08%) and 134 in the safety analysis subset. The adjusted MCR_12 was 86.6% (unadjusted 88.5%) for PHMB 0.02%+propamidine and 86.7% (unadjusted 84.9%) for PHMB 0.08%; the non-inferiority requirement for PHMB 0.08% was met (adjusted difference 0.1 percentage points, lower one-sided 95% confidence limit -8.3 percentage points). Secondary outcomes were similar for both treatments and not analysed statistically: median BCVA of 20/20, an overall treatment failure rate of 17/127 (13.4%) of whom 8/127 (6.3%) required therapeutic keratoplasty. There were no serious drug related adverse events.

CONCLUSIONS: PHMB 0.08% monotherapy may be as effective (or at worse only eight percentage points less effective) as dual therapy with PHMB 0.02%+propamidine (a widely used therapy) with medical cure rates of >86%, when used with the Trial treatment delivery protocol, in AK populations with similar disease severity.

PMID:37802392 | DOI:10.1016/j.ophtha.2023.09.031

Lancet Gastroenterol Hepatol. 2023 Oct 3:S2468-1253(23)00272-8. doi: 10.1016/S2468-1253(23)00272-8. Online ahead of print.

ABSTRACT

BACKGROUND: Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2c, or 3c. The aim of this phase 2b study was to assess its efficacy and safety in patients with non-alcoholic steatohepatitis (NASH) and moderate (F2) or severe (F3) fibrosis.

METHODS: HARMONY is a multicentre, randomised, double-blind, placebo-controlled, 96-week, phase 2b trial that was initiated at 41 clinics in the USA. Adults with biopsy-confirmed NASH, defined by a non-alcoholic fatty liver disease activity score (NAS) of 4 or higher and scores of 1 or higher in each of steatosis, ballooning, and lobular inflammation, with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive placebo or efruxifermin (28 mg or 50 mg), subcutaneously once weekly. Patients, investigators, pathologists, site staff, and the sponsor were masked to group assignments during the study. The primary endpoint was the proportion of patients with improvement in fibrosis of at least 1 stage and no worsening of NASH, based on analyses of baseline and week 24 biopsies (liver biopsy analysis set [LBAS]). A sensitivity analysis evaluated the endpoint in the full analysis set (FAS), for which patients with missing biopsies were considered non-responders. This trial is registered with ClinicalTrials.gov, NCT04767529, and is ongoing.

FINDINGS: Between March 22, 2021, and Feb 7, 2022, 747 patients were assessed for eligibility and 128 patients (mean age 54·7 years [SD 10·4]; 79 [62%] female and 49 male [38%]; 118 [92%] white; and 56 [41%] Hispanic or Latino) were enrolled and randomly assigned to receive placebo (n=43), efruxifermin 28 mg (n=42; two randomised patients were not dosed because of an administrative error), or efruxifermin 50 mg (n=43). In the LBAS (n=113), eight (20%) of 41 patients in the placebo group had an improvement in fibrosis of at least 1 stage and no worsening of NASH by week 24 versus 15 (39%) of 38 patients in the efruxifermin 28 mg group (risk ratio [RR] 2·3 [95% CI 1·1-4·8]; p=0·025) and 14 (41%) of 34 patients in the efruxifermin 50 mg group (2·2 [1·0-5·0]; p=0·036). Based on the FAS (n=128), eight (19%) of 43 patients in the placebo group met this endpoint versus 15 (36%) of 42 in the efruxifermin 28 mg group (RR 2·2 [95% CI 1·0-4·8]; p=0·033) and 14 (33%) of 43 in the efruxifermin 50 mg group (1·9 [0·8-4·3]; p=0·123). The most frequent efruxifermin-related adverse events were diarrhoea (16 [40%] of 40 patients in the efruxifermin 28 mg group and 17 [40%] of 43 patients in efruxifermin 50 mg group vs eight [19%] of 43 patients in the placebo group; all events except one were grade 1-2) and nausea (11 [28%] patients in the efruxifermin 28 mg group and 18 [42%] patients in the efruxifermin 50 mg group vs ten [23%] patients in the placebo group; all grade 1-2). Five patients (two in the 28 mg group and three in the 50 mg group) discontinued due to adverse events. Serious adverse events occurred in four patients in the 50 mg group; one was defined as drug related (ulcerative esophagitis in a participant with a history of gastro-oesophageal reflux disease). No deaths occurred.

INTERPRETATION: Efruxifermin improved liver fibrosis and resolved NASH over 24 weeks in patients with F2 or F3 fibrosis, with acceptable tolerability, supporting further assessment in phase 3 trials.

FUNDING: Akero Therapeutics.

PMID:37802088 | DOI:10.1016/S2468-1253(23)00272-8

Phytomedicine. 2023 Sep 18;121:155100. doi: 10.1016/j.phymed.2023.155100. Online ahead of print.

ABSTRACT

BACKGROUND: The liver is a well-known player in the metabolism and removal of drugs. Drug metabolizing enzymes in the liver detoxify drugs and xenobiotics, ultimately leading to the acquisition of homeostasis. However, liver toxicity and cell damage are not only related to the nature and dosage of a particular drug but are also influenced by other factors such as aging, immune status, environmental contaminants, microbial metabolites, gender, obesity, and expression of individual genes Furthermore, factors such as drugs, alcohol, and environmental contaminants could induce oxidative stress, thereby impairing the regenerative potential of the liver and causing several diseases. Persons suffering from other ailments and those with comorbidities are found to be more prone to drug-induced toxicities. Moreover, drug composition and drug-drug interactions could further aggravate the risk of drug-induced hepatotoxicity. A plethora of mechanisms are responsible for initiating liver cell damage and further aggravating liver cell injury, followed by impairment of homeostasis, ultimately leading to the generation of reactive oxygen species, immune-suppression, and oxidative stress.

OBJECTIVE: To summarize the potential of phytochemicals and natural bioactive compounds to treat hepatotoxicity and other liver diseases.

STUDY DESIGN: A deductive qualitative content analysis approach was employed to assess the overall outcomes of the research and review articles pertaining to hepatoprotection induced by natural drugs, along with analysis of the interventions.

METHODS: An extensive literature search of bibliographic databases, including Web of Science, PUBMED, SCOPUS, GOOGLE SCHOLAR, etc., was carried out to understand the role of hepatoprotective effects of natural drugs.

RESULTS: Bioactive natural products, including curcumin, resveratrol, etc., have been seen as neutralizing agents against the side effects induced by the drugs. Moreover, these natural products are dietary and are readily available; thus, could be supplemented along with drugs to reduce toxicity to cells. Probiotics, prebiotics, and synbiotics have shown promise of improving overall liver functioning, and these should be evaluated more extensively for their hepatoprotective potential. Therefore, selecting an appropriate natural product or a bioactive compound that is free of toxicity and offers a reliable solution for drug-induced liver toxicity is quintessential.

CONCLUSIONS: The current review highlights the role of natural bioactive products in neutralizing drug-induced hepatotoxicity. Efforts have been made to delineate the possible underlying mechanism associated with the neutralization process.

PMID:37801892 | DOI:10.1016/j.phymed.2023.155100

Anal Bioanal Chem. 2023 Oct 6. doi: 10.1007/s00216-023-04985-0. Online ahead of print.

ABSTRACT

Isoniazid (INH) and pyrazinamide (PZA) are both the first-line anti-tuberculosis drugs in clinical treatment. It is notable that there are serious side effects of the drugs along with upregulation of reactive nitrogen species, mainly including peripheral neuritis, gastrointestinal reactions, and acute drug-induced liver injury (DILI). Among them, DILI is the most common clinical symptom as well as the basic reason of treatment interruption, protocol change, and drug resistance. As vital reactive nitrogen species (RNS), peroxynitrite (ONOO-) has been demonstrated as a biomarker for evaluation and pre-diagnosis of drug-induced liver injury (DILI). In this work, we developed a red-emitting D-π-A type fluorescence probe DIC-NP which was based on 4'-hydroxy-4-biphenylcarbonitrile modified with dicyanoisophorone as a fluorescent reporter and diphenyl phosphinic chloride group as the reaction site for highly selective and sensitive sensing ONOO-. Probe DIC-NP displayed a low detection limit (14.9 nM) and 60-fold fluorescent enhancement at 669 nm in the sensing of ONOO-. Probe DIC-NP was successfully applied to monitor exogenous and endogenous ONOO- in living HeLa cells and zebrafish. Furthermore, we verified the toxicity of isoniazid (INH) and pyrazinamide (PZA) by taking the oxidative stress induced by APAP as a reference, and successfully imaged anti-tuberculosis drug-induced endogenous ONOO- in HepG2 cells. More importantly, we developed a series of mice models of liver injury and investigated the hepatotoxicity caused by the treatment of anti-tuberculosis drugs. At the same time, H&E of mice organs (heart, liver, spleen, lung, kidney) further confirmed the competence of probe DIC-NP for estimating the degree of drug-induced liver injury, which laid a solid foundation for medical research.

PMID:37801118 | DOI:10.1007/s00216-023-04985-0

Clin Geriatr Med. 2023 Nov;39(4):635-645. doi: 10.1016/j.cger.2023.04.008. Epub 2023 May 11.

ABSTRACT

Older adults are given therapies to enhance the quality and longevity of life, but with the benefits of medication therapy also comes the potential for adverse drug events (ADEs). Avoiding ADEs has become a national health priority with substantial impact on health outcomes and health care costs. The presence of multimorbidity, changes in physiologic function, and polypharmacy make older adults more vulnerable to medication-related ADEs. Use of interactive support tools in the form of geriatric-friendly medication order sets and geriatric consultations along with pharmacist-led medication review and optimization are imperative to decrease the occurrence of ADEs and unnecessary prescribing cascades.

PMID:37798069 | DOI:10.1016/j.cger.2023.04.008

Nephrol Ther. 2023 Oct 5;19(6):1-6. doi: 10.1684/ndt.2023.44. Online ahead of print.

ABSTRACT

OBJECTIVE: Data about efficacy and safety of the latest COVID-19 treatments as nirmatrelvir/ritonavir (n/r) or Sotrovimab is scarce in solid organ transplant recipients in the Omicron era. This study aims at describing the outcome of kidney transplant recipients (KTRs) presenting Omicron infection according to their management: n/r, sotrovimab or no specific treatment.

PATIENTS AND METHODS: We conducted a monocentric, retrospective observational study, including KTRs diagnosed Omicron infection between January and May 1st 2022 and compared their outcome (primary outcome defined as hospital admission for COVID-19 within a month after symptoms onset) according to early COVID-19 management.

RESULTS: Forty-five patients were included: 22 treated (12 n/r, 10 sotrovimab) and 23 with no specific treatment. The groups were statistically comparable. Two patients were admitted for COVID-19: one in each group, resulting in a non-different probability of the primary outcome at on month (p=0.9). Three patients presented tacrolimus overdose including two with acute kidney injury.

CONCLUSIONS: There was no difference in outcome according to early therapeutic management: n/r, sotrovimab or no specific treatment. Our study both underlines a decreased severity of Omicron COVID-19 in KTRs (probably related to vaccinal immunity and decreased virulence of Omicron) and a potential severe adverse effects with n/r.

PMID:37795932 | DOI:10.1684/ndt.2023.44

BMJ Open Diabetes Res Care. 2023 Oct;11(5):e003666. doi: 10.1136/bmjdrc-2023-003666.

ABSTRACT

Euglycemic diabetic ketoacidosis (EDKA) is an emerging complication of diabetes associated with an increasing use of sodium-glucose transporter type 2 (SGLT-2) inhibitor drugs. This review highlights the growing incidence of EDKA and its diagnostic challenges due to the absence of hallmark hyperglycemia seen in diabetic ketoacidosis (DKA). The paper presents a classification system for the severity of EDKA, categorizing it into mild, moderate, and severe based on serum pH and bicarbonate levels. Another classification system is proposed to define stages of EDKA based on anion gap and ketones at the time of diagnosis and during the treatment period. A treatment algorithm is proposed to guide clinicians in managing EDKA. This treatment algorithm includes monitoring anion gap and ketones to guide insulin and fluid management, and slower transition to subcutaneous insulin to prevent a relapse. Increased awareness of EDKA is essential for a timely diagnosis because an early diagnosis and treatment can improve clinical outcomes.

PMID:37797963 | DOI:10.1136/bmjdrc-2023-003666

Expert Rev Pharmacoecon Outcomes Res. 2023 Oct 5. doi: 10.1080/14737167.2023.2267176. Online ahead of print.

ABSTRACT

BACKGROUND: The Italian National Health Service (INHS) has recently reimbursed the monoclonal antibody inebilizumab as a second line monotherapy after rituximab use for neuromyelitis optica spectrum disorder (NMOSD) patients ≥18 years anti-aquaporin 4 antibody-immunoglobulin G positive, who experienced a relapse in the last year or cannot receive rituximab, if incident patients.Other INHS-reimbursed drugs for NMOSD treatment are satralizumab, eculizumab and, off-label, besides rituximab, ocrelizumab, tocilizumab, and immunosuppressants.

RESEARCH DESIGN AND METHODS: A 3-year (2023-2025) prevalence-based budget impact model following the INHS viewpoint compared the costs and the NMOSD attacks without (1st scenario) and with inebilizumab (2nd scenario). The epidemiology of NMOSD, and the INHS-funded healthcare resources (drugs and their administration; specialist visits; hospitalizations due to drug-related adverse events and NMOSD attacks) were obtained from the literature.One-way, threshold value and scenario sensitivity analyses investigated the robustness of the baseline findings.

RESULTS: During 2023-2025 inebilizumab saves the INHS €8,373,125.13 (1st scenario: €176,770,028.63; 2nd scenario: €168,396,903.50) and 12.74 NMOSD attacks (1st scenario: 213.94; 2nd scenario: 201.19).Sensitivity analyses confirmed the robustness of the baseline results.

CONCLUSION: Inebilizumab reduces the INHS expenditure for NMOSD drugs. Future research should explore the cost-effectiveness of inebilizumab vs other NMOSD-targeting drugs in Italy.

PMID:37795872 | DOI:10.1080/14737167.2023.2267176

J Pediatr Pharmacol Ther. 2023;28(4):308-315. doi: 10.5863/1551-6776-28.4.308. Epub 2023 Aug 9.

ABSTRACT

OBJECTIVE: This systematic review and meta-analysis aimed to explore rituximab (RTX) associated infectious complications in children with glomerular disease.

METHODS: We performed an electronic search of PubMed, International Scientific Information (ISI), Scopus, and EMBASE between January 2010 and July 2021. Infection rates and total drug-related adverse events were the outcomes. Statistical heterogeneity was evaluated by using the I2 statistic. When there was statistical evidence of heterogeneity (I2 > 50%, p > 0.1), a random-effect model was adopted. Data analysis was performed with Stata17.0 software.

RESULTS: A total of 7 studies with 668 patients (136 with lupus nephritis [LN] and 532 with nephrotic syndrome were included in the meta-analysis. The pooled risk ratio showed that the administration of RTX was significantly associated with lower risk of infectious complications in patients with LN and nephrotic syndrome (0.72 [95% CI 0.58, 0.85]) when compared with population data of patients without glomerular disease (p = 0.2). There was no significant difference between the LN and nephrotic syndrome groups in terms of total serious adverse events or the occurrence of infections. There was significant heterogeneity among the reported studies (Q = 42.39, p < 0.001, I2 = 81%).

CONCLUSION: Administration of RTX in children with glomerular disease is associated with a lower rate of infections when compared with population data of patients without LN or nephrotic syndrome. Additional high-quality randomized controlled trials with long-term follow-up are needed to identify the long-term potential complications. Trial registration PROPERO ID: CRD42021274869 (https://www.crd.york.ac/prospero/display_record.php?).

PMID:37795285 | PMC:PMC10547046 | DOI:10.5863/1551-6776-28.4.308

Eur J Breast Health. 2023 Oct 1;19(4):267-273. doi: 10.4274/ejbh.galenos.2023.2023-7-3. eCollection 2023 Oct.

ABSTRACT

OBJECTIVE: Risk-reducing therapy with selective estrogen receptor (ER) modulators and aromatase inhibitors reduce breast cancer risk. However, the effects are limited to ER-positive breast cancer. Therefore, new agents with improved toxicity profiles that reduce the risk in ER-negative breast cancers are urgently needed. The aim of this prospective, short-term, prevention study was to evaluate the effect of dasatinib, an inhibitor of the tyrosine kinase Src, on biomarkers in normal (but increased risk) breast tissue and serum of women at high risk for a second, contralateral primary breast cancer.

MATERIALS AND METHODS: Women with a history of unilateral stage I, II, or III ER-negative breast cancer, having no active disease, and who completed all adjuvant therapies were eligible. Patients underwent baseline fine-needle aspiration (FNA) of the contralateral breast and serum collection for biomarker analysis and were randomized to receive either no treatment (control) or dasatinib at 40 or 80 mg/day for three months. After three months, serum collection and breast FNA were repeated. Planned biomarker analysis consisted of changes in cytology and Ki-67 on breast FNA, and changes in serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1, and IGF-binding protein 3. The primary objective was to evaluate changes in Ki-67 and secondary objective included changes in cytology in breast tissue and IGF-related serum biomarkers. Toxicity was also evaluated.

RESULTS: Twenty-three patients started their assigned treatments. Compliance during the study was high, with 86.9% (20/23) of patients completing their assigned doses. Dasatinib was well tolerated and no drug-related grade 3 and 4 adverse events were observed. Since only one patient met the adequacy criteria for the paired FNA sample, we could not evaluate Ki-67 level or cytological changes. No significant change in serum biomarkers was observed among the three groups.

CONCLUSION: Dasatinib was well tolerated but did not induce any significant changes in serum biomarkers. The study could not fulfill its primary objective due to an inadequate number of paired FNA samples. Further, larger studies are needed to evaluate the effectiveness of Src inhibitors in breast cancer prevention.

PMID:37795002 | PMC:PMC10546803 | DOI:10.4274/ejbh.galenos.2023.2023-7-3

Bratisl Lek Listy. 2023;124(10):779-782. doi: 10.4149/BLL_2023_120.

ABSTRACT

OBJECTIVES: Ciprofloxacin induces rare neuro-psychiatric adverse drug reactions (ADRs) that are, as yet, not possible to predict due to unknown predisposition factors.

BACKGROUND: The aim of the analysis was to assess the frequency of neuro-psychiatric ADRs and to identify potential risk factors that predisposed patients to ciprofloxacin neurotoxicity.

METHODS: This observational retrospective study involved the evaluation of the medical records of patients in the Nephrology department and 3rd Internal Clinic of the General University Hospital in Prague.

RESULTS: The overall incidence of neurological ADRs was 3.6 %. No neurological ADRs developed in patients aged less than 70 years. The covariates that were significantly more prevalent in the patients who developed neuropsychiatric ADRs were as follows: higher age, a history of neuropsychiatric disorders and the use of anticonvulsants. The administration of drugs from other ATC groups, gender, weight, body mass index, body surface area, renal functions, level of C-reactive protein at the beginning of treatment and the total daily dose/kg did not differ significantly between the two groups.

CONCLUSION: Ciprofloxacin neuropsychiatric ADRs are more frequent in older patients with a history of neurologic or psychiatric disorders. No other tested covariates were proven to predispose patients to neuropsychiatric ADRs during treatment with ciprofloxacin (Tab. 2, Ref. 20).

PMID:37789796 | DOI:10.4149/BLL_2023_120

Reg Anesth Pain Med. 2023 Oct 4:rapm-2023-104830. doi: 10.1136/rapm-2023-104830. Online ahead of print.

NO ABSTRACT

PMID:37793914 | DOI:10.1136/rapm-2023-104830