Lancet Haematol. 2022 Nov 9:S2352-3026(22)00292-7. doi: 10.1016/S2352-3026(22)00292-7. Online ahead of print.

ABSTRACT

BACKGROUND: Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1.

METHODS: In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia or intermediate, high, or very high risk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibility criteria included Eastern Cooperative Oncology Group performance status 0-2 with adequate liver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose of olutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily, 150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously daily for 7 days on, 21 days off. The study was ongoing at the data cutoff (Oct 2, 2019) and is registered with ClinicalTrials.gov, NCT02719574.

FINDINGS: Patients were enrolled between Aug 8, 2016, and Nov 14, 2018. 78 patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). The median follow-up was 8·3 months (IQR 3·1-13·3) for monotherapy and 10·1 months (4·2-15·3) for combination therapy. 16 (50%) of 32 patients in the monotherapy group and 24 (52%) of 46 patients in the combination therapy group were women. Most patients were White (26 [81%] for monotherapy and 31 [67%] for combination therapy). No dose-limiting toxicities were reported in the dose-escalation cohorts and 150 mg twice per day was declared the recommended phase 2 dose on the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity. The most common (≥20%) grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients), febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and with combination therapy were thrombocytopenia (19 [41%] of 46), febrile neutropenia (13 [28%] of 46), neutropenia (13 [28%] of 46), and anaemia (nine [20%] of 46). 11 (34%) of 32 patients in the monotherapy group and nine (20%) of 46 patients in the combination therapy group died (most commonly from disease progression [three (9%) of 32 and four (9%) of 46]). No deaths were considered study-drug related. For patients with relapsed or refractory acute myeloid leukaemia, 41% (95% CI 21-64; nine of 22) receiving monotherapy and 46% (27-67; 12 of 26) receiving combination therapy had an overall response. For treatment-naive patients with acute myeloid leukaemia, 25% (1-81; one of four) receiving monotherapy and 77% (46-95; ten of 13) receiving combination therapy had an overall response.

INTERPRETATION: Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies.

FUNDING: Forma Therapeutics.

PMID:36370742 | DOI:10.1016/S2352-3026(22)00292-7

Respir Med Res. 2022 Nov 8;82:100969. doi: 10.1016/j.resmer.2022.100969. Online ahead of print.

ABSTRACT

BACKGROUND: Anticancer immune-checkpoint inhibitors (ICI) can cause immune-related adverse events (irAEs), including interstitial pneumonitis, which is managed chiefly with systemic corticosteroids. When corticosteroids fail, second-line immunosuppressive therapy is indicated. Our objective was to evaluate the prevalence and outcomes of ICI-induced pneumonitis requiring second-line immunosuppressive therapy (IS).

METHODS: We collected data form the REISAMIC pharmacovigilance registry and the multidisciplinary immunological toxicity board at Gustave Roussy (France). No response to steroids was called steroid-refractory pneumonitis and relapse after an initial response was defined as steroid-resistant pneumonitis.

RESULTS: Of the 1187 patients screened from the REISAMIC register, 48 (4%) patients had pneumonitis treated with corticosteroids. Five of them (10%) had corticosteroid refractory/resistant disease but only 2 were treated with immunosuppressive therapy. Four additional patients requiring immunosuppressive therapy identified via the immunological toxicity board were included. Immunosuppressive therapy were cyclophosphamide (n=4 pts), infliximab (n=1 pt), intravenous immunoglobulins (n=1 pt). Five of these six patients had corticosteroid-refractory disease and one had corticosteroid-resistant pneumonitis. Five patients had severe pneumonitis (Common Terminology Criteria for Adverse Events grade ≥3) at initial pneumonitis diagnosis. Two months mortality rate in patients treated with IS was 67% (4/6). Among the patients treated with IS, the two patients alive at 5 months were treated with cyclophosphamide.

CONCLUSION: Patients with ICI-pneumonitis treated by steroids received IS in 10% of cases. High mortality at 67% of patients was observed in ICI-pneumonitis after steroid failure. Cyclophosphamide could be a treatment option for pneumonitis after corticosteroid failure that requires further investigations.

PMID:36370683 | DOI:10.1016/j.resmer.2022.100969

Eur J Cancer. 2022 Oct 19;178:1-12. doi: 10.1016/j.ejca.2022.10.004. Online ahead of print.

ABSTRACT

BACKGROUND: KN026 is a novel human epidermal growth factor receptor 2 (HER2)-targeted bispecific antibody that binds two distinct domains of HER2. We report the safety and efficacy results of the phase 2 trial in patients with advanced HER2-expressing gastric or gastroesophageal junction cancer who failed from at least one prior line of standard treatment.

MATERIAL AND METHODS: In this open-label, multicentre, phase 2 trial, eligible patients were enrolled in the high-level HER2 cohort or low-level HER2 cohort and assigned to receive KN026 10 mg/kg (once a week), 20 mg/kg (once every two weeks) or 30 mg/kg (once every three weeks) intravenously. The primary end-points were the objective response rate (ORR) and duration of response assessed according to Response Evaluation Criteria in Solid Tumours (version 1.1).

RESULTS: Between 17th June 2019 and 23rd August 2021, 45 patients were enrolled and received at least one dose of KN026, including 27 patients in the high-level HER2 cohort, 14 patients in the low-level HER2 cohort and four patients who had no HER2 expression. The ORR in the high-level HER2 cohort was 56% (95% confidence interval [CI] 35%-76%), with a durable response duration of 9.7 months (95% CI 4.2-not evaluable); while for the patients with low-level HER2, the ORR was 14% (95% CI 2%-43%). The most frequent ≥ grade 3 treatment-emergent adverse events were gastrointestinal disorders (five patients, 11%). No drug-related deaths were reported.

CONCLUSIONS: KN026 showed a favourable safety profile and promising anti-tumour activity. Our results support further studies evaluating KN026 and the combination treatment with other active drugs in patients with advanced gastric or gastroesophageal junction cancer having high-level HER2 expression.

PMID:36370604 | DOI:10.1016/j.ejca.2022.10.004

Soc Sci Med. 2022 Dec;314:115484. doi: 10.1016/j.socscimed.2022.115484. Epub 2022 Nov 3.

ABSTRACT

Recent decades' hospital closures and consolidations have been rationalized with reference to arguments of efficiency and quality returns to scale and scope. However, closures are met with public outcry from patients living in areas affected by such closures if accompanying increases in travel time are not offset by a higher quality of care. It is broadly established that increases in patients' travel time to acute care lower the probability of survival, but in non-acute and scheduled care we lack knowledge about the quality of care that patients living in closure-affected areas receive. In the non-acute setting of scheduled breast cancer surgery, this study examines how hospital clinic closures affect the quality of care that closure-affected patients receive. The effects are identified using closures of breast cancer clinics in Denmark from 2000 to 2011, during which time the number of clinics was more than halved. Using event study designs on population-wide Danish register data from 1996 to 2014, this study examine changes in surgical outcomes for 9790 patients living in municipalities where the nearest clinic has been closed. The results show that closures have reduced the number of hospitalization days and shifted surgical procedures to state-of-the-art breast-conserving techniques without generating adverse health effects and without causing crowding in non-closing clinics. An examination of the mechanisms suggests that added volume returns at non-closing clinics were of less importance than simply reallocating patients to higher-quality clinics. Closures of clinics performing scheduled surgery may be an effective policy instrument if the goal is to reduce variation in the delivery of hospital care. Increased access to state-of-the-art care may counterbalance patients' concerns of losing their local clinic. However, if the clinics to be closed are small compared to non-closing clinics then there is no potential for added economies of scale or scope in non-closing clinics.

PMID:36368239 | DOI:10.1016/j.socscimed.2022.115484

BMC Cardiovasc Disord. 2022 Nov 11;22(1):480. doi: 10.1186/s12872-022-02937-7.

ABSTRACT

BACKGROUND: Adverse drug reaction (ADR) of medications remains an obstacle to achieving optimal disease outcomes. This study aimed to assess the prevalence and associated factors of ADR among Heart failure (HF) patients hospitalized at Mbarara Regional and Referral Hospital.

METHOD: A prospective observational study was conducted among hospitalized HF patients from November 2021 to January 2022. Univariate and multivariate logistic regression was employed to determine factors associated with the ADR.

RESULT: Overall, 118 HF patients were included in the study with a median age of 43 years. A total of 164 ADRs were identified during the follow-up period of 1011 days. The incidence of new ADRs was 106 ADRs/1000 person-days. The prevalence of ADR was 59.3%. Of the 164 ADRs, 118(71.9%) were probable. The gastrointestinal system was the most frequently (27.5%) affected system. Over half (86, 52.4%) of the ADRs were mild and 96(58.5%) were preventable. Age group 19-59(AOR 0.15[0.03-0.35] at 95%CI, p = 0.013), herbal use (AOR 3.07[1.01-9.32] at 95%CI, p = 0.048), poly-pharmacy (AOR 8.7[2.4-15.77] at 95%CI, p < 0.001) and drug-drug interaction (AOR 6.06[2.79-12.5] at 95%CI, p = 0.004) were significantly associated with ADRs among HF patients.

CONCLUSION: More than half of the hospitalized HF patients experienced at least one ADR during their hospital stay. The use of herbal medicines, poly-pharmacy, and drug-drug interaction were associated with a high risk of ARDs whereas the age group 19-59 years was less likely to experience ADRs.

PMID:36368954 | DOI:10.1186/s12872-022-02937-7

Molecules. 2022 Oct 25;27(21):7242. doi: 10.3390/molecules27217242.

ABSTRACT

The liver is a crucial organ among body organs due to its wide functions, in particular, detoxification and metabolism. Exposure to detrimental chemicals or viral infections may provoke liver dysfunction and ultimately induce liver tissue damage. Finding natural substances for liver disease treatment to overcome the conventional treatments' side effects has attracted the attention of researchers worldwide. Our current work was conducted to investigate the hepato-therapeutic activities of essential oil (EO) isolated from Tagetes patula flowers. EO was extracted using the hydro-distillation (HD) technique and its chemical composition was identified by GC/MS. Then, the hepatic treatment potential of extracted EO was evaluated in vivo against CCL4 in rats. HD of T. patula flowers yielded highly chemical constituents of EO along with significant antioxidant potential. A coherent molecular network was fashioned via the Global Natural Products Social Molecular Networking (GNPS) to visualize the essential components and revealed that the sesquiterpene (E)-β-caryophyllene was the most predominant volatile constituent which accounted for 24.1%. The treatment of CCL4 led to significant induced oxidative stress markers malonaldehyde, total protein, and non-protein sulfhydryl, as well as elevated serum aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and bilirubin. In addition, it disrupted the level of lipid profile. The post-treatment using T. patula EO succeeded in relieving all toxic effects of CCl4 and recuperating the histopathological signs induced by CCL4. Silymarin was used as a standard hepatoprotective agent. The obtained results demonstrated that the extracted EO exerted high protective activities against the toxicity of CCL4. Moreover, the T. patula flowers EO can be used as a natural remedy to relieve many contemporary liver diseases related to oxidative stress.

PMID:36364067 | DOI:10.3390/molecules27217242

Medicina (Kaunas). 2022 Nov 7;58(11):1609. doi: 10.3390/medicina58111609.

ABSTRACT

Background and Objectives: Acne vulgaris is one of the most common dermatological disorders among adolescents and adults in the Kingdom of Saudi Arabia (KSA). Isotretinoin is a cost-effective way of treating severe acne patients compared to other methods used for severe forms of acne management. The present study investigated the knowledge of the use of isotretinoin and its side effects among female acne patients of the reproductive age group who were on isotretinoin. This study also assessed participants' awareness of the Saudi FDA-Pregnancy Prevention Program (SFDA-PPP). Materials and Methods: The present population-based cross-sectional survey was conducted among 768 participants using a standard and validated Arabic version questionnaire. We have applied logistic regression analysis to determine the predictors for awareness of SFDA-PPP. A Chi-square test was applied to identify the factors associated with knowledge related to isotretinoin. Results: Regarding the side effects of isotretinoin, participated female acne patients were most commonly aware of dry mouth and lips (84.5%), teratogenicity (68.2%), and headache (44.8%). Nearly 60% of the participants belonged to the low knowledge category. The present study participants' knowledge was significantly associated with education status (p = 0.007), occupation (p = 0.01), and those participants who were aware of SFDA-PPP (p = 0.001). Furthermore, we explored that only 37.5% were aware of the SFDA-PPP program implemented in Saudi Arabia. The awareness of SFDA-PPP was significantly higher among those participants belonging to health sectors (Adjusted OR (95% CI) = 1.39 (1.01-1.92), p = 0.049). Conclusion: The present survey explored inadequate knowledge among reproductive age group female acne patients regarding isotretinoin uses, precautions to be followed, and side effects, especially teratogenic effects. This survey findings suggest that improving female acne patients' knowledge of isotretinoin through health promotion activities is crucial, especially by giving them precise instructions about the teratogenic effects.

PMID:36363566 | DOI:10.3390/medicina58111609

Medicina (Kaunas). 2022 Oct 26;58(11):1530. doi: 10.3390/medicina58111530.

ABSTRACT

Drugs and various medical substances have been used for many decades to diagnose or treat diseases. Procedures like surgery and anesthesia (either local or general) use different pharmacological products during these events. In most of the cases, the procedure is safe and the physician performs the technique without incidents. Although they are safe for use, these substances (including drugs) may have adverse effects, varying from mild ones to life-threatening reactions in a minority of patients. Artificial intelligence may be a useful tool in approximating the risk of anaphylaxis before undertaking a medical procedure. This material presents these undesirable responses produced by medical products from a multidisciplinary point of view. Moreover, we present a proof of concept for using artificial intelligence as a possible guardship against intraoperative anaphylaxis.

PMID:36363487 | DOI:10.3390/medicina58111530

Int J Mol Sci. 2022 Nov 7;23(21):13653. doi: 10.3390/ijms232113653.

ABSTRACT

Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature.

PMID:36362438 | DOI:10.3390/ijms232113653

Eur J Hosp Pharm. 2022 Nov 11:ejhpharm-2022-003596. doi: 10.1136/ejhpharm-2022-003596. Online ahead of print.

NO ABSTRACT

PMID:36368879 | DOI:10.1136/ejhpharm-2022-003596

BMJ Open Diabetes Res Care. 2022 Nov;10(6):e003062. doi: 10.1136/bmjdrc-2022-003062.

ABSTRACT

INTRODUCTION: Painful diabetic peripheral neuropathy (PDPN), a common complication of diabetes mellitus, is challenging to treat. Efficacy and tolerability of the topical lidocaine 700 mg medicated plaster (LMP) and well-established first-line oral medications (OM) were compared in refractory PDPN patients.

RESEARCH DESIGN AND METHODS: This is a subgroup analysis of a non-interventional, retrospective 24-week cohort study using anonymized routine medical care data from the German Pain eRegistry. Propensity score matching provided 732 datasets per treatment group. Primary effectiveness endpoint was the absolute change in average 24-hour Pain Intensity Index (0-100 mm) from baseline after 4, 12 and 24 weeks of treatment and over the entire treatment period.

RESULTS: The majority of this multimorbid and polymedicated study population of patients with PDPN had suffered pain for more than a year and presented with a high pain burden despite a median of seven previous analgesic medications. LMP treatment resulted in significant reductions in pain intensity and improvements in daily functioning already after 4 treatment weeks. Effectiveness was maintained over the treatment period even when concomitant analgesics were reduced or discontinued and quality of life improved. Mean change in the primary effectiveness parameter over the 24-week treatment period was -30.2 mm (SE 0.38) and -17.0 mm (SE 0.51) in the LMP and OM groups, respectively. Improvements in all effectiveness parameters were significantly greater under LMP than under OM treatment (p<0.001). Significantly fewer patients under LMP than OM experienced drug-related adverse events (DRAEs; 9.6% vs 61.6%, p<0.001) and discontinued treatment due to DRAEs (4.4% vs 35.8%, p<0.001).

CONCLUSIONS: LMP was effective and well tolerated in routine clinical care of patients with PDPN. The more favorable benefit/risk profile and greater reduction in intake of concomitant analgesics compared with OM suggest LMP as a useful treatment option for PDPN.

TRIAL REGISTRATION NUMBER: EUPAS 32826.

PMID:36368741 | DOI:10.1136/bmjdrc-2022-003062

Nutrients. 2022 Nov 3;14(21):4651. doi: 10.3390/nu14214651.

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease. In the absence of targeted therapies, it invariably progresses to advanced chronic kidney disease. To date, the only approved treatment is tolvaptan, a vasopressin V2 receptor antagonist that has been demonstrated to reduce cyst growth and attenuate the decline in kidney function. However, it has various side effects, the most frequent of which is aquaresis, leading to a significant discontinuation rate. The strategies proposed to combat aquaresis include the use of thiazides or metformin and a reduction in the dietary osmotic load. Beyond the prescription of tolvaptan, which is limited to those with a rapid and progressive decline in kidney function, dietary interventions have been suggested to protect against disease progression. Moderate sodium restriction, moderate protein intake (up to 0.8 g/kg/day), avoidance of being overweight, and increased water consumption are recommended in ADPKD guidelines, though all with low-grade evidence. The aim of the present review is to critically summarize the evidence on the effect of dietary modification on ADPKD and to offer some strategies to mitigate the adverse aquaretic effects of tolvaptan.

PMID:36364911 | DOI:10.3390/nu14214651

J Clin Med. 2022 Oct 24;11(21):6265. doi: 10.3390/jcm11216265.

ABSTRACT

Three types of enzyme replacement therapies (ERTs) and two substrate reduction therapies (SRTs) are approved for symptomatic patients with type 1 Gaucher disease (GD1). Eliglustat is the second SRT approved, yet the first to be approved as first-line therapy for any adult patients with compatible CYP2D6 metabolizer genotype. Herein we report safety and efficacy data of the first 29 patients switched from ERT to eliglustat from the Gaucher Unit at Shaare Zedek Medical Center (SZMC) between 07/2017 and 06/2022; the median (range) time on ERT was 13 (0.66-30) years, and the median (range) time on eliglustat was 7 (1-52) months. Most patients switched due to oral preference or sub-optimal response to low-dose ERT. Twelve patients stopped eliglustat after a median (range) of 4 (1-18) months; 11 due to adverse events (AEs) and one due to personal request. There were no drug-related serious AEs and no drug-related cardiac events. Most AEs were mild and transient, mainly dyspepsia. Efficacy achievements were reflected by maintaining stability. We concluded that switching from ERT to eliglustat is safe if choosing the appropriate patients. Reassuring patients to tolerate early AEs may reduce discontinuation. Following the response and compliance to therapy is important to ensure long-term efficacy.

PMID:36362492 | DOI:10.3390/jcm11216265

Neurol India. 2022 Sep-Oct;70(5):2031-2038. doi: 10.4103/0028-3886.359162.

ABSTRACT

BACKGROUND: Although epilepsy is a common neurological condition, there is paucity of nationwide data on treatment patterns and sociodemographic and clinical factors affecting treatment decisions in India.

OBJECTIVE: To assess clinical profiles, usage pattern of antiepileptic drugs (AEDs), and seizure control among patients with epilepsy in India.

METHODS: This was a cross-sectional, observational, multicenter study on adult patients with epilepsy who were on AEDs for at least six months before enrollment. Data were collected from patient interviews and medical records.

RESULTS: Out of 800 enrolled patients, a majority (69.0%) had generalized onset seizure in the six months before enrollment. The median age at epilepsy onset was 20.0 (1.0-64.0) years; 40.0% of the patients were females, 48.5% were married, 99.1% were literate, and 67.0% belonged to the lower or upper-middle socioeconomic class. Overall, 459 patients (57.4%) received AEDs as combination therapy. Most patients received levetiracetam (37.0%), sodium valproate (18.5%), carbamazepine (17.3%), or phenytoin (13.8%) as monotherapy, and clobazam (59.7%), levetiracetam (52.9%), carbamazepine (26.4%), sodium valproate (24.8%), or phenytoin (24.0%) in combination therapy. Quality of life was comparable for first- and third-generation AEDs. Adverse drug reactions were mostly attributed to dose modification or switching between drugs. No serious adverse drug reactions or new safety concerns were identified.

CONCLUSIONS: Findings from this large, cross-sectional, observational, multicenter study indicate that first-generation AEDs sodium valproate and phenytoin continued to be used in a substantial number of patients on monotherapy and combination therapy in India, even though an increasing trend toward use of second-generation AEDs was noted in clinical practice.

PMID:36352605 | DOI:10.4103/0028-3886.359162

Med J Aust. 2022 Nov 10. doi: 10.5694/mja2.51776. Online ahead of print.

NO ABSTRACT

PMID:36356936 | DOI:10.5694/mja2.51776

Blood Adv. 2022 Nov 10:bloodadvances.2022008209. doi: 10.1182/bloodadvances.2022008209. Online ahead of print.

ABSTRACT

Crizanlizumab is an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, non randomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety and efficacy of crizanlizumab 5.0 (N = 45) and 7.5 (N = 12) mg/kg in SCD patients with a history of VOCs (NCT03264989). Median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion and near complete and sustained ex vivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only one event was deemed treatment related (7.5 mg/kg group). No treatment-related serious AEs (SAEs) occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 'pain during infusion'), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug related. No treatment-related bleeding events were reported. No patients developed immunogenicity. Median (range) absolute reduction from baseline in annualized rate of VOCs leading to a healthcare visit was -0.88 (-14.7 to 13.3) and -0.93 (-2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in SCD patients, and the potential sustained efficacy and long-term safety of the drug after >12 months' treatment. This trial is registered at www.clinicaltrials.gov as NCT03264989.

PMID:36355805 | DOI:10.1182/bloodadvances.2022008209

J Mater Chem B. 2022 Nov 10. doi: 10.1039/d2tb02121h. Online ahead of print.

ABSTRACT

To date, cancer therapies largely consist of five pillars: surgery, radiation, chemotherapy, targeted therapy, and immunotherapy. Still, researchers are trying to innovate the current cancer therapies to pursue an ideal one without side effects. For developing such a therapy, we designed a chemically well-defined route to a PEG- and docetaxel (DTX)-conjugated inorganic polymer, polyphosphazene, named "polytaxel (PTX)" with a prolonged blood circulation time and tumor localization. Here, we conducted the proof-of-concept study of the ideal therapy in orthotopic and xenograft pancreatic cancer models. We found that the average tumor inhibition rates of PTX were similar to those of DTX without any DTX toxicity-related side effects, such as neutropenia and weight loss. In conclusion, PTX met the requirements of an ideal anticancer drug with high anticancer efficacy and 100% survival rate. PTX is expected to replace any existing anticancer therapies in clinical practice.

PMID:36354057 | DOI:10.1039/d2tb02121h

Curr Opin Support Palliat Care. 2022 Dec 1;16(4):216-222. doi: 10.1097/SPC.0000000000000624.

ABSTRACT

PURPOSE OF REVIEW: Androgen-deprivation therapy (ADT) is widely employed for treatment of advanced prostate cancer and it is considered the frontline therapy. However, the numerous adverse reactions associated with this treatment option are concerning and its potential association with cardiovascular diseases (CVD) should not be overlooked. In this review, we examine the literature on the cardiovascular side effects of ADT and the physiologic mechanisms underpinning the association with CVD. We will also specifically discuss the different findings regarding the interesting potential disparity in major cardiovascular events among GnRH agonist-treated patients compared with patients undergoing GnRH antagonist treatment.

RECENT FINDINGS: Androgen-deprivation therapy increases the risk of developing CVD by altering the body composition, metabolism, vascular system, and cardiac physiology. GnRH agonists may pose a higher risk of cardiovascular mortality and morbidity than GnRH antagonists; however, this link remains to be determined. Furthermore, screening for cardiovascular risk factors before and during ADT treatment is a crucial step in preventing major adverse cardiac events in prostate cancer patients. Notably, preexisting CVD and comorbidities have been identified as major key elements predicting cardiovascular events. Early implementation of pharmacological and nonpharmacological treatment strategies is strongly suggested, and regular follow-up visits should be scheduled to continuously assess patients' cardiovascular risk under ADT.

SUMMARY: ADT is a very powerful treatment option for advanced prostate cancer that improves survival outcomes but has the potential of considerably impacting patients' cardiovascular health. Medical optimization and close monitoring are crucial during treatment with ADT.

PMID:36349380 | DOI:10.1097/SPC.0000000000000624

Drug Ther Bull. 2022 Nov 9:dtb-2022-000061. doi: 10.1136/dtb.2022.000061. Online ahead of print.

ABSTRACT

Overview of: Zeng C, Rosenberg L, Li X, et al Sodium-containing acetaminophen and cardiovascular outcomes in individuals with and without hypertension. Eur Heart J 2022;43:1743-55.

PMID:36351781 | DOI:10.1136/dtb.2022.000061

BMC Geriatr. 2022 Nov 7;22(1):841. doi: 10.1186/s12877-022-03536-z.

ABSTRACT

BACKGROUND: Polypharmacy can be defined as using five or more medications simultaneously. "Medication-related problems", an extension of polypharmacy, includes inappropriate prescribing, poor adherence, overdosage, underdosage, inappropriate drug selection, inadequate monitoring, adverse drug effects, and drug interactions. Polypharmacy and the high risk of medication-related problems among older people are associated with adverse health consequences due to drug-drug interactions, drug-disease interactions, and adverse drug effects. This study aims to assess the factors associated with polypharmacy and the high risk of medication-related problems among community-dwelling older people in the Netherlands, Greece, Croatia, Spain, United Kingdom.

METHOD: This longitudinal study used baseline and follow-up data from 1791 participants of the Urban Health Center European project. Polypharmacy and the risk of medication-related problems were evaluated at baseline and follow-up using the Medication Risk Questionnaire. We studied factors in the domains (a) sociodemographic characteristics, (b) lifestyle and nutrition, and (c) health and health care use. Hierarchical logistic regression analyses were used to examine the factors associated with polypharmacy and the high risk of medication-related problems.

RESULTS: Mean age was 79.6 years (SD ± 5.6 years); 60.8% were women; 45.2% had polypharmacy, and 41.8% had a high risk of medication-related problems. Women participants had lower odds of polypharmacy (OR = 0.55;95%CI:0.42-0.72) and a high risk of medication-related problems (OR = 0.50; 95%CI:0.39-0.65). Participants with a migration background (OR = 1.67;95%CI:1.08-2.59), overweight (OR = 1.37; 95%CI:1.04-1.79) and obesity (OR = 1.78;95%CI:1.26-2.51) compared to 'normal weight', with lower physical HRQoL (OR = 0.96, 95%CI:0.95-0.98), multi-morbidity (OR = 3.73, 95%CI:2.18-6.37), frailty (OR = 1.69, 95%CI:1.24-2.30), visited outpatient services (OR = 1.77, 95%CI: 1.09-2.88) had higher odds of polypharmacy. The associations with the high risk of medication-related problems were similar.

CONCLUSIONS: Multiple factors in demography, lifestyle, nutrition, and health care use are associated with polypharmacy and the high risk of medication-related problems. Polypharmacy is a single element that may reflect the number of medications taken. The broader content of medication-related problems should be considered to assess the context of medication use among older people comprehensively. These provide starting points to improve interventions to reduce polypharmacy and high risk of medication-related problems. In the meantime, health professionals can apply these insights to identify subgroups of patients at a high risk of polypharmacy and medication-related problems.

TRIAL REGISTRATION: The intervention of the UHCE project was registered in the ISRCTN registry as ISRCTN52788952. The date of registration is 13/03/2017.

PMID:36344918 | DOI:10.1186/s12877-022-03536-z