Am J Gastroenterol. 2022 Dec 1;117(12):1917-1932. doi: 10.14309/ajg.0000000000001983. Epub 2022 Aug 22.

NO ABSTRACT

PMID:36455219 | DOI:10.14309/ajg.0000000000001983

PLoS One. 2022 Dec 1;17(12):e0275321. doi: 10.1371/journal.pone.0275321. eCollection 2022.

NO ABSTRACT

PMID:36454979 | DOI:10.1371/journal.pone.0275321

Forensic Toxicol. 2022 Jan;40(1):180-188. doi: 10.1007/s11419-021-00591-w. Epub 2021 Aug 11.

NO ABSTRACT

PMID:36454486 | PMC:PMC9715448 | DOI:10.1007/s11419-021-00591-w

Pak J Pharm Sci. 2022 Sep;35(5):1363-1369.

ABSTRACT

Acyclovir (ACY) is an antiviral class of drugs used to treat herpes simplex virus infections such as herpes simplex encephalitis (HSE). ACY is widely distributed; Systemic exposure of ACY leads to serious adverse effects. Because of its high pH, intravenous ACY may cause phlebitis and local inflammation if extravasation occurs. This study aims to enhance acyclovir delivery to the brain via the intranasal route by formulating ACY nano lipid carriers (ACY-NLCs) to circumvent the side-effects, as mentioned earlier. ACY-NLCs were prepared by emulsification, followed by ultrasonication. A Box-Behnken statistical design with three factors, three levels and 17 runs was selected for the optimization study using Design- Expert Software. Nanoparticles were characterized for particle size, entrapment efficiency and in-vitro drug release. ACY- NLC showed biphasic release pattern i.e. an initial faster release followed by sustained release. Biodistribution study by imaging, Nanoparticles were slowly cleared and biodistributed to the other organs was observed in 2nd and 3rd hr post-administration. From the toxicity studies, NLC formulation is safe and non-toxic for the nasal administration. Rhodamine loaeded NLCs were quickly adsorbed by the olfactory tract and distributed mainly to the lungs through respiratory tract and were also detected in the trachea and olfactory bulb. Biodistribution study of dye loaded NLCs reach brain compared to the Rhodamine-solution.

PMID:36451565

Medicine (Baltimore). 2022 Nov 25;101(47):e31885. doi: 10.1097/MD.0000000000031885.

ABSTRACT

BACKGROUND: Threatened miscarriage (TM) is an important factor endangering the health of pregnant women. It not only affects women's physical and mental health, but also destroys family happiness. To treat this disease, it is necessary to find a treatment with better clinical efficacy and fewer side effects. The purpose of this systematic study was to evaluate the efficacy and safety of phloroglucinol (PHL) combined with progesterone in the treatment of TM before 20 weeks of pregnancy.

METHODS: Electronic databases (EMBASE, PubMed, Cochrane Central Register of Controlled Trials, Web of Science, Elsevier, China National Knowledge Infrastructure, Chongqing VIP, and WanFang Data) were searched from inception until September. 2022. Randomized controlled trials of PHL combined with progesterone in the treatment of TM before 20 weeks of gestation will be included, and all articles will be independently screened and collected by 2 reviewers. Revman 5.3.5 software will be used for meta-analysis. The specific process is described in the Cochrane Handbook for Systematic Reviews.

RESULTS: The efficacy and safety of PHL combined with progesterone for the treatment of threatened abortion were comprehensively evaluated in terms of efficacy, efficiency, time of symptom relief, length of hospital stay, and incidence of adverse events.

CONCLUSION: This study provides reliable evidence for the clinical application of PHL combined with progesterone for the treatment of TM.

PMID:36451473 | DOI:10.1097/MD.0000000000031885

Anticancer Res. 2022 Dec;42(12):6127-6134. doi: 10.21873/anticanres.16126.

ABSTRACT

BACKGROUND/AIM: Surgical resection remains the mainstay of treatment for hepatocellular carcinoma (HCC). However, reducing the risk of postoperative recurrence is urgently needed. We planned a prospective observational study to investigate the efficacy and safety of adding sorafenib in a maintenance setting after surgery in HCC patients with high risk of recurrence.

PATIENTS AND METHODS: Patients with HCC (invasion of the hepatic vein or inferior vena cava or tumor size >7 cm or tumor to nontumor standardized uptake value ratio >2 by fluorodeoxyglucose positron emission tomography) who underwent macroscopically curative resection were eligible. Dose and schedule of sorafenib were set at 800 mg/day for six months after hepatic resection. The primary endpoint was progression-free survival, and the secondary endpoints were overall survival and safety. This study was registered with the UMIN Clinical Trials Registry (UMIN000013089).

RESULTS: Ten patients were evaluated. Six patients completed the pre-planned treatment. Three patients discontinued treatment because of disease progression (lung metastasis in two patients and liver metastasis in one), and one patient discontinued because of pneumonia. The most common drug-related adverse event was increased γ-glutamyl transpeptidase (γGTP). None of the patients suffered grade 4 adverse events. The median progression-free survival was 380 (range=38-1,555) days. The median overall survival was 1000 (range=850-1,705) days. Four patients survived without disease progression for more than 800 days.

CONCLUSION: Although the sample size was limited, this is the first study to demonstrate the safety and efficacy of sorafenib in a maintenance setting after surgery for HCC patients with high risk of recurrence.

PMID:36456121 | DOI:10.21873/anticanres.16126

ESMO Open. 2022 Nov 28;7(6):100645. doi: 10.1016/j.esmoop.2022.100645. Online ahead of print.

ABSTRACT

BACKGROUND: The PEOPLE trial aimed to identify new immune biomarkers in negative and low programmed death-ligand 1 (PD-L1) (0%-49%) advanced non-small-cell lung cancer (aNSCLC) patients treated with first-line pembrolizumab. Here we report the main outcomes and the circulating immune biomarkers analysis.

PATIENTS AND METHODS: The primary endpoint of this phase II trial was the identification of immune biomarkers associated with progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety were secondary endpoints. Absolute cell counts for 36 subsets belonging to innate and adaptive immunity were determined by multiparametric flow cytometry in peripheral blood at baseline and at first radiologic evaluation. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyze immune variables and their correlation with clinical endpoints.

RESULTS: From May 2018 to October 2020, 65 patients were enrolled. After a median follow-up of 26.4 months, the median PFS was 2.9 months [95% confidence interval (CI) 1.8-5.6 months] and median OS was 12.1 months (95% CI 8.7-17.1 months). The ORR was 21.5%, DCR was 47.7% and median DoR was 14.5 months (95% CI 6.4-24.9 months). Drug-related grade 3-4 adverse events were 9.2%. Higher T cell and natural killer (NK) cell count at baseline and at the first radiologic evaluation were associated with improved PFS, DCR and OS. On the contrary, higher myeloid cell count at baseline or at the first radiologic evaluation was significantly associated with worse OS and DCR.

CONCLUSIONS: Circulating immune biomarkers can contribute to predict outcomes in negative and low PD-L1 aNSCLC patients treated with first-line single-agent pembrolizumab.

PMID:36455507 | DOI:10.1016/j.esmoop.2022.100645

Br J Clin Pharmacol. 2022 Dec 1. doi: 10.1111/bcp.15621. Online ahead of print.

ABSTRACT

AIM: To identify older patients' risk factors for drug-related readmissions and 2) to assess the preventability of older patients' drug-related revisits.

METHODS: Post-hoc analysis of a randomised clinical trial with patients aged ≥ 65 years at eight wards within four hospitals in Sweden. 1) The primary outcome was risk factors for drug-related readmission within 12 months post-discharge. A Cox proportional hazards model was made with sociodemographic and clinical baseline characteristics. 2) Four hundred trial participants were randomly selected and their revisits (admissions and emergency department visits) were assessed to identify potentially preventable drug-related revisits, related diseases and causes.

RESULTS: Among 2,637 patients (median age 81 years), 582 (22%) experienced a drug-related readmission within 12 months. Sixteen risk factors (hazard ratio > 1, p < 0.05) related to age, previous hospital visits, medication use, multimorbidity and cardiovascular, liver, lung and peptic ulcer disease were identified. 2) The 400 patients experienced a total of 522 hospital revisits, of which 85 (16%) were potentially preventable drug-related revisits. The two most prevalent related diseases were heart failure (n=24, 28%) and chronic obstructive pulmonary disease (n=13, 15%). The two most prevalent causes were inadequate treatment (n=23, 27%) and insufficient or no follow-up (n=22, 26%).

CONCLUSION: Risk factors for drug-related readmissions in older hospitalised patients were age, previous hospital visits, medication use and multiple diseases. 2) Potentially preventable drug-related hospital revisits are common and might be prevented through adequate pharmacotherapy and continuity of care in older patients with cardiovascular or lung disease.

PMID:36454520 | DOI:10.1111/bcp.15621

Nat Commun. 2022 Dec 1;13(1):7394. doi: 10.1038/s41467-022-35269-3.

ABSTRACT

Transfusion of healthy red blood cells (RBCs) is a lifesaving process. However, upon storing RBCs, a wide range of damage-associate molecular patterns (DAMPs), such as cell-free DNA, nucleosomes, free-hemoglobin, and poly-unsaturated-fatty-acids are generated. DAMPs can further damage RBCs; thus, the quality of stored RBCs declines during the storage and limits their shelf-life. Since these DAMPs consist of either positive or negative charged species, we developed taurine and acridine containing electrospun-nanofibrous-sheets (Tau-AcrNFS), featuring anionic, cationic charges and an DNA intercalating group on their surfaces. We show that Tau-AcrNFS are efficient in scavenging DAMPs from stored human and mice RBCs ex vivo. We find that intermittent scavenging of DAMPs by Tau-AcrNFS during the storage reduces the loss of RBC membrane integrity and reduces discocytes-to-spheroechinocytes transformation in stored-old-RBCs. We perform RBC-transfusion studies in mice to reveal that intermittent removal of DAMPs enhances the quality of stored-old-RBCs equivalent to freshly collected RBCs, and increases their shelf-life by ~22%. Such prophylactic technology may lead to the development of novel blood bags or medical device, and may therefore impact healthcare by reducing transfusion-related adverse effects.

PMID:36450757 | PMC:PMC9712616 | DOI:10.1038/s41467-022-35269-3

Biol Pharm Bull. 2022;45(12):1832-1838. doi: 10.1248/bpb.b22-00620.

ABSTRACT

SMTP-7, a fungal metabolite, is reported to have a high degree of availability for the ischemia-reperfusion (IR)-induced acute kidney injury (AKI) model. Cisplatin, a widely used anticancer drug, has serious side effects, such as AKI. Hence, we aimed to examine the effect of SMTP-7 on cisplatin-induced AKI in this study. Significant increases in blood urea nitrogen (BUN) and serum creatinine (Scr) were observed at 72 h after the intravenous infusion of cisplatin (20 mg/kg). Histologically, necrosis and dilatation (hyaline casts) as well as regeneration were observed in proximal tubules. SMTP-7 inhibited the elevation on BUN and Scr caused by cisplatin dose dependently. The efficacy of SMTP-7 was notable when the drug was administered on the day after cisplatin treatment, whereas the repeated administration of the drug did not result in an enhanced efficacy. Moreover, 10 mg/kg of SMTP-7 considerably ameliorated tubular necrosis and dilatation. The cisplatin treatment also caused an up-regulation of tumor necrosis factor-α (TNF-α) mRNA expression prior to the elevation of the levels of BUN and Scr. Administration of SMTP-7 (10 mg/kg) at 24 h after the cisplatin infusion alleviated the up-regulation of TNF-α mRNA expression. These findings suggest that SMTP-7 exhibits a renoprotective effect against cisplatin infusion based on the inhibition of the expression of pro-inflammatory cytokines such as TNF-α and may be expected a new effective drug for the treatment of cisplatin-induced AKI.

PMID:36450536 | DOI:10.1248/bpb.b22-00620

Biol Pharm Bull. 2022;45(12):1805-1811. doi: 10.1248/bpb.b22-00496.

ABSTRACT

Bevacizumab is an inhibitor of vascular endothelial growth factor (VEGF) that prevents tumor growth. While bevacizumab is therapeutically effective, it induces several adverse events. Among these, central nervous system (CNS) ischemia can lead to death or permanent disability. In this study, we reviewed the Japanese Adverse Drug Event Report database to analyze the occurrence of CNS ischemia after bevacizumab administration. Significant associations between the occurrence of CNS ischemia and bevacizumab use were detected (adjusted reporting odds ratios (ROR): 2.68, 95% confidence interval (CI): 2.00-3.59, p < 0.001). Furthermore, an association between diagnosis of glioma and bevacizumab use was also detected (p < 0.001). These events occurred early after the start of treatment and then gradually decreased; however, more than half of CNS ischemia events were reported beyond 30 d after the first administration. In addition, a logistic regression suggested that CNS ischemia caused by bevacizumab was associated with glioma, underlying hypertension and aging. A poor prognosis was reported for several cases occurring in elderly patients (over 60 years of age). Although bevacizumab is a useful pharmacological treatment for cancer, caution should be taken to avoid severe adverse events. Accordingly, the patient's general and medical condition should be carefully examined before initiating treatment, and blood pressure should be continuously assessed throughout treatment with bevacizumab to prevent CNS ischemia.

PMID:36450533 | DOI:10.1248/bpb.b22-00496

Biol Pharm Bull. 2022;45(12):1754-1763. doi: 10.1248/bpb.b22-00398.

ABSTRACT

Pentazocine (PTZ) is a widely used drug for postoperative pain. It should be administered at appropriate dosing intervals not only because of its morphine-like side effects but also because frequent inappropriate dosing can lead to dependence. Although perioperative patients reportedly have nonnegligible effects on placebo drugs and postoperative wound healing, no pharmacokinetic (PK)/pharmacodynamic (PD) model has been established and simulated using real-world data for the perioperative period. This study aimed to perform PTZ modeling and simulation and to establish an indicator of the timing of drug efficacy evaluation in clinical practice. Participants were in-hospital orthopedic surgery patients who received 15 mg of PTZ within 48 h postoperatively. Pain severity was assessed using the numerical rating scale (NRS). A two-compartment model was selected for the population PK model and an indirect response model for the PK/PD model. Using these models, a virtual population of 1000 patients with Painbase NRS of 5 and 6 and body weights of 40, 80, and 120 kg were treated with single and multiple PTZ administrations (4, 8, and 24 h apart) of 15 mg. Simulation results indicate that its analgesic efficacy should be evaluated within 1 h after administration of 15 mg of PTZ. Additional doses should be considered every 8-12 h in postoperative patients with Painbase NRS of 5 weighing 40-80 kg. Simulation using the PK/PD model developed in this study may provide useful information for determining the analgesic effects and timing of the dosing interval after PTZ administration in perioperative patients.

PMID:36450528 | DOI:10.1248/bpb.b22-00398

Yakugaku Zasshi. 2022;142(12):1313-1319. doi: 10.1248/yakushi.22-00122.

ABSTRACT

Photoimmunotherapy (PIT) is a new cancer therapy that uses near-infrared (NIR) light and a conjugate of an antibody and a photosensitizer (IR700). Since both NIR light and the conjugate are not toxic for human, PIT has attracted attention as a promising cancer therapy with less side effects. However, there is no photosensitizer for PIT other than IR700. To improve the therapeutic effect, more light-sensitive dye is needed. To this end, we have studied the cytotoxic mechanism of PIT, showing that the hydrophilic axial ligand cleavage of IR700 by NIR light irradiation is important for the cytotoxicity. Herein, I focused on the triplet state (T1) of IR700 because the light-induced axial ligand cleavage reaction is thought to occur via the T1. First, the quantum yield of intersystem crossing, which is the transition efficiency from the excited singlet state (S1) to T1, was determined by analysis of the T1 kinetics using fluorescence correlation spectroscopy (FCS). Also, I examined whether the cytotoxicity of IR700 can be changed in the presence of a triplet quencher. The findings obtained here will be important information for the design of a new photosensitizer for PIT in the future.

PMID:36450507 | DOI:10.1248/yakushi.22-00122

Einstein (Sao Paulo). 2022 Nov 25;20:eAO0067. doi: 10.31744/einstein_journal/2022AO0067. eCollection 2022.

ABSTRACT

OBJECTIVE: So far, at least 18 different severe acute respiratory syndrome coronavirus-2 vaccines have been approved. Until October 2022, 12.8 billion doses had been administered all over the world. Vaccination of high-risk groups and healthcare professionals was initially prioritized. This cross-sectional survey aimed to investigate the occurrence of vaccine side effects, as well as the incidence of COVID-19 among vaccinated healthcare professionals.

METHODS: A survey was structured and shared with healthcare professionals using a digital platform to collect data between May and June 2021.

RESULTS: This study included 6,115 participants. The most prevalent age group was 30-39 years (31.3%), 67.3% were female and 73.2% accounted for physicians, and nearly half worked in frontline care for COVID-19. Approximately, two-thirds of them were vaccinated with CoronaVac, and about 60% reported at least one side effect following the vaccination. Nevertheless, minor reactions were more frequent, such as pain at site of injection, fatigue, and headache. Our data could be used to inform people on the likelihood of side effects of COVID-19 vaccines, particularly CoronaVac, since this is the largest study about vaccine reactions using this vaccine, to our best knowledge.

CONCLUSION: The incidence of side effects in Brazilian healthcare professionals was 60%, and the most common side effects included local swelling/pain, fatigue/tiredness, fever, headache, and limb pain.

PMID:36449755 | DOI:10.31744/einstein_journal/2022AO0067

PLoS One. 2022 Nov 30;17(11):e0278127. doi: 10.1371/journal.pone.0278127. eCollection 2022.

ABSTRACT

International evidence shows that people approaching end of life (EOL) have high prevalence of polypharmacy, including overprescribing. Overprescribing may have adverse side effects for mental and physical health and represents wasteful spending. Little is known about prescribing near EOL in Ireland. We aimed to describe the prevalence of two undesirable outcomes, and to identify factors associated with these outcomes: potentially questionable prescribing, and potentially inadequate prescribing, in the last year of life (LYOL). We used The Irish Longitudinal Study on Ageing, a biennial nationally representative dataset on people aged 50+ in Ireland. We analysed a sub-sample of participants with high mortality risk and categorised their self-reported medication use as potentially questionable or potentially inadequate based on previous research. We identified mortality through the national death registry (died in <365 days versus not). We used descriptive statistics to quantify prevalence of our outcomes, and we used multivariable logistic regression to identify factors associated with these outcomes. Of 525 observations, 401 (76%) had potentially inadequate and 294 (56%) potentially questionable medications. Of the 401 participants with potentially inadequate medications, 42 were in their LYOL. OF the 294 participants with potentially questionable medications, 26 were in their LYOL. One factor was significantly associated with potentially inadequate medications in LYOL: male (odds ratio (OR) 4.40, p = .004) Three factors were associated with potentially questionable medications in LYOL: male (OR 3.37, p = .002); three or more activities of daily living (ADLs) (OR 3.97, p = .003); and outpatient hospital visits (OR 1.03, p = .02). Thousands of older people die annually in Ireland with potentially inappropriate or questionable prescribing patterns. Gender differences for these outcomes are very large. Further work is needed to identify and reduce overprescribing near EOL in Ireland, particularly among men.

PMID:36449504 | DOI:10.1371/journal.pone.0278127

J Clin Psychiatry. 2022 Nov 30;83(6):22f14722. doi: 10.4088/JCP.22f14722.

ABSTRACT

Three drug dosing strategies can be employed to address dose-dependent drug adverse effects. The usual strategy is to continue the drug but at a lower dose; it would then take 5 half-lives of the drug for the new steady state to be attained and for a dose-dependent adverse effect to correspondingly attenuate. Such slow offset of the adverse effect could be disadvantageous for drugs such as fluoxetine, penfluridol, and cariprazine that have long half-lives. A second strategy is to stop the drug and to resume it at a lower dose when the adverse effect attenuates as the drug blood level falls. This strategy introduces subjectivity in timing the reintroduction of the drug, requires closer patient monitoring, and risks nonadherence and relapse. The third strategy is to stop the drug for a prespecified number of days and to then reintroduce it at a lower dose. From a knowledge of pharmacokinetics, it can be shown that stopping a drug for just 1 half-life and then resuming it at half the dose results in the immediate achievement of steady state; that is, there is no need to wait for 4 additional half-lives as with the usual strategy of dose reduction without dosing interruption. A limitation of this pharmacokinetically driven dosing strategy, however, is that it would work well in the average patient but not in those with outlying pharmacokinetic parameters.

PMID:36449476 | DOI:10.4088/JCP.22f14722

JAMA Netw Open. 2022 Nov 1;5(11):e2244412. doi: 10.1001/jamanetworkopen.2022.44412.

ABSTRACT

IMPORTANCE: Attrition in cancer clinical trials (CCTs) can lead to systematic bias, underpowered analyses, and a loss of scientific knowledge to improve treatments. Little attention has focused on retention, especially the role of perceived benefits and burdens, after participants have experienced the trial.

OBJECTIVES: To examine the association between patients' perceived benefits and burdens of research participation and CCT retention.

DESIGN, SETTING, AND PARTICIPANTS: This survey study was conducted at a National Cancer Institute-designated comprehensive cancer center in the Northeast region of the US. The sample included adult patients with a cancer diagnosis participating in cancer therapeutic trials. Data were collected from September 2015 to June 2019. Analysis of study data was ongoing since November 2019 through October 2022.

EXPOSURES: Self-reported validated survey instrument with a list of 22 benefits and 23 burdens of research participation that can be rated by patients with a 5-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree).

MAIN OUTCOMES AND MEASURES: A primary outcome was actual withdrawal from the CCT, and a composite outcome was composite withdrawal that included both actual withdrawal and thoughts of withdrawing. Bivariate and multivariable logistic regressions were used.

RESULTS: Among the 334 participants in the sample, the mean (SD) age was 61.9 (11.5) years and 174 women (52.1%) were included. Top-cited benefits included both aspirational and action-oriented goals, including helping others (94.2%), contributing to society (90.3%), being treated respectfully (86.2%), and hoping for a cure (86.0%). Worry over receiving a placebo (61.3%), rearranging one's life (41.9%), and experiencing bothersome adverse effects (41.6%) were notable burdens. An increased burden score was associated with a higher probability of actual withdrawal (adjusted odds ratio [OR], 1.86; 95% CI, 1.1-3.17; P = .02) or composite withdrawal (adjusted OR, 3.44; 95% CI, 2.09-5.67; P < .001). An increased benefit score was associated with lower composite withdrawal (adjusted OR, 0.40; 95% CI, 0.24-0.66; P < .001). For participants who reported the benefits as being equal to or greater than the burdens, 13.4% withdrew. For those who perceived the benefits as being less than the burdens, 33.3% withdrew (adjusted OR, 3.38; 95% CI, 1.13-10.14; P = .03). The risk of withdrawal was even higher for the composite outcome (adjusted OR, 7.70; 95% CI, 2.76-21.48; P < .001).

CONCLUSIONS AND RELEVANCE: This survey study found that patients perceived important benefits from CCT participation, and this perception was associated with trial retention, even among those who also perceived substantial burdens. A broader dialogue among stakeholders can inform an ethical and patient-centric focus on benefits throughout the course of a CCT to increase retention.

PMID:36449287 | DOI:10.1001/jamanetworkopen.2022.44412

Cancer Treat Res. 2022;184:141-149. doi: 10.1007/978-3-031-04402-1_10.

ABSTRACT

Adverse drug/device reactions (ADRs) serious enough to lead to box warnings on drug labels or drug withdrawals occur in about one fifth of all new molecular entities.

PMID:36449194 | DOI:10.1007/978-3-031-04402-1_10

Cancer Treat Res. 2022;184:129-140. doi: 10.1007/978-3-031-04402-1_9.

ABSTRACT

Severe adverse drug reactions (sADRs) are important causes of morbidity and mortality. The Southern Network on Adverse Drug Reactions (SONAR), a National Cancer Institute-funded pharmacovigilance program, has outlined a novel 9-stop methodology, termed ANTICIPATE, that has evaluated this methodology, among persons with chronic kidney disease (CKD).

PMID:36449193 | DOI:10.1007/978-3-031-04402-1_9

Cancer Treat Res. 2022;184:87-102. doi: 10.1007/978-3-031-04402-1_6.

ABSTRACT

More than half of all serious adverse drug reactions are identified seven years after FDA approval. One recent and unusual example involves a syndrome initially termed nephrogenic dermatopathic fibrosis, and then called nephrogenic systemic fibrosis (NSF).

PMID:36449190 | DOI:10.1007/978-3-031-04402-1_6