Front Endocrinol (Lausanne). 2022 Apr 29;13:864908. doi: 10.3389/fendo.2022.864908. eCollection 2022.

ABSTRACT

BACKGROUND: To evaluate the safety and efficacy of daily somatropin (Jintropin®), a recombinant human growth hormone, in prepubertal children with ISS in China.

METHODS: This study was a multicenter, randomized, controlled, open-label, phase 3 study. All subjects were randomized 3:1 to daily somatropin 0.05 mg/kg/day or no treatment for 52 weeks. A total of 481 subjects with a mean baseline age of 5.8 years were enrolled in the study. The primary endpoint was change in (△) height standard deviation score (HT-SDS) for chronological age (CA). Secondary endpoints included △height from baseline; △bone age (BA)/CA; △height velocity (HV) and △insulin-like growth factor 1 (IGF-1 SDS).

RESULTS: △HT-SDS at week 52 was 1.04 ± 0.31 in the treatment group and 0.20 ± 0.33 in the control group (P < 0.001). At week 52, statistical significance was observed in the treatment group compared with control for △height (10.19 ± 1.47 cm vs. 5.85 ± 1.80 cm; P < 0.001), △BA/CA (0.04 ± 0.09 vs. 0.004 ± 0.01; P < 0.001), △HV (5.17 ± 3.70 cm/year vs. 0.75 ± 4.34 cm/year; P < 0.001), and △IGF-1 SDS (2.31 ± 1.20 vs. 0.22 ± 0.98; P < 0.001). The frequencies of treatment-emergent adverse events (TEAEs) were similar for the treatment and the control groups (89.8% vs. 82.4%); most TEAEs were mild to moderate in severity and 23 AEs were considered study-drug related.

CONCLUSIONS: Daily subcutaneous administration of somatropin at 0.05 mg/kg/day for 52 weeks demonstrated improvement in growth outcomes and was well tolerated with a favorable safety profile.

TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT03635580). URL: https://clinicaltrials.gov/ct2/show/NCT03635580.

PMID:35573994 | PMC:PMC9102803 | DOI:10.3389/fendo.2022.864908

Arerugi. 2022;71(3):231-241. doi: 10.15036/arerugi.71.231.

ABSTRACT

BACKGROUND: The epidemiology of drug-induced anaphylaxis (AN) using the Japanese nationwide database has not been reported, even though drugs are a common trigger of AN.

OBJECTIVE: This study aimed to describe the epidemiological profile of drug-induced AN, including fatal cases, using the Japanese Adverse Drug Event Report database (JADER).

METHODS: We extracted data regarding drug-induced adverse events between April 2004 and February 2018 published in JADER by the Pharmaceuticals and Medical Devices Agency. We analyzed cases of anaphylaxis occurring between January 2005 and December 2017. The drug classification was based on the Japanese Standard Commodity Classification.

RESULTS: There were 16916 cases of anaphylaxis reported during the study period. Among them, 418 fatalities were registered. The incidence of drug-induced AN and fatal cases was 1.03 cases/year per 100000 population and 0.03 cases/year, respectively. The most frequent causes of AN were diagnostic agents including X-ray contrast media (20.3%) and biological agents including human blood preparations (20.1%). In fatal cases, diagnostic agents (28.7%) and antibiotics (23.9%) were the most frequent causes.

CONCLUSIONS: The frequency of drug-induced AN and fatalities in Japan remained unchanged over the 12-year period analyzed in this study. Diagnostic and biological agents were the most frequent causes of AN. Contrarily, fatalities were most frequently caused by diagnostic and antibiotic agents.

PMID:35569945 | DOI:10.15036/arerugi.71.231

Molecules. 2022 May 7;27(9):3004. doi: 10.3390/molecules27093004.

ABSTRACT

The treatment of complex diseases by using multiple drugs has become popular. However, drug-drug interactions (DDI) may give rise to the risk of unanticipated adverse effects and even unknown toxicity. Therefore, for polypharmacy safety it is crucial to identify DDIs and explore their underlying mechanisms. The detection of DDI in the wet lab is expensive and time-consuming, due to the need for experimental research over a large volume of drug combinations. Although many computational methods have been developed to predict DDIs, most of these are incapable of predicting potential DDIs between drugs within the DDI network and new drugs from outside the DDI network. In addition, they are not designed to explore the underlying mechanisms of DDIs and lack interpretative capacity. Thus, here we propose a novel method of GNN-DDI to predict potential DDIs by constructing a five-layer graph attention network to identify k-hops low-dimensional feature representations for each drug from its chemical molecular graph, concatenating all identified features of each drug pair, and inputting them into a MLP predictor to obtain the final DDI prediction score. The experimental results demonstrate that our GNN-DDI is suitable for each of two DDI predicting scenarios, namely the potential DDIs among known drugs in the DDI network and those between drugs within the DDI network and new drugs from outside DDI network. The case study indicates that our method can explore the specific drug substructures that lead to the potential DDIs, which helps to improve interpretability and discover the underlying interaction mechanisms of drug pairs.

PMID:35566354 | PMC:PMC9105425 | DOI:10.3390/molecules27093004

Molecules. 2022 May 4;27(9):2931. doi: 10.3390/molecules27092931.

ABSTRACT

Ketamine is an anesthetic drug that is widely used in human and veterinary medicine. In the developmental stage, long-term exposure to ketamine may cause serious side effects. MCC950 and VX765 play protective roles in many disease models by regulating the NLRP3/Caspase-1 pathway. This study aims to explore the potential protective effect of MCC950 and VX765 on ketamine-induced liver injury in neonatal rats and clarify its underlying mechanism. After administration of MCC950 and VX765 in a ketamine-induced liver injury rat model, liver function and inflammatory factors were determined, and immunohistochemistry and western blotting were performed. We found that ketamine caused liver injury in 7-day-old SD rats, decreased liver function indexes, and increased inflammation. MCC950 and VX765 effectively alleviated liver damage and inflammation, and downregulated the expression of proteins such as NLRP3, Caspase-1, and GSDMD-N. In summary, these results indicated that MCC950 and VX765 could have potential protective effects on ketamine-induced liver injury through inhibiting the NLRP3/Caspase-1 pathway.

PMID:35566282 | PMC:PMC9103672 | DOI:10.3390/molecules27092931

Int J Environ Res Public Health. 2022 May 4;19(9):5585. doi: 10.3390/ijerph19095585.

ABSTRACT

This retrospective cohort study analyzed the administrative hospital records of 91,500 patients with the aim of assessing adverse drug reaction (ADR)-related hospital admission risk after discharge from ADR and non-ADR-related admission. Patients aged ≥18 years with an acute admission to public hospitals in Tasmania, Australia between 2011 and 2015 were followed until May 2017. The index admissions (n = 91,550) were stratified based on whether they were ADR-related (n = 2843, 3.1%) or non-ADR-related (n = 88,707, 96.9%). Survival analysis assessed the post-index ADR-related admission risk using (1) the full dataset, and (2) a matched subset of patients using a propensity score analysis. Logistic regression was used to identify the risk factors for ADR-related admissions within 90 days of post-index discharge. The patients with an ADR-related index admission were almost five times more likely to experience another ADR-related admission within 90 days (p &lt; 0.001). An increased risk persisted for at least 5 years (p &lt; 0.001), which was substantially longer than previously reported. From the matched subset of patients, the risk of ADR-related admission within 90 and 365 days more than doubled in the patients with an ADR-related index admission (p &lt; 0.0001). These admissions were often attributed to the same drug class as the patients' index ADR-related admission. Cancer was a major risk factor for ADR-related re-hospitalization within 90 days; other factors included heart failure and increasing age.

PMID:35564982 | PMC:PMC9101512 | DOI:10.3390/ijerph19095585

Int J Mol Sci. 2022 May 4;23(9):5114. doi: 10.3390/ijms23095114.

ABSTRACT

Chronic pain is debilitating and represents a significant burden in terms of personal and socio-economic costs. Although opioid analgesics are widely used in chronic pain treatment, many patients report inadequate pain relief or relevant adverse effects, highlighting the need to develop analgesics with improved efficacy/safety. Multiple evidence suggests that G protein-dependent signaling triggers opioid-induced antinociception, whereas arrestin-mediated pathways are credited with modulating different opioid adverse effects, thus spurring extensive research for G protein-biased opioid agonists as analgesic candidates with improved pharmacology. Despite the increasing expectations of functional selectivity, translating G protein-biased opioid agonists into improved therapeutics is far from being fully achieved, due to the complex, multidimensional pharmacology of opioid receptors. The multifaceted network of signaling events and molecular processes underlying therapeutic and adverse effects induced by opioids is more complex than the mere dichotomy between G protein and arrestin and requires more comprehensive, integrated, network-centric approaches to be fully dissected. Quantitative Systems Pharmacology (QSP) models employing multidimensional assays associated with computational tools able to analyze large datasets may provide an intriguing approach to go beyond the greater complexity of opioid receptor pharmacology and the current limitations entailing the development of biased opioid agonists as improved analgesics.

PMID:35563502 | PMC:PMC9104178 | DOI:10.3390/ijms23095114

Liver Int. 2022 May 14. doi: 10.1111/liv.15290. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Evidence for using bicyclol in drug-induced liver injury (DILI) is limited. This study aimed to explore the efficacy and safety of bicyclol in acute DILI.

METHODS: This was a multicenter, randomized, double-blinded, double-dummy, active-controlled, superiority, phase II trial. Patients with idiosyncratic acute DILI were randomized 1:1:1 to low-dose bicyclol (25 mg times a day [TID]), high-dose bicyclol (50 mg TID), and polyene phosphatidylcholine (control) groups. The primary endpoint was the decrease from baseline in serum alanine aminotransferase (ALT) levels at post-treatment 4 weeks.

RESULTS: Overall, 241 patients were included in the full analysis set, with 81, 82, and 78 patients in the low-dose bicyclol, high-dose bicyclol, and control groups, respectively. ALT levels decreased across groups (-249.2 ± 151.1, -273.6 ± 203.1, and -180.8 ± 218.2 U/L in the low-dose bicyclol, high-dose bicyclol, and control groups, respectively; both P < 0.001, the bicyclol-dependent groups vs. control group). The ALT normalization rates at weeks 1, 2, 4, 6, and 8 were higher in the bicyclol-dependent groups than in the control group (P = 0.002 at week 1 and all P < 0.001 at weeks 2, 4, 6, and 8, respectively). The median times to ALT normalization in the low-dose bicyclol, high-dose bicyclol, and control groups were 29, 16, and 43 days, respectively. Adverse events, serious adverse events, and adverse drug reactions were similar across groups.

CONCLUSIONS: Bicyclol (25 and 50 mg TID) appeared efficacious and safe for treating idiosyncratic acute DILI, while bicyclol 50 mg TID showed higher efficacy.

PMID:35567757 | DOI:10.1111/liv.15290

Phytomedicine. 2022 Jul;101:154107. doi: 10.1016/j.phymed.2022.154107. Epub 2022 Apr 17.

ABSTRACT

BACKGROUND: Cisplatin (CDDP), one of the widely used chemotherapeutic drugs, can induce a series of side effects, such as hepatotoxicity and gastrointestinal toxicity. Astragali Radix (AR) is widely used as the tonic herbal medicine in traditional Chinese medicine (TCM). However, there was no report about the hepatoprotective effect of AR against the cisplatin-induced hepatic damage.

PURPOSE: This study aimed to investigate the protective effect and potential mechanism of AR water extract against the cisplatin-induced liver injury.

METHODS: Cisplatin was utilized to induce the liver injury using ICR mice, and the protective effect of AR was evaluated by serum biochemistry indices and liver histopathology. Then UHPLC Q-TOF-MS/MS-based untargeted serum metabolomics approach combined with 16S rRNA-based microbiota analysis was used to explore the underlying biomarkers and mechanism about the liver-protective effect of AR.

RESULTS: AR could decrease the serum AST and ALT, ameliorate hepatic pathological damages caused by cisplatin. Serum metabolomics indicated AR could regulate the biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, purine metabolism, and fatty acid biosynthesis. In addition, 16S rRNA gene sequencing analysis showed that AR could regulate cisplatin-induced gut microbiota disorder, especially the inflammation-related bacteria (p_Deferribacteres, g_Enterococcus, and g_Alistipes, etc.), and the short chain fatty acids (SCFAs)-producing bacteria (g_Alloprevotella, g_Intestinimoas, and g_Flavonifractor). Moreover, 7 mice (AR-7) showed better liver protective effect than the other 3 mice (AR-3), and their regulatory effect on the gut microbiota and serum metabolites were also different, indicating the presence of inter-individual variability for the liver protective effect of AR.

CONCLUSIONS: This study revealed the protective effect and the potential mechanisms of AR against cisplatin-induced liver injury, and found that inter-individual variability of the liver protective effect of AR was related to the host microbiome and metabolome. These findings provided new insight into the health effect of dietary AR as a functional food for cisplatin-based chemotherapy.

PMID:35561503 | DOI:10.1016/j.phymed.2022.154107

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R3296.

ABSTRACT

STUDY OBJECTIVE: To compare the adverse events (AEs) profiles of medications prescribed to treat obesity and identify factors associated with serious adverse events (SAEs) by utilizing nationwide spontaneous AE reporting database in Korea.

HYPOTHESIS: The AE profiles may differ by anti-obesity agents and patient-specific factors may aggravate the risk of SAEs.

METHODS: Retrospective analysis was performed on ADE records spontaneously reported from January 2010 to December 2019 to the Korean Adverse Event Reporting System (KAERS) constructed by Korea Institute of Drug Safety and Risk Management. This analysis included 10 anti-obesity agents prescribed for overweight, obesity (ICD-10 code E66) and abnormal weight gain (ICD10 Code E63.5). All AEs were grouped using preferred terms and System Oran Classes (SOC) per the WHO-Adverse Reaction Terminology. Logistic regression was performed to identify factors associated with SAEs identified based on International Conference on Harmonization E2D Guidelines, and the odds ratio (OR) was reported with 95% confidence intervals (CIs). Any p-values <0.05 was considered statistically significant. All statistical analyses were performed with SPSS 25.0 (Version 25.0; IBM SPSS Statistics for Windows, Armonk, NY, USA). The study protocol for utilizing the KAERS database was approved by KIDS (No.2007A0051) and the institutional review board of CHA University (Pocheon, South Korea).

RESULTS: Total of 4,215 AE records associated with anti-obesity agents were identified, and the most etiologic anti-obesity agent was phentermine (n=1,385; 32.8%), followed by liraglutide (n=1,155; 27.4%) and lorcaserin (n=690; 16.3%). AEs were frequently reported in females (n=3,458; 88.7%) and patients in their 30s (n=761; 18.1%) or 40s (n=672; 15.9%) of age. The prevalence of SAE was 2.5% (n=105). The highest number of nonserious AEs was gastro-intestinal system disorders (n=1,233; 30.0%), followed by central & peripheral nervous system disorders (n=782; 19.0%) and psychiatric disorders (n=682; 16.6%). The most common SAEs were associated with psychiatric disorders (n=27; 25.7%), central & peripheral nervous system disorders (n=20; 19.0%), and gastrointestinal system disorders (n=13; 12.4%). The reporting odds ratio of SAE in liver and biliary system disorders from anti-obesity agent administration was 3.145 (95% CI 6.689- 80.557). Factors associated with significantly elevated risk of SAEs was male sex (odds ratio (OR) 6.318; 95% CI 3.583-10.839), triple agent therapy (OR 3.49; 95% CI:1.481-8.170), increasing number of medications (OR 1.381; 95% CI 1.204-1.583), and concomitant administration of fluoxetine (OR 5.146; 95% CI 2.570-10.268).

CONCLUSION: This is the first study of the study investigating AEs induced by medications primarily prescribed for weight loss by utilizing nationwide spontaneous adverse event reporting system. AEs induced by anti-obesity agents are most frequently reported with phentermine and liraglutides, primarily manifested by gastrointestinal system disorders. SAEs are substantially associated with male gender, polypharmacy, and type of concomitant medications.

PMID:35554714 | DOI:10.1096/fasebj.2022.36.S1.R3296

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R3312.

ABSTRACT

BACKGROUND: Thiopurines are a key component for the immunosuppressive therapy of various leukemias, inflammatory bowels disease, and other autoimmune disorders. Thiopurine therapy discontinuation/interruption is associated with a higher risk of relapse, but is common due to the prevalence of severe and potentially fatal adverse events, such as hepatotoxicity. Drug transporter expression is a known factor for patient variability in drug response and toxicity. We have recently established that the SLC43A3-encoded transporter, equilibrative nucleobase transporter 1 (ENBT1), is the primary mechanism by which the thiopurine, 6-mercaptopurine (6-MP) enters cells. ENBT1 is known to be highly expressed in human hepatocytes, however, the relationship between ENBT1 and thiopurine-induced hepatotoxicity has not been explored in the literature. To investigate this paradigm, our lab has proposed developing a novel SLC43A3 knockout mouse model. However, the functional differences between human and murine ENBT1, in mediating 6-MP transport, has equally not been explored. Evidence that suggests ENBT1 is functionally similar between species, would be an essential foundation to assist bridging the gap between our proposed animal model and clinical studies within the literature.

HYPOTHESIS: We hypothesize that hSLC43A3-encoded hENBT1 and mslc43a3-encoded mENBT1 are functionally similar and will have non-significantly different 6-MP transport kinetics and resulting cytotoxicity.

METHODS: The ENBT1-deficient human embryonic kidney 293 (HEK293) cell line was stably transfected with either hSLC43A3 or mslc43a3. [3 H]Adenine and [3 H]6-MP were used in an oil-stop centrifugation assay to assess ENBT1-mediated transport activity in wildtype and transfected HEK293 cell lines. To determine cytotoxicity, wildtype and transfected HEK293 cell lines were incubated for 48 hours with a range of 6-MP concentrations (78 nM - 1.28 mM) before being assessed via MTT cell viability assay.

RESULTS: Oil stop centrifugation assay of ENBT1-mediated [3 H]adenine and [3 H]6-MP transport revealed that hENBT1 and mENBT1 have similar transport kinetics (Km and Vmax ), where resulting Michaelis-Menten curves were not significantly different (unpaired T-test: Adenine - t16 =0.32, p=0.76, n=5 & 6-MP - t16 =0.64, p=0.53, n=4). Adenine inhibition of ENBT1-mediated [3 H]6-MP transport and 6-MP inhibition of ENBT1-mediated [3 H]adenine transport also showed that hENBT1 and mENBT1 have concurring inhibition kinetics (Ki ), inhibition curves were not significantly different (unpaired T-test: Adenine: t17 =0.29, p=0.77, n=5 & 6-MP: t14 =0.18, p=0.86, n=4). Subsequent MTT cell viability assay showed that wildtype HEK293 are relatively 6-MP resistant, while the transfected-HEK293s are 6-MP sensitive and have non-significantly different cell viability curves (unpaired T-test: t28 =0.13, p=0.89, n=5).

CONCLUSION: Our results show that hENBT1 and mENBT1 are functionally similar in regards to ENBT1-mediated adenine and 6-MP transport in a stably transfected cell line. Additional work is necessary to investigate whether this is the case in human and murine hepatic cell lines/primary hepatocytes that have endogenous SLC43A3/ENBT1 expression and a larger range of xenobiotic metabolizing enzymes that may alter the equilibrium of 6-MP within cells.

PMID:35554128 | DOI:10.1096/fasebj.2022.36.S1.R3312

Acta Biomater. 2022 May 10:S1742-7061(22)00276-8. doi: 10.1016/j.actbio.2022.05.007. Online ahead of print.

ABSTRACT

Adequate treatment of pain arising from spinal surgery is a major clinical challenge. Opioids are the mainstay of current treatment methods, but the frequency and severity of their side effects display a clear need for opioid-free analgesia. Local anesthetics have been encapsulated into sustained-release drug delivery systems to provide postoperative pain relief. However, these formulations are limited by rapid diffusion out of the surgical site. To overcome this limitation, we synthesized ring-shaped hydrogels incorporating bupivacaine, designed to be co-implanted with pedicle screws during spinal surgery. Hydrogels were prepared by riboflavin-mediated crosslinking of gelatin functionalized with tyramine moieties. Additionally, oxidized β-cyclodextrin was introduced into the hydrogel formulation to form dynamic bonds with tyramine functionalities, which enables self-healing behavior and resistance to shear. Feasibility of hydrogel implantation combined with pedicle screws was qualitatively assessed in cadaveric sheep as a model for instrumented spinal surgery. The in-situ crystallization of bupivacaine within the hydrogel matrix provided a moderate burst decrease and sustained release that exceeded 72 hours in vitro. The use of bupivacaine crystals decreased drug-induced cytotoxicity in vitro compared to bupivacaine HCl. Thus, the presented robust hydrogel formulation provides promising properties to enable the stationary release of non-opioid analgesics following spinal surgery. STATEMENT OF SIGNIFICANCE: Currently, postoperative pain following spinal surgery is mainly treated with opioids. However, the use of opioids is associated with several side effects including addiction. Here we developed robust and cytocompatible gelatin hydrogels, prepared via riboflavin-mediated photocrosslinking, that can withstand orthopedic implantation. The implantability was confirmed in cadaveric instrumented spinal surgery. Further, hydrogels were loaded with bupivacaine crystals to provide sustained release beyond 72 hours in vitro. The use of crystallized bupivacaine decreased cytotoxicity compared to bupivacaine HCl. The present formulation can aid in enabling opioid-free analgesia following instrumented spinal surgery.

PMID:35562007 | DOI:10.1016/j.actbio.2022.05.007

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.R1947.

ABSTRACT

Diet (e.g., type and amount of food consumed) has been shown to impact drug sensitivity, in ways that might be relevant for the therapeutic effects and side effects of medications. For example, previous studies have demonstrated that rats eating a high fat diet are more sensitive to some of the effects of dopaminergic drugs. Considerably less is known about how eating a high fat diet might impact sensitivity to drugs that act on serotonin (5-HT) systems, many of which might be beneficial for the treatment of obesity, since they can decrease feeding. Drugs with agonist effects at 5-HT receptors can produce a collection of adverse effects, known as 5-HT syndrome. Animal models of 5-HT syndrome include lower lip retraction, flat body posture, penile erections, and forepaw treading. To test the hypothesis that eating a high fat diet enhances sensitivity of rats to 5-HT syndrome, male (n=16) and female (n=16) rats eating high fat (60% kcal from fat) or standard (17% kcal from fat) laboratory chow were tested once weekly with cumulative doses of 5-HT receptor agonists, including 8-OH-DPAT (0.01-1.0 mg/kg, s.c.), lorcaserin (1.0-32.0 mg/kg, i.p.) and WAY 163909 (1.0-32.0 mg/kg, i.p.). Agonists were also studied in combination with antagonists selective for 5-HT1A (WAY 100635; 0.178 mg/kg, s.c.), or 5-HT2C (SB 242084; 1.0 mg/kg; i.p.) receptors. Food consumption and body weight were measured throughout the study. Results were analyzed using either two-way or three-way mixed model ANOVAs with diet and dose, diet and day, or diet, sex, and drug as factors, and Bonferroni post hoc comparisons where appropriate. Effects mediated by the 5-HT2C receptor (e.g, penile erections as well as decreased food consumption), were only observed following injections of lorcaserin and WAY 163909 (but not 8-OH-DPAT), and were not different between rats eating standard or high fat chow. Regarding 5-HT1A receptor-mediated effects, all three 5-HT receptor agonists induced forepaw treading in rats; however, flat body posture and lower lip retraction were only induced by 8-OH-DPAT. Rats eating high fat chow were more sensitive to forepaw treading, regardless of which drug induced this behavior; however, WAY 163909 induced less forepaw treading as compared to the other two drugs, regardless of diet. Rats eating high fat chow were also more sensitive to 8-OH-DPAT-induced lower lip retraction, but not flat body posture. These results suggest that eating a high fat diet can impact sensitivity of rats to some of the effects of serotonergic drugs. Additionally, these results demonstrate that while both lorcaserin and WAY 163909 decrease feeding, WAY 163909 produces less 5-HT1A -mediated forepaw treading than lorcaserin, which might indicate that it will produce fewer side effects in humans as well. Finally, these results suggest that dietary history could influence sensitivity of individuals to the adverse effects of serotonergic drugs, such as 5-HT syndrome.

PMID:35555947 | DOI:10.1096/fasebj.2022.36.S1.R1947

FASEB J. 2022 May;36 Suppl 1. doi: 10.1096/fasebj.2022.36.S1.L7621.

ABSTRACT

Current chemotherapy methods are non-specific, killing cancerous and healthy cells alike. This drug-related cytotoxicity results in many side effects such as hair loss or lower blood cell count. Prodrug conjugates have been developed with the goal of preferentially targeting diseased cells to minimize interactions with healthy cells, thereby mitigating deleterious off-target effects. One powerful prodrug strategy exploits higher vitamin receptor expression levels in tumor cells. These abundant receptors drive their rapid, nutrient-demanding growth rates. As such, a vitamin structural motif may be included in the prodrug conjugate design to target the ever-growing tumor: a "targeting group" that acts as an appealing disguise for the drug. Biotin, folate, cyclic and acyclic RGD peptides have been found to be effective in targeting tumors over non-cancerous cells. To systematically compare the selectivity and potency of these targeting groups, we intend to construct fluorogenic prodrug conjugates based on a previously established scaffold. The conjugates include one of the four respective targeting groups, the anticancer drug (camptothecin), a naphthalimide fluorophore component to track drug delivery, and an activatable disulfide linker that cleaves upon entering the reducing cellular environment, activating both the drug and the fluorophore. After these conjugates have been synthesized, comparisons of efficacy and specificity among targeting groups will be made to gain a better understanding of targeted cancer prodrug conjugates. Currently, these conjugates are still in the synthesis stages.

PMID:35553582 | DOI:10.1096/fasebj.2022.36.S1.L7621

Nat Med. 2022 May 12. doi: 10.1038/s41591-022-01802-6. Online ahead of print.

ABSTRACT

Improving glucose sensitivity remains an unmet medical need in treating type 2 diabetes (T2D). Dorzagliatin is a dual-acting, orally bioavailable glucokinase activator that enhances glucokinase activity in a glucose-dependent manner, improves glucose-stimulated insulin secretion and demonstrates effects on glycemic control in patients with T2D. We report the findings of a randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy and safety of dorzagliatin in patients with T2D. Eligible drug-naïve patients with T2D (n = 463) were randomly assigned to the dorzagliatin or placebo group at a ratio of 2:1 for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin from baseline to week 24. Safety was assessed throughout the trial. At week 24, the least-squares mean change in glycated hemoglobin from baseline (95% confidence interval) was -1.07% (-1.19%, -0.95%) in the dorzagliatin group and -0.50% (-0.68%, -0.32%) in the placebo group (estimated treatment difference, -0.57%; 95% confidence interval: -0.79%, -0.36%; P < 0.001). The incidence of adverse events was similar between the two groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin group. In summary, dorzagliatin improved glycemic control in drug-naïve patients with T2D and showed a good tolerability and safety profile.

PMID:35551294 | DOI:10.1038/s41591-022-01802-6

Nat Med. 2022 May 12. doi: 10.1038/s41591-022-01803-5. Online ahead of print.

ABSTRACT

Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D (n = 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was -1.02% (-1.11, -0.93) in the dorzagliatin group and -0.36% (-0.45, -0.26) in the placebo group (estimated treatment difference, -0.66%; 95% CI: -0.79, -0.53; P < 0.0001). The incidence of adverse events was similar between groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin and metformin combined therapy group. In patients with T2D who experienced inadequate glycemic control with metformin alone, dorzagliatin resulted in effective glycemic control with good tolerability and safety profile ( NCT03141073 ).

PMID:35551292 | DOI:10.1038/s41591-022-01803-5

Drug Ther Bull. 2022 May 12:dtb-2021-000032. doi: 10.1136/dtb.2021.000032. Online ahead of print.

ABSTRACT

The serotonin syndrome is a life-threatening adverse drug reaction resulting from excess serotonergic agonism due to interactions between multiple drugs, poisoning, or less commonly due to therapeutic action of a single drug. The central triad of features in serotonin syndrome are altered mental state, autonomic hyperactivity, and neuromuscular abnormalities in the context of a patient with new/altered serotonergic therapy, although not all these features are consistently present in all patients. The severity of serotonin syndrome can be assessed clinically based on the number and severity of features. Severe serotonin syndrome warrants more careful management on a high-dependency unit. In case of temperature exceeding 38.5°C, urgent cooling measures and sedation should be employed, progressing to rapid sequence intubation and paralysis if cooling measures are ineffective.

PMID:35551099 | DOI:10.1136/dtb.2021.000032

Drug Ther Bull. 2022 May 12:dtb-2022-000027. doi: 10.1136/dtb.2022.000027. Online ahead of print.

ABSTRACT

Overview of: Deardorff WJ, Cenzer I, Nguyen B, et al Time to benefit of bisphosphonate therapy for the prevention of fractures among postmenopausal women with osteoporosis: a meta-analysis of randomised clinical trials. JAMA Intern Med 2022;182:33-41.

PMID:35551098 | DOI:10.1136/dtb.2022.000027

Int J Gen Med. 2022 May 4;15:4675-4683. doi: 10.2147/IJGM.S364146. eCollection 2022.

ABSTRACT

PURPOSE: Patients with the comorbidity of coronary artery disease (CAD) and depression are very common and always have poor prognosis. The relationship between thyroid-stimulating hormone (TSH) levels and major cardiovascular event (MACE) in these patients is still unknown. We aimed to explore this association.

PATIENTS AND METHODS: We enrolled 203 CAD patients proven by coronary angiography (CAG). In the meanwhile, they were all assessed to have depression symptom by professional psycho-cardiologists. After an average follow-up of 23.7 months, patients were divided into two groups (high TSH group with TSH ≥ 1.395μIU/mL and low TSH group with TSH < 1.395μIU/mL) according to the cut-off value of baseline TSH. The impact of two different TSH groups for adverse events in CAD patients with depression was evaluated.

RESULTS: The average age of these patients was 64.9 years old. The two TSH groups had no significant difference in the comparison of other baseline data. Area under the receiver operating characteristic (ROC) curves (AUC) analysis indicated the well-discriminatory power of TSH levels for the occurrence of MACE (AUC = 0.61, 95% CI: 0.52-0.70, P = 0.03). In the KM survival analysis, high TSH group had a higher risk of MACE (P = 0.029). After multi-factor adjustment, there still existed a higher risk of MACE in high TSH group (HR = 2.05, 95% CI: 1.08-3.88, P = 0.028).

CONCLUSION: In patients with the comorbidity of CAD and depression, higher TSH levels are associated with the occurrence of MACE. More researches need to be conducted to prove this association and explore whether the drug-related TSH reduction can decrease the occurrence of adverse events in the future.

PMID:35548588 | PMC:PMC9081036 | DOI:10.2147/IJGM.S364146

Cureus. 2022 Apr 8;14(4):e23958. doi: 10.7759/cureus.23958. eCollection 2022 Apr.

ABSTRACT

An uncommon but serious adverse drug reaction after phenytoin administration is known as purple glove syndrome (PGS). Initial presentation is characterized by pain, skin discoloration, and edema, that can progress to necrosis. The pathophysiology remains uncertain; however, multiple mechanisms have been reported including extravasation. We describe a case of a 61-year-old patient who was brought to the hospital with altered mental status due to status epilepticus. The patient received multiple doses of lorazepam; eventually was started on levetiracetam and valproate, including loading doses. The seizures were poorly controlled despite treatment, and intravenous (IV) phenytoin was added. The next day, bluish discoloration and swelling to bilateral upper distal extremities were noted on physical examination. Consequently, IV phenytoin was discontinued immediately due to high suspicion of PGS. Skin discoloration and edema gradually improved after one week, confirming a case of mild PGS.

PMID:35547441 | PMC:PMC9085657 | DOI:10.7759/cureus.23958

Front Neurol. 2022 Apr 25;13:872684. doi: 10.3389/fneur.2022.872684. eCollection 2022.

ABSTRACT

BACKGROUND AND OBJECTIVES: To describe a new case of neuromyelitis optica spectrum disorder (NMOSD) induced by the administration of interferon-alpha (IFNα) and to raise awareness of this rare drug-induced disease of IFNα treatment.

METHODS: A single case study and comprehensive literature review of eight cases.

RESULTS: A 24-year-old man was diagnosed with cerebral venous thrombosis and essential thrombocythemia. He had been undergoing IFNα treatment (IFNα-2b, 3 million IU per day) without any side effects for 18 months, at which point the patient developed persistent hiccups, nausea, urinary retention, and numbness. Spinal magnetic resonance imaging revealed a longitudinal abnormality extending from the medulla to the entire spinal cord. The patient was positive for anti-aquaporin-4 antibody (AQP4-IgG) in both the serum and cerebrospinal fluid (CSF), which confirmed the diagnosis of NMOSD. Thus, recombinant IFNα-2b was suspended immediately. Because his condition did not improve after 6-day treatment of methylprednisolone pulse therapy (1,000 mg for 3 days, then 500 mg for 3 days), intravenous immunoglobulin (0.4 g/kg/day for 5 days) was administered. The patient gradually improved. Low-dose prednisolone and mycophenolate mofetil were subsequently administered as a long-term treatment. The patient was discharged with subtle limb numbness and their expanded disability status score (EDSS) was 1. At the 1-year follow-up, the patient had not relapsed and tested negative for AQP4-IgG. We further identified the eight patients with IFNα-induced NMOSD. The median onset age was 59 years, and the median time of IFNα exposure was 18 months. Optic neuritis was the most common initial symptom (five, 55.6%), followed by myelitis in three patients and area postrema syndrome in one patient. More than half (five, 55.6%) of the patients were monophasic. After IFNα discontinuation and immunotherapy, most (seven, 77.8%) patients remained relapse-free. However, only one patient was free of sequelae.

CONCLUSION: This study highlights the potential pathogenic risk of NMOSD of IFNα treatment. Given the high disability rates of this rare drug-induced disease, it is crucial to monitor the early manifestations of NMOSD during IFNα treatment.

PMID:35547376 | PMC:PMC9081932 | DOI:10.3389/fneur.2022.872684