Adjunctive Drug Research Articles

Role of ripasudil as an adjunct treatment in the management of pseudoexfoliative glaucoma.

Ripasudil is a class of drug which alters the trabecular meshwork to increase the aqueous outflow and has been shown to be effective in pseudoexfoliative glaucoma (PXF G). This study aimed at assessing the efficacy and safety profile of ripasudil as an adjunct treatment in patients with PXF G at maximal tolerated antiglaucoma medications. In this prospective, interventional study, 40 patients with PXF G were enrolled between May 2021 and Jan 2022. Ripasudil 0.4% was started as an adjunctive drug to the ongoing antiglaucoma medications. On follow-up visits at 1, 3, and 6 months, the visual acuity, intraocular pressure (IOP), anterior segment, and fundus findings were evaluated. The premedication and postmedication IOP values were compared by paired t-test, and a P-value <0.05 was considered statistically significant. Average age at recruitment was 60.02 ± 8.74 years. Baseline premedication IOP was 25.375 ± 3.276 mmHg. IOP reduction at 6 months was found to be statistically significant in all patients, with the maximal response being 24.13%. Also, 87.5% (35/40) of patients reached target IOP or even lower IOP at the end of study. There was no statistically significant association between the PXF grade and IOP. However, the grade of inferior iridocorneal angle pigmentation was found to be higher in eyes with elevated IOP (P < 0.05). Only three patients developed conjunctival hyperemia as an adverse reaction, which was mild and transient. Ripasudil showed additional IOP-lowering effect with other antiglaucoma medications and exhibited no significant side effects.

Rho-kinase Inhibitors in Ocular Diseases: A Translational Research Journey.

This review summarizes current data on Rho-kinase (ROCK) inhibitors use in ocular diseases, primarily glaucoma. Translational research over the last decade culminating in the development of ROCK inhibitors has provided a much-needed shot in the arm to glaucoma pharmacopeia. ROCK pathway is intricately involved in cytoskeletal modulation with action on cell morphology, cell motility, cell adhesion, cell apoptosis, and smooth muscle contraction. This cytoskeletal modulation property has been utilized to modify trabecular meshwork (TM) resistance, resulting in the discovery of ROCK inhibitors to increase trabecular outflow. Multicentric trials on ROCK inhibitors for antiglaucoma medications are summarized. The focus is on linking pharmacological action to the clinical utility of these drugs. While the Rho Kinase Elevated intraocular Pressure (IOP) Treatment (ROCKET) trials compared monotherapy with ROCK inhibitor netarsudil vs timolol, MERCURY trials compared a fixed dose combination of latanoprost and ROCK inhibitor netarsudil [fixed combination netarsudil-latanoprost (FCNL)] vs monotherapy with either and bimatoprost-timolol combination. While ROCKET trials showed ROCK inhibitors to be non-inferior to timolol, MERCURY trials showed FCNL achieving a much greater IOP reduction than monotherapy with either. Conjunctival hyperemia was the most common side effect reported with ROCK inhibitor use. Moderate efficacy of ROCK inhibitors with a common side effect of conjunctival hyperemia, makes it an adjunctive antiglaucoma drug of choice and not a first-line therapy. ROCK inhibitors' action on diseased TM is more physiological compared to available antiglaucoma medications that either reduce aqueous secretion or enhance uveoscleral outflow. The property of ROCK inhibition to stabilize the endothelium of both retinal vasculature and cornea has opened a new chapter in the treatment of diabetic retinopathy and corneal decompensation. Singh K, Singh A. Rho-kinase Inhibitors in Ocular Diseases: A Translational Research Journey. J Curr Glaucoma Pract 2023;17(1):44-48.

Effects of Rho-Associated Kinase (Rock) Inhibitors (Alternative to Y-27632) on Primary Human Corneal Endothelial Cells.

(1) Rho-associated coiled-coil protein kinase (ROCK) signaling cascade impacts a wide array of cellular events. For cellular therapeutics, scalable expansion of primary human corneal endothelial cells (CECs) is crucial, and the inhibition of ROCK signaling using a well characterized ROCK inhibitor (ROCKi) Y-27632 had been shown to enhance overall endothelial cell yield. (2) In this study, we compared several classes of ROCK inhibitors to both ROCK-I and ROCK-II, using in silico binding simulation. We then evaluated nine ROCK inhibitors for their effects on primary CECs, before narrowing it down to the two most efficacious compounds-AR-13324 (Netarsudil) and its active metabolite, AR-13503-and assessed their impact on cellular proliferation in vitro. Finally, we evaluated the use of AR-13324 on the regenerative capacity of donor cornea with an ex vivo corneal wound closure model. Donor-matched control groups supplemented with Y-27632 were used for comparative analyses. (3) Our in silico simulation revealed that most of the compounds had stronger binding strength than Y-27632. Most of the nine ROCK inhibitors assessed worked within the concentrations of between 100 nM to 30 µM, with comparable adherence to that of Y-27632. Of note, both AR-13324 and AR-13503 showed better cellular adherence when compared to Y-27632. Similarly, the proliferation rates of CECs exposed to AR-13324 were comparable to those of Y-27632. Interestingly, CECs expanded in a medium supplemented with AR-13503 were significantly more proliferative in (i) untreated vs. AR-13503 (1 μM; * p < 0.05); (ii) untreated vs. AR-13503 (10 μM; *** p < 0.001); (iii) Y-27632 vs. AR-13503 (10 μM; ** p < 0.005); (iv) AR-13324 (1 μM) vs. AR-13503 (10 μM; ** p < 0.005); and (v) AR-13324 (0.1 μM) vs. AR-13503 (10 μM; * p < 0.05). Lastly, an ex vivo corneal wound healing study showed a comparable wound healing rate for the final healed area in corneas exposed to Y-27632 or AR-13324. (4) In conclusion, we were able to demonstrate that various classes of ROCKi compounds other than Y-27632 were able to exert positive effects on primary CECs, and systematic donor-match controlled comparisons revealed that the FDA-approved ROCK inhibitor, AR-13324, is a potential candidate for cellular therapeutics or as an adjunct drug in regenerative treatment for corneal endothelial diseases in humans.

Baicalein Suppresses NLRP3 and AIM2 Inflammasome-Mediated Pyroptosis in Macrophages Infected by Mycobacterium tuberculosis via Induced Autophagy.

Mycobacterium tuberculosis (Mtb) continues to pose a significant threat to global health because it causes granulomas and systemic inflammatory responses during active tuberculosis (TB). Mtb can induce macrophage pyroptosis, which results in the release of IL-1β and causes tissue damage, thereby promoting its spread. In the absence of anti-TB drugs, host-directed therapy (HDT) has been demonstrated to be an effective strategy against TB. In this study, we used an in vitro Mtb-infected macrophage model to assess the effect of baicalein, derived from Scutellariae radix, on pyroptosis induced in Mtb-infected macrophages. Further, we investigated the molecular mechanisms underlying the actions of baicalein. The results of the study suggest that baicalein inhibits pyroptosis in Mtb-infected macrophages by downregulating the assembly of AIM2 and NLRP3 inflammasome and promoting autophagy. Further research has also shown that the mechanism by which baicalein promotes autophagy may involve the inhibition of the activation of the Akt/mTOR pathway and the inhibition of the AIM2 protein, which affects the levels of CHMP2A protein required to promote autophagy. Thus, our data show that baicalein can inhibit Mtb infection-induced macrophage pyroptosis and has the potential to be a new adjunctive HDT drug. IMPORTANCE Current strategies for treating drug-resistant tuberculosis have limited efficacy and undesirable side effects; hence, research on new treatments, including innovative medications, is required. Host-directed therapy (HDT) has emerged as a viable strategy for modulating host cell responses in order to enhance protective immunity against infections. Baicalein, extracted from Scutellariae radix, was shown to inhibit pyroptosis caused by Mycobacterium tuberculosis-infected macrophages and was associated with autophagy. Our findings reveal that baicalein can be used as an adjunctive treatment for tuberculosis or other inflammatory diseases by regulating immune function and enhancing the antibacterial ability of the host. It also provides a new idea for exploring the anti-inflammatory mechanism of baicalein.

Pharmacological Treatment of Tardive Dyskinesia

Tardive dyskinesia (TD) is a serious, intractable, and potentially disabling side effect. Adjunctive drug treatment is used after optimizing the causative drugs. This article describes valbenazine, the first drug for treating TD that was recently approved in Japan, clonazepam, and vitamin E.

The Nitric Oxide (NO) Donor Molsidomine Counteract Social Withdrawal and Cognition Deficits Induced by Blockade of the NMDA Receptor in the Rat

The deficiency of the gaseous molecule nitric oxide (NO) seems to be critically involved in the pathogenesis of schizophrenia. Thus, molecules that can normalize NO levels, as are NO donors, might be of utility for the medication of this psychiatric disease. The aim of the present study was to detect the ability of the NO donor molsidomine to reduce schizophrenia-like impairments produced by the blockade of the N-methyl-D-aspartate (NMDA) receptor in rats. Molsidomine's ability to attenuate social withdrawal and spatial recognition memory deficits induced by the NMDA receptor antagonist ketamine were assessed using the social interaction and the object location test, respectively. Further, the efficacy of the combination of sub-effective doses of molsidomine with sub-effective doses of the atypical antipsychotic clozapine in alleviating non-spatial recognition memory deficits was evaluated utilizing the object recognition task. Molsidomine (2 and 4 mg/kg) attenuated social withdrawal and spatial recognition memory deficits induced by ketamine. Co-administration of inactive doses of molsidomine (1 mg/kg) and clozapine (0.1 mg/kg) counteracted delay-dependent and ketamine-induced non-spatial recognition memory deficits. The current findings suggest that molsidomine is sensitive to glutamate hypofunction since it attenuated behavioral impairments in animal models mimicking the negative symptoms and cognitive deficits of schizophrenia. Additionally, the present results support the potential of molsidomine as an adjunctive drug for the therapy of schizophrenia.

Effect of adjunctive drug therapy on early expulsion of distal ureteral calculi after extracorporeal shock wave lithotripsy

Objective: To evaluate the efficacy of ketochromate tromethamine and phloroglucinol combination therapy in early expulsion of ureteral calculi after extracorporeal shockwave lithotripsy (ESWL) in patients with distal ureteral clculi. The clinical and follow-up data of 275 patients with lower ureteral calculi who underwent ESWL were collected retrospectively in Civil Aviation General Hospital from January 1st 2021 to June 30th 2021. According to whether adjunctive medication used before ESWL patients were divided into control group and medication group (with ketochromate tromethamine 30 mg and phloroglucinol 80 mg before ESWL). Primary endpoint is the clearance rate of ureteral calculi after ESWL, secondary endpoint are the other outcomes and drug allergy. There were 138 cases in control group [117 were males and mean age (42±13) years]. Meanwhile, there were 137 cases in medication group [118 were males and mean age (42±12) years]. The clearance rate of ureteral calculi at 24 h (67.88% vs 48.55%, P=0.001)、one week (76.64% vs 57.97%, P=0.001) and four weeks (89.05% vs 76.08%, P=0.005)after ESWL in medication group were significant higher than that in control group. There was a significant difference in the VAS score of pain scale after ESWL (1.77±0.80 vs 2.06±1.04, P=0.012) and re-ESWL rate (8.03% vs 17.39%,P=0.02) between two groups, but no difference with gross hematuria in 6 h after ESWL and drug allergy. Conclusions combination use of ketochromate tromethamine and phloroglucinol significantly improve early expulsion of ureteral calculi after ESWL in patients with distal ureteral calculi, with no side effect.

The Evaluation Retinal Toxicity of Intravitreal Infliximab Injection

Objective To evaluate toxicity of varying doses of Infliximab injecting intravitreally in rabbits. Infliximab, an FDA approved anti-inflammatory drug for Rheumatoid arthritis and Crohn’s disease. It has been reported as an alternative or adjunct drug to chronic recurrent uveitis especially Behcet’s disease, Diabetic retinopathy and PVR Materials and Methods Twenty New Zeland albino rabbits were used for this study and divided into five groups (n=4 each). ARVO guidelines were followed in treatment of animals. The rabbits were injected intravitreally with, 0.125mg 0.250mg, 0.500mg, 1.25mg or 2.5mg Infliximab in 0.1 ml in one eye and 0.1 ml saline solution was used in the contralateral eye. All the animals were examined using indirect ophthalmoscopy and slit-lamp biomicroscopic examination before intravitreal injection and at days 1,7 and 14. An ERG was performed before any treatment and at day 14. On day 14 the animals were euthanized. Histological preparations of the enucleated eyes were examined for retinal toxicity. Results We found no retinal toxicity up to 1.25mg groups according to ERG results and Histological signs. 1of 4 eyes in the 2.5mg group had some significant decrease in Electroretinogram and histological toxicity signs. Conclusions Infliximab injection up to 1.25 mg is nontoxic to the rabbit’s retina. Intravitreal injected Infliximab may be a useful treatment for Uveitis especially Behcet’s disease, Diabetic retinopathy, Age Related Macular Degeneration and Proliferative Vitreoretinopathy.

Seventy years of evidence on the efficacy and safety of drugs for treating leprosy: a network meta-analysis

The World Health Organization (WHO) recommends multidrug therapy (MDT) with rifampicin, dapsone, and clofazimine for treating leprosy, which is based on very low-quality evidence. Here, we performed a network meta-analysis (NMA) to produce quantitative evidence to strengthen current WHO recommendations. All studies were obtained from Embase and PubMed from the date of establishment to October 9, 2021. Data were synthesized with frequentist random-effects network meta-analyses. Outcomes were assessed using odds ratios (ORs), 95% confidence intervals (95% CIs), and P score. Sixty controlled clinical trials and 9256 patients were included. MDT was effective (range of OR: 1.06-1255584.25) for treating leprosy and multibacillary leprosy. Six treatments (Range of OR: 1.199-4.50) were more effective than MDT. Clofazimine (P score=0.9141) and dapsone+rifampicin (P score=0.8785) were effective for treating type 2 leprosy reaction. There were no significant differences in the safety of any of the tested drug regimens. The WHO MDT is effective for treating leprosy and multibacillary leprosy, but it may not be effective enough. Pefloxacin and ofloxacin may be good adjunct drugs for increasing MDT efficacy. Clofazimine and dapsone+rifampicin can be used in the treatment of a type 2 leprosy reaction. Single-drug regimens are not efficient enough to treat leprosy, multibacillary leprosy, or a type 2 leprosy reaction. All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Dexmedetomidine or Fentanyl, Which One Is Better as an Adjunct Drug in Epidural Anesthesia and Causes More Postoperative Pain Reduction? A Comparative Study, a Randomized Clinical Trial.

This study compared dexmedetomidine to fentanyl as an adjunct to ropivacaine for epidural anesthesia in patients undergoing femoral neck fracture surgery. A total of 56 patients in two different groups with dexmedetomidine and fentanyl underwent the epidural anesthesia method by ropivacaine. This study compared the onset and duration of sensory block, duration of motor block, visual analog scale (VAS) analgesia, and sedation score. The VAS and hemodynamics (e.g., heart rate and mean arterial pressure) were measured every 5 to 15 minutes, then every 15 minutes to the end of the surgery, and then in the 1st, 2nd, 4th, 6th, 12th, and 24th hours after surgery. In the fentanyl group, the onset time of the sensory block was longer (P < 0.001), and the duration of the block was shorter than in the dexmedetomidine group (P = 0.045). In the fentanyl group, the onset time of motor block was longer than in the dexmedetomidine group (P < 0.001). The mean highest VAS score for each patient in the dexmedetomidine group was 4.9 ± 0.6, compared to the fentanyl group (5.8 ± 0.9), with a significant difference between the two groups (P < 0.001). The sedation score was higher from the 30th minute (P = 0.01) to the 120th minute (P = 0.04) in the patients of the dexmedetomidine group than in the fentanyl group. Side effects, such as dry mouth, hypotension, and bradycardia, were more common in the dexmedetomidine group, and nausea and vomiting were more common in the fentanyl group; however, there were no differences between the groups. There was no respiratory depression in both groups. This study presented that dexmedetomidine as an adjuvant in epidural anesthesia for orthopedic femoral fracture surgery shortens the onset time of sensory and motor block, increases analgesia length, and prolongs anesthesia. Sedation with dexmedetomidine is better than fentanyl, with fewer side effects, and more effective as preemptive analgesia.

Comparative efficacy, acceptability, and tolerability of adjunctive anti-inflammatory agents on bipolar disorder: A systemic review and network meta-analysis.

We performed a network meta-analysis (NMA) with up-to-date evidence to compare different anti-inflammatory agents to improve the treatment of bipolar disorder (BD) patients. Four databases (i.e., the Cochrane Library, Web of Science, PubMed, and Embase) were searched for randomized controlled trials (RCTs) published between 1995 and 2022 on the use of anti-inflammatory agents in the treatment of BD. A systematic review and NMA were conducted. Adjunctive N-acetylcysteine (NAC) was superior to placebo for the treatment of BD according to the endpoint scale score (SMD -0.65, 95% confidence interval (CI): -0.99 to -0.31), response rate (odds ratio (OR) 3.42, 95% CI: 1.23-9.52), remission rate (OR 4.94, 95% CI: 1.03-41.38) and surface under the cumulative ranking curve (SUCRA) value of the endpoint scale score (0.84). Adjunctive nonsteroidal anti-inflammatory drugs (NSAIDs) were more favorable than placebo based on the remission rate (OR 3.93, 95% CI: 1.15-13.43) and were significantly more acceptable than other treatments (OR 0.60, 95% CI: 0.36-0.99). Adjunctive coenzyme Q10 (CoQ10) was superior to other agents in terms of the response rate (OR 18.85, 95% CI: 2.63-135.00), with a SUCRA value for the response rate of 0.90 and that for the remission rate of 0.71. Adjunctive NAC is recommended for the treatment of BD. Adjunctive NSAIDs and CoQ10 are still seen as effective, but more high-quality clinical studies are needed to verify their efficacy. Other anti-inflammatory agents may not be recommended for clinical use at present. All anti-inflammatory agents demonstrated a good safety profile. We call for further research on the combined treatment of BD with different anti-inflammatory agents to be included in future trials.

Astragalus propinquus schischkin and Salvia miltiorrhiza bunge promote angiogenesis to treat myocardial ischemia via Ang-1/Tie-2/FAK pathway.

Astragalus propinquus Schischkin and Salvia miltiorrhiza Bunge (AS) have been clinically used as adjunctive drugs in the treatment of myocardial ischemia (MI). However, the effect and mechanism of AS on MI have yet to be fully recognized. Here, we explored the cardioprotective effect of their combined use, and the mechanism of promoting angiogenesis through pericyte recruitment. Our data revealed that AS reduced MI and protects cardiac function. AS-treated MI mice exhibited reduced ST-segment displacement and repolarization time, increased ejection fraction, and less BNP and NT-proBNP expression. Pathological studies showed that, AS reduced the area of infarcted myocardium and slowed down the progress of cardiac remodelling and fibrosis. In addition, AS increased the content of platelet-derived growth factor receptors β (PDGFR-β), platelet endothelial cell adhesion molecule-1 (CD31) and angiogenesis-related proteins including vascular endothelial cadherin (VE-cadherin), Vascular Endothelial Growth Factor (VEGF) and transforming growth factor β (TGF-β). Moreover, these botanical drugs upregulated the expression of Angiopoietin-1 (Ang-1), phosphorylated angiopoietin-1 receptor (p-Tie-2), focal adhesion kinase (FAK) and growth factor receptor bound protein 7 (GRB7), indicating that the cardioprotection-related angiogenesis effect was related to pericyte recruitment, which may be through Ang-1/Tie-2/FAK pathway. In summary, AS can treat MI by protecting cardiac function, attenuating cardiac pathological changes, and hindering the progression of heart failure, which is related to angiogenesis after pericyte recruitment. Therefore, AS at a certain dose can be a promising treatment for MI with broad application prospects.

Evaluation of in-vitro colistin susceptibility and clinical profile of carbapenem resistant Enterobacteriaceae related invasive infections

PurposeTo determine the colistin susceptibility. To compare E-test vs broth-microdilution (BMD) method for invasive carbapenem resistant Enterobacteriaceae (CRE) infections. To study treatment options for the CRE. To analyze the clinical profile and outcome of CRE infections. MethodsAntimicrobial susceptibility testing was performed for 100 invasive CRE isolates. Gradient diffusion and BMD methods were performed to determine colistin MICs. Essential agreement (EA), categorical agreement (CA), very major error (VME), and major error (ME) were worked out between BMD method and E-test. The clinical profile of patients was analyzed. ResultsThe majority of the patients suffered from bacteremia [47(47%)]. Klebsiella pneumoniae was the most common organism isolated overall as well as among bacteremic isolates. 9(9%) CRE isolates were colistin resistant by BMD of which six were Klebsiella pneumoniae. There was 97% CA between E-test and BMD. EA was 68%. VME was found in three out of nine colistin resistant isolates. No ME was found. Among the other antibiotics tested for CRE isolates, the highest susceptibility was seen to tigecycline [43(43%)] followed by amikacin [19 (19%)]. The most common underlying condition was post solid organ transplantation [36(36%)]. A higher survival rate was seen among non-bacteremic CRE infections (58.49%) than bacteremic CRE infections (42.6%). Four out of nine patients with colistin resistant CRE infections survived and had a satisfactory outcome. ConclusionKlebsiella pneumoniae was the most common organism causing invasive infection. Survival rates were higher in non-bacteremic CRE infections than bacteremic infections. Good CA was seen between E-test and BMD for colistin susceptibility, but the EA was poor. VME was more common than ME when E-tests were used for colistin susceptibility testing resulting in false susceptibility. Tigecycline and aminoglycosides are possible adjunct drugs for the treatment of invasive CRE infections.

Orexin Receptor Antagonists as Adjunct Drugs for the Treatment of Depression: A Mini Meta-Analysis.

There is growing interest in the efficacy of orexin receptor antagonists (ORA), one of the new psychopharmacological agents used in the treatment of insomnia, in other psychiatric disorders such as depression. This meta-analysis was conducted in accordance with PRISMA requirements. Literature searches were conducted using PubMed, Scopus and EBSCO (Medline) databases. Search words were (depression OR mood disorder OR affective disorder) AND (orexin OR orx OR hypocretin OR orx1 OR orx2 OR orexin receptor antagonist OR almorexant OR suvorexant OR lemborexant OR daridorexant OR seltorexant OR vornorexant OR filorexant). No date restrictions were used. The random effects model was used for analyses with I2 values above 50% and fixed effects model was used for analyses with I2 values below 50%. In the acute phase, ORAs had no significant effect on core, sleep-adjusted and total symptoms of depression respectively; Standardized Mean Difference (SMD) for random effect -0.422, 95% CI [-0.90; 0.06], p=0.089, I2=62.4%; SMD for random effect -0.375, 95% CI [-1.24; 0.49], p=0.400; I2=66.6% and SMD for random effect -0.477, 95% CI [-0.97; 0.01], p=0.059; I2=83.1%). However, they had a significant effect on core and total symptoms of depression in the early period respectively; SMD for fixed effect=-0.228, 95% CI [-0.44; -0.01], p=0.036, I2=9.1%; and SMD for fixed effect=-0.186, 95% CI [-0.37; -0.001], p=0.048, I2=0.0%, respectively). The results of this meta-analysis suggest that ORAs may provide direct antidepressant efficacy when added to existing antidepressant treatment and may also have indirect antidepressant effects through improvement in sleep symptoms. Considering the physiological effects of orexin on behaviors, ORAs may be promising new treatment modalities in the treatment of many psychiatric disorders other than insomnia. However, these results are preliminary and further studies with different ORAs at different doses and with different samples are needed.

Ginger Could Improve Gestational Diabetes by Targeting Genes Involved in Nutrient Metabolism, Oxidative Stress, Inflammation, and the WNT/β-Catenin/GSK3β Signaling Pathway

This study aimed to evaluate the effect in female rats of 6 weeks of ginger consumption on gestational diabetes by assessing glucose and lipid metabolism, oxidative damage, inflammation, and the WNT/β-catenin/glycogen synthase kinase-3 beta (GSK3β) signaling pathway. In this study, 40 adult female rats were divided into 4 equal groups as follows: pregnant rats, pregnant rats with diabetes, pregnant rats consuming ginger, and pregnant rats with diabetes consuming ginger. Induction of diabetes on day 0 of pregnancy was induced by streptozotocin (STZ) injection. Insulin, glucose, and lipid profiles as metabolic factors were measured along with the hepatic expression of glucose transporter type 4 (GLUT4), mechanistic target of rapamycin complex 1 (mTORc1), sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor α (PPAR-α), β-catenin, GSK3β, PPAR-g, nuclear factor-κB (NF-kB), and nuclear factor erythroid 2-related factor 2 (Nrf2). The levels of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and oxidative parameters were measured in the liver. The level of metabolic factors was significantly impaired in diabetic pregnant rats compared to the control group. However, ginger improved these parameters in the diabetic pregnant—ginger group compared to the diabetic pregnant group. The hepatic expression of genes involved in metabolism, oxidative stress, inflammation, and the wingless and int-1 (WNT) signaling pathway was significantly impaired in diabetic pregnant rats, while ginger improved them in the hepatic tissue of diabetic pregnant rats. It can be concluded that ginger could improve gestational diabetes by genes involved in metabolism, the WNT signaling pathway, oxidative stress, and inflammation. These results suggest that ginger can be an adjunct drug during pregnancy as a metabolic modulator.

NETosis is critical in patients with severe community-acquired pneumonia.

Pneumonia is the fourth leading cause of death globally, and the reason for the high mortality rate of patients with severe community-acquired pneumonia (SCAP) remains elusive. Corticosteroid treatment reduces mortality in adults with SCAP but can cause numerous adverse events. Therefore, novel therapeutic targets need to be explored and new adjunctive immune drugs are urgently required. We analyzed the transcriptome data of peripheral blood leukocytes from patients with SCAP and healthy controls from three perspectives: differentially expressed genes, predicted functions of differentially expressed long non-coding RNAs, and transcriptional read-through. We discovered that the NETosis pathway was top-ranked in patients with SCAP caused by diverse kinds of pathogens. This provides a potential therapeutic strategy for treating patients. Furthermore, we calculated the correlation between the expression of genes involved in NETosis and the ratio of arterial oxygen partial pressure to fractional inspired oxygen. We identified four novel potential therapeutic targets for NETosis in patients with SCAP, including H4C15, H3-5, DNASE1, and PRKCB. In addition, a higher occurrence of transcriptional read-through is associated with a worse outcome in patients with SCAP, which probably can explain the high mortality rate of patients with SCAP.

DRUG UTILIZATION STUDY IN A RADIOTHERAPY UNIT OF A TERTIARY CARE TEACHING HOSPITAL IN RURAL WEST BENGAL, INDIA

Objective: Drug utilization studies lay special emphasis on the medical social and economic consequences of use of medications in special settings. This study was undertaken to identify the pattern of drugs prescribed frequently among patients attending the radiotherapy department. Methods: This is a prospective study undertaken between January 1, 2018, and December 31, 2018. Prescriptions and patient records were reviewed and analyzed using the World Health Organization (WHO) indicators for drug utilization studies. Results: We encountered a total of 618 patients during the study period. Among them, 340 (55.01%) were female. The most common age groups presenting were between 21 and 60 years. Carcinoma breast was the most common type encountered (total cases 181, 29.28%), followed by carcinoma lung (total cases 92, 14.88%), carcinoma cervix, hematological malignancies, carcinoma prostate, and carcinoma rectum. Total number of drugs prescribed was 3008 in total 618 prescriptions making it 4.86 drugs per prescription on average. Among them on average per prescription, 2.82 drugs were cytotoxic drugs (1745 total), whereas 2.04 drugs were supportive or adjunct drugs (1263 total). Among the drugs prescribed, 96.24% were in generic names, 6.95% prescriptions contained antibiotics, and 96.44% (596) prescriptions contained injections. About 85.23% of drugs were prescribed from essential drug list. Average consulting was 8.2 min and dispensing time for adjunct drugs was 4 min on average. On average, 52.42% of patients (324) had complete correct knowledge of the dosage and schedule prescribed. Adverse drug reactions were common, out of 618 patients, 542 (87.7%) experienced ADRs most common being gastrointestinal and dermatological ADRs. The most common implicated drug was cisplatin. Six serious adverse events were encountered. Conclusions: This study provides a clear picture of drug use in this special clinic in rural Bengal and paves the way for larger and long-term study.

In situ gelation strategy based on ferrocene-hyaluronic acid organic copolymer biomaterial for exudate management and multi-modal wound healing

Exudate management remains a major concern in slow or non-healing wound management. Therefore, there is a need to devise a massive exudate-absorbing, exudate-locking, and stable extracellular matrix structure-maintaining functional wound dressing. Inspired by metal-organic frameworks, we chemically introduced sandwich ferrocene (Fc) into hyaluronic acid (HA) to fabricate an innovative metal Fc-HA organic copolymer (FHoC) as the skeleton material for in situ gelation, which was then gently compressed into a pre-hydrogel patch (FHoCP). Fc promoted the rearrangement of polymer chains to form additional microcrystalline and hydrophobic regions, which improved hydrogel transition and the exudate-locking ability. Thus, the simple composition FHoCP(5) absorbed 150 times its weight of water and maintained a firm three-dimensional network, which contributed to reducing inflammation and acted as a physical barrier against hemostasis and anti-bacterial invasion. Meanwhile, multi-modal processes, including fibroblast migration, angiogenesis, and antibacterial effects, were integrated into the gelled FHoCP(5) guided by Fe to promote wound healing. This study suggested that FHoC biomaterial could accelerate the closure of chronic wounds. We believe that this unique FHoCP(5)-based in situ gelation strategy could provide a solid drug-loaded scaffold for cell or adjunctive drug therapies, which holds great potential for the development of multifunctional biomaterials. Statement of significanceHydrogels that absorb excessive exudates while maintaining stable ECM-like network as well as exert multimodal wound healing activities are ideal dressings for accelerating chronic wound contraction. Herein, we reported an innovative metal ferrocene-hyaluronic acid organic copolymer patch (FHoCP) and FHoCP-mediated in situ gelation strategy. Ferrocene (Fc) induced in situ gelation by promoting polymer chain rearrangement, acting as a physical barrier for hemostasis and anti-bacterial invasion, and absorbing massive exudates, resulting in reducing delayed inflammation. As the structural core, rigid Fc enhanced the stability of the hydrogel backbone, and hydrophobic Fc improved fibroblast migration. In addition, Fe2+ chemically inhibited bacteria and increased angiogenesis. These results indicated the potential of FHoCP-based hydrogel for application in clinical skin reconstruction.

Preincision Adjunctive Prophylaxis for Cesarean Deliveries: A Systematic Review and Meta-analysis

(Am J Obstet Gynecol. 2021;225:382.e1–382.e13) Surgical site infections (SSI) occur after 2% to 7% of cesarean deliveries. While the administration of preincision beta-lactam antibiotics is recommended, there is a high rate of SSIs following cesarean delivery. Adjunctive prophylaxis, or the administration of a second antibiotic, has been shown to decrease postcesarean SSI rates. Azithromycin has been the adjunctive prophylaxis drug of choice in addition to cefazolin. As azithromycin was more difficult to obtain during the COVID-19 pandemic, clarithromycin has been used in its place. This study aimed to evaluate the use of preincision cefazolin with macrolides or metronidazole compared with cefazolin alone in terms of decreasing the incidence of SSIs following cesarean delivery.

Melatonin arrests excessive inflammatory response and apoptosis in lipopolysaccharide-damaged rat liver: A deeper insight into its mechanism of action

Sepsis is a life-threatening organ dysfunction. An animal model mimicking sepsis utilizes lipopolysaccharide (LPS), an endotoxin recognized as the most potent bacterial mediator of sepsis. Melatonin (MLT), an effective anti-inflammatory and antioxidant agent, is a promising adjunctive drug for sepsis. This study aimed to estimate the potential of MLT in preventing LPS-induced liver damage in Wistar rats by determining the levels of serum and tissue biochemical markers that reflect liver state and function, i.e., serum levels of transaminases and albumin, as well as a panel of oxidative stress-related biomarkers. Additionally, a pathohistological analysis of liver tissue was conducted. Pre-treatment with MLT prevented an LPS-induced increase in serum and tissue liver damage markers and a decrease in the tissue antioxidant capacity, in both enzymatic and non-enzymatic systems. Micromorphological liver tissue changes mirrored the alterations observed in the biochemical status. In rats with LPS-induced sepsis, melatonin was shown to be a crucial antioxidant and anti-inflammatory agent, with vital roles in the alleviation of oxidative stress, causing an increase of the antioxidant capacities and the improvement of the liver's microscopic appearance.