A fruit fly-based approach to unraveling enteropathy-causing pharmaceuticals.

Enteropathy is a gastrointestinal disorder characterized by inflammation in the small intestine and one of the causes of enteropathy is the side effects of certain drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs). The mechanism of NSAIDs, such as indomethacin, could inhibit prostaglandin synthesis, leading to a decrease in mucus production and small intestine integrity. To test the effects of a drug, it is necessary to undergo preclinical testing using animal models. Commonly used animal models such as mice and rats have several drawbacks including high cost, ethical issues, and long lifespan. Therefore, alternatives such as using invertebrate animals like Drosophila melanogaster as a more economical in vivo platform with genetic similarity to mammals and devoid of ethical concerns are needed. The aim of this study was to evaluate Drosophila melanogaster as an in vivo model organism in testing the side effects of pharmaceuticals that cause enteropathy. In this study, flies aged 3-5 days were starved and then placed into treatment vials comprising untreated control and indomethacin-treated (3.75 mM, 7.5 mM, and 15 mM). Survival analysis was conducted during the treatment period, followed by a Smurf assay test after seven days of treatment. Subsequently, the expression of pro-inflammatory cytokine-related genes (drs and totA), mitochondria stability-related genes (tom40), and endogenous antioxidant-related genes (sod1, sod2, and cat) was performed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Our data indicated that indomethacin did not impact lifespan or cause intestinal damage. However, we observed increased expression of pro-inflammatory cytokine-related genes, including drs, and a twofold increase in totA gene expression. Furthermore, there was a significant upregulation of mitochondrial stability gene tom40, endogenous antioxidant genes sod1 and cat, and a threefold increase in sod2 at 15 mM indomethacin. Although no phenotypical changes in gut integrity were detected, the increased expression of pro-inflammatory cytokine genes suggests the occurrence of inflammation in the indomethacin-treated flies.

Development of Transdermal Formulation Integrating Polymer-Based Solid Microneedles and Thermoresponsive Gel Fucoidan for Antiaging: Proof of Concept Study.

Skin can be damaged by intense and prolonged exposure to ultraviolet (UV) radiation. Photoaging and acute damage from sun exposure result in collagen degradation and enzymatic activity decline in the skin. Fucoidan (FUC) exhibits potential antiaging properties, including collagen synthesis promotion and enzyme activity inhibition. However, FUC's limited ability to penetrate the skin layers due to its large molecular weight makes it a challenge for topical application. In this study, we successfully developed a new approach by integrating thermoresponsive gel (TRG) containing FUC with solid microneedles (SMNs) as a delivery system. TRG is formulated using a combination of Pluronic F127 (PF127) and Pluronic F68 (PF68) polymers, while SMNs are made from a mixture of poly(vinyl alcohol) (PVA) and poly(vinylpyrrolidone) (PVP) polymers with a variety of cross-linkers. Based on the results of ex vivo testing, it was shown that more than 80% of FUC can be delivered using the optimized formula. Furthermore, the results of the in vitro blood hemolytic test showed that TRG-FUC-SMNs were relatively biocompatible. In vivo antiaging activity tests using a rat model exposed to UV for 14 days showed that histological assessment, skin elasticity measurement, wrinkle evaluation, and skin moisture content had no significant differences (p < 0.05) compared to the positive control group. In contrast, a significant difference (p < 0.05) was observed when comparing the TRG-FUC-SMNs group with the group that received only TRG-FUC without pretreatment and negative controls. These findings suggest that FUC has potential to be delivered using the TRG system in combination with SMNs to harness its antiaging properties.

Formulation and evaluation of dissolving microneedle for transdermal delivery of piperine: the effect of polymers concentration.

This research aims to develop the formulation of Dissolving Microneedle Piperine (DMNs PIP) and evaluate the effect of polymer concentration on characterisation and permeation testing results in ex vivo. DMNs PIP were prepared from varying concentrations of piperine (PIP) (10, 15, and 20% w/w) and polymers of polyvinyl alcohol (PVA): Polyvinyl pyrrolidone (30:60 and 60:25), respectively. Then the morphological evaluation of the formula was carried out, followed by mechanical strength testing. Furthermore, the density, LOD, and weight percentage of piperine in the dried microneedle were calculated and the determination of volume, needle weight and piperine weight and analysed. Ex vivo testing, X-Ray Diffraction, FTIR and hemolysis tests were carried out. PIP with PVA and PVP (F1) polymers produced DMN with mechanical strength (8.35 ± 0.11%) and good penetration ability. In vitro tests showed that the F1 polymer mixture gave good penetration (95.02 ± 1.42 µg/cm2), significantly higher than the F2, F3, F4, and F5 polymer mixtures. The DMNs PIP characterisation results through XRD analysis showed a distinctive peak in the 20-30 region, indicating the presence of crystals. The FTIR study showed that the characteristics of piperine found in DMNs PIP indicated that piperine did not undergo interactions with polymers. The results of the ex vivo study through DMNs PIP hemolytic testing showed no hemolysis occurred, with the hemolysis index below the 5% threshold reported in the literature. These findings indicate that DMNs PIP is non-toxic and safe to use as alternative for treating inflammation.

Healthcare Quality Received by Insured Patients in Two Indonesian Regional Public Hospitals.

Background: Hospitals are required to improve the quality of health services provided to patients. Purpose: Evaluating and comparing the healthcare quality received by insured patients hospitalized in two Indonesian regional public hospitals. Methods: Secondary data analysis used the 2019 and 2020 Indonesian National Health Insurance e-claim databases of Hospital A and Hospital B. Descriptive and crosstabs analyses were used to determine INA-CBGs diagnoses that were categorized as high volume, high risk, and high cost. Results: The admissions that caused financial loss at the Hospital A were 21.1% in 2019 and 19.8% in 2020, while 30.3% in 2019 and 27.5% at the Hospital B. More than 60% of these admissions were placed in the 3rd class of inpatient wards of the two hospitals. Of these admissions, < 5% at the Hospital A and >5% at the Hospital B were readmitted within 30 days, although more than 90% were previously discharged based on physicians' approval. Conclusions: Inadequate healthcare quality received by insured patients. Hence, an integrated clinical pathways based professional nursing practice model is highly recommended to increase patient outcomes and decrease 30 days hospital readmission rates.

Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches.

Cancer is one of the leading causes of death worldwide. Several treatments are available for cancer treatment, but many treatment methods are ineffective against multidrug-resistant cancer. Multidrug resistance (MDR) represents a major obstacle to effective therapeutic interventions against cancer. This review describes the known MDR mechanisms in cancer cells and discusses ongoing laboratory approaches and novel therapeutic strategies that aim to inhibit, circumvent, or reverse MDR development in various cancer types. In this review, we discuss both intrinsic and acquired drug resistance, in addition to highlighting hypoxia- and autophagy-mediated drug resistance mechanisms. Several factors, including individual genetic differences, such as mutations, altered epigenetics, enhanced drug efflux, cell death inhibition, and various other molecular and cellular mechanisms, are responsible for the development of resistance against anticancer agents. Drug resistance can also depend on cellular autophagic and hypoxic status. The expression of drug-resistant genes and the regulatory mechanisms that determine drug resistance are also discussed. Methods to circumvent MDR, including immunoprevention, the use of microparticles and nanomedicine might result in better strategies for fighting cancer.

Evaluation of health care quality among insured patients in Indonesian mother & child hospital: A secondary data analysis.

OBJECTIVE: This study aimed to evaluate the health care quality among insured patients hospitalized in the Indonesian mother and child hospital. METHOD: A secondary data analysis was performed to evaluate the health care services received by the insured patients hospitalized in the Indonesian mother and child hospital. Data were extracted from the BPJS health insurance e-claim database from January 1 to December 31, 2019 and from January 1 to June 30, 2020. A descriptive and bivariate analysis were used to examine total patients and hospital admissions; INACBGs diagnoses, procedures by severity; types of inpatient wards; length of stay; discharge status; hospital costs; and 30-day readmissions. RESULTS: Total inpatient unit admissions were 2870 in 2019 and 1533 in 2020. From total hospital admissions in 2019 and 2020, over 50% were admitted to the 3rd class of inpatient units, less than 10% had length of stays more than 5 days, and over 98% were discharged based on physician approval. However, hospital readmissions were also found for about 20.1% in 2019 and 2.9% in 2020 and about 42.9% in 2019 and 61.3% in 2020 were found causing hospital financial losses. Older patients, longer hospital stays, inpatient ward class 1 & 2, high hospital tariff, inadequate clinical pathway implementation, lack of interprofessional collaboration, and ineffective nurse manager supervision were identified as contributing factors to the hospital financial losses. CONCLUSION: Integrated clinical pathways with interprofessional collaboration that are implemented through professional nursing practice model are suggested for health care quality improvement.

New and sensitive HPLC-UV method for concomitant quantification of a combination of antifilariasis drugs in rat plasma and organs after simultaneous oral administration.

A combination treatment comprising ivermectin (IVM), albendazole (ABZ) and doxycycline (DOX) is often prescribed for lymphatic filariasis patients. Nevertheless, there has not been an analytical method established and documented to determine these compounds simultaneously. Herein, we report a new high-performance liquid chromatographic method coupled with a UV detector (HPLC-UV) to quantify these drugs in plasma and organs. This developed analytical method was validated according to the International Conference on Harmonization (ICH) and US Food and Drug Administration (FDA) guidelines. The validated method was successfully employed to analyze IVM, ABZ along with its metabolites (albendazole sulfoxide (ABZ-OX) and albendazole sulfone (ABZ-ON)), and DOX in the plasma and organs of Wistar rats after simultaneous oral administration. An Xselect CSH™ C18 HPLC column was utilized as a stationary phase, with a mobile phase consisting of 0.1% v/v trifluoracetic acid in water and acetonitrile with a run time of 20 min. The calibration curves in biological samples were found to be linear across the concentration range of 0.01-5 µg mL-1 for IVM, ABZ and ABZ metabolites, and 0.025-10 µg mL-1 for DOX with an R value ≥0.998 in each case. The validated method was found to be selective, precise and accurate. Finally, the method developed in this study was deployed to assess the pharmacokinetic profiles and biodistribution of the combination of drugs after oral administration to Wistar rats. The validated HPLC-UV method in this study provides an extensive range of prospective applications for pharmacokinetic-based studies, therapeutic drug monitoring and toxicology.

Inhibition of cholesteryl ester synthesis by polyacetylenes from Atractylodes rhizome.

Using activity guided purification, four known compounds, sesquiterpene atractylenolide III (1), and the polyacetylenes 14-acetoxy-12-senecioyloxytetradeca-2E,8E,10E-trien-4,6-diyn-1-ol (2), 14-acetoxy-12-α-methylbutyl-2E,8E,10E-trien-4,6-diyn-1-ol (3), and 14-acetoxy-12-ß -methylbutyl-2E,8E,10E-trien-4,6-diyn-1-ol (4), were isolated from a traditional herbal medicine, Atractylodes rhizome. Structurally similar 3 and 4 (3/4 mixture) were obtained as a mixture. In intact Chinese hamster ovary (CHO) K1 cell assays, 1, 2, and a 3/4 mixture selectively inhibited cholesterol [14C]oleate synthesis from [14C]oleate with IC50 values of 73.5 µM, 35.4 µM, and 10.2 µM, respectively, without any effects on cytotoxicity. As a potential target of these inhibitors involved in cholesteryl ester (CE) synthesis, effects on sterol O-acyltransferase (SOAT) activity were investigated using microsomes prepared from CHO-K1 cells as an enzyme source. Hence, these compounds inhibit SOAT activity with IC50 values (211 µM for 1, 29.0 µM for 2, and 11.8 µM for 3/4 mixture) that correlate well with those measured from intact cell assays. Our results strongly suggest that these compounds inhibit CE synthesis by blocking SOAT activity in CHO-K1 cells.

Synthesis, Molecular Mechanism and Pharmacokinetic Studies of New Epoxy Lignan-Based Derivatives.

The oxidative demethylation procedure for a new epoxy lignan isolated from Piper nigrum was applied to the synthesis of 3'-methoxy-3",4"-(methylenedioxy)-2,5-epoxylignan-4'-ol-6'-one. This compound inhibited the mRNA expression of the protein patched homolog (Ptch) in human pancreatic cancer cells (PANC1) and therefore might be valuable as a probe for tumor-related disease. The pharmacokinetic profile of 3'-methoxy-3",4"-(methylenedioxy)-2,5-epoxylignan-4'-ol-6'-one was rapidly determined using ultra-fast liquid chromatography. The compound was rapidly absorbed in blood.