Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

Prediction of the Liver Safety Profile of a First-in-Class Myeloperoxidase Inhibitor Using Quantitative Systems Toxicology Modeling.

The novel myeloperoxidase inhibitor verdiperstat was developed as a treatment for neuroinflammatory and neurodegenerative diseases. During development, a computational prediction of verdiperstat liver safety was performed using DILIsym v8A, a quantitative systems toxicology (QST) model of liver safety.A physiologically-based pharmacokinetic (PBPK) model of verdiperstat was constructed in GastroPlus 9.8, and outputs for liver and plasma time courses of verdiperstat were input into DILIsym. In vitro experiments measured the likelihood that verdiperstat would inhibit mitochondrial function, inhibit bile acid transporters, and generate reactive oxygen species (ROS); these results were used as inputs into DILIsym, with two alternate sets of parameters used in order to fully explore the sensitivity of model predictions. Verdiperstat dosing protocols up to 600 mg BID were simulated for up to 48 weeks using a simulated population (SimPops) in DILIsym.Verdiperstat was predicted to be safe, with only very rare, mild liver enzyme increases as a potential possibility in highly sensitive individuals. Subsequent Phase 3 clinical trials found that ALT elevations in the verdiperstat treatment group were generally similar to those in the placebo group. This validates the DILIsym simulation results and demonstrates the power of QST modeling to predict the liver safety profile of novel therapeutics.

Testing of acute and sub-acute toxicity profile of novel naproxen sodium nanoformulation in male and female mice.

Nanodrugs offer promising alternatives to conventionally used over the counter drugs. Compared to its free form, therapeutic benefits, and gastric tissue safety of naproxen sodium nanoformulation (NpNF) were recently demonstrated. Essential regulatory safety data for this formulation are, however, not available. To address this, male and female BALB/c mice were subjected to acute and 14-day repeated-oral dose assessments. Our data indicate that NpNF was well tolerated up to 2000 mg/kg b.w. A 14-day subacute toxicity testing revealed that the oral administration of low dose (30 mg/kg) NpNF did not produce any adverse effects on blood profile and serum biochemical parameters. Levels of oxidative stress markers and antioxidant enzymes neared normal. Histology of selected tissues also showed no evidence of toxicity. In contrast, a ten-fold increase in NpNF dosage (300 mg/kg), demonstrated, irrespective of gender, mild to moderate toxicity (p < 0.05) in the brain, stomach, and heart tissues, while ROS, LPO, CAT, SOD, POD, and GSH levels remained unaffected in the liver, kidney, spleen, testis, and seminal vesicles. No effect on serum biochemical parameters, overall indicated a no-observed-adverse-effect level (NOAEL) is 300 mg/kg. Further increase in dosage (1000 mg/kg) significantly altered all parameters demonstrating that high dose is toxic.

Naproxen sodium nanoparticles are less toxic and gastroprotective agents than the conventional NSAID drug naproxen sodium in Balb/c mice.

Use of non-steroidal anti-inflammatory drugs (NSAIDs) is one of the leading causes of gastric ulcers. Excellent therapeutic properties have made the use of NSAIDs widespread. Nano-drug delivery to reduce systemic toxicity through modulating drug pharmacokinetics may be a better choice. Presently, we investigated if naproxen nanoformulation (PVA capped NPRS-MgO NPs) is less toxic to be used as an alternative drug. Groups of mice were assigned to control, NPRS-treated, CNF-treated, UNF-treated, and MgO NPs-treated groups. Analyses included gross examination of gastric mucosa, calculation of ulcer and inhibition indices, determination of tissue levels of reactive oxygen species (ROS), malondialdehyde (MDA), catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and reduced glutathione (GSH), histological and immunohistochemical assessment of i-NOS, COX-2, and caspase-3 of stomach mucosa, q-PCR for the detection of mRNA expression of IL-1ß, IL-6, and TNF-α. Results were compared statistically at P < 0.05. Compared to NPRS-treated mice which developed multiple ulcers, had elevated MDA and ROS levels, and deceased CAT, POD, SOD, and GSH levels, significantly increased expression of IL-1ß, IL-6, and TNF-α mRNA, damaged surface epithelium with disrupted glandular architecture and leucocyte infiltration of lamina propria with a marked increase in mucosal COX-2, i-NOS, and caspase-3 expression, oral administration of coated and uncoated naproxen nanoformulations prevented the gross mucosal damage by a restoration of all biochemical, histological, and immunohistochemical alterations to near control levels. The present study demonstrates that naproxen sodium nanoformulation has a gastroprotective action and in the clinical setting can be a better alternative to conventional naproxen.

Intraperitoneal kisspeptin-10 administration ameliorates sodium arsenite-induced reproductive toxicity in adult male mice.

The current study investigated the protective ameliorative effect of intraperitoneally administered kisspeptin-10 (50 nmol/day) against reproductive toxicity in adult male mice challenged with 35 days of exposure to sodium arsenite in drinking water. Mice were divided into tap water control, sodium arsenite-alone (4 ppm and 10 ppm), kisspeptin-alone (intermittent and continuous) and combined (sodium arsenite +kisspeptin-10 intermittent and continuous) treatment groups. Results revealed protective effect of both intermittent and continuous kisspeptin doses on reproductive organs against sodium arsenite-induced toxicity. This was indicated by an increase (p < 0.001) in the activity of antioxidant enzymes and a decrease (p < 0.001) in the levels of oxidative stress biomarkers. Concomitant significant increase was noticeable in the relative organ weight (p < 0.01), and serum testosterone and seminal fructose (p < 0.001), and a significant improvement in sperm parameters was also observed. A significant downregulation of lactate dehydrogenase concentration demonstrated further the protective effect of kisspeptin against tissue damage. Histologically, both treatment regimens of kisspeptin combined with sodium arsenite exposure prevented massive germ cell loss and tissue damage, a condition prominent in sodium arsenite-alone-treated mice. The study demonstrates for the first time kisspeptin's potential to mitigate the biochemical and histotoxic effects of arsenic on male reproductive system.

Social determinants and causes of child mortality in Pakistan: Analysis of national demographic health surveys from 1990 to 2013.

AIM: The aim of the study was to define social determinants, causes and trends in child mortality from 1990 to 2013 in Pakistan. Understanding social determinants, causes and temporal trends in child mortality can inform strategies aimed at improving child health in low and middle income countries. METHODS: We characterised temporal trends and social determinants of child mortality in Pakistan using national demographic health survey data (1990-1991, 2006-2007 and 2012-2013). We analysed national data to generate regional estimates of health programme effectiveness. RESULTS: The annual rates of reduction for child mortality between 1990 and 2013 were estimated as follows: neonatal (-0.33% per annum), post-neonatal (3.13% per annum), infant (0.9% per annum), child (2.47% per annum) and under 5 (1.19% per annum). Bivariate analyses of 2013 data showed that living in Punjab or Balochistan province, belonging to lowest wealth quintile, lack of maternal education, previous birth interval < 2 years, first birth order and below average birth size were associated (p < 0.05) with greater risk of child mortality in Pakistan. Common factors associated with child mortality were fever, diarrhoea and pneumonia, while among stillbirths, intrapartum asphyxia, unexplained antepartum and antepartum maternal disorders were most frequent. CONCLUSION: Child survival strategies should integrate leading biosocial indicators and causes of death. Further research is needed to define the role(s) of social factors in child health and survival. These data should inform the implementation of cost-effective interventions for child survival and advance targeting of interventions to populations at increased risk of child mortality.

In vitro application of sodium arsenite to mice testicular and epididymal organ cultures induces oxidative, biochemical, hormonal, and genotoxic stress.

Arsenic poisoning is well-known for its innumerable toxic and carcinogenic effects. In vivo data on reproductive toxicity are also known but in vitro data are scant. Presently, we evaluated the in vitro toxic effects of sodium arsenite (NaAsO2) on adult mice testes and epididymal tissues using organ cultures. Testicular and epididymal fragments were incubated at 37°C and 33°C, respectively, with 1, 10, 50, and 100 µM concentrations of NaAsO2. Cultures were allowed to incubate for 2 and 24 h. Levels of oxidative stress markers, the reactive oxygen species (ROS) and thiobarbituric acid reactive substance assay (TBARS), antioxidant enzymes, testosterone concentrations, and the extent of sperm DNA damage, were estimated. Results were analyzed statistically at p < 0.05. Results demonstrated both time- and dose-dependent alterations whereby, following 24-h incubation with NaAsO2, substantial increases were noticeable in ROS and TBARS levels and sperm DNA damage (p < 0.001), while decreases (p < 0.001) occurred in catalase, peroxidase, and superoxide dismutase levels at 10, 50, and 100 µM concentrations. Incubations for 2 h revealed similar but relatively less toxic effects. Testosterone concentrations decreased significantly only after 24 h of incubation with 50 (1.95 vs. 2.93 ng g-1; p < 0.01) and 100 µM (1.32 vs. 2.93 ng g-1; p < 0.001) NaAsO2 concentrations. The study concluded that exposure of testicular and epididymal tissue fragments to arsenic under in vitro conditions induces rapid and immediate metabolic and genotoxic damage at higher concentrations.

Short-term exposure of Balb/c mice to buprofezin insecticide induces biochemical, enzymatic, histopathologic and genotoxic damage in liver and kidney tissues.

Buprofezin is a type-1 chitin synthesis inhibitor insecticide used to control hemipteran insects. It is generally considered safe for humans, but its persistent nature may become a health hazard if long-term exposure takes place. Adverse effects on mammals are remaining to be explored. The present study investigated buprofezin toxicity on liver and kidney tissues of Balb/c mice treated intraperitoneally with 4.0, 6.0 and 8.0 µg/kg b.w doses respectively for 24 h. Statistical analyses demonstrated increased activities (p < 0.05) of serum alanine aminotransferase, aspartate aminotransferase, creatinine and urea, ROS and TBARS (thiobarbutaric acid) in liver and kidney tissues. Concomitant significant decrease occurred in tissue total protein, antioxidants enzymes, the superoxide dismutase, catalase and peroxidase and non-enzymatic reduced glutathione. Significantly altered histomorphology of liver and kidney tissues revealed excessive tissue damage. Congestion, hepatocyte necrosis, decreases sinusoidal damage in liver, while in kidneys, glomerular shrinkage, capillary damage, widened Bowman's space and lumens of tubules and collecting ducts and necrosis of tubular epithelial cells were evident. TUNEL assay confirmed apoptosis, the Comet assay demonstrated DNA damage by an increase in the head length, tail length, comet length, tail moment and olive tail moment. The study concludes that buprofezin is highly toxic for mammalian tissues and warrants further biochemical, molecular and cellular studies.

Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease.

Novel classes of small and long non-coding RNAs (ncRNAs) are being characterized at a rapid pace, driven by recent paradigm shifts in our understanding of genomic architecture, regulation and transcriptional output, as well as by innovations in sequencing technologies and computational and systems biology. These ncRNAs can interact with DNA, RNA and protein molecules; engage in diverse structural, functional and regulatory activities; and have roles in nuclear organization and transcriptional, post-transcriptional and epigenetic processes. This expanding inventory of ncRNAs is implicated in mediating a broad spectrum of processes including brain evolution, development, synaptic plasticity and disease pathogenesis.

Serum APOE, leptin, CFH and HTRA1 levels in Pakistani age related macular degeneration patients.

OBJECTIVE: To determine the association between serum levels of apolipoprotein E, leptin, complimentary factor H and high temperature requirement A-1 in patients with age-related macular degeneration. METHODS: This case-control study was conducted at the Quaid-i-Azam University, Islamabad, Pakistan, from May to October 2013, and comprised patients with age-related macular degeneration and matching controls. The confirmation of age-related macular degeneration was carried out through slit lamp examination, fundoscopy and ocular coherence tomography. The selected subjects were not suffering with any other systemic or ophthalmic complication(s). Serum apolipoprotein E, leptin, complimentary factor H and high temperature requirement A-1 were estimated in serum samples of all subjects. SPSS 18 was used for data analysis. RESULTS: Of the 190 participants, 90(47.4%) were patients with age-related macular degeneration and 100(52.6%) were controls. Significantly elevated serum apolipoprotein E (p<0.0024) and high temperature requirement A-1 (p<0.0001) levels were observed in the patients, while serum leptin (p<0.008) and complimentary factor H (p<0.0001) levels were significantly reduced. Logistic regression showed that lower leptin (p<0.026) and elevated high temperature requirement A-1 (p<0.0001) were the relevant risk factors. CONCLUSIONS: Serum apolipoprotein E, leptin, complimentary factor H and high temperature requirement A-1 levels were altered in age-related macular degeneration patients.

Association of gene polymorphism with serum levels of inflammatory and angiogenic factors in Pakistani patients with age-related macular degeneration.

PURPOSE: To study the association of serum levels of inflammatory mediators and angiogenic factors with genetic polymorphism in Pakistani age-related macular degeneration (AMD) patients. METHODS: This was a cross-sectional and case-control study that included 90 AMD patients diagnosed through slit-lamp examination, fundoscopy, and ocular coherence tomography. For reference and comparison purposes, 100 healthy age-matched subjects (controls) were also recruited. IL-6, IL-8, VEGF, and CRP levels were estimated in the serum samples of patients and control subjects. Using restriction fragment length polymorphism, single nucleotide polymorphisms were studied in IL-6 (rs1800795, rs1800796, rs1800797), IL-8 (rs4073, rs2227306, rs2227543), VEGF (rs3025039, rs699947), and CRP genes (rs1205, rs1130864). Since the data were obtained from a sample population, the Box-Cox transformation algorithm was applied to reduce heterogeneity of error. Multivariate analyses of variance (M-ANOVA) were applied on the transformed data to investigate the association of serum levels of IL-6, IL-8, VEGF, and CRP with AMD. Genotype and allele frequencies were compared through χ(2) tests applying Hardy-Weinberg equilibrium. The serum concentrations of IL-6 and IL-8, VEGF, and CRP between homozygotes and heterozygotes were compared through one-way ANOVA. Significance level was p<0.05. RESULTS: Compared to control subjects, serum IL-6 (p<0.0001), IL-8 (p<0.0001), VEGF (p<0.0001), and CRP (p<0.0001) levels were significantly elevated in the AMD patients. For rs1800795, patients with the GG genotype showed significantly raised levels of IL-6 compared to those with GC and CC genotypes (p<0.0001). Serum IL-8 levels were significantly higher in patients with the GG genotype compared to the GC and CC genotypes for the single nucleotide polymorphism (SNP) rs2227543 (p<0.002). Similarly, significantly higher VEGF levels were detected for genotype TT for rs3025039 SNP (p<0.038). However, no significant alteration in serum CRP levels was detected in hetero- or homozygotes for rs1205 and rs1130864 SNPs. CONCLUSIONS: Serum IL-6, IL-8, and VEGF levels are substantially increased in AMD, and the levels coincide with polymorphism in the respective gene. No such relationship appears to exist with regard to SNPs of CRP.

Sex, epilepsy, and epigenetics.

Epilepsy refers to a heterogeneous group of disorders that are associated with a wide range of pathogenic mechanisms, seizure manifestations, comorbidity profiles, and therapeutic responses. These characteristics are all influenced quite significantly by sex. As with other conditions exhibiting such patterns, sex differences in epilepsy are thought to arise-at the most fundamental level-from the "organizational" and "activational" effects of sex hormones as well as from the direct actions of the sex chromosomes. However, our understanding of the specific molecular, cellular, and network level processes responsible for mediating sex differences in epilepsy remains limited. Because increasing evidence suggests that epigenetic mechanisms are involved both in epilepsy and in brain sexual dimorphism, we make the case here that analyzing epigenetic regulation will provide novel insights into the basis for sex differences in epilepsy.

Epigenetics of sleep and chronobiology.

The circadian clock choreographs fundamental biological rhythms. This system is comprised of the master circadian pacemaker in the suprachiasmatic nucleus and associated pacemakers in other tissues that coordinate complex physiological processes and behaviors, such as sleep, feeding, and metabolism. The molecular circuitry that underlies these clocks and orchestrates circadian gene expression has been the focus of intensive investigation, and it is becoming clear that epigenetic factors are highly integrated into these networks. In this review, we draw attention to the fundamental roles played by epigenetic mechanisms in transcriptional and post-transcriptional regulation within the circadian clock system. We also highlight how alterations in epigenetic factors and mechanisms are being linked with sleep-wake disorders. These observations provide important insights into the pathogenesis and potential treatment of these disorders and implicate epigenetic deregulation in the significant but poorly understood interconnections now emerging between circadian processes and neurodegeneration, metabolic diseases, cancer, and aging.

Assessment of serum lipids in patients with age related macular degeneration from Pakistan.

OBJECTIVE: To determine serum lipids in patients with age related macular degeneration from Pakistani population. METHODS: The study was a cross sectional, randomized and case-control. Selected subjects ages were > or = 50 years and were normotensive, non-diabetic with no family history of any such disease and no complication of posterior ocular chamber other than age related macular degeneration (AMD). Controls were age matched healthy individuals with no symptoms of AMD. Diagnosis of AMD was done through conventional diagnostic techniques by professional ophthalmologists. Serum samples were analyzed for total cholesterol, triglycerides, LDL and HDL using commercially available kits. Data were compared with Student's t-test. Pearson correlation was calculated for relationship between different parameters. P < 0.05 was considered significant. RESULTS: Compared to controls, AMD patients had significantly greater total cholesterol concentration (p < 0.041), and power HDL/LDL ratio (p < 0.038), while serum triglycerides, HDL and LDL were non-significantly different from control subjects. Total cholesterol in AMD patients was significantly correlated with TG, LDL and HDL (p < 0.0001). CONCLUSION: The study indicates that high cholesterol might be a predictor of AMD and can be a diagnostic parameter.

Photoactive metabolite mediated photodynamic therapy of Rhabdomyosarcoma cell lines using medicinal plants and Doxorubicin co-treatments.

BACKGROUND: Medicinal plant-mediated combinational therapies have gained importance globally due to minimal side effects and enhanced treatment outcomes compared to single-drug modalities. We aimed to analyze the cytotoxic potential of each conventional treatment i.e., photodynamic therapy (PDT), chemotherapy (doxorubicin hydrochloride; Dox-HCl) with or without various concentrations of medicinal plant extracts (PE) on soft tissue cancer Rhabdomyosarcoma (RD) cell line. METHODS: The Rhabdomyosarcoma (RD) cell line was cultured and treated with Photosensitizer (Photosense (AlPc4)), Chemo (Dox-HCl), and their combinations with different concentrations of each plant extract i.e., Thuja occidentalis, Moringa oleifera, Solanum surattense. For the source of illumination, a Diode laser (λ = 630 nm ± 1 nm, Pmax = 1.5 mW) was used. Photosensitizer uptake time (∼ 45 min) was optimized through spectrophotometric measurements (absorption spectroscopy). Drug response of each treatment arm was assessed post 24 h of administration using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5- 5-diphenyl-2 H- tetrazolium bromide (MTT) assay. RESULTS: PE-mediated Chemo-Photodynamic therapy (PDT) exhibited synergistic effects (CI < 1). Moreover, Rhabdomyosarcoma culture pretreated with various plant extracts for 24 h exhibited significant inhibition of cell viability however most effective outcomes were shown by low and high doses of Moringa oleifera compared to other plant extracts. Post low doses treated culture with all plant extracts followed by PDT came up with more effectiveness when compared to all di-therapy treatments. CONCLUSION: The general outcome of this work shows that the ethanolic plant extracts (higher doses) promote the death of cancerous cells in a dose-dependent way and combining Dox-HCl and photo-mediated photodynamic therapy can yield better therapeutic outcomes.

Targeting myeloperoxidase to reduce neuroinflammation in X-linked dystonia parkinsonism.

Although the genetic locus of X-linked dystonia parkinsonism (XDP), a neurodegenerative disease endemic in the Philippines, is well-characterized, the exact molecular mechanisms leading to neuronal loss are not yet fully understood. Recently, we demonstrated a significant increase in astrogliosis and microgliosis together with an increase in myeloperoxidase (MPO) levels in XDP post-mortem prefrontal cortex (PFC), suggesting a role for neuroinflammation in XDP pathogenesis. Here, we demonstrated a significant increase in MPO activity in XDP PFC using a novel specific MPO-activatable fluorescent agent (MAFA). Additionally, we demonstrated a significant increase in reactive oxygen species (ROS) in XDP-derived fibroblasts as well as in SH-SY5Y cells treated with post-mortem XDP PFC, further supporting a role for MPO in XDP. To determine whether increases in MPO activity were linked to increases in ROS, MPO content was immuno-depleted from XDP PFC [MPO(-)], which resulted in a significant decrease in ROS in SH-SY5Y cells. Consistently, the treatment with verdiperstat, a potent and selective MPO inhibitor, significantly decreased ROS in both XDP-derived fibroblasts and XDP PFC-treated SH-SY5Y cells. Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment. Highlights: MPO activity is increased in XDP post-mortem prefrontal cortex.MPO activity is increased in cellular models of XDP.MPO increases reactive oxygen species (ROS) in vitro.Inhibiting MPO mitigates ROS in XDP.The MPO inhibitor, verdiperstat, dampens ROS suggesting a potential therapeutic strategy for XDP.

Kisspeptin-10 induces dose dependent degeneration in prepubertal rat prostate gland.

BACKGROUND: Kisspeptin peptides mediate their actions through the GnRH loop system. How kisspeptins affect prostate gland in prepubertal male mammals remains elusive. METHODS: To address this kisspeptin was administered as subchronic (12 days) twice daily i.p. dose at three different dosage regimens: 10 pg, 1 ng and 1 µg, to prepubertal male Sprague-Dawley rats (PND 35). Control rats were maintained in parallel. At the end of the experiment prostate gland was dissected out and processed for light and electron microscopy. DNA damage was also estimated by DNA ladder assay and DNA fragmentation assay. RESULTS: Prostate weights decreased significantly (P < 0.05) at 1 µg treatment dose of kisspeptin. The epithelial height of secretory acini of prostate decreased at 10 pg (P < 0.05), 1 ng, and 1 µg doses (P < 0.001). Histomorphology and ultrastructure demonstrated, decrease in epithelial cell height, epithelial folding and dilatation of the organelles with kisspeptin treatment. Percent DNA damage to the prostatic tissue was 20.74 ± 2.18, 43.60 ± 2.39, and 58.18 ± 2.59 at 10 pg, 1 ng and 1 µg doses, respectively. CONCLUSION: The study reveals that continuous administration of kisspeptin does not lead to an early maturation but instead severe degeneration of prepubertal prostate gland. Wiley Periodicals, Inc.

Dual action spirobicycloimidazolidine-2,4-diones: antidiabetic agents and inhibitors of aldose reductase-an enzyme involved in diabetic complications.

The desired 3-(arylsulfonyl)spiroimidazolidine-2,4-diones were synthesized by reacting spiroiminoimidazolidine-2,4-dione with arylsulfonyl chlorides. Spiroimidazolidine-2,4-dione was in turn synthesized from norcamphor. Structures of the synthesized molecules were established by modern spectroscopic techniques. The synthesized compounds were screened for in vivo antidiabetic activity and aldose reductase inhibition. Compounds 2a, 2b and 2g exhibited excellent dual activity, compound 2a being most prominent. These results reveal that the synthesized compounds may serve as the molecule of choice to treat diabetes and diabetic complications using a single medication.