Effective Oral Drugs Research Articles

Efficacy of Nitrofurantoin and Fosfomycin against Extended Spectrum Beta Lactamase Producing Uropathogens in the Era of Antibiotic Resistance: A Cross-sectional Study

Background: Urinary Tract Infection (UTI) is one of the most common bacterial infections that require medical care. It accounts for 25% of all infections. Limited number of antibiotics are available for the treatment of UTI due to increased resistance among uropathogens. Aim of the study is to determine the causative agents of UTI and to evaluate the action of nitrofurantoin and fosfomycin against Enterobacteriaceae in ESBL (Extended spectrum beta-lactamase) producing strains. Material and Methods: It is a retrospective study carried out in the department of Microbiology, MAMC, Agroha. Data related to urine culture and antibiotic susceptibility pattern from January 2023 to December 2023 was taken from the records and analysed. Results: Out of 1648 urine samples processed, 569 showed significant bacterial growth. Escherichia coli (45.3%) was the most common isolate followed by Klebsiella pneumoniae (20.5%), Enterococcus (17.2%), Staphylococcus aureus (5%). Among the gram negative bacilli, 40% were ESBL producers. These ESBL producing strains were 99% sensitive to Fosfomycin and 75% sensitive to Nitrofurantoin. Conclusion: The study revealed that Nitrofurantoin and Fosfomycin are very effective oral drugs for empirical treatment against gram negative uropathogens causing UTI, especially multi drug resistant strains.

PHYSICOCHEMICAL AND PHARMACOKINETIC ANALYSIS AND DOCKING OF DRUG REPOSITIONING AGAINST SARS-COV-2: AN IN SILICO STUDY

Studies on the development of effective and cost-effective oral drugs are the new priority of the pharmaceutical industry for the prevention and treatment of COVID-19. This work was based on the computational analysis of physicochemical parameters, pharmacokinetic and toxicological measurements, molecular docking and in silico measurement of the antiviral activity of 12 repositionable drugs. The Molinspiration platform (physical-chemical parameters), pkCSM® (absorption, distribution, metabolism and excretion), OSIRIS Property Explorer® (toxicological measurements), Seam® (Docking with the RdRp protein) and AVCpred server® (antiviral activity) were used. Considering the 12 selected repositionable drugs, molecular anchoring data with the RdRp protein, only the drug tilorone had lower binding energy than the control used in this study (Molnupiravir). Ledipasvir, daclatasvir and piperaquine showed the best percentage of antiviral inhibition considering the control pattern. ADMETox data showed that piperaquine has a high toxicological potential for mutagenesis, tumorigenesis and irritant effects. The findings of this study indicate that ledipasvir and daclatasvir showed greatest potential for inhibition RdRp and action against COVID-19.

Andrographolide Alleviates Oxidative Damage and Inhibits Apoptosis Induced by IHNV Infection via CTSK/BCL2/Cytc Axis.

Infectious hematopoietic necrosis virus (IHNV) is an important pathogen that causes significant economic losses to salmon trout farming. Although vaccines have been invented for the treatment of IHNV, findings from our previous survey show that breeding enterprises and farmers require effective oral drugs or immune enhancers. However, studies on the development of oral drugs are limited. In the present study, we used bioinformatics methods to predict the protein targets of andrographolide (Andro) in IHNV. Cells were infected with IHNV, and the effect of andrographolide was explored by evaluating the expression levels of genes implicated in oxidative stress, activities of antioxidant enzymes, and the expression of genes implicated in apoptosis and necrosis. In the present study, cells were divided into NC, IHNV, IHNV+10 μM andrographolide, and IHNV+20 μM andrographolide groups. qRT-PCR was performed to determine the expression level of genes, and an antioxidant enzyme detection kit was used to evaluate the activities of antioxidant enzymes. Fluorescent staining was performed using a reactive oxygen species detection kit (ROS) and Hoechst 33342/PI double staining kit, and the mechanism of alleviation of apoptosis and oxidative stress andrographolide after IHNV infection was determined. The results indicated that andrographolide inhibits viral growth by binding to the NV protein of IHNV and increasing the antioxidant capacity of the body through the CTSK/BCL2/Cytc axis, thereby inhibiting the occurrence of IHNV-induced apoptosis. This is the first study to explore the antagonistic mechanism of action of andrographolide in alleviating IHNV infection. The results provide valuable information on alternative strategies for the treatment of IHNV infection during salmon family and provide a reference for the use of andrographolide as an antioxidant agent in agricultural settings.

Rational design of oral drugs targeting mucosa delivery with gut organoid platforms.

Effective oral drugs and vaccines require high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads (i.e., immunogens) against gastric damage. In this study, hollowed nanocarriers (NCs: silica nanospheres and gold nanocages) with poly-l-lysine (PLL) coating and mammalian orthoreovirus cell attachment protein σ1 functionalization (NC-PLL-σ1) were explored as functional oral drug delivery vehicles (ODDVs). The transport of these ODDVs to mucosal lymphoid tissues could be facilitated by microfold cells (M-cells) mediated transcytosis (via σ1-α2-3-linked sialic acids adherence) across gastrointestinal epithelia. PLL coating provided protection and slow-release of rhodamine 6G(R6G), a model payload. The transport effectiveness of these ODDVs was tested on intestinal organoid monolayers in vitro. When compared with other experimental groups, the fully functionalized ODDV system (with PLL-σ1) demonstrated two significant advantages: a significantly higher transport efficiency (198% over blank control at 48h); and protection of payloads which led to both better transport efficiency and extended-release of payloads (61% over uncoated carriers at 48h). In addition, it was shown that the M cell presence in intestinal organoid monolayers (modulated by Rank L stimulation) was a determining factor on the transport efficiency of the ODDVs: more M-cells (induced by higher Rank L) in the organoid monolayers led to higher transport efficiency for ODDV-delivered model payload (R6G). The fully functionalized ODDVs showed great potential as effective oral delivery vehicles for drugs and vaccines.

Five Decades of HBV Infection in Italy: A Continuous Challenge.

In Italy, Hepatitis B virus (HBV) infection has been characterized by several changes over the last five decades. In 2019, the incidence of acute HBV among subjects targeted by the vaccination campaign was 0 cases in the age group 0-14 years and 0.1/100,000 in the age group 15-24. Nowadays, the burden of different stages of HBV-related chronic liver diseases is minimal. Intravenous drug use is no longer a risk factor (O.R. 0.7; 95% C.I. 0.5-1.02) for acquiring acute HBV; the proportion of cases reporting this exposure fell from 29.8% to 3.3% over the last two decades. The key public health intervention has been the compulsory vaccination campaign started in 1991 for infants 3 months old and 1-2 years old (the latter group for the first 12 years of the campaign). Moreover, non-immunogenic factors and the availability of effective oral antiviral drugs have played and continue to play a prominent role. The potential availability of new oral antiviral drugs with the inherent ability to eliminate the genomic HBV reservoirs may represent a further crucial step in the elimination of the virus in people that are already infected.

Oral Ionic Liquid for Transdermal Delivery and Obesity Treatment.

Obesity is currently a prerequisite for more than 70% of adults, including chronic obesity and long-term obesity. With the increase of diabetes patients in the world, it is urgent to develop effective oral drugs to replace insulin. However, the gastrointestinal tract is a main obstacle to oral drug preparations. Here, a highly effective oral drug was developed, mainly formulated as an ionic liquid (IL) prepared by l-(-)-carnitine and geranic acid. Density functional theory (DFT) calculations showed that l-(-)-carnitine and geranic acid can exist stably through hydrogen bonding. IL can significantly enhance the transdermal transport of drugs. In vitro study of intestinal permeability showed that particles formed by IL can prevent the absorption of intestinal fat. Compared with the control group, oral administration of IL (10 mL kg-1) significantly reduced blood glucose, white adipose tissue in the liver and epididymis, and the expression of SREBP-1c and ACC in IL. Therefore, these results and high-throughput sequencing analysis showed that IL can effectively reduce the intestinal absorption of adipose tissue to reduce blood glucose. IL has good biocompatibility and stability. Therefore, IL has a certain application value in the field of oral drug-delivery carriers, which provides an effective means for the treatment of diabetes and is a potential tool to solve the epidemic of obesity.

Recent advance in management of herpes simplex in Japan.

Herpes simplex, a common infection caused by the herpes simplex virus (HSV), is transmitted through contact of the skin/mucous membrane and establishes latency in the sensory ganglia for the rest of the life of the host. HSV occasionally reactivates and forms blisters around the lips or genitalia in some patients. Repeated overt symptoms, and, much more frequent, subclinical reactivation in the mucosa, make the host retain anti-HSV immunity continuously, resulting in maintaining steadily elevated antibody titer at any point after infection. Clinical symptoms differ in primary infection and recurrence. Primary infections sometimes manifest as severe symptoms such as fever and lymphadenopathy in addition to blisters/erosions of the skin, gingiva, lips, and oral mucosa, while recurrent herpes is generally mild. Diagnosing typical herpes simplex is not difficult, but when the course and manifestations are typical, definitive tests to identify HSV infection are limited since serology is not useful except with primary infection. For treatment, safe and effective oral antiviral drugs are available. Patient-initiated therapy is a new method of administration labeled in Japan. Amenamevir, an inhibitor of viral helicase primase, is available in Japan and labeled in addition to herpes zoster. These new diagnostic and therapeutic tools should be used for better management of herpes simplex.

Identifying Structural Features of Nucleotide Analogues to Overcome SARS-CoV-2 Exonuclease Activity.

With the recent global spread of new SARS-CoV-2 variants, there remains an urgent need to develop effective and variant-resistant oral drugs. Recently, we reported in vitro results validating the use of combination drugs targeting both the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and proofreading exonuclease (ExoN) as potential COVID-19 therapeutics. For the nucleotide analogues to be efficient SARS-CoV-2 inhibitors, two properties are required: efficient incorporation by RdRp and substantial resistance to excision by ExoN. Here, we have selected and evaluated nucleotide analogues with a variety of structural features for resistance to ExoN removal when they are attached at the 3′ RNA terminus. We found that dideoxynucleotides and other nucleotides lacking both 2′- and 3′-OH groups were most resistant to ExoN excision, whereas those possessing both 2′- and 3′-OH groups were efficiently removed. We also found that the 3′-OH group in the nucleotide analogues was more critical than the 2′-OH for excision by ExoN. Since the functionally important sequences in Nsp14/10 are highly conserved among all SARS-CoV-2 variants, these identified structural features of nucleotide analogues offer invaluable insights for designing effective RdRp inhibitors that can be simultaneously efficiently incorporated by the RdRp and substantially resist ExoN excision. Such newly developed RdRp terminators would be good candidates to evaluate their ability to inhibit SARS-CoV-2 in cell culture and animal models, perhaps combined with additional exonuclease inhibitors to increase their overall effectiveness.

Abstract 5274: Mechanisms of action (MOA) for proxalutamide, an androgen receptor (AR) antagonist, for the treatment of mild, moderate and severe COVID-19 patients

Abstract As of November 2021, there were 21 million confirmed active cases of COVID-19, including 77,016 patients in serious or critical condition (virusncov.com). However, there are no effective oral drugs for the treatment of severe COVID 19 patients. We here discuss the mechanism of action for Proxalutaminde to treat mild, moderate and severe COVID-19 Patients. Cellular entry and infection of SARS-CoV-2 virus are mediated by two key proteins in host cells, angiotensin converting enzyme 2 (ACE2), a host transmembrane protein, providing the binding sites for SARS-CoV-2 on the host cell surface, and transmembrane protease serine 2 protein (TMPRSS2), priming the S protein of SARS-Cov-2 to facilitate the viral entry into the host cells. Both ACE2 and TMPRSS2 proteins are regulated by androgen receptor (AR) signaling. Previously, Proxalutamide has been reported to downregulate the expression of ACE2 and TMPRSS2 in cells derived from prostate, lung cancer and normal lung epithelial cells. In this study, we demonstrate that Proxalutamide inhibited the infection of SARS-COV-2 wild type, alpha and delta variants, with IC50s of 69, 48 and 39 nM, respectively. Moreover, Proxalutamide reduced SARS-COV-2 viral load in outpatients with COVID-19 (82% viral RT-PCR negative rate in active group vs. 31% in placebo group after treatment for 7 days (p-value<0.0001). Severe COVID-19 disease leads to cytokine storm resulting in pulmonary inflammation and extensive damage in lung and other organs. Anti-inflammatory drugs, including Baricitinib and dexamethasone, have shown limited clinical benefit for hospitalized COVID-19 patients. Therefore, more effective drugs are in urgent need for patients suffering from severe COVID-19. Recently, Proxalutamide has been reported to reduce the mortality rate (HR=0.16) and lung injury (by 57%, active drug vs placebo groups) in hospitalized patients with COVID-19 in an IIT phase III study. We presented here the mechanism of action of Proxalutamide for targeting cytokine storm in severe COVID-19 patients. Proxalutamide was demonstrated to activate nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages, which stimulates the antioxidant response element (ARE) for reducing cytokine storm-induced organ damage in COVID-19. In addition, Proxalutamide inhibited TNF alpha and IL-6 expression and blocked INF gamma signaling by downregulating STAT1 expression in immune cells. Importantly, Proxalutamide reduced inflammatory cells in lungs in a Poly (I:C), pseudoviral induced-lung injury animal models. Further, Proxalutamide decreased C-reactive protein, D-Dimer and improved lymphocyte count, biomarkers for COVID-19 progression in clinical studies. Together, these results provide a strong rationale for the treatment of severe COVID-19 patients with Proxalutamide. Citation Format: Liandong Ma, Youzhi Tong, Qianxiang Zhou, Hongha Yan, Xiaodan Hou, Zhiha Ren, Jiangwei Li, Huiyuan Wang, Weidong Qian, Yu Zhang, Andy Goren, Arul Chinnaiyan. Mechanisms of action (MOA) for proxalutamide, an androgen receptor (AR) antagonist, for the treatment of mild, moderate and severe COVID-19 patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5274.

Engineering designer biologics in plant cells for oral treatment of inflammatory bowel disease (IBD)

Inflammatory bowel disease (IBD), including the two most common subtypes: Crohn’s disease (CD) and ulcerative colitis (UC), represents a group of intestinal disorders that cause prolonged inflammation of the digestive tract. The current treatment strategies, including the conventional anti‐inflammatory medications and the new biological drugs targeting the pro‐inflammatory cytokine tumor necrosis factor alpha (TNFα), have limited therapeutic efficacy and adverse drug reactions resulted from systemic administration. Colon‐targeted oral delivery of anti‐TNFα agents is highly desirable for the treatment of IBD, as it improves drugs’ efficacy while reducing systemic toxicity. Plant cell culture has emerged as a safe and cost‐effective bioproduction platform for therapeutic proteins. A unique feature of the plant cells is that they could serve not only as the “bio‐factory,” but also the oral delivery vehicle for recombinant biologics. Recent advances have demonstrated that plant cell walls, made primarily of cellulose microfibrils, can act as an excellent natural capsule for oral delivery of biologic drugs. This project aims to leverage two unique posttranslational modifications – “glycosyl‐phosphatidylinositol (GPI) anchor” and “plant‐specific hydroxyproline (Hyp)‐O‐glycosylation” – to strategically design and engineer novel anti‐TNFα biomolecules in plant cells to develop a new class of oral biologic drugs for the treatment of UC. The designer anti‐TNFα biomolecules consist of three functional domains: a N‐terminal single‐chain fragment variable (scFv) of an anti‐TNFα antibody, a proprietary Hyp‐O‐glycosylation module comprised of tandem repeats of the “Ser‐Pro” motif, or (SP)n (n= 5 to 30), and a C‐terminal GPI anchor. While the GPI anchor “displays” the expressed anti‐TNFα biomolecules at the plant cell surface to presumably create a high local concentration of the biologics, the (SP)n glycomodule stabilizes the protein from degradation during both the bioproduction and oral delivery processes. Designer anti‐TNFα biomolecules consisting of different sizes of the (SP)n glycomodule are investigated for their accumulations in tobacco BY‐2 cells, biological activity, and stability in a simulated gastric fluid, which determines the (SP)20 module as an optimal design for the biomolecules. The therapeutic effectiveness of the orally administrated designer anti‐TNFα biologic (optimal design) in mitigating the UC symptom is assessed in a dextran sulfate sodium (DSS)‐induced colitis mouse model. The immune‐modulatory effects of the anti‐TNFα biologics are determined by histopathological analysis and assay of the inflammatory markers. The research may develops a new platform to produce effective oral biologic drugs for the treatment of UC and other inflammatory diseases of colon.

Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.

The Evolution of Liver Fibrosis in Patients with Viral C Infection Post Oral Antiviral Treatment

Abstract Hepatitis C virus infection has been for several decades the major cause of cirrhosis and its complications worldwide. However, an arsenal of new and highly effective oral direct-acting antiviral drugs has changed the course of HCV treatment. The effects of HCV elimination are broad and include an overall reduction in mortality in patients with advanced fibrosis, a reduction of the risk of HCC in patients with advanced fibrosis and a reduction in extrahepatic manifestations including HCV-related non-Hodgkin’s lymphoma, other lymphoproliferative disorders and cryoglobulinemic vasculitis. Fibrosis regression is associated with a broad clinical benefit and remains an important therapeutic target in HCV patients who have obtained RSV.

Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches.

Atherosclerosis-caused cardiovascular diseases (CVD) are the leading cause of mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective oral drugs for the treatment of T2DM patients. Multiple pre-clinical and clinical studies have indicated that SGLT2 inhibitors not only reduce blood glucose but also confer benefits with regard to body weight, insulin resistance, lipid profiles and blood pressure. Recently, some cardiovascular outcome trials have demonstrated the safety and cardiovascular benefits of SGLT2 inhibitors beyond glycemic control. The SGLT2 inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin reduce the rates of major adverse cardiovascular events and of hospitalization for heart failure in T2DM patients regardless of CVD. The potential mechanisms of SGLT2 inhibitors on cardioprotection may be involved in improving the function of vascular endothelial cells, suppressing oxidative stress, inhibiting inflammation and regulating autophagy, which further protect from the progression of atherosclerosis. Here, we summarized the pre-clinical and clinical evidence of SGLT2 inhibitors on cardioprotection and discussed the potential molecular mechanisms of SGLT2 inhibitors in preventing the pathogenesis of atherosclerosis and CVD.

A comparative study of efficacy of oral pregabalin and clonidine for attenuation of pressor response to intubation

Background: Endotracheal intubation is associated with hemodynamic stress responses. Various drugs have been used in the past to attenuate the pressor response; however, none has been proved to be ideal. Present study was planned to evaluate the oral pregabalin 150 mg and clonidine 200 µg for attenuation of pressor response to intubation.Methods: The study was conducted on 100 adult patients of either gender scheduled to undergo elective surgeries under general anaesthesia (GA). The patients were randomly allocated into 2 groups. In group A patients received pregabalin 150mg and in group B patients received clonidine 200µg orally. The hemodynamic parameters were recorded until 10 minutes after intubation. The sedation, anxiety and side effects were also assessed.Results: In clonidine group, the mean HR remained below the baseline value at all the time intervals. In pregabalin group, the mean HR remained below the baseline value at most of the time intervals but increased above baseline just after intubation (T0i) and 1 minute after intubation (T1i) where increase was only 1.488±1.20% and 0.45±1.16% respectively from baseline. In both pregabalin and clonidine groups, the mean SBP and MAP remained below the baseline value (Tb) at all the time intervals from T0.5 to T10i. Both clonidine and pregabalin provided adequate anxiolysis and sedation with pregabalin providing more pronounced sedation and anxiolysis than clonidine.Conclusions: Both clonidine and pregabalin are effective oral premedication drugs for attenuation of the pressor response to laryngoscopy and endotracheal intubation.

Enhanced Gas Chromatography-Mass Spectrometry (GC-MS)-Based Analysis of Metformin and Guanylurea in Water Samples

Metformin is widely used as one of the most effective first-line oral drugs for type 2 diabetes. It is difficult to be metabolized by the human body thus commonly exists in both urine and feces samples. Guanylurea is metformin’s main biotransformation product with increased concentrations in the aquatic environments. Liquid chromatography-tandem mass spectrometry (LC-MS)-based methods used for measuring the two compounds have been well developed, but extremely limited studies have tracked gas chromatography-mass spectrometry (GC-MS)-based analysis. To help better track the occurrence of the two non-volatile biguanide compounds in liquid samples, the improvement of existing GC-MS based methods for reliable metformin and guanylurea analysis is conducted. Derivatization of metformin and guanylurea is the key pretreatment procedure before the associated GC-MS analysis. Four selected factors affecting for the derivatization were evaluated, and the optimal factors include temperature (90°C), reacting time (40 min), solvent (1,4-dioxane), and ratio (1.5:1) of reagent to target component. Buformin and N-methyl-bis(trifluoroacetamide) (MBTFA) were used as the internal standard and the derivatization reagent, respectively. Calibration curves were made based on the optimal conditions of derivatization for metformin and guanylurea with the R2 values of calibration linearity achieved as 99.35% and 99.2%, respectively. The values of relative standard deviation (RSD%) of metformin and guanylurea based on seven repeated trails are 2.67% and 15.37%, respectively. The optimal conditions for enhancing the sensitization of metformin and guanylurea derivatization performance were obtained. The improved GC-MS analysis method was eventually applied for metformin and guanylurea analysis in real water samples.

Antileishmanial Drug Development: A Review of Modern Molecular Chemical Tools and Research Strategies.

Leishmaniasis, a complex disease caused by at least 20 species of unicellular parasites of the genus Leishmania, disproportionately affects impoverished regions of about 90 tropical and sub-tropical countries. Currently available antileishmanial therapies, particularly for visceral leishmaniasis, are severely limited, with treatment outcome depending on many factors, including the immune status of the patient, comorbidities, malnutrition, and socio-economic conditions in the patient's geographic location. There is an urgent need for new therapeutics, particularly new effective oral drugs, for visceral leishmaniasis. Despite the availability of the Leishmania genome sequence information and significant research into the biology of the parasites, antileishmanial drug development is hampered by the lack of knowledge about druggable targets in the parasite and difficulties in identifying the molecular targets of compounds that show activity. In this context, we analyzed recent progress in antileishmanial drug development programs, which take advantage of different powerful approaches, such as high-throughput screening of compound libraries, recent developments in genetic methods for assessing essentiality of parasite genes, and chemical, genetic, and proteomics-based target discovery and target validation methods.

The emergence of azithromycin-resistant Salmonella Typhi in Nepal.

BackgroundTyphoid fever remains a significant cause of morbidity and mortality in Asia and Africa. The emergence of azithromycin resistance in South Asia is concerning, as azithromycin is one of the last effective oral drugs for treating typhoid.ObjectivesTo describe the molecular mechanism and phylogenetics of azithromycin-resistant (AzithR) Salmonella Typhi isolates from Patan Hospital, Kathmandu, Nepal.MethodsWhole-genome sequences of three AzithR S. Typhi isolates (MIC >256 mg/L) were analysed and compared with a global collection to investigate the azithromycin resistance mechanism and phylogenetic structure. Clinical information is reported for one of the three patients infected with AzithR S. Typhi.ResultsThe three AzithR isolates belonged to the H58 lineage and were genetically identical; they were distantly related to contemporaneous S. Typhi from Nepal and AzithR S. Typhi recently described in Bangladesh. Azithromycin resistance was mediated by a non-synonymous mutation in the acrB gene (R717L). The three AzithR isolates showed reduced susceptibility to ciprofloxacin (double mutation in the gyrA: S83F and D87G), and were susceptible to ampicillin, chloramphenicol and co-trimoxazole. Clinical information from one patient suggested non-response to azithromycin treatment.ConclusionsThis is the first molecular description of AzithR S. Typhi in Nepal. These organisms showed no phylogenetic link to AzithR S. Typhi in Bangladesh. Our data suggest that increasing use of azithromycin may pose a strong selective pressure driving the emergence of AzithR S. Typhi in South Asia. Further investigations are needed to evaluate treatment responses to azithromycin, predict evolutionary trajectories, and track the transmission of these organisms.

Effectiveness of Oral Clonidine & Oral Gabapentin in Attenuation of Haemodynamic Stress Response to Laparoscopic Cholecystectomy

Background: In laparoscopic surgery, Carbondioxide (CO2) is routinely used to create pneumoperitoneum.Elevated intra-abdominal pressure, due to pneumoperitoneum, and Carbondioxide (CO2) insufflationhave adverse effects on the cardiovascular system. Plasma level of catecholamines and vasopressin areincreased immediately after pneumoperitoneum. Increased catecholamine level activates the renin–angiotensin–aldosterone system, leading to characteristic hemodynamic alterations such as decreasedcardiac output, elevated arterial pressure and increased systemic/pulmonary vascular resistance. Variousdrugs have been used to attenuate these hemodynamic responses. Objectives: Purpose of this study was to evaluate the efficacy of oral Clonidine and oral Gabapentinpremedication in attenuation of haemodynamic stress responses to laparoscopic cholecystectomy. Setting & study design: This Placebo control study was conducted in Department of Anaesthesiologyand ICU, Dhaka Medical College Hospital from 1st March 2015 to 31st August 2015. Total 60 patients withASA grade I, II and planned for elective laparoscopic cholecystectomy were selected. Exclusion criteriawere patients with history of hypersensitivity to Clonidine, Gabapentin, and patients with chronic pain,history of cardiovascular, psychiatric disease, use of psychotropic drugs, pregnancy other comorbidcondition- CKD, COPD, IHD etc. Study subjects were allocated in to groups as placebo or control group(or Group P), gabapentin (300 mg) or Group G and clonidine (100 ìg) or Group C. Tested drugs were given75 to 90 minutes before surgery as oral premedication. All groups were compared for sedation, anxietylevel along with changes of haemodynamic status. Result: Majority of patients (40%) belongs to age 41 to 50 yrs. Out of 60 cases 55% were male and 45%were female. Male – female ratio was 1.22:1. A clear increase in sedation and a moderate decrease inanxiety were observed in both premedicated groups as compared with control groups. Preoperativeanxiolysis and sedation was higher in oral clonidine group as compared with Gabapentin group. Comparedwith group P, gabapentin & clonidine group showed statistically significant decrease in heart rate beforeinduction (98, 80, 74 beat/min respectively). The heart rate increased significantly immediately afterintubation in control group P, whereas no such changes were observed in group G and in group C (132,125, 112 beat/min respectively). After laparoscopy, the attenuation of mean arterial blood pressure inpremedicated group was statistically significant as to control group (Group P) and remained stabilizedduring intraoperative period. Study showed that premedication (Group C and G) patients werecomparatively well oriented and were able to obey commands than control (Group P) in the postoperativecare unit. Postoperative analgesic need was much less with gabapentin (Group G) and clonidine group(Group C) as compared with control (Group P). Conclusion: The gabapentin and clonidine are effective oral premedicant drugs with safe and multimodaldrug profile as they cause sedation, anxiolysis, and analgesia, with successful attenuation of thehemodynamic response of laparoscopy. Efficacy of Clonidine is superior to other also proven. JBSA 2020; 33(2): 48-54

Inhibition of carbohydrate degrading enzymes by the root of Borassus flabellifer – an in vitro evaluation

Diabetes mellitus is a metabolic disorder which is characterized by hyperglycemia. Chronic elevation in blood glucose level causes micro and macrovascular complications. Therapeutic management of diabetes involves the control of hyperglycemia by inhibiting carbohydrate degrading enzymes like amylase and glucosidase. This study was aimed at investigating the inhibitory potential of the root of Borassus flabellifer against enzymes such as amylase and glucosidase. The hexane, chloroform, petroleum ether, ethanol, and hydroalcoholic extracts of the root of Borassus flabellifer were studied for their inhibitory potential against amylase and glucosidase. The inhibitory potential of the extracts were compared to the potential exhibited by the standard inhibitor, acarbose. The hydroalcoholic extract was found to be the most potent inhibitor of both the enzymes with an IC50 of 652.37 and 607.06 µg/ml, much comparable to that of acarbose (612.55 and 550.38 µg/ml). The extract could inhibit 50 % of aldose reductase activity at a concentration of 1 mg/ml. The observations of this study suggest that the root of Borassus flabellifer may be a promising source for developing effective oral anti-hyperglycemic drugs.

Oxidovanadium (IV) and iron (III) complexes with O2N2 donor linkage as plausible antidiabetic candidates: Synthesis, structural characterizations, glucose uptake and model biological media studies

With the upsurging cases of type II diabetic patients, the demand for safe and effective oral antidiabetic drugs is also increasing. Coordination complexes have proven their mettle as efficient oral drug candidates, which thereby motivated us in this work to design new transition metal complexes as plausible candidates for the treatment of diabetes. A reduced salen ligand, {H2(hpdbal)2‐an} (1) derived vanadium (IV) and iron (III) complexes, namely, [VIVO{(hpdbal)2‐an}] (2) and [{FeIII (OH2)((hpdbal)2‐an)}2 μ2‐SO4] (3) were synthesized in this study. The newly obtained ligand and complexes were characterized using usual analytical and spectroscopic techniques. The potential of these compounds in inducing increased glucose uptake by diabetic cells were studied by using insulin resistant HepG2 cells as model diabetic cells and 2‐NBDG molecule as a D‐glucose analogue and fluorescent tracker. The cells added with the vanadium (IV) complex 3 induced significant NBDG uptake of 95.4% which was higher than that induced by metformin, the standard antidiabetic drug. To elucidate the behavior of the complexes in biological media, model solution studies were conducted with a wide range of pH conditions and protein bovine serum albumin (BSA). The complexes demonstrated effective binding with BSA which was concluded through spectroscopic titration studies and were also found to be sufficiently stable over physiological pH conditions. The study can thus prove to be beneficial in the quest for new antidiabetic drugs.