Implantable microchip: the futuristic controlled drug delivery system

There is no doubt that controlled and pulsatile drug delivery system is an important challenge in medicine over the conventional drug delivery system in case of therapeutic efficacy. However, the conventional drug delivery systems often offer a limited by their inability to drug delivery which consists of systemic toxicity, narrow therapeutic window, complex dosing schedule for long term treatment etc. Therefore, there has been a search for the drug delivery system that exhibit broad enhancing activity for more drugs with less complication. More recently, some elegant study has noted that, a new type of micro-electrochemical system or MEMS-based drug delivery systems called microchip has been improved to overcome the problems related to conventional drug delivery. Moreover, micro-fabrication technology has enabled to develop the implantable controlled released microchip devices with improved drug administration and patient compliance. In this article, we have presented an overview of the investigations on the feasibility and application of microchip as an advanced drug delivery system. Commercial manufacturing materials and methods, related other research works and current advancement of the microchips for controlled drug delivery have also been summarized

Evaluation of antinociceptive activity of hydromethanol extract of Cyperus rotundus in mice

Background: Cyperus rotundus Linn. (Cyperaceae) is used to treat inflammation, pain, fever, wounds, boils and blisters in folk medicine. This study evaluated the antinociceptive effect of the hydromethanol extract of whole plant of C. rotundus (HMCR).Methods: The antinociceptive activity of HMCR was investigated in thermal- induced (hot plate and tail immersion) and chemical- induced (formalin) nociception models in mice at three different doses (50, 100 and 200 mg/ kg; p. o.). Morphine sulphate (5 mg/kg, i.p.) and diclofenac sodium (10 mg/kg, i.p.) were used as reference analgesic agents.Results: In the hot-plate and tail-immersion tests HMCR significantly increased the latency period to the thermal stimuli at all the tested doses (50, 100 and 200 mg/kg) (p < 0.05). The significant increase in latency is clear from the observations at 60 and 90 min. In formalin-induced paw licking test oral administration of HMCR at 100 and 200 mg/kg doses decreased the licking of paw in early phase. All the tested doses (50, 100 and 200 mg/kg) significantly decreased the licking of paw in late phase of the test (p < 0.001). The dose 200 mg/kg was most effective showing maximum percentage of inhibition of licking in both early (61.60%) and late phase (87.41%).Conclusion: These results indicate the antinociceptive effect of C. rotundus and suggest that this effect is mediated by both peripheral and central mechanisms. These results support the traditional use of this plant in different painful conditions

Antimicrobial peptides of the genus Bacillus: a new era for antibiotics

The rapid onset of resistance reduces the efficacy of most conventional antimicrobial drugs and is a general cause of concern for human well-being. Thus, there is great demand for a continuous supply of novel antibiotics to combat this problem. Bacteria-derived antimicrobial peptides (AMPs) have long been used as food preservatives; moreover, prior to the development of conventional antibiotics, these AMPs served as an efficient source of antibiotics. Recently, peptides produced by members of the genus Bacillus were shown to have a broad spectrum of antimicrobial activity against pathogenic microbes. Bacillus-derived AMPs can be synthesized both ribosomally and nonribosomally and can be classified according to peptide biosynthesis, structure, and molecular weight. The precise mechanism of action of these AMPs is not yet clear; however, one proposed mechanism is that these AMPs kill bacteria by forming channels in and (or) disrupting the bacterial cell wall. Bacillus-derived AMPs have potential in the pharmaceutical industry, as well as the food and agricultural sectors. Here, we focus on Bacillus-derived AMPs as a novel alternative approach to antibacterial drug development. We also provide an overview of the biosynthesis, mechanisms of action, applications, and effectiveness of different AMPs produced by members of the Bacillus genus, including several recently identified novel AMPs

What Antibiotic Exposures Are Required to Suppress the Emergence of Resistance for Gram‑Negative Bacteria? A Systematic Review

Background The rates of antibiotic resistance in Gram-negative bacteria are increasing. One method to minimize resistance emergence may be optimization of antibiotic dosing regimens to achieve drug exposure that suppress the emergence of resistance. Objective The aim of this systematic review was to describe the antibiotic exposures associated with suppression of the emergence of resistance for Gram-negative bacteria. Methods We conducted a search of four electronic databases. Articles were included if the antibiotic exposure required to suppress the emergence of resistance in a Gram-negative bacterial isolate was described. Among studies, 57 preclinical studies (in vitro and in vivo) and 2 clinical studies 59 included investigated the monotherapy of antibiotics against susceptible and/or intermediate Gram-negative bacteria. Results The pharmacokinetic/pharmacodynamic (PK/PD) indices reported to suppress the emergence of antibiotic resistance for various classes were β-lactam antibiotic minimum concentration to minimum inhibitory concentration (Cmin/MIC) ≥ 4; aminoglycoside maximum concentration to MIC (Cmax/MIC) ratio ≥ 20; fluoroquinolones, area under the concentration-time curve from 0 to 24 h to mutant prevention concentration (AUC24/MPC) ≥ 35; tetracyclines, AUC24 to MIC (AUC24/MIC) ratio ≥ 50; polymyxin B, AUC24/MIC ≥ 808; and fosfomycin, AUC24/MIC ≥ 3136. However, the exposures required to suppress the emergence of resistance varied depending on the specific antibiotic tested, the duration of the experiment, the bacterial species and the specific bacterial isolate tested. Importantly, antibiotic exposures required to suppress the emergence of resistance generally exceeded that associated with clinical efficacy. Conclusion The benefits of implementing such high PK/PD targets must be balanced with the potential risks of antibiotic-associated toxicity

RNA-Seq analysis of antibiotic-producing Bacillus subtilis SC-8 reveals a role for small peptides in controlling PapR signaling

Bacillus subtilis SC-8 (BSSC8) shows a narrow antimicrobial activity against the Bacillus cereus group. Previously, B. cereus-derived PapR as a signal peptide to stimulate PlcR, which plays a significant role in regulating the transcription of virulence factors, was assumed to stimulate antibiotic production in BSSC8. To better understand the functional role of PapR in the antibiotic production of BSSC8 and the interspecies interaction, the global transcriptomic profiling of BSSC8 was investigated using RNA-Seq in this study. Small peptides derived from B. cereus wild type (WTBC) and a papR-deleted mutant strain (MTBC) were individually supplied to BSSC8 cultures, and changes in global transcription levels were compared by RNA-Seq. In the presence of WTBC small peptides, more genes (80.9%) were significantly upregulated than in cells exposed to MTBC small peptides. Specifically, 48.8 and 83.4% of genes involved in glycolysis and the TCA cycle, respectively, showed changes in transcription levels in response to small peptides from both strains. Of the genes showing the alterations, 35.0% (glycolysis) and 60.0% (TCA cycle) of transcripts were significantly regulated only in response to WTBC-derived small peptides. Furthermore, the expression of biosynthetic genes encoding several known antibiotics in BSSC8 was further decreased in response to WTBC small peptides

Evaluation of antidiarrheal activity of methanolic extract of Maranta arundinacea Linn. leaves

Diarrhea is one of the most common causes for thousands of deaths every year. Therefore, identification of new source of antidiarrheal drugs becomes one of the most prominent focuses in modern research. Our aim was to investigate the antidiarrheal and cytotoxic activities of methanolic extract of Maranta arundinacea linn. (MEMA) leaves in rats and brine shrimp, respectively. Antidiarrheal effect was evaluated by using castor oil-induced diarrhea, enteropooling, and gastrointestinal motility tests at 200 mg/kg and 400 mg/kg body weight in rats where the cytotoxic activity was justified using brine shrimp lethality bioassay at different concentrations of MEMA. The extract showed considerable antidiarrheal effect by inhibiting 42.67% and 57.75% of diarrheal episode at the doses of 200 and 400 mg/kg, respectively. MEMA also significantly (p < 0.01) reduced the castor oil-induced intestinal volume (2.14 +/- 0.16 to 1.61 +/- 0.12 mL) in enteropooling test as well as intestinal transit (33.00 to 43.36%) in GI motility test, compared to their respective control. These observed effects are comparable to that of standard drug loperamide (5 mg/kg). On the other hand, in brine shrimp lethality test after 24 h, surviving brine shrimp larvae were counted and LD50 was assessed. Result showed that MEMA was potent against brine shrimp with LD50 value of 420 mu g/mL. So the highest dose of 400 mu g/mL of MEMA was not toxic to mice. So these results indicate that bioactive compounds are present in methanolic extract of Maranta arundinacea leaves including significant antidiarrheal activity and could be accounted for pharmacological effects

The burden of bacterial antimicrobial resistance in the WHO European region in 2019: a cross-country systematic analysis

Background Antimicrobial resistance (AMR) represents one of the most crucial threats to public health and modern health care. Previous studies have identified challenges with estimating the magnitude of the problem and its downstream effect on human health and mortality. To our knowledge, this study presents the most comprehensive set of regional and country-level estimates of AMR burden in the WHO European region to date. Methods We estimated deaths and disability-adjusted life-years attributable to and associated with AMR for 23 bacterial pathogens and 88 pathogen–drug combinations for the WHO European region and its countries in 2019. Our methodological approach consisted of five broad components: the number of deaths in which infection had a role, the proportion of infectious deaths attributable to a given infectious syndrome, the proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antimicrobial drug of interest, and the excess risk of mortality (or duration of an infection) associated with this resistance. These components were then used to estimate the disease burden by using two counterfactual scenarios: deaths attributable to AMR (considering an alternative scenario where infections with resistant pathogens are replaced with susceptible ones) and deaths associated with AMR (considering an alternative scenario where drug-resistant infections would not occur at all). Data were solicited from a wide array of international stakeholders; these included research hospitals, surveillance networks, and infection databases maintained by private laboratories and medical technology companies. We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. Findings We estimated 541 000 deaths (95% UI 370 000–763 000) associated with bacterial AMR and 133 000 deaths (90 100–188 000) attributable to bacterial AMR in the whole WHO European region in 2019. The largest fatal burden of AMR in the region came from bloodstream infections, with 195 000 deaths (104 000–333 000) associated with resistance, followed by intra-abdominal infections (127 000 deaths [81 900–185 000]) and respiratory infections (120 000 deaths [94 500–154 000]). Seven leading pathogens were responsible for about 457 000 deaths associated with resistance in 53 countries of this region; these pathogens were, in descending order of mortality, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, Streptococcus pneumoniae, and Acinetobacter baumannii. Methicillin-resistant S aureus was shown to be the leading pathogen–drug combination in 27 countries for deaths attributable to AMR, while aminopenicillin-resistant E coli predominated in 47 countries for deaths associated with AMR. Interpretation The high levels of resistance for several important bacterial pathogens and pathogen–drug combinations, together with the high mortality rates associated with these pathogens, show that AMR is a serious threat to public health in the WHO European region. Our regional and cross-country analyses open the door for strategies that can be tailored to leading pathogen–drug combinations and the available resources in a specific location. These results underscore that the most effective way to tackle AMR in this region will require targeted efforts and investments in conjunction with continuous outcome-based research endeavours. Funding Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.Funding was provided by the Bill & Melinda Gates Foundation (OPP1176062), the Wellcome Trust (A126042), and the UK Department of Health and Social Care using UK aid funding managed by the Fleming Fund (R52354 CN001). Coauthors affiliated with this organisation provided feedback on the initial maps and drafts of this manuscript. MA acknowledges partial support by the Romanian National Authority for Scientific Research and Innovation, under the UEFISCDI PN-III-P4-ID-PCCF-2016-0084 research grant. VBG and VKG acknowledge funding support from the National Health and Medical Research Council Australia. CH is partially supported by a grant from the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084, and by a grant from the Romanian Ministry of Research Innovation and Digitalization, MCID, project number ID-585-CTR-42-PFE-2021. SH was supported by the operational programme Research, Development and Education, Postdoc2MUNI (CZ.02.2.69/0.0/0.0/18_053/0016952). GL was supported by national funds through the Fundação para a Ciência e Tecnologia (FCT) under the Scientific Employment Stimulus–Individual Call (CEECIND/01768/2021). AGM was supported by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre and by an NIHR Clinical Lectureship in Respiratory Medicine. AP is partially supported by a grant of the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084. JP was supported by FCT through the Scientific Employment Stimulus–Individual Call (CEECIND/00394/2017 and UID/DTP/04138/2019). AS acknowledges support from Health Data Research UK. LRS was supported by project CENTRO-04-3559-FSE-000162, Fundo Social Europeu. SBZ acknowledges receiving a scholarship from the Australian Government Research Training Program in support of his academic career.info:eu-repo/semantics/publishedVersio