Prescribing cascades in ambulatory care: A structured synthesis of evidence.

The strength of evidence for specific ambulatory care prescribing cascades, in which a marker drug is used to treat an adverse event caused by an index drug, has not been well characterized. To perform a structured, systematic, and transparent review of the evidence supporting ambulatory care prescribing cascades. Ninety-four potential prescribing cascades identified through a previously published systematic review. Systematic search of the literature to further characterize prescribing cascades. (1) Grading of evidence based on observational studies investigating associations between index and marker drugs, including: Level I-strong evidence [i.e. multiple high-quality studies]; Level II-moderate evidence [i.e. single high-quality study]; Level III-fair evidence [no high-quality studies but one or more moderate-quality studies]; and Level IV-poor evidence [other]. (2) Listing of the adverse event associated with the index drug in the product's United States Food and Drug Administration (FDA) label. (3) Synthesis of the evidence supporting mechanisms linking index drugs and associated adverse events. Of 99 potential cascades, 94 were supported by one or more confirmatory observational studies and were therefore included in this review. The 94 cascades related to 30 types of adverse drug reactions affecting 10 different anatomic/physiologic systems and were investigated by a total of 88 confirmatory studies, including prescription sequential symmetry analysis (n = 51), cohort (n = 30), and case-control (n = 7) studies. Overall, the evidence from observational studies was strong for 18 (19.1%) prescribing cascades, moderate for 61 (64.9%), fair for 13 (13.8%), and poor for 2 (2.1%). Although the evidence supporting mechanisms that link index drugs and associated adverse events was variable, FDA labels included information about the adverse event associated with the index drug for most (n = 86) but not all of the 94 prescribing cascades. Although we identified 18 of 94 prescribing cascades supported by strong clinical evidence and most adverse events associated with index drugs are included in FDA label, the evidentiary basis for prescribing cascades varies, with many requiring further evidence of clinical relevance.

Which Adverse Events and Which Drugs Are Implicated in Drug-Related Hospital Admissions? A Systematic Review and Meta-Analysis.

Adverse drug events (ADEs) and adverse drug reactions (ADRs) are leading causes of iatrogenic injury, which can result in emergency department (ED) visits or admissions to inpatient wards. The aim of this systematic review and meta-analysis was to provide up-to-date estimates of the prevalence of (preventable) drug-related ED visits and hospital admissions, as well as the type and prevalence of implicated ADRs/ADEs and drugs. A literature search of studies published between January 2012 and December 2021 was performed in PubMed, Medline, EMBASE, Cochrane Library, and Web of Science. Retrospective and prospective observational studies investigating acute admissions to EDs or inpatient wards due to ADRs or ADEs in the general population were included. Meta-analyses of prevalence rates were conducted using generalized linear mixed models (GLMM) with the random-effect method. Seventeen studies reporting ADRs and/or ADEs were eligible for inclusion. The prevalence rates of ADR- and ADE-related admissions to EDs or inpatient wards were estimated at 8.3% ([95% CI, 6.4-10.7%]) and 13.9% ([95% CI, 8.1-22.8%]), respectively, of which almost half (ADRs: 44.7% [95% CI: 28.1; 62.4]) and more than two thirds (ADEs: 71.0% [95% CI, 65.9-75.6%]) had been classified as at least possibly preventable. The ADR categories most frequently implicated in ADR-related admissions were gastrointestinal disorders, electrolyte disturbances, bleeding events, and renal and urinary disorders. Nervous system drugs were found to be the most commonly implicated drug groups, followed by cardiovascular and antithrombotic agents. Our findings demonstrate that ADR-related admissions to EDs and inpatient wards still represent a major and often preventable health care problem. In comparison to previous systematic reviews, cardiovascular and antithrombotic drugs remain common causes of drug-related admissions, while nervous system drugs appear to have become more commonly implicated. These developments may be considered in future efforts to improve medication safety in primary care.

Pharmacological Potential of the Standardized Methanolic Extract of Prunus armeniaca L. in the Haloperidol-Induced Parkinsonism Rat Model.

Parkinson's disease (PD) is a complex, age-related neurodegenerative disease that causes neuronal loss and dysfunction over time. An imbalance of redox potential of oxidative stress in the cell causes neurodegenerative diseases and dysfunction of neurons. Plants are a rich source of bioactive substances that attenuate oxidative stress in a variety of neurological disorders. The aim of the present study was to evaluate the Prunus armeniaca L. methanolic extract (PAME) for anti-Parkinson activity in rats. PD was induced with haloperidol (1 mg/kg, IP). The PAME was administered orally at 100, 300, and 800 mg/kg dose levels for 21 days. Behavioral studies (catalepsy test, hang test, open-field test, narrow beam walk, and hole-board test), oxidative stress biomarkers (SOD, CAT, GSH, and MDA) levels, neurotransmitters (dopamine, serotonin, and noradrenaline) levels, and acetylcholinesterase activity were quantified in the brain homogenate. Liver function tests (LFTs), renal function tests (RFTs), complete blood count (CBC), and lipid profiles were measured in the blood/serum samples to note the side effects of PAME at the selected doses. Histopathological analysis was performed on the brain (anti-PD study), liver, heart, and kidney (to check the toxicity of PAME on these vital organs). Motor functions were improved in the behavioral studies. Dopamine, serotonin, and noradrenaline levels were significantly increased (P < 0.001), whereas the level of acetylcholinesterase was decreased significantly (P < 0.001). The levels of superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) were increased, while malondialdehyde (MDA) and nitrite levels were decreased in the PAME-treated groups significantly compared with the disease control group, hence reducing oxidative stress. The incidence of toxicity was determined by biochemical analysis of LFT and RFT biomarkers testing. The histopathological analysis indicated that neurofibrillary tangles and plaques decreased in a dose-dependent manner in the PAME-treated groups. Based on the data, it is concluded that PAME possessed good anti-Parkinson activity, rationalizing the plant's traditional use as a neuroprotective agent.

Prescribing Cascades: How to Detect Them, Prevent Them, and Use Them Appropriately.

BACKGROUND: A prescribing cascade is the treatment of an adverse drug reaction (ADR) with another drug. In this review, we discuss (a) the different types of prescribing cascade and (b) the measures that can be taken so that they will be recognized and dealt with appropriately, both in the hospital and in the outpatient setting. METHODS: This review is based on pertinent publications retrieved by a selective literature search. RESULTS: The literature distinguishes intentional from unintentional prescribing cascades, and appropriate from inappropriate ones. We further distinguish prophylactic from therapeutic prescribing cascades and draw a line between those that are necessary and those that are merely appropriate. The following main questions are essential for dealing with prescribing cascades appropriately: (1) Did the precipitating drug cause a clinically relevant ADR or risk of an ADR? (2) Is the precipitating drug still indicated? (3) Can an ADR be avoided by altering the treatment with the precipitating drug, or by (4) switching to another drug instead? (5) Can the drug used to treat the ADR actually affect it beneficially? (6) Do the benefits of the prescribing cascade outweigh its risks? CONCLUSION: Prescribing cascades are not problematic in themselves; on the contrary, they are sometimes a necessary part of good prescribing practice. There is still a lack of practically implementable instruments to help physicians detect prescribing cascades reliably, assess them properly, and put them to appropriate use.

Prescribing cascades in community-dwelling adults: A systematic review.

The misattribution of an adverse drug reaction (ADR) as a symptom or illness can lead to the prescribing of additional medication, referred to as a prescribing cascade. The aim of this systematic review is to identify published prescribing cascades in community-dwelling adults. A systematic review was reported in line with the PRISMA guidelines and pre-registered with PROSPERO. Electronic databases (Medline [Ovid], EMBASE, PsycINFO, CINAHL, Cochrane Library) and grey literature sources were searched. Inclusion criteria: community-dwelling adults; risk-prescription medication; outcomes-initiation of new medicine to "treat" or reduce ADR risk; study type-cohort, cross-sectional, case-control, and case-series studies. Title/abstract screening, full-text screening, data extraction, and methodological quality assessment were conducted independently in duplicate. A narrative synthesis was conducted. A total of 101 studies (reported in 103 publications) were included. Study sample sizes ranged from 126 to 11 593 989 participants and 15 studies examined older adults specifically (≥60 years). Seventy-eight of 101 studies reported a potential prescribing cascade including calcium channel blockers to loop diuretic (n = 5), amiodarone to levothyroxine (n = 5), inhaled corticosteroid to topical antifungal (n = 4), antipsychotic to anti-Parkinson drug (n = 4), and acetylcholinesterase inhibitor to urinary incontinence drugs (n = 4). Identified prescribing cascades occurred within three months to one year following initial medication. Methodological quality varied across included studies. Prescribing cascades occur for a broad range of medications. ADRs should be included in the differential diagnosis for patients presenting with new symptoms, particularly older adults and those who started a new medication in the preceding 12 months.

Exploration of a three-dimensional matrix as micro-reactor in the form of reactive polyaminosaccharide hydrogel beads using multipoint covalent interaction approach.

OBJECTIVES: Diversity in backbone polymer composition makes hydrogel-based resources open to broad spectrum of applications. Biomacromolecules which have reactive functional groups in their structural frame and can also exhibit hydrogel properties could be utilized in biomedical, pharmaceutical and drug delivery applications after some chemical modifications. RESULTS: Present study aims towards development of chitosan-based hydrogel system crosslinked together with glucosyltransferase. Hydrogel structure worked as an immobilization matrix and as a microreactor system to catalyze the cleavage of a disaccharide. Uniform chitosan hydrogel beads were prepared and dextransucrase was attached using multipoint covalent interaction approach. Strong interaction was developed by linking polymeric hydrogel with the biocatalyst utilizing glutaraldehyde as spacer arms. This bifunctional crosslinking agent performed two important tasks that includes functionalization of hydrogel beads and crosslinking of this activated matrix system with enzyme fragments. Hydrogel beads required 18.0 h crosslinking time with enzyme (6.5 mg ml-1, 189.9 DSU) under specific environment (4 °C, 100 rpm) to saturate all available ends. Enzyme fragments were observed bound with hydrogel beads when screened for surface topology indicating successful crosslinking. Steady state kinetics of crosslinked dextransucrase was studied in detail and it was revealed that it can catalyse sucrose in 30.0 min at 35 °C (pH 5.5) with an energy of activation around 15.23 kJ mol-1 with increased Vmax (785 DSU ml-1) and Km (256 mM) values as compared to soluble enzyme version. Thermal stability of the crosslinked dextransucrase also particularly improved 2.5 fold at 45 °C in comparison with soluble enzyme. Improved catalytic performance suggests that multipoint covalent immobilization protocol adapted using hydrogel system could be tailored as microreactor for catalysis of profitable macromolecules.

Characterization of cross-linked amyloglucosidase aggregates from Aspergillus fumigatus KIBGE-IB33 for continuous production of glucose.

Current research deals with immobilization of amyloglucosidase through carrier-free approach using cross-linking strategy. Cross-linked amyloglucosidase aggregates (CLAAs) with aggregation yield of 94% were prepared in 04 h by incorporating 40% ammonium sulfate and 1.5% glutaraldehyde in enzyme solution. CLAAs were characterized by optimizing various conditions including reaction time, pH, temperature and substrate concentration. It was noticed that after cross-linking no change in optimum reaction time and substrate concentration was observed however, a 5-degree shift in optimum temperature from 60 °C to 65 °C was obtained as compared to soluble amyloglucosidase. Activation energy (Ea) of amyloglucosidase as calculated from Arrhenius plot was 5.5 kcal mol-1 and 5.2 kcal mol-1 for soluble and cross-linked aggregates, respectively. Stability studies revealed that CLAAs can be used at higher temperatures for longer time period than soluble amyloglucosidase. Furthermore, data of recycling studies showed that CLAAs can be efficiently reused for 20 cycles with the retention of 63% of its initial activity. Due to the continuous reusability of CLAAs, the product formation is also increased 8 times from 5.71 mg ml-1 (soluble enzyme) to 46.548 mg ml-1 (CLAAs). Findings of this research show that carrier-free strategy is more effective for continuous hydrolysis of starch and production of glucose.

REPORT- Role of metal ions on the catalytic efficiency of dextran hydrolyzing biocatalyst.

Hydrothermal spring isolate Bacillus megaterium KIBGE-IB31was utilized to produce dextranase. Enzyme was partially purified up to 11.8 fold after dialysis. Different metals ions were tested to explore their behavior with dextranase. It was noticed that cobalt (Co+2), copper (Cu+2), magnesium (Mg+2), manganese (Mn+2), nickle (Ni+2) and zinc (Zn+2) act as activator whilst potassium (K+), sodium (Na+), barium (Ba+), calcium (Ca+), mercury (Hg+), vanadium (V+2), aluminum (Al+3) and ferric (Fe+3) ions display inhibitory action.

Bioprospecting of indigenous resources for the exploration of exopolysaccharide producing lactic acid bacteria.

Exploration of biodiversity lead towards the discovery of novel exopolysaccharide (EPS) producing microbes that have multiple applications. The safety compatibility status of lactic acid bacteria (LAB) makes it an attractive candidate for the production of EPS in industries. Therefore, new bacterial isolates are continuously being identified from different habitats. Current research was conducted to explore indigenous biodiversity for the production of dextransucrase, which is involved in the synthesis of dextran. Dextran is an EPS which is used in different industries. In this study, thirty-nine LAB were isolated from different food samples. The isolates were identified as genus Leuconostoc, Weissella and Streptococcus based on genotypic and phenotypic characteristics. Screening revealed that only eight isolates can produce dextransucrase in high titres. Fermentation conditions of dextran producing LAB was optimized. The results indicated that Weissella confusa exhibited maximum specific activity (1.50 DSU mg-1) in 8 h at 25 °C with pH 7.5. Dextran produced from Weissella proved to be a useful alternative to commercially used dextran produced by Leuconostoc mesenteroides in industries for various applications.

Utilization of agro waste pectin for the production of industrially important polygalacturonase.

In the present study, a variety of agro-industrial wastes have been utilized for meaningful purpose to produce valuable biocatalyst. All wastes used were low cost and easily accessible while, some available throughout the year. A number of bacterial strains isolated from rotten fruits and vegetables were screened for the production of industrially important polygalacturonase (PGase) using pectin present in these agro-industrial wastes. The strain producing maximum PGase was identified as Bacillus licheniformis KIBE-IB3 on the basis of taxonomic studies and 16S rDNA analysis. Among different agro-industrial wastes studied, high yield of PGase was achieved from fermentation broth having wheat bran (1.0%) as a substrate in to the medium supplemented with nitrogen sources in combination of NaNO3 and yeast extract while KH2PO4 was selected as suitable micronutrient. After optimizing fermentation parameters it was noticed that Bacillus licheniformis KIBE-IB3 was capable of producing maximum PGase at 37 °C, pH 7.0 and after 48 h of incubation time. From the current research, wheat bran was proven as a cheap and easily available source throughout the year for hyper production of pectinase. The utilization of the waste will also help to minimize the concerned environmental issues.

Synthesis, characterization and enzyme inhibitory activity of new pyrazinamide iron complexes.

The present paper deals with synthesis, characterization and amylase inhibitory activity of pyrazinamide (PYZ) with iron in its both (II) and (III) oxidation states. The synthesized complexes were characterized on the basis of IR, UV, 1H-NMR, 13C-NMR, elemental analysis and SEM. Changes in IR data shows that PYZ form complex with octahedral geometry and binding sites are ring nitrogen and carbonyl group, wherein two sides are satisfied with two chloride ions. SEM images indicate the crystalline state and surface morphology of PYZ and its complexes. Elemental analysis proves the composition of complexes. Pyrazinamide and the complexes showed no significant effect on amylase activity but the activity was inhibited in the presence of ferrous chloride.

Chitosan hydrogel microspheres: an effective covalent matrix for crosslinking of soluble dextranase to increase stability and recycling efficiency.

Dextranase is a unique biocatalyst that has high specificity and stereo-selectivity towards a complex biopolymer known as dextran. Dextranase has wide industrial application, but most of the time harsh environmental conditions adversely affect the functionality and stability of the enzyme. To overcome this issue, a covalent cross-linking immobilization method was adapted in the current study utilizing a nontoxic and biocompatible matrix known as chitosan. Chitosan hydrogel microspheres were synthesized using chitosan which exhibited noteworthy physical and mechanical strength. After treatment with glutaraldehyde, chitosan hydrogel microspheres were used for immobilization of dextranase. The kinetic characteristics of immobilized dextranase were compared with that of the soluble enzyme. A shift in optimum pH and temperature from 7.0 to 7.5 and 50 to 60 °C was observed after immobilization, respectively. Recycling efficiency, thermal stability, and activation energy distinctly improved after immobilization, whereas anchoring of substrate at the active site of the soluble dextranase exhibited an increase in K m with no change in V max after crosslinking. This technique involves the reduction in the size of carrier molecules (microspheres) that provide a larger surface area for improved immobilization efficiency. Therefore, it is concluded that increased stability and reusability of this immobilized biocatalyst makes it a promising aspirant for the utilization at commercial level.

Agar-agar entrapment increases the stability of endo-ß-1,4-xylanase for repeated biodegradation of xylan.

Microbial xylanases, specially endo-ß-1,4-xylanase catalyzes the hydrolysis of xylan, is considered one of the most significant hydrolases. It has numerous applications but most extensively is utilized in paper and pulp industry as a bio-bleaching agent. Immobilization technique is comprehensively studied with the expectation of modifying and improving enzyme stability and characteristics for commercial purposes. Currently, matrix entrapment technique is applied to immobilize endo-ß-1,4-xylanase within agar-agar gel beads produced by Geobacillus stearothermophilus KIBGE-IB29. Maximal enzyme immobilization yield was achieved at 2.5% of agar-agar concentration. Optimized conditions demonstrated an increase in the optimal reaction time from 05 min to 30 min and incubation temperature from 50 °C to 60 °C with reference to free enzyme whereas; no effect was observed for optimum pH. Entrapment technique uniquely changed the kinetic parameters of immobilized endo-ß-1,4-xylanase (Km: 0.5074 mg min(-1) to 0.5230 mg min(-1) and Vmax: 4773 U min(-1) to 968 U min(-1)) as compared to free enzyme. However, immobilized enzyme displayed broad thermal stability and retained 79.0% of its initial activity at 80 °C up to 30 min whereas; free enzyme completely lost its activity at this temperature. With respect to economic feasibility, the immobilized enzyme showed impressive recycling efficiency up to six reaction cycles.