Quality-by-design based development of fast dispersible nimodipine tablets: Formulation attributes and release kinetic assessment.

In the present study fast dispersible nimodipine tablets were developed by direct compression method using quality by design (QbD) approach as per the central composite design by selecting avicel PH 102 (X1) and crospovidone (X2) as independent variables while % friability (R1), disintegration (R2) and hardness (R3) as output variables. Powder blends were assessed for flow characterization. At post compressional stage, several quality assessments were carried out. Particles morphology was observed using scanning electron microscopy (SEM). The stability study on the drug and optimized formulation were determined using thermal gravimetric analysis (TGA) and differential thermal analysis (DTA). RSM plots expressed the interaction of avicel PH 102 and crospovidone to determine the adequate quantities of excipients for the optimized formulation. Polynomial equations were used to validate the experimental design. The optimized formulations were evaluated for friability, disintegration and hardness. Results indicated that formulation (F4) containing avicel PH 102 (35%) and crospovidone (5%) was selected as best optimized formulation having friability 0.59%, disintegration 9 sec, % dissolution 95.703% and hardness 4.14 kg. Results of kinetics models indicated that all the developed formulations followed weibull model.

Empagliflozin: HPLC based analytical method development and application to pharmaceutical raw material and dosage form.

The current investigation is based on efficient method development for the quantification of empagliflozin in raw and pharmaceutical dosage forms, as no pharmacopoeial method for the drug is available so far. The developed analytical method was validated as per ICH guidelines. C18 column with mobile phase (pH 4.8) consisted of 0.1% trifluoroacetic acid solution and acetonitrile (70:30 v/v) was used for drug analysis. The calibration plot showed good linear regression (r2>0.999) over the concentration of 0.025-30 µg mL-1. The LOD and LOQ were found to be 0.020 µg mL-1 and 0.061 µg mL-1, respectively. The percentage recovery was estimated between 98.0 to 100.13%. Accuracy and precision data were found to be less than 2%, indicating the suitability of method for routine analysis in pharmaceutical industries. Moreover, the drug solution was found to be stable in refrigerator and ambient room temperature with mean % accuracy of >98%. Empagliflozin contents were also tested in both the raw API and marketed tablet brands using this newly developed method. The mean assay of raw empagliflozin and tablet brands were ranged from 99.29%±1.12 to 100.95%±1.69 and 97.18%±1.59 to 98.92%±1.00 respectively. Based on these findings, the present investigated approach is suitable for quantification of empagliflozin in raw and pharmaceutical dosage forms.

Optimization of empagliflozin immediate release tablets (10 mg) using central composite rotatable design with response surface methodology.

Empagliflozin is a selective inhibitor of sodium glucose co-transporter II, given as mono therapy or an add-on treatment to reduce the glycated hemoglobin levels in type 2 diabetes. This work deals with designing, formulating and optimizing empagliflozin (10mg) immediate release (IR) tablets by direct compression technique using different excipients. Through central composite rotatable design (CCRD), total nine formulations (EF1-EF9) were generated by changing the composition of binder avicel PH 102® (X1) and superdisintegrant acdisol⌖ (X2). Formulation runs with in suitable weight range and powder properties were subjected to compression. The influence of interaction of excipients on friability (Y1), hardness (Y2) and disintegration (Y3) were analyzed by fitting the polynomial quadratic model with response surface methodology (RSM). Trials EF2, EF7, EF8 and EF9 exhibited acceptable tablet attributes upon physico-chemical testing. Different dissolution models were applied to observe the in vitro drug release pattern in phosphate buffer of pH 6.8. The cumulative drug release of IR tablet batches followed the Weibull kinetics with regression coefficient (r2) values of 0.983-0.992. Empagliflozin trials were exposed to accelerated storage conditions (40±2°C/ 75±5% RH) for stability testing. Shelf life period of exposed formulations were computed in range of 22 to 25 months. Keeping in view of the results, it is concluded that the employed technique of preparation and optimization are observed to be excellent for developing immediate release empagliflozin (10mg) tablets.

SARS-CoV-2 and Stroke in a New York Healthcare System.

BACKGROUND AND PURPOSE: With the spread of coronavirus disease 2019 (COVID-19) during the current worldwide pandemic, there is mounting evidence that patients affected by the illness may develop clinically significant coagulopathy with thromboembolic complications including ischemic stroke. However, there is limited data on the clinical characteristics, stroke mechanism, and outcomes of patients who have a stroke and COVID-19. METHODS: We conducted a retrospective cohort study of consecutive patients with ischemic stroke who were hospitalized between March 15, 2020, and April 19, 2020, within a major health system in New York, the current global epicenter of the pandemic. We compared the clinical characteristics of stroke patients with a concurrent diagnosis of COVID-19 to stroke patients without COVID-19 (contemporary controls). In addition, we compared patients to a historical cohort of patients with ischemic stroke discharged from our hospital system between March 15, 2019, and April 15, 2019 (historical controls). RESULTS: During the study period in 2020, out of 3556 hospitalized patients with diagnosis of COVID-19 infection, 32 patients (0.9%) had imaging proven ischemic stroke. Cryptogenic stroke was more common in patients with COVID-19 (65.6%) as compared to contemporary controls (30.4%, P=0.003) and historical controls (25.0%, P<0.001). When compared with contemporary controls, COVID-19 positive patients had higher admission National Institutes of Health Stroke Scale score and higher peak D-dimer levels. When compared with historical controls, COVID-19 positive patients were more likely to be younger men with elevated troponin, higher admission National Institutes of Health Stroke Scale score, and higher erythrocyte sedimentation rate. Patients with COVID-19 and stroke had significantly higher mortality than historical and contemporary controls. CONCLUSIONS: We observed a low rate of imaging-confirmed ischemic stroke in hospitalized patients with COVID-19. Most strokes were cryptogenic, possibly related to an acquired hypercoagulability, and mortality was increased. Studies are needed to determine the utility of therapeutic anticoagulation for stroke and other thrombotic event prevention in patients with COVID-19.

Effects of superdisintegrants in oral dissolving formulation of cinitapride tablets.

The initiation of newer techniques and development of mouth dissolving (MD) products has created new avenues of higher patients' compliance. MD formulations are actually lessen the difficulties associated with solid swallowing with better bioavailability of especially poorly soluble drugs. In the current study mouth dissolving tablet (MDT) formulations of cinitapride (1 mg) were prepared by direct compression method using various proportion and combination of superdisintegrants. Nine formulations in three batches were compressed by incorporating low (2%), intermediate (6%) and higher (10%) levels of crospovidone, croscarmellose sodium, sodium starch glycolate. Micromeritic assessment of the powder blends were carried out and were found within the acceptable official limits. All newly developed trial formulations were exposed to different pharmacopoeial and non-pharmacopoeial testing. It was found that FC2 trial tablets containing polyplasdone XL® (crospovidone) at level of 6% (4.5 mg) presented the best physico-chemical attributes deemed to be desirable for the ODT products. Disintegration and wetting time of optimized FC2 was computed between 15-17 and 12-15 seconds respectively. The assay and content uniformity of FC2 were estimated to be 100.02±0.36 and 99.66±1.70 percent correspondingly. On the basis of the findings it was concluded that MDT could be successfully developed by incorporating appropriate concentration of superdisintegrant and their combinations.

Incidence of drug interactions in intensive care units in tertiary care settings: Classification, facts and measures.

Drug-drug interactions (DDIs) are extremely significant concern, particularly in sensitive population including pediatric and geriatric. Propensity for the development of DDIs is high in patients admitted at intensive care units (ICU). This study was conducted to evaluate the DDIs incidence, facts and measures in ICU. From a total of 150 cases studied for ICU patients, with the mean age of 56.37±12.45 years, 55.33% were male and the rest were female 44.66%. The demographic information like age, gender and main diagnosis details of study participants that were extracted from the patients' clinical record. A statistically significant association between the drug interaction and the number of drugs prescribed per prescription was observed (p<0.0001). Concerning the onset of outcome, 52% of DDIs distinguished as delayed onset of effect (past 24 hours) and 35% were categorized as rapid onset (within 24 hours). Despite the facts regarding patient safety and minimizing DIs error, polypharmacy is still frequent in critically ill patients admitted in ICU attributed high risk of adverse reactions due to use of multiple interventions to treat severity of disease condition. Such studies may be used to develop an effective tool for the diagnosis and management of DDIs.

Drug utilization and prescribing pattern of antibiotics in a tertiary care setups; trends and practices.

Irrational, over and misuse of antibiotics arise as global concern in both hospital and community settings and lead to adverse events including antimicrobial resistance, associated health problems, amplified hospitalization stay and cost. Hence, Drug Utilization Evaluation (DUE) studies are designed to evaluate and improve the prescribing, administration and the rational use of medications. The present study was designed to assess the pattern of antimicrobial drug utilization in in-patients cohort of tertiary care setup in Karachi, Pakistan. This cross sectional observational study was conducted in retrospective manner. World health organization (WHO) guidelines and criteria are considered to evaluate the appropriateness of drug use in various disease conditions. ATC/DDD system was applied to determine the study outcome. High frequency of antibiotics utilization found in respiratory tract infections of both lower (LRTI) 16.8% (n=42) and upper (UTI) 13.2% (n=33). The estimated total number of drug units administered per month was greater with cefixime (46) and ciprofloxacin (45) both. DDD/100 bed days drug utilization of antibiotics was higher with ciprofloxacin, cefexime and meropenem (47, 46 and 29.25) correspondingly. In conclusion, the current investigation signifies extensive scope for progress in prescribing trend. Drug adherence to customary guidelines of disease management and constraint policies to endorse judicious drug use may be considered vital in healthcare setup.

Quality surveillance of immediate release aceclofenac tablets (100 mg) available in local market.

Aceclofenac is considered to be an effective drug that has been widely prescribed for multi-medical complaints globally. Owing to high demand many generic counterpart of aceclofenac tablets are now available in the commercial market. The aim of the present work is to evaluate and compare the quality attributes of various national/local brands of aceclofenac immediate release tablets (100mg) with the standard multi-national brand available in Pakistan. Physico-chemical evaluation was performed by determining the average tablet weight, thickness, hardness, disintegration time, percent dissolution and assay. Moreover, brands and reference formulation were exposed to multipoint dissolution. The in vitro drug release pattern was examined in various pH environment (1.2, 4.5 and 6.8) using USP dissolution apparatus 2 (paddle) at 50 rpm. The data was then analyzed by model dependent (Zero-order, first-order, Higuchi, Hixson-Crowell, Korsmeyer & Peppas, and Weibull model), pair wise procedure (f1 & f2) and one-way ANOVA methods. Results showed that the all aceclofenac brands and the reference tablets followed Weibull kinetics at pH 6.8. f1 & f2 were also found to be within the acceptable FDA limits. Furthermore, the values of One-way ANOVA also confirmed the absence of any significant difference among various aceclofenac brands.

Addition of hyperacute MRI AIDS in patient selection, decreasing the use of endovascular stroke therapy.

BACKGROUND AND PURPOSE: The failure of recent trials to show the effectiveness of acute endovascular stroke therapy (EST) may be because of inadequate patient selection. We implemented a protocol to perform pretreatment MRI on patients with large-vessel occlusion eligible for EST to aid in patient selection. METHODS: We retrospectively identified patients with large-vessel occlusion considered for EST from January 2008 to August 2012. Patients before April 30, 2010, were selected based on computed tomography/computed tomography angiography (prehyperacute protocol), whereas patients on or after April 30, 2010, were selected based on computed tomography/computed tomography angiography and MRI (hyperacute MRI protocol). Demographic, clinical features, and outcomes were collected. Univariate and multivariate analyses were performed. RESULTS: We identified 267 patients: 88 patients in prehyperacute MRI period and 179 in hyperacute MRI period. Fewer patients evaluated in the hyperacute MRI period received EST (85 of 88, 96.6% versus 92 of 179, 51.7%; P<0.05). The hyperacute-MRI group had a more favorable outcome of a modified Rankin scale 0 to 2 at 30 days as a group (6 of 66, 9.1% versus 33 of 140, 23.6%; P=0.01), and when taken for EST (6 of 63, 9.5% versus 17 of 71, 23.9%; P=0.03). On adjusted multivariate analysis, the EST in the hyperacute MRI period was associated with a more favorable outcome (odds ratio, 3.4; 95% confidence interval, 1.1-10.6; P=0.03) and reduced mortality rate (odds ratio, 0.16; 95% confidence interval, 0.03-0.37; P<0.001). CONCLUSIONS: Implementation of hyperacute MRI protocol decreases the number of endovascular stroke interventions by half. Further investigation of MRI use for patient selection is warranted.

Gadolinium for hysterosalpingography.

OBJECTIVE: To evaluate the use of gadolinium as an alternative to iodinated contrast medium for hysterosalpingography in patients with an increased risk for iodinated contrast hypersensitivity. STUDY DESIGN: Between March 2003 and March 2006, 3,616 hysterosalpingography examinations were performed. Hysterosalpingography was routinely performed using water-soluble, nonionic, iodinated contrast medium. Hysterosalpingography was performed with gadolinium in patients at risk for contrast hypersensitivity. We retrospectively reviewed the diagnostic quality, safety and clinical outcome in patients who underwent gadolinium hysterosalpingography. RESULTS: Hysterosalpingograms of diagnostic quality were successfully performed without adverse reactions in 11 patients. The density of gadolinium contrast opacification was diminished as compared with a conventional hysterosalpingogram with iodinated contrast. Two of the 8 patients who were not on oral contraceptives and had patent fallopian tubes became pregnant within 6 months of the hysterosalpingogram procedure. CONCLUSION: Gadolinium hysterosalpingography is of diagnostic value and is a safe alternative to iodinated contrast medium for hysterosalpingography in patients at increased risk for iodinated contrast hypersensitivity.

The role of very high high-sensitivity C-reactive protein levels on mortality after stroke.

High-sensitivity C-reaction protein (hsCRP) levels are correlated with risk of vascular disease. The clinical implications of markedly elevated hsCRP levels in the setting of acute stroke are less understood. OBJECTIVE: To determine the association of very high admission hsCRP levels (≥10mg/L) on all-cause mortality in patients with acute stroke. METHODS: A retrospective cohort study of 1176 patients hospitalized with acute stroke between 2005 and 2012 who had a hsCRP assay drawn within seven days of admission. Mortality data was obtained using Ohio Death Index. Cox proportional analysis was used to determine hazard ratios of death among patients with hsCRP values >10mg/L after adjusting for age, sex, race and relevant co-morbid conditions. NIHSS was also adjusted in a subset of patients in whom it was available (n=378). RESULTS: Patients with hsCRP >10mg/L had 2.65 (95% CI: 1.99, 3.53) increased hazard of all-cause mortality compared to stroke patients with hsCRP ≤10mg/L. Association of hsCRP with mortality was greater for patients with low NIHSS and declined in patients with increasing NIHSS scores. A higher proportion of patients with hsCRP >10 died from nonvascular causes than patients with hsCRP ≤10mg/L. CONCLUSION: Very high levels of hsCRP may be a useful marker to identify stroke patients at increased risk for death, especially those with stroke of mild severity. More research is needed to determine how this information can be used to improve patient care, especially in patients with mild stroke.

Pattern of injury in fatal road traffic accidents in a rural area of western Maharashtra, India.

BACKGROUND: Fatal road traffic accidents (RTA) are a major cause of concern all over the world. The outcome of injuries sustained in an RTA depends on various factors including but not limited to: the location of the event, type of vehicle involved, nature of the roads, the time of accident, etc. AIMS: This study aims to investigate and evaluate prospectively the socio-demographic profile and pattern of injuries in victims of RTA in the rural area of the Ahmedanagar district of Maharashtra state. METHOD: This prospective study included all victims of RTA that presented to our emergency room from 1 June 2007 to 31 May 2009 and were either found dead on arrival or died during treatment. All the victims were autopsied at the post-mortem centre of Rural Medical College, Loni. RESULTS: Ninety-eight RTA victims were studied during the period. The most commonly affected age group was 20-39 years. Men died in RTA more than women. Fatal RTA were more prevalent on the secondary road system (47.97 per cent) and especially involved pedestrian and two wheeler vehicle users. Large numbers (n=63, 64.28%) of victims either died on the scene or during transportation. Numbers of skeletal injuries (199) and internal organ injuries (202) exceeded the total number of victims (98) clearly indicating the multiplicity of injuries. The majority of RTA victims (n=46, 46.93%) died due to head injury. The study showed that most deaths in RTA, brought to a tertiary care rural hospital, took place either on the spot or within 24 hours of injury which is very alarming and highlights the need to take urgent steps to establish good pre-hospital care and provision of trauma services at site. CONCLUSION: A computerised trauma registry is urgently needed to highlight risk factors, circumstances and chains of events leading to accidents. This would be extremely helpful in policy making and health management in India.