Formulation and Evaluation of Proniosomes for Anticancer Drugs

INTRODUCTION : Cancer is a leading cause of death worldwide; There were an estimated 14.1 million cancer cases around the world in 2012, of these 7.4 million cases were in men and 6.7 million in women .More than half of these – 8 million – occurred in economically developing countries. Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 2030. The four most common cancers occurring worldwide are lung, female breast, bowel and prostate cancer. These four account for around 4 in 10 of all cancers diagnosed worldwide. Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer-related death in women worldwide.The incidenceand mortality of breast cancer have been rising in low tomiddle-income countries. Today the challenge for the pharmaceutical formulators is to work and investigate to deliver the drug using promising drug carriers including biodegradable polymers. The systems that are capable of releasing the therapeutic agents by well defined kinetics are available at present. But in many cases these donot yet represent the ultimate therapy to needs of recipient. Hence attention should also be focused to fabricate controlled, modulated drug delivery system that are capable of receiving the physiological feedback information and adjusting the drug output and system that are capable of precisely targeting the specific tissue or cells. Current attempts to overcome these limitations include the development of novel drug delivery systems that can improve the efficacy of existing anti cancer drugs. AIM : The aim of the present research work is to develop stable Letrozole loaded proniosome formulation and stable Raloxifene loaded proniosome formulation and to evaluate in vitro characteristics and in vivo pharmacokinetic parameters of prepared formulations. OBJECTIVES : Cancer is a leading cause of death worldwide. Worldwide in 2012, an estimated 14.1 million new cases of cancer occurred and an estimated 8.2 million people died from cancer. Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 2030.The current focus in development of cancer therapies is on targeted drug delivery to provide therapeutic concentrations of anticancer agents at the site of action and spare the normal tissues Worldwide, breast cancer is the second most common type of cancer after lung cancer. It is the primary cause of cancer death among women globally, responsible for about 40000 US women deaths in 2001. Aromatase inhibitors are used for the treatment of breast cancer in postmenopausal women. Letrozole is the hormonal anticancer drug which can be employed to treat aromatase dependent breast cancer. Aromatase is an enzyme that catalyses biosynthesis of estrogen from testosterone (androgen). Letrozole is potent & selective inhibitor of aromatase. It inhibits the production of estrogens in postmenopausal women. It works by blocking cytochrome P-450 (CYP) which turns the hormone androgen to small amount of estrogen in the body. This means that less estrogen is available to stimulate the growth of hormone receptor positive breast cancer cells. It does not stop the ovaries from making estrogen, therefore, aromatase inhibitors affects only on postmenopausal females. The objective of present work was to utilize potential of novel drug delivery system for improvement in oral bioavailability of Raloxifene hydrochloride and the most important goal of cancer chemotherapy is to minimize the exposure of normal tissues to drugs while maintaining their therapeutic concentration in tumors. Now the pharmaceutical formulators are looking for vehicles through which drugs can be delivered to the specific target.One of the vehicles which can be employed to deliver the drug to specific site is niosome. i. Niosomes can be used to vesiculize both hydrophilic and lipophilic drugs. ii. Niosomal vesicles are composed of non-ionic surfactant with/without cholesterol or other lipids. iii. Niosomes have lower toxicity due to non-ionic nature of the surfactant and act to improve the therapeutic index of the drug A number of vesicular drug delivery systems such as liposomes, niosomes, transferosomes, and ethosomes and proniosomes were used to target the drug. Among these vesicular systems proniosomes gains more attention because of their advantages such as targeting the drugs to the specific sites, greater physical and chemical stability during sterilization and storage, entrap both hydrophilic and hydrophobic drugs, ease of transfer, distribution and dosing.The main objective of the present study was to formulate & evaluate letrozole proniosome and raloxifene proniosome. MATERIALS : Letrozole was obtained from Sun pharmaceuticals Advanced Research Centre, Vadodara, India;Raloxifene was obtained from Cipla Ltd, India, Cholesterol, Span 20, Span 60, Maltodexrin was purchased from S.D. Fine Chem Ltd, Mumbai. All other chemicals and solvents are analytical grade. The instruments which used for this experiment were Rotary flash evaporator (Super fit, India), Electronic digital balance (Shimadzu, Japan), Dialysis membrane 50 (Hi media, India), Digital pH meter (ELICO, India), Double beam UV/ Visible spectrophotometer (Lab India), Zetasizer (Malvern, England), Probe sonicator (Electro sonic Industries, India), Trinocular Optical microscope (Olympus, Japan), Scanning electron microscope (Hitachi, Japan), Refrigirated Centrifuge (Plasto Crafts Industries Private Limited, India), FTIR Spectrophotometer (Bruker Alpha- E), Differential Scanning Calorimeter (Shimadzu, Japan) and High Performance Liquid Chromatography (Shimadzu, Japan). EXPERIMENTAL PROTOCOL: a) Procurement of drugs, surfactants, cholesterol and other excipients for formulation development. b) Preformulation study: i. Solubility, ii. Characterization of the drug, excipients and its mixture using melting point determination, UV spectroscopy, Infrared spectroscopy and differential scanning calorimetry, iii. Preparation of calibration curve of drug. c) Primary development of trial batches to establish the required profiles, d) Physico chemical evaluation of prepared formulations, e) Selection of best formulation in each category based on the evaluation, f) In vitro drug release study, g) Stability study of best formulation, h) Pharmacokinetic study of best formulation. CONCLUSION : In conclusion, we can state that, besides providing the controlled systemic delivery of Letrozole and Raloxifene, an attempt was made to prepare proniosomal drug delivery system and evaluate its performance. Proniosome provides an effective means of delivering the drug through the oral route. The stable proniosome formulation was prepared and it is highly successful in enhancing oral bioavailability of the drug. Thus a dry free flowing product like proniosomes will be a promising industrial product

Formulation and Evaluation of Proniosomes for Anticancer Drugs

Currently proniosomes have been studied by researcher as a choice of oral drug delivery system for anticancer drugs to provide a better oral bioavailability considering, high penetration property of the niosome encapsulated agents through biological membrane and the stability of them. Cancer is a leading cause of death worldwide. The four most common cancers occurring worldwide are lung, female breast, bowel and prostate cancer. Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer-related death in women worldwide. Aromatase inhibitors and selective oestrogen receptor modulator are used for the treatment of breast cancer in postmenopausal women. The most important goal of cancer chemotherapy is to minimize the exposure of normal tissues to drugs while maintaining their therapeutic concentration in tumors. Proniosomes proved to be the potential carriers for efficient oral delivery of lipophilic or amphiphilic drugs. Henceforth an attempt was made to improve the oral delivery of letrozole and raloxifene by loading into maltodextrin based proniosome powders separately. Letrozole loaded maltodextrin based proniosomes and raloxifene loaded maltodextrin based proniosomes were prepared by slurry method with different ratio of span 20, span 60 and cholesterol and evaluated for flow properties and the results indicated acceptable flow properties. The formation of niosomes and surface morphology of optimized proniosome formulations were studied by optical and scanning electron microscopy, respectively which has showed smooth surface of proniosome. FT IR, differential scanning calorimetry studies performed to understand the solid state properties of the drug revealed the absence of chemical interaction.Further evaluated for entrapment efficiency, in vitro release, kinetic data analysis, stability study and pharmacokinetic analysis. The formulation LS604, RS606 which showed higher entrapment efficiency (83.64%, 82.44%) and in vitro releases of 99.87% and 99.42% respectively at the end of 24 hours was found to be best among all formulations. The drug release was explained by zero order kinetics. The stability study results showed that the prepared proniosome formulations were stable. The pharmacokinetic data obtained from in vivo study shows better bioavailability when compared with pure letrozole and raloxifene. In conclusion, we can state that, besides providing the controlled systemic delivery of letrozole and raloxifene, an attempt was made to prepare proniosomal drug delivery system and evaluate its performance. Proniosome provides an effective means of delivering the drug through the oral route. The stable proniosome formulation was prepared and it is highly successful in enhancing oral bioavailability of the drug. Thus a dry free flowing product like proniosomes will be a promising industrial product. IMPACT OF THE STUDY: The ultimate goal of drug delivery research is to help patients by developing clinically useful formulation. • The above research proposal is expected to give a newer and safer anticancer proniosome formulation to solve the problem associated with the currently available formulations. • Formulating the chemotherapeutic agents in proniosome, maximize the efficacy of the drug by targeting the drug at the site. • Due to its site specific delivery it may reduce systemic side effects of chemotherapeutic agents. • When compared to conventional drug delivery systems we can minimize the quantity of drug to the patient thereby we can improve patient convenience. • Effective nature of proniosome drug delivery may minimize duration of hospitalization and reduce the health care cost. • Based on the above reasons such drug delivery system is currently needed for effective drug delivery in chronic conditions

Patterns and Factors Influencing Anaemia in Chronic Renal Failure

INTRODUCTION: Fishberg defined uremia in accord with its etymology and original meaning, as a complex of symptoms resulting from failing renal function caused by retention of constituents of normal urine. It is a generalized symptom complex due to a dynamic imbalance between the organism’s current metabolism and appropriate renal function. Richard Bright first described the association between anaemia and chronic renal failure. A normocytic normochromic anaemia is present in majority of patients with chronic renal disease, usually observed when glomerular filtration rate falls below 30 ml/min. AIMS OF THE STUDY: Much of the morbidity and mortality in renal failure patients can be attributed to secondary consequences of chronic anaemia31. Other factors associated with chronic renal failure may contribute to development of anaemia but erythropoietin deficiency is by far the major factor. Life long replacement therapy with erythropoietin for anaemia correction in chronic renal failure is out of reach for most of our patients who belong to the lower socioeconomic strata. More over many other factors like malnutrition, iron deficiency etc., may be contributing to renal anaemia, correction of which can reduce morbidity due to anaemia considerabley. The purpose of the study is to identify such additional risk factors of anaemia in chronic renal failure. Rationale: By this study, we try to analyze on morphological and distribution patterns of anaemia and its correctable contributing factors if any, so that some benefits can be extended to non affluent renal disease patients also. MATERIALS AND METHODS: Study Design: This will be a cross-sectional study of patients with chronic renal disease and anaemia chosen from Department of Nephrology based on the criteria from January 2008 to August 2008. We propose to study 50 cases of hospital admission for minor ailment (e.g. viral fever) as controls. Selection and Enrolement of Cases: Inclusion Criteria: a. All patients should be diagnosed cases of chronic renal disease with anaemia. b. None of the patients should have received erythropoietin therapy. c. Patients should not be having other significant systemic involvement other than due to uraemia. Exclusion Criteria: Patients having any contraindications as per inclusion criteria shall be excluded from the study. Data Collection: Simple proforma containing details of patients will be filled up. The following biochemical parameters were assessed as follows: Haemoglobin: cyanmeth method, Serum creatinine: alkaline picrate method, Feritin: antiferritin labeled with lodine 125, TIBC: Incubating with serum ferric ammonium citrate, Protein: Biuret method, Albumin: using bromocresol green, Cholesterol: Enzymatic colourimetric test, Alkaline phosphatase: p-nitro phenol phosphate, Cholesterol: Enzymatic colourimetric test, Alkaline phosphatase: p-nitro phenol phosphate, Phosphorous: Molydate u.v. method, Stoll occult blood: Guaic test, Uric acid: Spectrophotometric uricase/peroxidase. CONCLUSIONS: This study indicates that: 1. Severity of anemia correlates well with the degree of renal disease. 2. Normochromic normocytic morphology anemia caused by erythropoietin deficiency is by far the commonest pattern. 3. Other morphologies in peripheral smear usually indicates presence of additional risk factors for anemia like blood loss, iron deficiency and malnutrition. 4. Presence of such risk factors is associated with significant reduction in mean haemoglobin values. 5. This suggests need for treatment of iron deficiency and correction of other anaemic risk factors in chronic renal disease. 6. Diabetic nephropathy is the commonest aetiology of chronic renal failure

Real Time Static and Dynamic Sign Language Recognition using Deep Learning

Sign language recognition systems are used for enabling communication between deaf-mute people and normal user. Spatial localization of the hands could be a challenging task when hands-only occupies 10% of the entire image. This is overcome by designing a real-time efficient system that is capable of performing the task of extraction, recognition, and classification within a single network with the use of a deep convolution network. The recognition is performed for static image dataset with a simple and complex background, dynamic video dataset. Static image dataset is trained and tested using a 2D deep-convolution neural network whereas dynamic video dataset is trained and tested using a 3D deep-convolution neural network. Spatial augmentation is done to increase the number of images of static dataset and key-frame extraction to extract the key-frames from the videos for dynamic dataset. To improve the system performance and accuracy Batch-Normalization layer is added to the convolution network. The accuracy is nearly 99% for dataset with a simple background, 92% for dataset with complex background, and 84% for the video dataset. By obtaining a good accuracy, the system is proved to be real-time efficient in recognizing and interpreting the sign language gestures

Mortality and pulmonary complications in patients undergoing surgery with perioperative sars-cov-2 infection: An international cohort study

Background The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (740%) had emergency surgery and 280 (248%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (261%) patients. 30-day mortality was 238% (268 of 1128). Pulmonary complications occurred in 577 (512%) of 1128 patients; 30-day mortality in these patients was 380% (219 of 577), accounting for 817% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 175 [95% CI 128-240], p<00001), age 70 years or older versus younger than 70 years (230 [165-322], p<00001), American Society of Anesthesiologists grades 3-5 versus grades 1-2 (235 [157-353], p<00001), malignant versus benign or obstetric diagnosis (155 [101-239], p=0046), emergency versus elective surgery (167 [106-263], p=0026), and major versus minor surgery (152 [101-231], p=0047). Interpretation Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques

Nephrolog