MODIFIED FORMULATION OF FEBUXOSTAT: IMPROVED EFFICACY AND SAFETY

Objective: Febuxostat, a xanthine oxidoreductase inhibitor, is a drug of choice for hyperuricemia and Gout. But it also suffers from drawbacks in terms of pharmacokinetic profile and toxicity. It is available as immediate release formulation in the market. The objective is to develop a modified release formulation of febuxostat that can serve the dual purpose of increasing the efficacy and decreasing the toxicity, thereby improving safety.Methods: Pharmacokinetic and pharmacodynamic data, including drug concentration profile, efficacy data and toxicity data have been reviewed thoroughly. Based on available data, target pharmacokinetic profile has been identified as about 50 % reduction in Cmax and improvement in plasma drug concentration above required level during 6-24 hour. Desired in-vitro dissolution profile has been selected, and formulation modification has been sought to achieve the desired profile. The formulation has been prepared with a partial dose in the form of immediate release (IR) and remaining dose as an extended release (ER). IR and ER formulations have been developed separately and combined to form Inlay tablets containing ER inner tablet surrounded by IR.Results: Based on dissolution data and Wagner-Nelson calculations, the plasma concentration profile has been predicted for the developed formulation. It reconfirms that developed formulation will achieve the desired objectives. Formulation stability has been established up to 6 months under accelerated conditions.Conclusion: The developed formulation is a potential candidate for filing to a regulatory agency with the advantage of higher efficacy and less toxicity, which will be beneficial to the patient population and has good commercial viability.Â

Histology Verification Demonstrates That Biospectroscopy Analysis of Cervical Cytology Identifies Underlying Disease More Accurately than Conventional Screening:Removing the Confounder of Discordance

Background Subjective visual assessment of cervical cytology is flawed, and this can manifest itself by inter- and intra-observer variability resulting ultimately in the degree of discordance in the grading categorisation of samples in screening vs. representative histology. Biospectroscopy methods have been suggested as sensor-based tools that can deliver objective assessments of cytology. However, studies to date have been apparently flawed by a corresponding lack of diagnostic efficiency when samples have previously been classed using cytology screening. This raises the question as to whether categorisation of cervical cytology based on imperfect conventional screening reduces the diagnostic accuracy of biospectroscopy approaches; are these latter methods more accurate and diagnose underlying disease? The purpose of this study was to compare the objective accuracy of infrared (IR) spectroscopy of cervical cytology samples using conventional cytology vs. histology-based categorisation. Methods Within a typical clinical setting, a total of n = 322 liquid-based cytology samples were collected immediately before biopsy. Of these, it was possible to acquire subsequent histology for n = 154. Cytology samples were categorised according to conventional screening methods and subsequently interrogated employing attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy. IR spectra were pre-processed and analysed using linear discriminant analysis. Dunn?s test was applied to identify the differences in spectra. Within the diagnostic categories, histology allowed us to determine the comparative efficiency of conventional screening vs. biospectroscopy to correctly identify either true atypia or underlying disease. Results Conventional cytology-based screening results in poor sensitivity and specificity. IR spectra derived from cervical cytology do not appear to discriminate in a diagnostic fashion when categories were based on conventional screening. Scores plots of IR spectra exhibit marked crossover of spectral points between different cytological categories. Although, significant differences between spectral bands in different categories are noted, crossover samples point to the potential for poor specificity and hampers the development of biospectroscopy as a diagnostic tool. However, when histology-based categories are used to conduct analyses, the scores plot of IR spectra exhibit markedly better segregation. Conclusions Histology demonstrates that ATR-FTIR spectroscopy of liquid-based cytology identifies the presence of underlying atypia or disease missed in conventional cytology screening. This study points to an urgent need for a future biospectroscopy study where categories are based on such histology. It will allow for the validation of this approach as a screening tool

British Gynaecological Cancer Society recommendations and guidance on patient-initiated follow-up (PIFU)

The National Cancer Survivorship Initiative through the National Health Service (NHS) improvement in the UK started the implementation of stratified pathways of patient-initiated follow-up (PIFU) across various tumor types. Now the initiative is continued through the Living With and Beyond Cancer program by NHS England. Evidence from non-randomized studies and systematic reviews does not demonstrate a survival advantage to the long-established practice of hospital-based follow-up regimens, traditionally over 5 years. Evidence shows that patient needs are inadequately met under the traditional follow-up programs and there is therefore an urgent need to adapt pathways to the needs of patients. The assumption that hospital-based follow-up is able to detect cancer recurrences early and hence improve patient prognosis has not been validated. A recent survey demonstrates that follow-up practice across the UK varies widely, with telephone follow-up clinics, nurse-led clinics and PIFU becoming increasingly common. There are currently no completed randomized controlled trials in PIFU in gynecological malignancies, although there is a drive towards implementing PIFU. PIFU aims to individualize patient care, based on risk of recurrence and holistic needs, and optimizing resources. The British Gynaecological Cancer Society wishes to provide the gynecological oncology community with guidance and a recommendations statement regarding the value, indications, and limitations of PIFU in endometrial, cervical, ovarian, and vulvar cancers in an effort to standardize practice and improve patient care. [Abstract copyright: © IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Cytochrome P1B1 gene (CYP1B1) polymorphisms and ovarian cancer risk:a meta-analysis

CYP1B1 is a key P450 enzyme involved in the metabolism of exogenous and endogenous substrates and plays a key role in hormone-induced carcinogenesis. Risk factors for ovarian cancer are related to hormonal exposure and reproduction, and polymorphisms within genes involved in metabolism of oestrogen and certain xenobiotics may influence the risk of developing ovarian cancer. Current meta-analysis evaluated four CYP1B1 polymorphisms (Leu432Val, Arg48Gly, Ala119Ser and Asn453Ser) for their association with ovarian cancer risk. A search of MEDLINE bibliographic database for the period up to April 2012 identified five studies. With regards to Leu432Val polymorphism, all of the five studies were eligible (1199 cases and 2596 controls) for analysis, while for Arg48Gly (799 cases and 1169 controls), Ala119Ser (799 cases and 1172 controls) and Asn453Ser (361cases and 1577 controls) only two studies were eligible for analysis. Fixed-effect models were used to estimate pooled odds ratios (OR) with 95% confidence intervals (95% CI) and chi-square based Q-test was used to test for heterogeneity. The pooled OR (95% CI) for CYP1B1_Leu432Val polymorphism were 1.1 (0.84-1.31) for heterozygous subjects and 0.82 (0.57-1.17) for homozygous Val subjects. In a recessive model, homozygous carriers of Leu432Val showed a weak trend towards reduced risk as compared to 'wild type' and heterozygous carriers (OR 0.8, 95% CI; 0.66-0.99); however, this association was of limited significance. Regarding Arg48Gly, the pooled OR (95% CI) were 1.06 (0.89-1.27) for heterozygous and 0.98 (1.72-1.33) for homozygous Gly subjects. With respect to Ala119Ser and Asn453Ser, the pooled OR were 1.06 (0.87-1.29) and 1.24 (0.94-1.63) for heterozygous and 1.1 (0.8-1.52) and 1.09 (0.5-2.34) for homozygous respectively. In conclusion, this meta-analysis suggests that CYP1B1 polymorphisms are not associated with ovarian cancer risk. Studies evaluating CYP1B1_Leu432Val polymorphism are required to further elucidate the risk of ovarian cancer with this polymorphism. Additionally, studies amongst Asian and African subjects are required to estimate race-specific effects

Vibration spectroscopy of biofluids for disease screaning or diagnosis:translation from the laboratory to a clinical setting

There remains a need for objective and cost-effective approaches capable of diagnosing early-stage disease in point-of-care clinical settings. Given an increasingly ageing population resulting in a rising prevalence of chronic diseases, the need for screening to facilitate the personalising of therapies to prevent or slow down pathology development will increase. Such a tool needs to be robust but simple enough to be implemented into clinical practice. There is interest in extracting biomarkers from biofluids (e.g., plasma or serum); techniques based on vibrational spectroscopy provide an option. Sample preparation is minimal, techniques involved are relatively low-cost, and data frameworks are available. This review explores the evidence supporting the applicability of vibrational spectroscopy to generate spectral biomarkers of disease in biofluids. We extend the inter-disciplinary nature of this approach to hypothesise a microfluidic platform that could allow such measurements. With an appropriate lightsource, such engineering could revolutionize screening in the 21st century