A Phase 0/1 Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas.

PURPOSE: High grade gliomas (HGGs) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our pre-clinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA approved aromatase inhibitor, has marked activity against HGGs. METHODS: We conducted a phase 0/I single center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety and tolerability of LTZ in recurrent HGG patients. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5 and 20 mg of LTZ administered daily pre- and post-surgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The Recommended Phase 2 Dose (R2PD) was determined as the dose that resulted in predicted steady state tumoral extracellular fluid (ECF) (Css,ecf) > 2 µM and did not result in ≥ 33% dose limiting adverse events (AEs) assessed using CTCAE v5.0. RESULTS: Twenty-one patients were enrolled. Common LTZ related AEs included fatigue, nausea, musculoskeletal, anxiety and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 +/- 0.59 µM. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-seq analysis. CONCLUSION: Based on safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials.

A study of the pharmacokinetics, safety, and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed pregnant women with HIV.

OBJECTIVE: The objective of this study was to assess the pharmacokinetics, safety, and efficacy and confirm the dose of once-daily bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF; B/F/TAF) during pregnancy. DESIGN: An open-label, multicenter, single-arm, phase 1b study (NCT03960645) was conducted in 33 virologically suppressed pregnant women with HIV-1. METHODS: Participants received B/F/TAF (50/200/25 mg) from the second or third trimester through ∼16 weeks postpartum. Steady-state maternal plasma pharmacokinetic samples were collected at the second and third trimesters and 6 and 12 weeks postpartum for BIC, FTC, and TAF. Neonates ( n  = 29) were followed from birth to 4-8 weeks with sparse washout pharmacokinetic sampling for BIC and TAF. The proportion of participants with HIV-1 RNA less than 50 copies/ml at delivery (missing = excluded) was evaluated. RESULTS: Mean areas under the concentration-time curve over the dosing interval (AUC tau ) for BIC, FTC, and TAF were lower during pregnancy versus postpartum but were closer to AUC tau values for nonpregnant adults with HIV reported in other studies. Geometric least-squares mean ratios for BIC, FTC, and TAF AUC tau during pregnancy versus postpartum ranged from 41 to 45%, 64 to 69% and 57 to 78%, respectively. Mean BIC trough concentrations during pregnancy were more than 6.5-fold greater than the protein-adjusted 95% effective concentration. In neonates, the median BIC half-life was 43 h. Virologic suppression was maintained in all adult participants throughout the study, with no virologic failure or treatment-emergent resistance to HIV-1, no discontinuations because of adverse events, and no perinatal transmission. CONCLUSION: Exposures to BIC, FTC, and TAF were lower during pregnancy than postpartum. However, mean BIC trough concentrations were maintained at levels indicative of efficacious exposure, and FTC/TAF data were concordant with published literature in this population. Pharmacokinetic and safety data, combined with maintenance of robust virologic suppression, suggest that once-daily B/F/TAF without dose adjustment is appropriate during pregnancy.

Safety and efficacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression.

BACKGROUND & AIMS: Selgantolimod (GS-9688) is a Toll-like receptor 8 (TLR8) agonist that suppresses HBV in vitro. In a phase II study, we evaluated the safety and efficacy of weekly selgantolimod treatment in virally suppressed individuals with chronic HBV taking oral antiviral treatment. METHODS: Forty-eight patients were randomized into two cohorts (hepatitis B e antigen [HBeAg]-positive and -negative [n = 24 each]) to receive oral selgantolimod 3 mg, 1.5 mg, or placebo (2:2:1) once weekly for 24 weeks while maintaining oral antivirals. The primary efficacy endpoint was the percentage of patients with a ≥1 log10 IU/ml decline in hepatitis B surface antigen (HBsAg) from baseline to week 24. Post-treatment, patients continued on oral antivirals for 24 weeks. RESULTS: The primary endpoint was reached by one participant, who was HBeAg-negative and received selgantolimod 1.5 mg. In contrast with placebo-treated patients (n = 9), only selgantolimod-treated patients (n = 39 total) had HBsAg declines greater than 0.1 log10 IU/ml at weeks 24 (18%, 7/39) and 48 (26%, 10/39), HBsAg loss (5%, 2/39 through 48 weeks), or HBeAg loss (16%, 3/19 through 48 weeks). The most common adverse events in selgantolimod-treated groups were nausea (46%), upper respiratory tract infection (23%), and vomiting (23%). Gastrointestinal disorders were mostly mild and transient. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40, IFN-γ, and IL-1RA, as well as rapid redistribution of some circulating immune cell subsets. CONCLUSION: Oral selgantolimod up to 3 mg once weekly for 24 weeks was generally safe and well tolerated and led to serologic changes associated with progression to durable cure in two individuals by week 48. GOV IDENTIFIER: NCT03491553. IMPACT AND IMPLICATIONS: The only robust criterion for stopping treatment in chronic hepatitis B is loss of hepatitis B surface antigen (known as functional cure), which is rare during nucleos(t)ide analogue therapy. It is likely that novel antiviral and immunomodulatory therapies will be needed to achieve finite functional cure. Selgantolimod is an oral Toll-like receptor 8 agonist that has shown antiviral activity in vitro as well as safety in a phase I clinical trial with weekly dosing. In this phase II study, selgantolimod therapy was associated with transient increases in serum cytokines, rapid redistribution of circulating immune cell subsets, modest reductions in HBsAg and HBeAg levels, and occasional loss of HBsAg (5%) and HBeAg (16%) among participants with chronic hepatitis B on nucleos(t)ide analogue therapy with viral suppression. Our results support continued development of selgantolimod as a component of a future hepatitis B cure regimen.

High pre-pregnancy body mass index and gestational weight gain among women belonging to upper SES from Delhi, India.

Background and objective: With increase in prevalence of obesity and an increasing trend in the birth of macrosomic infants, Institute of Medicine (IOM) guidelines pertaining to optimal gestational weight gain (GWG) required for positive pregnancy outcome were revised in 1990 and 2009. Since, in the Indian scenario, no recommendations exist for optimum GWG for obese (OB) and overweight (OW) women, we assessed the pattern of GWG w.r.t Institute of Medicine (IOM), 2009 among the subjects with different body mass index (BMI). Study design: Present data were a part of a longitudinal observational study wherein, 312 pregnant women (≤12th week of gestation) attending private antenatal clinics were followed till term and their weight was monitored regularly at pre-determined intervals i.e., 12th-14th, 18th-20th, 24th-26th, 30th-32nd, 36th + week of gestation and compared w.r.t IOM guidelines 2009. Results: 66.37 %, 57.89 % and 11.69 % of OB, OW and normal weight (NW) subjects respectively had weight gain exceeding their GWG limits. About 5 %,10.53 %, 33.77 % of OB, OW and NW subjects respectively had gained weight less than GWG limits (p = 0.000***). Conclusion: An increase in GWG inadequacy with increase in BMI and pronounced variations in GWG among OB and OW subjects underscore the necessity to monitor GWG especially among the subjects with high BMI.

Choroidal Thickness in Patients with Unilateral Amblyopia and Comparison between Anisometropic and Strabismic Amblyopia: A Prospective Cross-Sectional Study.

Aims and Objectives: To determine the choroidal thickness (mainly subfoveal) using spectral domain optical coherence tomography (SD-OCT) in amblyopic eyes and to compare it with the choroidal thickness (CT) of healthy fellow eyes. Materials and Methods: In this prospective study, 140 eyes of 70 patients (aged 5-40 years) with strabismic and anisometropic amblyopia were examined using enhanced depth imaging (EDI) mode in SD-OCT. The CT was measured directly below the fovea and six other locations: 500 µ, 1000 µ, and 1500 µ from fovea in both nasal and temporal quadrants. Results: The mean age of the patients was 22.5 ± 11.2 years. The mean Best Corrected Visual Acuity (BCVA) in the amblyopic eyes was 0.87 ± 0.47 logMAR and 0 ± 0.02 logMAR in control eyes. The average subfoveal CT was 341.73 ± 60.39 µm in the amblyopic eyes and 314.77 ± 48.12 µm in the fellow eyes. Subgroup analysis showed that the patients with anisometropic amblyopia had a significantly thicker choroid as compared to the fellow healthy eyes (P = 0.00), whereas in strabismic amblyopic eyes, this difference was not significantly significant (P = 0.064). Conclusion: Significant choroidal thickening was observed in subjects with amblyopia, which may contribute to the amblyopia pathogenesis and this could be used as a diagnostic parameter for amblyopia. These changes were more pronounced in patients with anisometropic amblyopia than strabismic amblyopia.

Retinopathy of Prematurity: Incidence and Risk Factor Analysis in Small for Gestational Age Neonates Compared to Appropriate for Gestational Age.

Objective: To analyze the incidence of retinopathy of prematurity (ROP) among preterm neonates who were born small for gestational age (SGA) and appropriate for gestational age (AGA). Materials and Methods: A prospective cohort study among preterm neonates born <34 weeks of gestational age (GA) and <2000 grams birth weight (BW) was conducted. The neonates were divided into AGA and SGA group. Incidence of ROP and risk factors was compared among the groups. Result: 290 neonates were screened [AGA: 240 (82.8%); SGA: 50 (17.2%)]. The mean birth-weight and gestational age were 1510.7 ± 390.64 grams and 31.4 ± 4.8 weeks, respectively. The incidence of ROP in AGA and SGA was 30.2% and 33%, respectively (P = 0.58), whereas the incidence of type 1 ROP in AGA and SGA was 14% and 19% (P = 0.41). Male sex, anemia, oxygen administration, surfactant administration, sepsis, and PIH were independent significant risk factors for ROP on multivariate analysis. Conclusion: This study showed that both AGA and SGA premature infants have similar incidence of ROP. SGA is not an independent risk factor for ROP.

CADNet: an advanced architecture for automatic detection of coronary artery calcification and shadow border in intravascular ultrasound (IVUS) images.

Intravascular Ultrasound (IVUS) is a medical imaging modality widely used for the detection and treatment of coronary heart disease. The detection of vascular structures is extremely important for accurate treatment procedures. Manual detection of lumen and calcification is very time-consuming and requires technical experience. Ultrasound imaging suffers from the generation of artifacts which obstructs the clear delineation among structures. Considering, the need, to provide special attention to crucial areas, convolutional block attention modules (CBAM) is integrated into an encoder-decoder-based U-Net architecture along with Atrous Spatial Pyramid Pooling (ASPP) to detect vessel components: lumen, calcification and shadow borders. The attention modules prove effective in dealing with areas of special attention by assigning additional weights to crucial channels and preserving spatial features. The IVUS data of 12 patients undergoing the treatment is taken for this study. The novelty of the model design is such that it is able to detect the lumen area in the presence/absence of calcification and bifurcation artifacts too. Also, the model efficiently detects the calcification area even in case of severely complex lesions with shadows behind them. The main contribution of the work is that IVUS images of varying degrees of calcification till 360° are also considered in this work, which is usually neglected in previous studies. The experimental results of 1097 IVUS images of 12 patients resulted in meanIoU (0.7894 ± 0.011), Dice Coefficient (0.8763 ± 0.070), precision (0.8768 ± 0.069) and recall (0.8774 ± 0.071) of the proposed model CADNet which show the model's effectiveness relative to other state-of-the art methods.

Calcification Detection in Intravascular Ultrasound (IVUS) Images Using Transfer Learning Based MultiSVM model.

Cardiovascular disease serves as the leading cause of death worldwide. Calcification detection is considered an important factor in cardiovascular diseases. Currently, medical practitioners visually inspect the presence of calcification using intravascular ultrasound (IVUS) images. The study aims to detect the extent of calcification as belonging to class I, II as mild calcification, and class III, IV as dense calcification from IVUS images acquired at 40 MHz. To detect calcification, the features were extracted using improved AlexNet architecture and then were fed into machine learning classifiers. The experiments were carried out using 14 real IVUS pullbacks of 10 patients. Experimental results show that the combination of traditional machine learning with deep learning approaches significantly improves accuracy. The results show that support vector machines outperform all other classifiers. The proposed model is compared with two other pre-trained models GoogLeNet (98.8%), SqueezeNet (99.2%), and exhibits considerable improvement in classification accuracy (99.8%). In the future other models such as Vision Transformers could be explored with additional feature selection methods such as ReliefF, PSO, ACO, etc. to improve the overall accuracy of diagnosis.

A State-Of-The-Art Review on Coronary Artery Border Segmentation Algorithms for Intravascular Ultrasound (IVUS) Images.

Intravascular Ultrasound images (IVUS) is a useful guide for medical practitioners to identify the vascular status of coronary arteries in human beings. IVUS is a unique intracoronary imaging modality that is used as an adjunct to angioplasty to view vessel structures using a catheter with high resolutions. Segmentation of IVUS images has always remained a challenging task due to various impediments, for example, similar tissue components, vessel structures, and artifacts imposed during the acquisition process. Many researchers have applied various techniques to develop standard methods of image interpretation, however, the ultimate goal is still elusive to most researchers. This challenge was presented at the MICCAI- Computing and Visualization for (Intra)Vascular Imaging (CVII) workshop in 2011. This paper presents a major review of recently reported work in the field, with a detailed analysis of various segmentation techniques applied in IVUS, and highlights the directions for future research. The findings recommend a reference database with a larger number of samples acquired at varied transducer frequencies with special consideration towards complex lesions, suitable validation metrics, and ground-truth definition as a standard against which to compare new and current algorithms.

Refractive Error Profile of Preterm Infants at 1-Year Follow-up in a Tertiary Care Hospital.

PURPOSE: To study the refractive outcome in preterm infants with and without retinopathy of prematurity (ROP) in a tertiary care hospital in North India. METHODS: This prospective study was conducted on 300 consecutive premature infants with a birth weight of 2 kg or less and a gestational age of 34 weeks or less at birth. The infants were divided into three groups (no ROP, spontaneously regressed ROP, and laser-treated ROP) and were followed up at 1 year of age to assess the presence and type of refractive error in each group. RESULTS: The refractive error data were available for 277 neonates (554 eyes). On cycloplegic retinoscopy at 1 year of follow-up, the incidence of myopia was 12.29%, 29.55%, and 48.83% in all three groups, respectively, being most common in the laser-treated group, and the values were statistically significant (P < .05). Moreover, high myopia was most prevalent in the laser-treated group (23.25%). A correlation between birth weight and gestational age with spherical equivalent showed that a low birth weight and a low gestational age are more commonly found in infants with a more negative spherical equivalent. CONCLUSIONS: Infants with laser-treated ROP have a higher incidence of myopia than those with spontaneously regressed ROP or no ROP. [J Pediatr Ophthalmol Strabismus. 2022;59(3):151-155.].

Increasing postpartum IUCD coverage through a QI initiative: a step towards reducing the unmet need of postpartum contraception.

BACKGROUND: Unintended pregnancies have a negative impact on the health and economy of a nation, which can be prevented by effective family planning (FP) services. Postpartum intrauterine device (PPIUCD) is a safe and effective FP method which allows women to obtain long-acting contraception before discharge from the point of delivery. We observed poor coverage of deliveries with PPIUCD at our facility. This was the trigger to initiate a quality improvement (QI) initiative to increase the PPIUCD coverage from current rate of 4.5%-10% in 3-month period. METHOD: A fishbone analysis of the problem was done and the following causes were identified: lack of focused counselling for FP, lack of sensitisation and training of resident doctors and inconsistent supply of intrauterine contraceptive devices (IUCDs). A QI team was constituted with representatives from faculty members, residents, interns, nursing officers and FP counsellors. The point of care quality improvement methodology was used. INTERVENTIONS: Daily counselling of antenatal women was started by the counsellors and interns in antenatal wards. A WhatsApp group of residents was made initially to sensitise them; and later for parking of problems and trouble shooting. The residents were provided hands-on training at skills lab. Uninterrupted supply of IUCDs was ensured by provision of buffer stock of IUCDs with respective store keepers. RESULT: The PPIUCD insertion rates improved from 4.5% to 19.2% at 3 months and have been sustained to a current 30%-35% after 1 ½ years of initiation of the project tiding through the turbulence during the COVID-19 pandemic using QI techniques. CONCLUSION: Sensitisation and training of residents as well as creation of awareness among antenatal women through targeted counselling helped improve PPIUCD coverage at the facility. QI initiatives have the potential to facilitate effective implementation of the FP programmes by strategic utilisation of the resources.

Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights.

Based on the discovery that the estrogen synthase aromatase (CYP19A1) is abundantly expressed in high- grade gliomas, the aromatase inhibitor, letrozole is being investigated in pre-clinical models as a novel agent against this malignancy. Here, we investigated the systemic and brain pharmacokinetics of letrozole following single and steady state dosing in both male and female Sprague-Dawley rats. Furthermore, we employed physiologically-based pharmacokinetic (PBPK) modeling to gain quantitative insights into the blood-brain barrier penetration of this drug. Letrozole (4 mg/kg) was administered intraperitoneally daily for 5 days (for males) and 11 days (for females) and intracerebral microdialysis was performed for brain extracellular fluid (ECF) collection simultaneously with venous blood sampling. Drug levels were measured using HPLC and non-compartmental analysis was conducted employing WinNonlin®. Simcyp animal simulator was used for conducting bottom-up PBPK approach incorporating the specified multi-compartment brain model. Overall, marked gender-specific differences in the systemic and brain pharmacokinetics of letrozole were observed. Letrozole clearance was much slower in female rats resulting in markedly higher plasma and brain drug concentrations. At steady state, the plasma AUC 0-24 was 103.0 and 24.8 µg*h/ml and brain ECF AUC 0-12 was 24.0 and 4.8 µg*h/ml in female and male rats, respectively. The PBPK model simulated brain concentration profiles were in close agreement with the observed profiles. While gender-specific differences in letrozole PK are not observed in the clinical setting, these findings will guide the dose optimization during pre-clinical investigations of this compound. The PBPK model will serve as an important clinical translational tool.

Safety, Pharmacokinetics, and Pharmacodynamics of the Oral TLR8 Agonist Selgantolimod in Chronic Hepatitis B.

BACKGROUND AND AIMS: In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 may induce antiviral immunity and drive functional cure. Selgantolimod, a toll-like receptor 8 agonist, was evaluated in patients with CHB who were virally suppressed on oral antiviral treatment or viremic and not on oral antiviral treatment. APPROACH AND RESULTS: In this phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once weekly. Virally suppressed patients received either 1.5 mg (for 2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from six sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%), and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, which are important for the expansion and activity of multiple T- cell subsets and innate immunity. CONCLUSION: Selgantolimod was safe and well-tolerated in virally suppressed and viremic patients with CHB and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.

Mechanisms of stearoyl CoA desaturase inhibitor sensitivity and acquired resistance in cancer.

The lipogenic enzyme stearoyl CoA desaturase (SCD) plays a key role in tumor lipid metabolism and membrane architecture. SCD is often up-regulated and a therapeutic target in cancer. Here, we report the unexpected finding that median expression of SCD is low in glioblastoma relative to normal brain due to hypermethylation and unintentional monoallelic co-deletion with phosphatase and tensin homolog (PTEN) in a subset of patients. Cell lines from this subset expressed undetectable SCD, yet retained residual SCD enzymatic activity. Unexpectedly, these lines evolved to survive independent of SCD through unknown mechanisms. Cell lines that escaped such genetic and epigenetic alterations expressed higher levels of SCD and were highly dependent on SCD for survival. Last, we identify that SCD-dependent lines acquire resistance through a previously unknown FBJ murine osteosarcoma viral oncogene homolog B (FOSB)-mediated mechanism. Accordingly, FOSB inhibition blunted acquired resistance and extended survival of tumor-bearing mice treated with SCD inhibitor.

Sternoclavicular tuberculosis: an atypical imitator of refractory shoulder pain.

INTRODUCTION: Sternoclavicular joint tuberculosis is rare and has been presented in literature with few sporadic case reports or small case series. Rarity of the condition, nonspecific symptoms, difficulty to visualise the area on X-rays, and minimal clinical signs make diagnosis of sternoclavicular tuberculosis extremely difficult. Delay in diagnosis is therefore the common feature of all presented reports in literature. We here present our experience of treating 19 cases of sternoclavicular tuberculosis at our centre. MATERIALS AND METHOD: This is an observational study from 2010 to 2017 in a tertiary care referral hospital. All patients with clinical tenderness of sternoclavicular joint and shoulder joint pain of over three week duration were subjected to MRI. Patients who showed radiological lesions (radiography/MRI) were subjected to core biopsy under image guidance. A total of 26 patients had biopsy confirmed sternoclavicular tuberculosis (TB) during this period. RESULTS: All patients had improvement in shoulder function after treatment completion. Mean CSS pre-treatment was 29 which improved to mean of 8 after 18 months of ATT. Eight patients had excellent results, seven good, three fair, and one patient poor result. High initial ESR, late commencement of ATT from initial symptoms, and surgery of the involved joint were considered poor prognostic factors. DISCUSSION: Sternoclavicular tuberculosis is a rare disease with controversial etiology. Both haematogenous spread through suprascapular artery and contiguous spread through latent disease in apical lungs has been postulated. Delay in diagnosis is common to most reports in literature. Early MRI is useful in diagnosis of the lesion. The treatment for sternoclavicular joint in literature is controversial with proponents of both surgery and conservative management. CONCLUSION: Primary sternoclavicular tuberculosis is rare condition and requires a high index of suspicion for an early diagnosis. A focused sternoclavicular MRI and early biopsy may help in timely diagnosis. Early commencement of ATT has overall good clinical and functional results.

Gestational Weight Gain among Healthy Pregnant Women from Asia in Comparison with Institute of Medicine (IOM) Guidelines-2009: A Systematic Review.

In 1990, Institute of Medicine (IOM) recommended gestational weight gain (GWG) ranges for women in the United States primarily to improve infant birth weight. Changes in key aspects of reproductive health of women of child bearing age, a rising prevalence of obesity, and noncommunicable diseases prompted the revision of IOM guidelines in 2009. However, there is no such recommendation available for Asian women. This systematic review assesses the utility of IOM-2009 guidelines among Indian and other Asian pregnant women in terms of maternal and fetal outcomes. 624 citations were identified using PubMed and Google Scholar, out of which 13 were included. Prospective/retrospective studies of healthy Asian women with a singleton pregnancy which specifically examined fetal-maternal outcomes relative to IOM-2009 guidelines were included. Results. Majority of pregnant Indian women achieved less GWG than the recommendations whereas a mixed trend was noticed among the other Asian pregnant women. The most common fetal-maternal complications among the excessive GWG women were found to be macrosomia, large for gestational age and caesarean section followed by gestational diabetes and hypertension, whereas low birth weight, small for gestational age and preterm birth, was found to be associated with low GWG women. The findings highlight the need for appropriate GWG limits across the different body mass index levels specifically for Indians and other Asian population. However, there are not enough publications regarding the utility of IOM-2009 guidelines among the Indian and other Asian women. Thus, higher-quality researches are warranted in future to further validate the findings of the present review.

Plasma and brain pharmacokinetics of letrozole and drug interaction studies with temozolomide in NOD-scid gamma mice and sprague dawley rats.

PURPOSE: The aromatase inhibitor, letrozole, is being investigated in experimental animal models as a novel treatment for high-grade gliomas (HGGs). To facilitate optimal dosing for such studies, we evaluated the plasma and brain pharmacokinetics (PK) of letrozole in NOD-scid gamma (NSG) mice, which are frequently employed for assessing efficacy against patient-derived tumor cells. Furthermore, we evaluated the potential PK interactions between letrozole and temozolomide (TMZ) in Sprague-Dawley rats. METHODS: NSG mice were administered letrozole (8 mg/kg; i.p) as a single or multiple dose (b.i.d, 10 days). Brain tissue and blood samples were collected over 24 h. Letrozole and TMZ interaction study employed jugular vein-cannulated rats (three groups; TMZ alone, letrozole alone and TMZ + letrozole). Intracerebral microdialysis was performed for brain extracellular fluid (ECF) collection simultaneously with venous blood sampling. Drug levels were measured employing HPLC and PK analysis was conducted using Phoenix WinNonlin®. RESULTS: In NSG mice, peak plasma and brain tissue letrozole concentrations (Cmax) were 3-4 and 0.8-0.9 µg/ml, respectively. The elimination half-life was 2.6 h with minimal accumulation following multiple dosing. In the drug interaction study, no PK changes were evident when TMZ and letrozole were given in combination. For instance, peak plasma and brain ECF TMZ levels when given alone were 14.7 ± 1.1 and 4.6 ± 0.6 µg/ml, respectively, and 12.6 ± 2.4 and 3.4 ± 0.8 µg/ml, respectively, when given with letrozole. CONCLUSIONS: These results will guide the optimization of dosing regimen for further development of letrozole for HGG treatment.