Total ablative stereotactic body radiotherapy to primary and oligometastatic renal cell carcinoma in medically inoperable cases: An institutional analysis.

Introduction: Stereotactic body radiotherapy (SBRT) has been found to be an effective and safe modality with excellent oncological outcome in medically inoperable primary renal cell carcinoma (RCC) and oligometastases. There is scarcity of data on the synchronous delivery of SBRT to primary and oligometastatic RCC in patients unfit for nephrectomy. Here, we report the findings of a retrospective study of prospectively collected data on "total ablative SBRT." Methods: Oligometastatic RCC patients with intact primary tumors were enrolled between May 2021 and June 2022. SBRT was synchronously delivered to the primary tumor and metastases. Demographics, treatment, oncologic outcomes, and toxicity were assessed. Kaplan-Meier estimates were generated for oncologic outcomes. The primary endpoint of this study was feasibility and tolerability. Results: Eleven patients were enrolled between May 2021 and June 2022. One patient died at 2 months after SBRT due to viral pneumonitis (possibly COVID pneumonia). Nine patients (82%) had metastatic disease, while 2 (18%) were stage II. The average maximal diameter of primary was 68.7 mm (range, 23-128 mm). The SBRT doses for primary and metastasis ranged from 40 to 55 Gray (Gy) in 5 to 7 fractions and 22 to 40Gy in 2 to 5 fractions, respectively. The median follow-up period was 10.5 months (Range: 4-15 months). Response assessment was available for ten patients. Local control, marginal control, regional control and initial oligometastatic control (OMC) rates were 100%. OMC declined to 87.5% as one patient had recurrence in irradiated subcarinal lymphnode at 7 months. The metastatic control rate was 80% and loco-regional progression-free survival was 8 months (range, 4-15 months). Toxicities were minimal and manageable. At the last follow-up, 7 of 11 patients were alive with an overall survival of 63.5%. Six patients received systemic therapy after SBRT. Conclusions: Synchronous delivery of SBRT to primary and oligometastatic sites in patients unfit for nephrectomy was feasible and tolerable with good locoregional control. The total ablative SBRT strategy needs to be explored in similar cohorts.

Rilzabrutinib, a reversible covalent Bruton's tyrosine kinase inhibitor: Absorption, metabolism, excretion, and absolute bioavailability in healthy participants.

This single-center, open-label, non-randomized, two-part, phase I study was conducted (1) to evaluate the absolute oral bioavailability of rilzabrutinib 400 mg tablet following an i.v. microtracer dose of ~100 µg [14C]-rilzabrutinib (~1 µCi) and single oral dose of 400 mg rilzabrutinib tablet (part 1), and (2) to characterize the absorption, metabolism, and excretion (AME) of 14C-radiolabeled rilzabrutinib following single oral dose (300 mg) of [14C]-rilzabrutinib (~1000 µCi; administered as a liquid) in healthy male participants (part 2). A total of 18 subjects were enrolled (n = 8 in part 1; n = 10 in part 2). The absolute bioavailability of 400 mg rilzabrutinib oral tablet was low (<5%). In part 1, rilzabrutinib was absorbed rapidly after single oral dose of rilzabrutinib 400 mg tablet with a median (range) time to maximum concentration (Tmax ) value of 2.03 h (1.83-2.50 h). The geometric mean (coefficient of variation) terminal half-life following the oral dose and i.v. microtracer dose of ~100 µg [14C]-rilzabrutinib, were 3.20 (51.0%) and 1.78 (37.6%) h, respectively. In part 2, rilzabrutinib was also absorbed rapidly following single oral dose of 300 mg [14C]-rilzabrutinib solution with a median (range) Tmax value of 1.00 h (1.00-2.00 h). The majority of total radioactivity was in the feces for both non-bile collection subjects (92.9%) and bile collection subjects (87.6%), and ~5% of radioactivity was recovered in urine after oral administration. Urinary excretion of unchanged rilzabrutinib was low (3.02%). The results of this study advance the understanding of the absolute bioavailability and AME of rilzabrutinib and can help inform its further investigation.

Preclinical Mechanisms of Topical PRN473, a Bruton Tyrosine Kinase Inhibitor, in Immune-Mediated Skin Disease Models.

The expression of Bruton tyrosine kinase (BTK) in B cells and innate immune cells provides essential downstream signaling for BCR, Fc receptors, and other innate immune cell pathways. The topical covalent BTK inhibitor PRN473 has shown durable, reversible BTK occupancy with rapid on-rate and slow off-rate binding kinetics and long residence time, resulting in prolonged, localized efficacy with low systemic exposure in vivo. Mechanisms of PRN473 include inhibition of IgE (FcεR)-mediated activation of mast cells and basophils, IgG (FcγR)-mediated activation of monocytes, and neutrophil migration. In vivo, oral PRN473 was efficacious and well tolerated in the treatment of canine pemphigus foliaceus. In this study, we evaluated in vitro selectivity and functionality, in vivo skin Ab inflammatory responses, and systemic pharmacology with topically administered PRN473. Significant dose-dependent inhibition of IgG-mediated passive Arthus reaction in rats was observed with topical PRN473 and was maintained when given 16 h prior to challenge, reinforcing extended activity with once-daily administration. Similarly, topical PRN473 resulted in significant dose-dependent inhibition of the mouse passive cutaneous anaphylaxis IgE-mediated reaction. Multiday treatment with topical PRN473 in rodents resulted in low-to-no systemic accumulation, suggesting that efficacy was mainly due to localized exposure. Reduced skin Ab inflammatory activity was also confirmed with oral PRN473. These preclinical studies provide a strong biologic basis for targeting innate immune cell responses locally in the skin, with rapid onset of action following once-daily topical PRN473 administration and minimal systemic exposure. Dose-dependent inhibition in these preclinical models of immune-mediated skin diseases support future clinical studies.

Clinical Characteristics and Outcome Trends of Adjuvant Anthracycline and Taxane Regimen for Early Stage Breast Cancer.

BACKGROUND: The anthracycline and taxane-based chemotherapy treatment regimen remains the gold standard for treatment of early stage breast cancer. However, studies examining the effectiveness and use of this treatment regimen in Indian context are limited. This study examined patients treated with anthracycline and taxane-based chemotherapy at a tertiary care cancer center in India. METHODS: Patients with confirmed early stage breast cancer who had undergone primary breast surgery followed by treatment with anthracycline and taxane-based chemotherapy between 2009 and 2015 were included in the study. Data on clinical characteristics and treatment details were collected from the patients' medical records. RESULTS: Two hundred sixty-four women were included in the analysis. The median age at presentation was 50 years. Among the 264 women, 40.5% were premenopausal, 1.2% were perimenopausal, and 58.3% were postmenopausal. The number of patients undergoing breast-conserving surgery (BCS) and modified radical mastectomy (MRM) were 35.2% and 64.7%, respectively. Patients with a tumor grade of 1, 2, and 3 were 7.2%, 53.1%, and 39.7%, respectively. Tumors were unifocal in 81.1% and multifocal in 18.2% of patients. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2) positivity was detected in 58.3%, 54.2%, and 3.1% of patients, respectively and 38.6% of patients were triple negative. With a median follow-up of 36.2 months, the invasive disease-free survival rate was 90.9% and mean disease-free survival time was 65.4 ± 1.13 months. CONCLUSIONS: The results of this study confirm the clinical utility of anthracycline and taxane-based chemotherapy regimen as the adjuvant chemotherapy treatment of early stage breast cancer.

Improved uptake and therapeutic intervention of curcumin via designing binary lipid nanoparticulate formulation for oral delivery in inflammatory bowel disorder.

This study was focussed on development of curcumin loaded solid binary lipid nanoparticles (C-SBLNs) to ameliorate stability, uptake and therapeutic potential of curcumin during inflammatory bowel disease (IBD). C-SBLNs with nano-size range (210.56 ± 41.22 nm) and high entrapment efficiency (83.12 ± 6.57%) were prepared by solvent emulsification evaporation method using binary lipids i.e. stearic acid and tristearin after optimizing various formulation and process variables. Physicochemical characterization of C-SBLNs by ATR-FTIR confirmed drug entrapment whereas thermal and pXRD study corroborated loss of crystallinity of drug into C-SBLNs. Lyophilized C-SBLNs were found to be spherical shaped with good gastrointestinal stability and prolonged drug release up to 24 h. Optimized C-SBLNs formulation displayed significantly enhanced cellular uptake and localization in inflamed tissues during IBD. Oral administration of C-SBLNs in DSS induced colitis model revealed significant reduction in leucocyte infiltration, oxidative stress, pro-inflammatory cytokine (TNF-α) secretion and maintenance of colonic structure similar to healthy animal group compared to curcumin. Thus, in vitro and preclinical findings of study clearly confirmed that C-SBLNs could be a stable and efficacious alternative platform for curcumin delivery with strong competence in IBD chemotherapy.

Development and evaluation of nanoemulsifying preconcentrate of curcumin for colon delivery.

The present study aimed to develop and optimize a nanoemulsifying preconcentrate formulation of curcumin with good emulsification ability and optimal globule size, for controlled targeting in colon. Content of formulation variables, namely, X1 (Peceol), X2 (Cremophor-EL), and X3 (Transcutol HP), were optimized by Box-Behnken design of experiments for its impact on mean globule size (Y1), emulsification time (Y2), and time required for drug release (85%) in phosphate buffer (pH 7.2), t 85% (Y3). Transmission electron micrographs confirmed that there is no coalescence among globules, with size range concordant with the globule size analysis by dynamic light scattering technique (100 nm). 3D plots indicated that concentration of formulation ingredients significantly influences the formulation properties (globule size, emulsification time, and drug release). In vitro release profile (in phosphate buffer; pH 7.2) represents the fact that more than 50% of the drug was released within initial 15 min whereas in vivo release showed limited systemic absorption (C max 200 ng/mL) of curcumin. Stability study ensures the protection of drug in alkaline media which may further confirm the localised delivery of drug to colonic region. Study demonstrated that the nanoemulsifying preconcentrate can be a promising system for the colon specific delivery of curcumin to treat local pathologies.

Development and optimization of polymeric self-emulsifying nanocapsules for localized drug delivery: design of experiment approach.

The purpose of the present study was to formulate polymeric self-emulsifying curcumin nanocapsules with high encapsulation efficiency, good emulsification ability, and optimal globule size for localized targeting in the colon. Formulations were prepared using modified quasiemulsion solvent diffusion method. Concentration of formulation variables, namely, X1 (oil), X2 (polymeric emulsifier), and X3 (adsorbent), was optimized by design of experiments using Box-Behnken design, for its impact on mean globule size (Y1) and encapsulation efficiency (Y2) of the formulation. Polymeric nanocapsules with an average diameter of 100-180 nm and an encapsulation efficiency of 64.85±0.12% were obtained. In vitro studies revealed that formulations released the drug after 5 h lag time corresponding to the time to reach the colonic region. Pronounced localized action was inferred from the plasma concentration profile (C max 200 ng/mL) that depicts limited systemic absorption. Roentgenography study confirms the localized presence of carrier (0-2 h in upper GIT; 2-4 h in small intestine; and 4-24 h in the lower intestine). Optimized formulation showed significantly higher cytotoxicity (IC50 value 20.32 µM) in HT 29 colonic cancer cell line. The present study demonstrates systematic development of polymeric self-emulsifying nanocapsule formulation of curcumin for localized targeting in colon.

Enhanced oral bioavailability of acyclovir by inclusion complex using hydroxypropyl-ß-cyclodextrin.

The therapeutic potential of acyclovir is limited by the low oral bioavailability owing to its limited aqueous solubility and low permeability. The present study was a systematic investigation on the development and evaluation of inclusion complex using hydroxypropyl-ß-cyclodextrin for the enhancement of oral bioavailability of acyclovir. The inclusion complex of acyclovir was prepared by kneading method using drug: hydroxypropyl-ß-cyclodextrin (1:1 mole). The prepared inclusion complex was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, NMR spectroscopy and evaluated in vitro by dissolution studies. In vivo bioavailability of acyclovir was compared for inclusion complex and physical mixture in rat model. Phase solubility studies indicate the formation of acyclovir-hydroxypropyl-ß-cyclodextrin complex with higher stability constant and linear enhancement in drug solubility with increase in hydroxypropyl-ß-cyclodextrin concentration. Characterization of the prepared formulation confirms the formation of acyclovir-hydroxypropyl-ß-cyclodextrin inclusion complex. Dissolution profile of inclusion complex demonstrated rapid and complete release of acyclovir in 30 min with greater dissolution efficiency (90.05 ± 2.94%). In vivo pharmacokinetic data signify increased rate and extent of acyclovir absorption (relative bioavailability ∼160%; p < 0.0001) from inclusion complex, compared to physical mixture. Given the promising results in the in vivo studies, it can be concluded that the inclusion complex of acyclovir could be an effective and promising approach for successful oral therapy of acyclovir in the treatment of herpes viruses.

Oral buccoadhesive films of ondansetron: Development and evaluation.

INTRODUCTION: Difficulty or inability in swallowing tablets/capsules during or after chemotherapy is common due to chemotherapy induced nausea and vomiting in patients. Buccoadhesive films of ondansetron hydrochloride were prepared for the prevention and treatment of chemotherapy-induced emesis. Films of varying polymeric composition were prepared in order to facilitate initial as well as prolonged drug release that could take care of acute as well as delayed emesis. MATERIALS AND METHODS: Mucoadhesive films were prepared using polymers such as hydroxypropyl methylcellulose (HPMC) E5, HPMC K100, and Eudragit(®) NE 30 D. The effect of concentration of these polymers on physical properties and drug release were studied. All the films were prepared by solvent casting method. In another part of the study, the effect of drug concentration on physical and mucoadhesive properties of film were assessed, keeping the polymer concentration fixed. RESULTS: Films containing HPMC showed good mucoadhesion. Increasing the concentration of Eudragit(®) NE 30 D in the films retarded drug release and increased residence time, however, reduced mucoadhesion. At a fixed polymer concentration and ratio, films prepared using an increased drug content showed an increased mucoadhesion. CONCLUSION: Films prepared using HPMC E5 (1000 mg), HPMC K100 (500 mg), and Eudragit(®) NE 30 D (750 mg) provided initial rapid followed by sustained drug release over a period of 6 h. Given the promising results, the study concluded that the developed buccal films have the potential to release ondansetron required for chemotherapy induced acute and delayed emesis.

Corticosteroid responsive prolonged thrombocytopenia in a case of dengue fever.

Thrombocytopenia and bleeding manifestations are consistent features of dengue fever. Usually thrombocytopenia resolves and platelet count normalises by day 10 of fever. Persistent thrombocytopenia is not a feature of dengue fever. Proposed mechanisms behind thrombocytopenia are many. Direct platelet destruction by dengue virus, immune-mediated platelet destruction and even megakaryocytic immune injury have been proposed as underlying mechanisms. We are reporting a case of an old man who presented in dengue season in 2012 with fever and bleeding and was diagnosed as a case of dengue fever. He developed persistent thrombocytopenia requiring treatment on the lines of immune thrombocytopenia and responded to steroids. Other causes of thrombocytopenia were ruled out.

Potential of plant mucilages in pharmaceuticals and therapy.

Mucilages, and in particular plant mucilages, have gained more attention over the last few decades due to their reputable medicinal properties. Some publications have appeared in reputable Scientific Journals that have made appreciable contributions to the discovery of the functions and utilizations of such naturally occurring products. Therapeutic value of mucilages has been extended to wound healing, diabetes, immunostimulation, cancer, angiotensin converting enzyme inhibition, stomachic, and antioxidant properties. Based on their sustaining capacities as well as binding and gelling properties, mucilages have been proposed to be one of the most useful materials to modulate drug delivery. Chemical analysis reveals that generally these contain monosachrides along with a range of other organic and inorganic components. Although physiological properties of various plant mucialges have been described, it still remains uncertain as to which of the component(s) is responsible for these physiological properties. Further research needs to be done to unravel the myth surrounding the biological activities and the functional properties of them. This review presents an overview of the current status and knowledge on the applications of plant mucilages as therapeutic agent and pharmaceutical additives.

Old drugs: new complications.

This is a case of acute splenic and bilateral renal infarction in a patient with non-small cell lung carcinoma during chemotherapy with gemcitabine and cisplatin. Till date, bilateral renal infarction following gemcitabine and cisplatin has been reported only once in the past. The case that is being reported has had acute splenic and bilateral renal infarct and has not been reported previously. Splenic and renal infarction should be considered in the differential diagnosis of excruciating abdominal pain and backache in a patient on gemcitabine-based and cisplatin-based chemotherapy.

Emulsion forming drug delivery system for lipophilic drugs.

In the recent years, there is a growing interest in the lipid-based formulations for delivery of lipophilic drugs. Due to their potential as therapeutic agents, preferably these lipid soluble drugs are incorporated into inert lipid carriers such as oils, surfactant dispersions, emulsions, liposomes etc. Among them, emulsion forming drug delivery systems appear to be a unique and industrially feasible approach to overcome the problem of low oral bioavailability associated with the BCS class II drugs. Self-emulsifying formulations are ideally isotropic mixtures of oils, surfactants and co-solvents that emulsify to form fine oil in water emulsions when introduced in aqueous media. Fine oil droplets would pass rapidly from stomach and promote wide distribution of drug throughout the GI tract, thereby overcome the slow dissolution step typically observed with solid dosage forms. Recent advances in drug carrier technologies have promulgated the development of novel drug carriers such as control release self-emulsifying pellets, microspheres, tablets, capsules etc. that have boosted the use of "self-emulsification" in drug delivery. This article reviews the different types of formulations and excipients used in emulsion forming drug delivery system to enhance the bioavailability of lipophilic drugs.

Self-emulsifying therapeutic system: a potential approach for delivery of lipophilic drugs / Sistema terapêutico auto-emulsionável: uma abordagem potencial para a entrega dos fármacos lipofílicos

Self-emulsifying therapeutic system (SETs) provide an effective and intelligent solution to the various issues related to the formulation of hydrophobic drugs with limited solubility in gastrointestinal fluid. Although the potential utility of SETs is well known, only in recent years has a mechanistic understanding of the impact of these systems on drug disposition emerged. These in situ emulsion-forming systems have a high stability when incorporated in various dosage forms. SETs are being looked upon as systems which can overcome the problems associated with delivery of poorly water soluble drugs. An in-depth knowledge about lipids and surfactants that can contribute to these systems, criterion for their selection and the proportion in which they can be used, represent some crucial factors determining the in vivo performance of these systems. This article presents a comprehensive account of various types of self-emulsifying formulations with emphasis on their composition and examples of currently marketed preparations.

O sistema terapêutico auto-emulsionante (SETs) fornece solução eficaz e inteligente para os vários problemas relativos à formulação de fármacos hidrofóbicos com solubilidade limitada no fluido gastrintestinal. Embora a utilidade potencial dos SETs seja bem conhecida, só recentemente se compreendeu, mecanisticamente,o impacto desses sistemas na disposição de fármacos. Estes sistemas de formação de emulsão in situ têm alta estabilidade, quando incorporados em várias formas de dosagem. Os SETs têm sido considerados como sistemas que podem resolver problemas associados à liberação de fármacos pouco solúveis em água. O conhecimento profundo dos lipídios e tensoativos que podem ser utilizados para estes sistemas e o critério para a sua seleção e proporção na qual eles são utilizados são alguns dos fatores cruciais que determinam o desempenho do sistema in vivo. Este artigo apresenta o relato abrangente de vários tipos de formulações auto-emulsificantes, com ênfase em sua composição e exemplos das preparações que são correntemente comercializadas.

ST-deviation, C-reactive protein and CPK-MB as mortality predictors in acute myocardial infarction.

Prognosis varies widely in patients with acute coronary syndromes because of the heterogeneous nature of this condition. Successful outcome depends upon early risk stratification and an early decision regarding the approach of management of these patients. We studied 120 patients admitted with acute myocardial infarction, who were subsequently divided into two groups based on their final outcome (improvement or expiry). C-reactive protein and CPK-MB were quantitatively estimated at the time of hospital admission. Also, the number of ECG leads showing ST deviation and its sum was calculated and correlated with the biochemical markers. Differences in these variables were analysed between the two groups of patients. Significant differences were found in the mean levels of CRP, CPK-MB, the number of ECG leads with ST deviation and its sum between the two groups. Also, significant correlation was found between the levels of biochemical markers and the sum of ST deviation at admission in all patients of acute myocardial infarction.

POEMS syndrome: experience with fourteen cases.

The POEMS syndrome, also known as Crow-Fukase disease, is a rare multisystem disorder, which may take several years to evolve fully. The combination of symptoms and signs is highly complex and some of the features are detected at sub-clinical level requiring high level of suspicion. The clinical data on POEMS is still evolving with only a few case reports from India. Herein, we report a series of 14 cases with POEMS syndrome at our centre over the past 8 years, which were analysed retrospectively for their clinical features, response to therapy and treatment outcome. Presence of plasma cell dyscrasia (PCD) was essential for inclusion in this study. Confirmation of PCD was done by positive "M" spike in serum and/or urine, bone marrow plasmacytosis or presence of plasmacytoma on biopsy. In addition, the diagnosis of POEMS syndrome needed the presence of at least two of the following features: polyneuropathy, organomegaly, endocrinopathy and/or skin changes. Patients were excluded from study if there was a secondary cause of polyneuropathy like amyloidosis, drugs like vincristine, nerve root or spinal cord compression. Two patients had complete form (all five features) of the syndrome, whereas 12 had incomplete form. Median age was 48 years (range 32-65). Peripheral neuropathy was seen in 13 (92.85%) cases, organomegaly 10 (71.42%), endocrinal involvement 7 (50%) and skin changes 9 (64.28%). An association with Castleman's disease and vasculitis was also noted. With different chemotherapy protocols, all treated patients (n = 12), had significant symptomatic improvement with or without objective improvement at median follow up of 48 months (range 6-120). In conclusion, high level of suspicion is required to detect this rare entity.

VAD followed by VMCP: an alternative regimen for multiple myeloma.

In patients with multiple myeloma, a good complete response rate and disease-free survival may be achieved with sequential chemotherapy using VAD and VMCP, which is an alternative effective and less expensive treatment regimen. This regimen thus assumes particular significance in developing nations like India, where the majority of patients with myeloma cannot afford the cost of high-dose chemotherapy with stem cell rescue.