Evaluation of numerical rating scale and neuropathic pain symptom inventory pain scores in advanced ovarian carcinoma patients undergoing surgery and first-line chemotherapy.

BACKGROUND AND AIM: Advanced epithelial ovarian cancer (OC) has a high disease manifestation with difficult-to-manage symptoms that limit the patients' functionality. Abdominal pain, persistent back pain, and neuropathic pain are among the common discomforts associated with OC and its treatment. Our study aims to determine pain scores in advanced OC patients undergoing surgery and chemotherapeutic treatment with carboplatin and paclitaxel. METHODS: One hundred and ten patients with advanced epithelial OC were enrolled and treated with surgery and an adjuvant/neoadjuvant chemotherapy regimen of carboplatin-paclitaxel for six cycles (triweekly). Pain intensity was analyzed using the validated numerical rating scale for resting, movement, sleep interference-associated pain, and neuropathic pain scores were evaluated using the neuropathic pain symptom inventory scale. Pain was correlated with Qol according to Fact-O questionnaires. Chemo-response was evaluated using the CA125 blood biomarker and CT scan of the abdomen and thorax. Data were recorded at baseline, 2, 4, and 6 months of the six chemotherapy cycles. RESULTS: Of the 110 patients, no statistically significant differences were found in pain at baseline and after treatment (P > 0.05) and between the responder and non-responder categories (P > 0.05). However, movement-associated pain had a significant correlation with chemo-response and a strong positive correlation with the patients' physical and functional wellbeing. There were more chemo-induced neuropathy occurrences (P = 0.001) in the neoadjuvant chemotherapy group. CONCLUSION: Patients in the neoadjuvant chemotherapy arm experienced more chemo-induced neuropathy that was persistent and did not improve with the treatment. RELEVANCE FOR PATIENTS: Peripheral neuropathy is a common adverse effect of platinum and taxane chemotherapeutic drugs that persists throughout cancer treatment and in survivorship. This research provides evidence that chemotherapy-associated neuropathy affects Qol of patients and it will be helpful to improve pain and palliative care management policies.

Assessment of quality of life among advanced ovarian cancer patients in a tertiary care hospital in India.

PURPOSE: The study aims to record the quality of life (Qol) and its changes while ovarian cancer (OC) patients undergo debulking surgeries and chemotherapy in a tertiary care hospital of Eastern India. METHODS: Patients with advanced epithelial OC (FIGO stages III-IV) were recruited. They underwent primary/interval debulking surgeries with classical chemotherapy (adjuvant/neoadjuvant) of intravenous tri-weekly doses of paclitaxel + carboplatin. QoL was assessed using Fact- O + FACIT-Sp-12 questionnaire with a set of 51 questions in different domains (spiritual, physical, social, emotional, and functional factors) and a special set for OC patients under the heading "Additional concerns." The responses from patients were recorded at baseline (diagnosis/study entry), 2, 4, and 6 months during the treatment visits. Overall survival (OS) was assessed using Kaplan Meier curve. RESULTS: A majority of patients were 49.15±10.8 years of age, school-educated (54%), unemployed/homemakers (73.5%), belonging from rural setup (64.6%) with a monthly income of Rs. 2000/- to Rs. 5000/-. There was no statistically significant (p>0.05) improvement found in Qol from the baseline till the end of the study, neither overall nor in subsets (responders (Rs)/partial responders (PRs)/non-responder (NRs) groups or the adjuvant and neoadjuvant chemotherapy groups). The common toxicities like anemia, constipation, and weight loss were significantly (p<0.05) correlated with the patients' physical, functional, emotional, and social well-being. CONCLUSION: Ovarian cancer patients represent a poor functional, social, and disease-specific quality of life that needs to be addressed, identified, and improved by the growing nexus of healthcare providers and researchers.

Mitotic checkpoint defects: en route to cancer and drug resistance.

Loss of mitosis regulation is a common feature of malignant cells that leads to aberrant cell division with inaccurate chromosome segregation. The mitotic checkpoint is responsible for faithful transmission of genetic material to the progeny. Defects in this checkpoint, such as mutations and changes in gene expression, lead to abnormal chromosome content or aneuploidy that may facilitate cancer development. Furthermore, a defective checkpoint response is indicated in the development of drug resistance to microtubule poisons that are used in treatment of various blood and solid cancers for several decades. Mitotic slippage and senescence are important cell fates that occur even with an active mitotic checkpoint and are held responsible for the resistance. However, contradictory findings in both the scenarios of carcinogenesis and drug resistance have aroused questions on whether mitotic checkpoint defects are truly responsible for these dismal outcomes. Here, we discuss the possible contribution of the faulty checkpoint signaling in cancer development and drug resistance, followed by the latest research on this pathway for better outcomes in cancer treatment.

Andrographolide engineered gold nanoparticle to overcome drug resistant visceral leishmaniasis.

Visceral leishmaniasis (VL) is World Health Organization designated most serious leishmaniasis with an annual mortality rate of 50,000. Even after country specific eradication programs, the disease continues to multiply with added complexities like resistance development, drug hypersensitivity and associated infections. Newer therapeutic interventions are urgently warranted to control the spread. Present study aims to arrive at terpenoid andrographolide engineered gold nanoparticle (AGAunps) facile synthesis and its efficacy evaluations against wild and drug resistant VL strains for the first time. Molecular bio-organic conjugation of AGAunp was confirmed in FT-IR and EDAX studies. Nano-gold plasmon response was recorded at 543 nm and the average size in TEM was 14 nm. SAED pattern and XRD observations proved fcc crystalline structure of nano-gold. AGAunp recorded spherical geometry in AFM and TEM. PDI value of 0.137 revealed the monodisperse nature of the nano-scale population. AGAunp exhibited strong antileishmanicidal effect both against wild type (IC50 19 ± 1.7 µM) and sodium stibogluconate (IC50 55 ± 7.3 µM)/paromomycin (IC50 41 ± 6 µM) resistant strains. Complete macrophage uptake AGAunp's occured within two hours exposure. AGAunp macrophage cytotoxicity was significantly lower as compared to Amphotericin-B. Low toxic Andrographolide engineered gold nanoparticle emerged as promising alternatives in the control of wild and drug resistant VL.

Inhibitory effect of a new orally active cedrol-loaded nanostructured lipid carrier on compound 48/80-induced mast cell degranulation and anaphylactic shock in mice.

BACKGROUND: Type I hypersensitivity is an allergic reaction characterized by the overactivity of the immune system provoked by normally harmless substances. Glucocorticoids, anti-histamines, or mast cell stabilizers are the choices of treatment for type I hypersensitivity. Even though these drugs have the anti-allergic effect, they can have several side effects in prolong use. Cedrol is the main bioactive compound of Cedrus atlantica with anti-tumor, anti-oxidative, and platelet-activating factor inhibiting properties. METHODS: In this study, the preparation and anti-anaphylactic effect of cedrol-loaded nanostructured lipid carriers (NLCs) were evaluated. NLCs were prepared using Compritol® 888 ATO and triolein as lipid phase and vitamin E d-α-tocopherylpolyethyleneglycol 1000 succinate, soya lecithin, and sodium deoxycholate as nanoparticle stabilizers. RESULTS: The average diameter of cedrol-NLCs (CR-NLCs) was 71.2 nm (NLC-C1) and 91.93 nm (NLC-C2). The particle had negative zeta potential values of -31.9 mV (NLC-C1) and -44.5 mV (NLC-C2). Type I anaphylactoid reaction in the animal model is significantly reduced by cedrol and cedrol-NLC. This in vivo activity of cedrol resulted that cedrol suppressed compound 48/80-induced peritoneal mast cell degranulation and histamine release from mast cells. Furthermore, compound 48/80-evoked Ca2+ uptake into mast cells was reduced in a dose-dependent manner by cedrol and cedrol-NLC. Studies confirmed that the inhibition of type I anaphylactoid response in vivo in mice and compound 48/80-induced mast cell activation in vitro are greatly enhanced by the loading of cedrol into the NLCs. The safety of cedrol and CR-NLC was evaluated as selectivity index (SI) with prednisolone and cromolyn sodium as positive control. SI of CR-NLC-C2 was found to be 11.5-fold greater than both prednisolone and cromolyn sodium. CONCLUSION: Administration of CR-NLC 24 hours before the onset of anaphylaxis can prevent an anaphylactoid reaction. NLCs could be a promising vehicle for the oral delivery of cedrol to protect anaphylactic reactions.

Oral delivery of ursolic acid-loaded nanostructured lipid carrier coated with chitosan oligosaccharides: Development, characterization, in vitro and in vivo assessment for the therapy of leishmaniasis.

Visceral leishmaniasis (VL) is a life-threatening disease caused by Leishmania donovani due to uncontrolled parasitisation of liver, spleen, and bone marrow. Ursolic acid (UA), a promising anti-inflammatory, anti-bacterial and anti-diabetic drug used successfully for treatment of ailments. Development of new delivery system is extremely urgent for UA with better efficacy and fewer side effects. The aim of present research work was to formulate and evaluate the potential anti-leishmanial activity of UA loaded N-octyl-chitosan surface decorated nanostructured lipid carrier system (UA-NLC) for delivery to the macrophages for VL. UA-NLC were prepared and characterized for shape, size, fourier transforms scanning electron microscopy (FESEM), transmittance electron microscopy (TEM), entrapment efficiency and in vitro drug release. The results indicate that the formulated UA-NLC had nano size range (103.7±2.8nm to 143.0±3.8nm) with high drug loading capacity (12.05±0.54%) and entrapment efficiency (88.63±2.7%). Ex vivo drug uptake by macrophage was also evaluated. The UA-NLC was more effective against AG83 wild type (12 fold), SSG-R (4 fold), PMM-R (4 fold) and GE1 field isolated (3 fold) cellular amastigotes than its free form. In vivo study showed orally effective UA-NLC could suppress the parasite burden to 98.75%.

Oleanolic acid loaded poly lactic co- glycolic acid- vitamin E TPGS nanoparticles for the treatment of Leishmania donovani infected visceral leishmaniasis.

Oleanolic acid (OA) has low aqueous solubility and low permeability, which results poor bioavailability. To surmount the inadequacy, our aim was to fabricate oleanolic acid loaded poly lactic co- glycolic acid (PLGA)- d-α- tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles, which could be efficacious for the treatment of Leishmania donovani mediated visceral leishmaniasis (VL). OA loaded PLGA- TPGS nanoparticles were prepared by emulsion solvent evaporation technique. Cellular uptake was investigated. In vitro cumulative drug release study was carried out. In vitro susceptibility was confirmed against the amastigotes of Leishmania donovani AG83 wild and drug resistant strains. In vivo antileishmanial activity was evaluated against wild type amastigotes of L. donovani. OA loaded nanoparticles were successfully formulated. The highest drug loading was found to be 11.08%±0.35%. 85.66%±0.56% was the highest in vitro OA release for 30days among the formulations. In vivo study revealed that, 98.82±1.92% amastigote burden in spleen of BALB/c mice were suppressed by the polymeric nanoformulation of OA. Experimental OA nanoparticle formulation proved itself as an attractive carrier for OA which was significantly efficacious against both in vitro and in vivo amastigote form of Leishmania donovani than pure OA for chemotherapeutic intervention of visceral leishmaniasis.

Generation of adenosine tri-phosphate in Leishmania donovani amastigote forms.

Leishmania, the causative agent of various forms of leishmaniasis, is the significant cause of morbidity and mortality. Regarding energy metabolism, which is an essential factor for the survival, parasites adapt to the environment under low oxygen tension in the host using metabolic systems which are very different from that of the host mammals. We carried out the study of susceptibilities to different inhibitors of mitochondrial electron transport chain and studies on substrate level phosphorylation in wild-type L. donovani. The amastigote forms of L. donovani are independent on oxidative phosphorylation for ATP production. Indeed, its cell growth was not inhibited by excess oligomycin and dicyclohexylcarbodiimide, which are the most specific inhibitors of the mitochondrial Fo/F1-ATP synthase. In contrast, mitochondrial complex I inhibitor rotenone and complex III inhibitor antimycin A inhibited amastigote cell growth, suggesting the role of complex I and complex III in cell survival. Complex II appeared to have no role in cell survival. To further investigate the site of ATP production, we studied the substrate level phosphorylation, which was involved in the synthesis of ATP. Succinate-pyruvate couple showed the highest substrate level phosphorylation in amastigotes whereas NADH-fumarate and NADH-pyruvate couples failed to produce ATP. In contrast, NADPH-fumarate showed the highest rate of ATP formation in promastigotes. Therefore, we can conclude that substrate level phosphorylation is essential for the survival of amastigote forms of Leishmania donovani.

One pot synthesis of gold nanoparticles and application in chemotherapy of wild and resistant type visceral leishmaniasis.

Gold nanoparticles (Aunp) through biogenetic processes have induced enormous interest for lower toxicity and precise applications. A rapid, one pot synthesis for uniformly sized gold nanoparticles was developed using polyphenolic compound quercetin. Reduction process was followed at low temperatures in a simple bath type sonicator. Nanoparticle plasmon response was recorded at 540 nm and the average size in TEM was observed at 15.07 nm. Detailed X-ray diffraction (XRD) observations proved fcc crystalline structure of metallic gold and the Fourier transform infrared (FTIR) analysis has confirmed nanoparticles conjugation with quercetin. Leishmaniasis, is a neglected tropical disease (NTD) classified by the World Health Organization (WHO). The leishmanial parasite multiply in host macrophages and most strains have developed drug resistance to available chemotherapeutics. Drug delivery is therefore a major problem in macrophage specific leishmanial parasite infections. New quercetin conjugated gold nanoparticles (QAunp) were successfully evaluated for the first time against leishmanial macrophage infections. Antileishmanial efficiency of QAunp was established against wild type (IC50 15±3), sodium stibogluconate resistant strain (IC50 40±8) and the paramomycin resistant (IC50 30±6) strains. Macrophage uptake of QAunp was complete within an hour as observed in TEM experiments.

Immuno-modulation effect of sulphated polysaccharide (porphyran) from Porphyra vietnamensis.

Our investigation explores the immuno-efficiency of sulphated polysaccharides enriched Porphyra vietnamenis. Isolated polysaccharide fraction (17.1-25.8%) was characterized by FTIR and NMR spectroscopy which showed the presence of typical linear backbone structure called as porphyran. Oral administration of porphyran (200-500 mg/kg) evoked a significant (P ≤ 0.05) increase in weight of the thymus, spleen and lymphoid organ cellularity. The total leucocyte and lymphocyte count was increased significantly (P<0.005). The increase in the percent neutrophil adhesion to nylon fibres as well as a dose-dependent increase in antibody titre values was observed. A decreased response to DTH reaction induced by SRBC was recorded. A potential phagocytic response was seen and significant changes were observed in the formation of formazone crystals. It also prevented myelosuppression in cyclophosphamide drug treated rats. The results indicated that P. vietnamenis possesses potential immunomodulatory activity and has therapeutic potential for the prevention of autoimmune diseases.

Submicron-size biodegradable polymer-based didanosine particles for treating HIV at early stage: an in vitro study.

Human immunodeficiency viruses (HIV) hide themselves in macrophages at the early stage of infection. Delivering drug in a sustained manner from polymeric nanoparticles in those cells could control the disease effectively. The study was intended to develop poly(d,l-lactic-co-glycolic acid)-based nanoparticles containing didanosine and to observe their uptake by macrophages in vitro. Various physicochemical evaluations related to nanoparticles, such as drug-excipient interaction, surface morphology, particle size, zeta potential, polydispersity index, drug loading, in vitro drug release and nanoparticle-uptake by macrophages in vitro were determined. Homogenising speeds and drug-polymer ratio varied drug loading and polydispersity index of nanoparticles, providing sustained drug release. Dimethyl sulphoxide/polyethylene glycol improved drug loading predominantly. Nanoparticle-uptake by macrophages was concentration dependent. Experimental nanoparticles successfully transported didanosine to macrophages in vitro, suggesting reduction of dose, thus minimising toxicity and side effects. Developed nanoparticle may control HIV infection effectively at an early stage.

Involvement of thermoplasmaquinone-7 in transplasma membrane electron transport of Entamoeba histolytica trophozoites: a key molecule for future rational chemotherapeutic drug designing.

The quinone composition of the transplasma membrane electron transport chain of parasitic protozoa Entamoeba histolytica was investigated. Purification of quinone from the plasma membrane of E. histolytica and its subsequent structural elucidation revealed the structure of the quinone as a methylmenaquinone-7 (thermoplasmaquinone-7), a napthoquinone. Membrane bound thermoplasmaquinone-7 can be destroyed by UV irradiation with a concomitant loss of plasma membrane electron transport activity. The abilities of different quinones to restore transplasma membrane electron transport activity in UV irradiated trophozoites were compared. The lost activity was recovered completely by the addition of thermoplasmaquinone-7, but ubiquinones are unable to restore the same. These findings clearly indicate that thermoplasmaquinone-7 acts as a lipid shuttle in the plasma membrane of the parasite to mediate electron transfer between cytosolic reductant and non permeable electron acceptors. This thermoplasmaquinone-7 differs from that of the mammalian host and can provide a novel target for future rational chemotherapeutic drug designing.