Clofarabine: a next-generation deoxyadenosine analogue

Acute lymphoblastic leukaemia (ALL) is the most common of the paediatric leukaemias. It is estimated that the use of modern combination chemotherapy results in long-term remission in nearly 80% of children diagnosed with ALL. Despite therapy advances, approximately 20% of children with ALL, experience leukaemia relapse. Clofarabine (2-chloro-2’-fluoro-2’-deoxy-9-β-D-arabinofuranosyladenine) is a second-generation nucleoside analogue and is structurally related to fludarabine and cladribine which are widely used in the treatment of lymphoproliferative disorders. Clofarabine exhibits greater affinity to deoxycytidine kinase (dCyd kinase) and prolonged retention in leukaemic blasts compared to fludarabine and cladribine. Clofarabine inhibits both DNA polymerases and ribonucleotide reductase (RNR). This results in impaired DNA synthesis through inhibition of DNA elongation as well as depletion of deoxyribonucleotides. Accumulation of clofarabine triphosphate, in the blasts of patients with refractory leukemia has been demonstrated. Prolonged intracellular half-life of 24 hours for clofarabine triphosphate. Clofarabine is indicated for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens

Advances in therapy of breast cancer: overexpression and therapeutic implications of targeting human epidermal growth factor receptors

The human epidermal growth factor receptor 2 (HER2) ERbb2 gene is amplified in approximately 25% of breast cancers. Characteristics of HER2-amplified tumors include increased proliferation rates and a propensity for distant metastasis. The discovery of overexpression of HER2 in a subset of breast cancers was an important milestone in our understanding of the biology of the disease. This paved the way for the discovery of trastuzumab, a humanized monoclonal antibody targeting HER2. Trastuzumab is the foundation of treatment of HER2- positive breast cancers, demonstrating dramatic responses in patients with metastatic disease. Recent advances in our understanding of the interaction between HER2 and other members of the epidermal growth factor receptor family have led to the identification of newer agents, resulting in the expansion of the clinical armamentarium of available agents for the treatment of HER2-positive tumors. The biology of the ERbb receptor family, the use of HER2-targeted agents in breast cancer, and the advances in anti-HER2 agents that are currently in clinical development are reviewed here

Hydrocarbon reduction of manganese ores

A thesis submitted to the Faculty of Engineering and the Built Environment, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy. Johannesburg, March, 2018Reduction behavior of South African Mamatwan manganese ore using methane-argon- hydrogen gas mixture was investigated experimentally in the temperature range of 1050ºC to 1250ºC. The effect of changing gas mixture composition, time and temperature was studied using a vertical tube furnace. After each test, three representative samples were prepared; one was analyzed by chemical analysis to obtain metallization results as a function of each reducing condition for each time interval over the total reduction period of two hours. Second sample was analyzed by X-ray diffraction to determine the progress of phase changes; the third sample was mounted, polished and submitted for SEM-EDAX in order to examine the morphology of the ore and its changes in the course of reduction. It was seen that CH4 was an effective reductant as it cracked, supplying the reaction site with hydrogen gas and very fine solid carbon. The excess carbon from cracking of methane ensures regeneration of reductants CO and H2 from reaction product gases of CO2 and H2O ensuring low partial pressure of oxygen at the reaction site. Hydrogen gas may also be involved in the reduction of iron oxide components of the ore. Moreover, depending upon temperature and CH4/H2 ratio in the gas phase the activity of carbon in the system reaches values much higher than unity, shifting the reduction reaction by carbon to lower temperatures. It was observed that bulk of the metallization occurred in the first thirty to forty minutes and the metallization reached some kind of a reduction maximum at 73% metallization. The Mn/Fe ratios in the resulting alloy were higher than those in ordinary carbothermic solid-state reduction, indicating the simultaneous reduction of Fe and Mn at these low reducing temperatures due to a low oxygen potential set up by the methane bearing gas mixtures. It was seen that metallization of Mamatwan ore proceed in two stages. First, reduction of the higher oxides to MnO and metallic iron. Second, reduction of any remaining oxides and MnO to mixed carbide of iron and manganese. During first stage values of effective CO-CO2 diffusivities generated by the model were found to lie in the range from 1.45 *10-6 cm2sec-1 to 8.43*10-6 cm2sec-1 at 1100ºC. Apparent activation energy for first stage calculated in the temperature range of 1050ºC to 1250ºC varied from 1.47 kJ/mol to 24.72 kJ/mol indicating possibility of diffusional control. For the second stage the experimental curves could be duplicated with the mathematical model reasonably well with a maximum difference between the experimental and predicted values being about 5 percent. Rate of metallization values during the second stage (Ms) changed between 1.83*10-8 mol.sec-1.cm-2 and 8.55*10-8 mol.sec-1.cm-2. Specific rate constant values (ks) for the second stage, varied from 5.53*10-6 cm/sec to 3.16*10-5 cm/sec which are much smaller than specific rate constant for the first stage of reduction (kf), which varied from 1.64*10-4 cm/sec to 1.15*10-4 cm/sec, as the rate of second stage of the reduction is much slower than the rate of the first stage. X ray analysis revealed that manganese ore was reduced primarily to carbide Mn7C3 at lower temperature range of the experiments, but at 1200ºC the dominant reaction product was Mn5C2 in both mixtures of methane-argon and methane-hydrogen. The S.E.M images revealed that the product metallic phase occurred all throughout the surface, with globular formation in case of reduction where hydrogen was the carrier gas.MT 201

Carbetocin: a therapy advance for prevention of postpartum haemorrhage

Postpartum haemorrhage (PPH) is the major cause of maternal death. To prevent PPH, the routine administration of a uterus-contracting (‘uterotonic’) agent is a standard practice across the world. Oxytocin is the standard uterotonic agent recommended for this purpose, and is recommended for all women giving birth. Oxytocin is problematic as it requires cold storage and transport, and in low-resource settings, the cold chain is not commonly available. Heat-stable carbetocin is a promising alternative to oxytocin. Because of its heat stability, it can overcome the persistent problems with oxytocin quality as it does not require cold chain for storage and transport. Considering the totality of the evidence, it appears to have some additional desirable effects compared with oxytocin and a very favourable side effect profile similar to oxytocin. With a standardized dosing of single injection recommendation, it can address the variations in dosing regimen as is with oxytocin. Carbetocin has been added to the World Health Organization (WHO) essential medicines list of uterotonics for the prevention of excessive bleeding after childbirth, we might see a new standard of care in coming months for prevention of uterine atony

Acotiamide: a novel drug for the treatment of patients with functional dyspepsia

Functional dyspepsia (FD) is a highly prevalent condition with major socioeconomic and healthcare impact. Previously, no pharmacotherapeutic agent had approved for the treatment of this condition. Acotiamide, a new first-in-class oral prokinetic drug, is an upper gastrointestinal motility modulator for the treatment of abdominal symptoms resulting from hypomotility and delayed gastric emptying in patients with functional dyspepsia. It exerts its activity in the stomach via muscarinic receptor inhibition, resulting in enhanced acetylcholine release and inhibition of acetylcholinesterase activity. Unlike other prokinetic drugs that are utilized in the management of functional dyspepsia, acotiamide shows little/no affinity for serotonin or dopamine D2 receptors. Acotiamide is the world’s first approved treatment for functional dyspepsia diagnosed by Rome III criteria, with its first approval occurring in Japan. A favourable clinical course with acotiamide 100mg t.i.d was demonstrated with high symptom elimination rate for patients of FD

Successful delivery in a case of sickle cell disease with bilateral avascular necrosis: a case report

Sickle cell disease is an inherited hemoglobinopathy. The patients with sickle cell disease had a small life years, before the advancement of medical science and development of newer drugs. These have improved the life expectancy among the sickle cell disease patients. Females are reaching reproductive age and are expectant of becoming mothers. But pregnancy in a sickle cell disease carries major fetal and maternal complications. Managing the pregnancy from conception to delivery is a difficult task and needs a team effort. Here we presented a case report of a female who got pregnant without any planning and was already on hydroxyurea. On top of that she was not willing to get her pregnancy terminated

The reducibilty of chromite ore and reactivity of carbonaceous reductants.

The purpose of this dissertation is to study the reducibility of chromite ore and reactivity of carbonaceous reductants. The effect of temperature, particle size, composition, reducing agent and reducing atmosphere on the kinetics of the reduction of given chromite (obtained from Xstrata) was studied.using tga,and to test reactivity of the reductant, present experimental data was applied to Arrhenius model. The ore is reduced by reductants namely coke, coal, charcoal and graphite at temperatures between 1000 ºC and 1300 ºC under argon atmosphere. Particle size range of as received, (+50μm-100μm), (+100μm-150 μm), (+150μm–200 μm) were used. For each experiment a calculated mixture of chromite and reductant was mixed with acetone and the mixture was reduced using a TGA furnace.The results indicated that the reduction rate was a function of temperature and particle size.The reduction at 1000 ºC under argon atmosphere is minimal.As temperature is increased to 1100 ºC, 1200 ºC and 1300 ºC it was observed that reduction rate of this chromite increased and sample having finer particle size fraction showed higher reduction rate at all temperature. The effect of the type of reducing agent namely coal, coke, charcoal and graphite was variable.At lower temperatures: 1000ºC and 1100ºC coke, coal, charcoal and graphite was order of reduction from highest reduction to lowest whereas at higher temperatures: 1200 ºC and 1300ºC order was coal, coke, charcoal and graphite.The phases formed at the end of each reduction stage were studied using SEM and optical microscope which helped to confirm the experimental data. To test reactivity of the reductant, present experimental data was applied to various models.A model which was found to be suitable was the Arrhenius model.The value of the activation energies obtained from fitting the data into the Arrhenius equation was used to determine the relative reactivity of the reductants, the values of the chemical reaction rate constants and effective diffusion constants were used to determine the relative speed at which the reductants can reduce the chromite ore. The TGA test suggest that coke has the highest reactivity since its activation energies are lowest and require less energy to induce the reductants reaction The tests also suggest that the rate controlling mechanism is diffusion of species to the reactive site since the effective diffusion coefficients were of the order 10-11, which were far less then the chemical rate constant of the order 10-6 to 10-5.Test also suggest that coal is fastest to react since its De values are hig

Oxytocin and Its Congeners in Obstetrics Practice: An Update on Carbetocin

There are no standardised recommendations for the use of oxytocin in obstetric indications. To prevent postpartum haemorrhage (PPH), the routine administration of oxytocin is standard practice. Failure of prophylactic therapy with oxytocin occurs commonly, necessitating the use of further oxytocin or other treatments to maintain haemodynamic stability. Oxytocin has its limitations as it requires cold storage and transport, and in low-resource settings, the cold chain is not commonly available. By modifying the oxytocin molecule, its half-life has been prolonged and its enzymatic degradation reduced. The modified molecule is named carbetocin. Heat-stable carbetocin is a promising alternative to oxytocin, which can overcome the persistent problems with oxytocin quality as it does not require a cold chain for storage and transport

PHYTOCHEMICAL EVALUATION OF MONOCOT GRASS KYLLINGA TRICEPS ROTTB.

Kyllinga triceps rottb. A monocot perennial herb found in various parts of India is traditionally used in vitiated conditions pitta and vata, hyperdipsia, fever, liver disorders, verminosis, cough, splenopathy, diabetes and dermatitis. The aim of the present study was to evaluate the phytochemical and pharmacognostical study of ignored ayurvedic medicinal herb kyllinga triceps rottb. The plant is monocot grass belongs to the family cyperaceae, commonly used in various ayurvedic preparation’s and called musta. In various ayurvedic texts it is also known as nirvishi. Many species of family cyperaceae resembles the original drug thus the present study will help in identification and collection of original plant. The study includes identification and characterization of chemical component and preliminary phytochemical screening of the plant extract. The generated information of the present study will provide data which are helpful in the correct identification and authentication of medicinal plant kyllinga triceps rottb. and may help in prevention of its adulteration. Keywords: Kyllinga triceps rottb., phytochemical, cyperaceae, adulteration, ayurevedic

Validation of a noninvasive aMMP-8 point-of-care diagnostic methodology in COVID-19 patients with periodontal disease

Objectives: The aim of this study was to validate an active matrix metalloproteinase (MMP-8) point-of-care diagnostic tool in COVID-19 patients with periodontal disease. Subjects, Materials, and Methods: Seventy-two COVID-19-positive and 30 COVID-19-negative subjects were enrolled in the study. Demographic data were recorded, periodontal examination carried out, and chairside tests run for evaluating the expression of active MMP-8 (aMMP-8) in the site with maximum periodontal breakdown via gingival crevicular fluid sampling as well as via a mouth rinse-based kit for general disease activity. In COVID-19-positive patients, the kits were run again once the patients turned COVID-19 negative. Results: The overall (n = 102) sensitivity/specificity of the mouthrinse-based kits to detect periodontal disease was 79.41%136.76% and that of site-specific kits was 64.71%/55.88% while adjusting for age, gender, and smoking status increased the sensitivity and specificity (82.35%/76.47% and 73.53%/88.24, respectively). Receiver operating characteristic (ROC) analysis for the adjusted model revealed very good area under the ROC curve 0.746-0.869 (p < .001) and 0.740-0.872 (p < .001) (the aMMP-8 mouth rinse and site-specific kits, respectively). No statistically significant difference was observed in the distribution of results of aMMP-8 mouth rinse test (p = .302) and aMMP-8 site-specific test (p = .189) once the subjects recovered from COVID-19. Conclusions: The findings of the present study support the aMMP-8 point-of-care testing (PoCT) kits as screening tools for periodontitis in COVID-19 patients. The overall screening accuracy can be further increased by utilizing adjunctively risk factors of periodontitis. The reported noninvasive, user-friendly, and objective PoCT diagnostic methodology may provide a way of stratifying risk groups, deciding upon referrals, and in the institution of diligent oral hygiene regimens.Peer reviewe