Improved use of buthionine sulfoximine to prevent cisplatin nephrotoxicity in rats

Summary Male Sprague Dawley rats were treated with buthionine sulfoximine (BSO) and cisplatin in different doses and schedules to optimize the chemoprotective effect of BSO against cisplatin nephrotoxicity. BSO at 4 mmol/kg, administered s.c. 2 h prior to cisplatin, resulted in normal blood urea nitrogen (BUN) levels in rats treated with 3 or 4 mg/kg cisplatin, and modestly, but significantly reduced the toxicity of cisplatin at 5 mg/kg. Administration of BSO (4 mmol/kg) at intervals ranging from 0 to 16 h prior to cisplatin (5 mg/kg) resulted in a significant reduction in BUN values. A BSO dose as low as 0.04 mmol/kg was found to be as effective as 4 mmol/kg against nephrotoxicity associated with cisplatin at 4 mg/kg. Repetitive injections of BSO (1 mmol/kg every 12 h, four times, beginning 2 h prior to cisplatin) significantly inhibited elevations of BUN associated with high-dose cisplatin (6 mg/kg), whereas a single BSO injection of 4 mmol/kg was ineffective. The degree and duration of renal glutathione depletion was related to the dose of BSO. Renal glutathione content following 4 mmol/kg BSO was 38% of control at 2 h and 40% at 24 h; following 0.04 mg/kg, glutathione was 47% at 2 h and almost 100% at 24 h. Simultaneous in vitro administration of BSO did not inactivate cisplatin cytotoxicity as measured by the colony-forming ability of MBT-2 cells in soft agar. These data indicate that repeated injections of BSO, beginning prior to cisplatin administration, would improve the nephroprotective effect without compromising the chemotherapeutic efficacy of cisplatin. It is suggested that the ability of BSO to reduce cisplatin nephrotoxicity may not correlate with the degree of renal glutathione depletion and that the mechanism of action is unlikely to involve direct inactivation of cisplatin.Abbreviations BSO -buthionine sulfoximine - BUN blood urea nitrogen     

Multicentre pharmacokinetic evaluation of rFVIII‐Fc (efmoroctocog alfa) in a real life and comparison with non‐extended half‐life FVIII concentrates

The use of enhanced half‐life (EHL) FVIII has improved the quality of prophylaxis in haemophilia A, but with a benefit that may vary from one patient to another. We analysed the pharmacokinetic data obtained with efmoroctocog alfa (rFVIII‐Fc) in 114 patients and, in 47 cases, compared them to those previously measured with non‐EHL FVIII. The in vivo recovery (IVR) of rFVIII‐Fc measured with one stage clotting assay (OSA) and chromogenic assay (CSA) was 2.2 and 2.8 IU/mL per IU/kg, respectively. The median half‐life (T_1/2) of rFVIII‐Fc was 14.5 hours whatever the FVIII:C assay used, but variable and correlated with preinfusion VWF:Ag levels (r = .76). Both IVR and T_1/2 were lower in patients under 12 years old (2.4 IU/mL per IU/kg and 11.1 hours, respectively; CSA). PK study of rFVIII‐Fc vs non‐EHL FVIII showed a T_1/2 ratio of 1.4 in favour of rFVIII‐Fc, regardless of the patient's age. However the relative increase in T_1/2 with rFVIII‐Fc was lower than 30% in one‐third of patients evaluated, particularly when the previous FVIII administered was a BHK‐derived product. This study therefore suggests that analysis of individual PK profile in response to a specific FVIII concentrate is potentially useful before a switch in haemophilia A patients.     

Stability and Release Kinetics of an Advanced Gliclazide-Cholic Acid Formulation: The Use of Artificial-Cell Microencapsulation in Slow Release Targeted Oral Delivery of Antidiabetics

Introduction

In previous studies carried out in our laboratory, a bile acid (BA) formulation exerted a hypoglycaemic effect in a rat model of type-1 diabetes (T1D). When the antidiabetic drug gliclazide (G) was added to the bile acid, it augmented the hypoglycaemic effect. In a recent study, we designed a new formulation of gliclazide-cholic acid (G-CA), with good structural properties, excipient compatibility and exhibits pseudoplastic-thixotropic characteristics. The aim of this study is to test the slow release and pH-controlled properties of this new formulation. The aim is also to examine the effect of CA on G release kinetics at various pH values and different temperatures.

Method

Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) and G-CA-SA (test) at a constant ratio (1:3:30), respectively. Microcapsules were examined for efficiency, size, release kinetics, stability and swelling studies at pH 1.5, pH 3, pH 7.4 and pH 7.8 and temperatures of 20 and 30 °C.

Results

The new formulation is further optimised by the addition of CA. CA reduced microcapsule swelling of the microcapsules at pH 7.8 and pH 3 at 30 °C and pH 3 at 20 °C, and, even though microcapsule size remains similar after CA addition, percent G release was enhanced at high pH values (pH 7.4 and pH 7.8, p?<?0.01).

Conclusion

The new formulation exhibits colon-targeted delivery and the addition of CA prolonged G release suggesting its suitability for the sustained and targeted delivery of G and CA to the lower intestine.     

Risk Factors for Coronary Artery Disease in Indians

Background

A case control study was carried out to study the emerging risk factors for coronary artery disease in Indians. Methods: The diagnosis of coronary artery disease was based on correlation of clinical, biochemical, electrocardiography, echocardiography, treadmill testing and coronary arteriography findings. The study comprised 100 cases of coronary artery disease (acute coronary syndrome and chronic coronary artery disease) and 100 controls in two tertiary care service hospitals. The subjects were evaluated for total plasma homocysteine, insulin, C-reactive protein (CRP), lipoprotein fibrinogen and anti-chlamydial anti-bodies.

Result

Male to female ratio was 10:1 in study group with similar predominance of males in controls. Mean age of the cases was 47 years (range 25-59 years) and that of controls was 43 years (range 23-56 years). 64% cases had acute coronary syndrome and 34% had chronic coronary artery disease. In the coronary artery disease population, 76% cases had hyperhomocyteinemia, 9% hyperinsulinaemia, 11% abnormal CRP values, 23% abnormal lipoprotein (a) levels, 40% IgG anti-chlamydial anti-bodies and only 11% had Ig M anti-chlamydial antibodies. In the control population, 72% had hyperhomocystinaemia and 6% hyperinsulinaemia while 23% and 9% controls had IgG and IgM anti chlamydial antibodies respectively. In control group 19% cases had abnormal lipoprotein(a) levels and only 2% had abnormal C reactive protein values. Significant correlation of CAD was seen with CRP values and Ig G anti-chlamydial antibodies. Both the study group and controls had higher homocysteine levels than that observed in some Indian and Western studies.

Conclusion

High C reactive protein levels and Ig G anti-chlamydial antibodies are associated with coronary artery disease in Indians. Insulin, lipoprotein A, fibrinogen, lgM anti-chlamydial antibodies and higher levels of total plasma homocysteine have no significant association with coronary artery disease.Key Words: Emerging risk factors, Coronary artery disease     

Fanconi anemia genes act to suppress a cross-linker-inducible p53- independent apoptosis pathway in lymphoblastoid cell lines

Hypersensitivity to cross-linking agents such as mitomycin C (MMC) is characteristic of cells from patients suffering from the inherited bone marrow failure syndrome. Fanconi anemia (FA). Here, we link MMC hypersensitivity of Epstein-Barr virus (EBV)-immortalized FA lymphoblasts to a high susceptibility for apoptosis and p53 activation. In MMC-treated FA cells belonging to complementation group C (FA-C), apoptosis followed cell cycle arrest in the G2 phase. In stably transfected FA-C cells, plasmid-driven expression of the wild-type cytoplasmic FAC protein relieved MMC-dependent G2 arrest and suppressed p53 activation. However, in both FA and non-FA lymphoblasts, p53 seemed not to be instrumental in the induction of MMC-dependent apoptosis, since overexpression of a dominant-negative p53 mutant failed to affect cell survival. In addition, no differences in the level of Bcl-2 expression, an inhibitor of apoptosis, were detected between FA and non- FA cells either in the absence or presence of MMC. Our findings suggest that FAC and the other putative FA gene products may function in a yet to be identified p53-independent apoptosis pathway.     

Progression of joint damage in early active severe rheumatoid arthritis during 18 months of treatment: comparison of low-dose cyclosporin and parenteral gold

OBJECTIVE: This study compared the progression of joint damage in patients with early active severe rheumatoid arthritis (RA) treated with cyclosporin or parenteral gold. METHODS: In this open, randomized, multicentre study with a blinded radiological endpoint, 375 patients who had suffered from active severe RA for <3 yr were randomized to be treated for 18 months with low-dose cyclosporin or parenteral gold. The groups were stratified with regard to corticosteroid use. Primary efficacy variables were numbers of erosions, erosion score and the Larsen-Dale joint damage score. RESULTS: Joint damage progressed at similar rates in both treatment arms. In both groups, patients receiving corticosteroids had less X-ray progression. Rheumatoid factor positivity, high swollen joint count, high erythrocyte sedimentation rate and pre-existing X-ray abnormalities predicted progression of joint damage. Although numbers of serious adverse events were similar, more gold patients (n = 65) than cyclosporin patients (n = 45) withdrew from study medication because of adverse events. CONCLUSION: Cyclosporin was comparable to parenteral gold in retarding progression of joint damage and was better tolerated in terms of adherence to therapy. The open label design should be kept in mind when assessing this difference.      

Redefining vaccination coverage and timeliness measures using electronic immunization registry data in low- and middle-income countries

Vaccine coverage is routinely used as a performance indicator for immunization programs both at local and global levels. For many national immunization programs, there are challenges with accurately estimating vaccination coverage based on available data sources, however an increasing number of low- and middle-income countries (LMICs) have begun implementing electronic immunization registries to replace health facilities’ paper-based tools and aggregate reporting systems. These systems allow for more efficient capture and use of routinely reported individual-level data that can be used to calculate dose-specific and cohort vaccination coverage, replacing the commonly used aggregate routine health information system data. With these individual-level data immunization programs have the opportunity to redefine performance measures to enhance programmatic decision-making at all levels of the health system. In this commentary, we discuss how measures for assessing vaccination status and program performance can be redefined and recalculated using these data when generated at the health facility level and the implications of the use and availability of electronic individual-level data.     

Multiple eccrine hidrocystomas

The clinical and pathological features and treatment of two patients with multiple eccrine hidrocystomas are presented. The first case is characterized by multiple pearly papules with a bluish hue located in the periorbital region and the bridge of the nose. The second case is characterized by multiple, skin-coloured papules located in the periorbital area, forehead, chin and nose. Both were exacerbated by a hot and humid environment. Histopathologically, both demonstrated a unilocular cyst located in the dermis, with a 2-3-layer wall composed of cuboidal epithelium that was non-keratinizing. Treatment with topical atropine sulphate 1% in aqueous solution three times a day was instituted in the first case; however, this was poorly tolerated because of blurred vision and nausea. The lesions were subsequently hyfrecated with a good response. The second case was treated with topical atropine sulphate 1% in aqueous solution three times a day with a good response.