Understanding the mechanisms for metabolism-linked hemolytic toxicity of primaquine against glucose 6-phosphate dehydrogenase deficient human erythrocytes: evaluation of eryptotic pathway

Therapeutic utility of primaquine, an 8-aminoquinoline antimalarial drug, has been limited due to its hemolytic toxicity in population with glucose 6-phosphate dehydrogenase deficiency. Recent investigations at our lab have shown that the metabolites generated through cytochrome P(450)-dependent metabolic reactions are responsible for hemotoxic effects of primaquine, which could be monitored with accumulation of methemoglobin and increased oxidative stress. The molecular markers for succeeding cascade of events associated with early clearance of the erythrocytes from the circulation were evaluated for understanding the mechanism for hemolytic toxicity of primaquine. Primaquine alone though did not induce noticeable methemoglobin accumulation, but produced significant oxidative stress, which was higher in G6PD-deficient than in normal erythrocytes. Primaquine, presumably through redox active hemotoxic metabolites generated in situ in human liver microsomal metabolism-linked assay, induced a dose-dependent methemoglobin accumulation and oxidative stress, which were almost similar in normal and G6PD-deficient erythrocytes. Primaquine alone or in presence of pooled human liver microsomes neither produced significant effect on intraerythrocytic calcium levels nor affected the phosphatidyl serine asymmetry of the normal and G6PD-deficient human erythrocytes as monitored flowcytometrically with Annexin V binding assay. The studies suggest that eryptosis mechanisms are not involved in accelerated removal of erythrocytes due to hemolytic toxicity of primaquine.     

Glutathione S transferase activity in Indian vectors of malaria: A defense mechanism against DDT

Glutathione S transferases (GSTs) are multifunctional enzymes involved in detoxification of xenobiotic compounds in majority of the insect groups. Significance of insect GSTs is their elevated level of activity in association with insecticide resistance. This investigation was to explore the metabolic status of GSTs in two Indian DDT-resistant malaria vectors, Anopheles culicifacies and Anopheles annularis, and one DDT-susceptible vector, Anopheles fluviatilis. Malkangiri and Koraput districts of Orissa State, endemic for falciparum malaria and having a long insecticide spraying history, were the study areas. F1 progeny was raised from wild-caught females of the three vectors and used for biochemical assays to detect the GST-mediated DDT resistance mechanism. Results of the enzyme assay showed a significant 3-fold increase in GST activity in DDT-resistant An. annularis compared with its susceptible population. In DDT-resistant An. culicifacies, the median GST activity (71.8 micromol/min/mg) was almost the same as estimated in the DDT-resistant An. annularis (74.6 micromol/ min/mg), suggesting that the GST activity estimated in An. culicifacies could be an elevated level for detoxification of DDT. Furthermore, the GST activity in DDT-resistant An. culicifacies and An. annularis was significantly higher than that in the DDT-susceptible An. fluviatilis, which had a GST activity of 20.0 micromol/min/mg. Also, the GST-mediated DDT detoxification was confirmed by comparing GST activity in wild-caught females with that in their F1 progeny.     

Idiopathic sclerosing encapsulating peritonitis — Is a preoperative diagnosis possible? Report of three cases

Sclerosing encapsulating peritonitis (SEP) is a rare cause of intestinal obstruction that is usually diagnosed during a laparotomy; however, a preoperative diagnosis is possible. Sclerosing encapsulating peritonitis can be classified as primary or idiopathic and secondary types and only about 70 cases of idiopathic type have been reported since it was first described. It is characterized by a total or partial encasement of the small bowel by a thick fibrotic membrane. This report presents a series of three cases in which a diagnosis of idiopathic SEP was made preoperatively based on the clinical features and radiological findings, which were confirmed by a laparotomy and histopathology. All of the cases were successfully managed by the excision of the membrane. This report demonstrates that based on the clinical features and radiological investigations, in the absence of other plausible etiologies for intestinal obstruction, it is possible to suspect a preoperative diagnosis of SEP, thereby preventing a “surprise“ finding during a laparotomy and allowing for better management.     

Secondary chondrosarcoma in an enchondroma in a proximal phalanx of toe. A diagnostic problem. A case report

The authors present a case of secondary chondrosarcomatous transformation in enchondroma in toe. The authors have discussed the available literature to throw light on differentiation of benign and malignant form.     

Diclofenac-induced biochemical and histopathological changes in white leghorn birds (Gallus domesticus)

Objective:

Objective: To evaluate diclofenac-induced biochemical and histopathological changes in White Leghorn birds.

Materials and Methods:

Six-week-old birds were equally divided into three groups of six birds each. Group I served as control and received vehicle orally. The birds of Group II and III were orally administered with a single low (2 mg/kg) and high dose (20 mg/kg) of diclofenac sodium, respectively, and were observed for 7 days. The acute toxicity was assessed by observing the clinical signs and symptoms, mortality, alterations in blood biochemistry, and necropsy findings.

Results:

The birds of Group II showed only mild symptoms of diarrhea. In Group III, 50% of birds died in between 24 and 36 h post-treatment showing the symptoms of segregatory behavior, lethargy, terminal anorexia, and severe bloody diarrhea. The birds of Group II and the surviving birds of Group III showed a significantly (P<0.05) increased plasma uric acid, creatinine and plasma glutamic pyruvic transaminase (PGPT), and decreased total protein and albumin at 12 and 24 h post-treatment which returned to the normal levels at 36 h post-treatment. The dead birds of the high-dose group also showed similar pattern of biochemical changes at 12 and 24 h post-treatment and revealed extensive visceral gout with characteristic histopathological lesions in liver, kidney, heart, spleen, and intestine on post-mortem.

Conclusion:

The results indicate that diclofenac sodium has hepatotoxic, nephrotoxic, and visceral gout inducing potentials in White Leghorn birds, especially at higher dose.     

Two novel AIRE mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) among Indians

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive disorder resulting from mutations in the autoimmune regulator ( AIRE ) gene. There is no information on AIRE mutations in Indians. In a cross-sectional study, nine patients (eight families), from four referral hospitals in India, were studied for AIRE mutations by direct sequencing. We screened for new mutations in 150 controls by allele-specific PCR. The patients had 1–7 known components of APECED. Three patients had unusual manifestations: presentation with type 1 diabetes; chronic sinusitis and otitis media; and facial dysmorphism. All patients carried homozygous, probably recessive, AIRE mutations. Two unrelated patients from a small in-bred community (Vanika Vaisya) in south India carried an unreported missense mutation, p.V80G, in the N-terminal caspase recruitment domain. Another unique mutation, p.C302X, resulting in a truncated protein with deletion of both zinc-finger domains, was detected in a patient from Gujarat. Neither mutation was detected in controls. Other mutations, previously described in Caucasians, were: 13 base pair deletion (p.C322fsX372) in 4 (38%), and Finn-major (p.R257X) and p.R139X (Sardinian) mutation in one subject each. In conclusion, in this first series of APECED in Indians, we detected AIRE mutations previously reported in Caucasians, as well as unique mutations. Of these, p.V80G is possibly an ancestral mutation in an in-bred community.     

The emerging role of P-glycoprotein inhibitors in drug delivery: a patent review

INTRODUCTION: The ATP-binding cassette superfamily contains membrane transporter proteins that transport a wide range of diverse compounds across cellular membranes. The P-glycoprotein (P-gp) is an important member of this family and a multi-specific drug efflux transporter that plays a significant role in governing the bioavailability of many clinically active drugs. The inhibition of this efflux transporter by various P-gp inhibitors forms a distinctive approach in improving bioavailability and conquering drug resistance. Most P-gp inhibitors exhibit limitations associated with their safety and unwanted pharmacokinetic interactions, thereby restraining their clinical applicability. AREAS COVERED: This review explores the investigations on the feasibility and applicability of various classes of P-gp inhibitors as described in recent patents for enhanced drug delivery. EXPERT OPINION: Several candidates presently under development look promising as P-gp inhibitors, e.g., tariquidar and elacridar. Pharmaceutical excipients currently constitute the most promising class of P-gp inhibitors and are considered safe and pharmaceutically acceptable for use in formulations. In addition, lipid-based excipients and thiolated polymers play an active role in affecting P-gp-mediated transport not only by altering the membrane fluidity or ATPase activity but by down regulating P-gp expression. An additional overture such as the prodrug derivatization of P-gp substrates is a feasible approach to bypass P-gp-mediated efflux.     

Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma

Eosinophils have been implicated as playing a major role in allergic airway responses. However, the importance of these cells to the development of this disease has remained ambiguous despite many studies, partly because of lack of appropriate model systems. In this study, using transgenic murine models, we more clearly delineate a role for eosinophils in asthma. We report that, in contrast to results obtained on a BALB/c background, eosinophil-deficient C57BL/6 Delta dblGATA mice (eosinophil-null mice via the Delta DblGATA1 mutation) have reduced airway hyperresponsiveness, and cytokine production of interleukin (IL)-4, -5, and -13 in ovalbumin-induced allergic airway inflammation. This was caused by reduced T cell recruitment into the lung, as these mouse lungs had reduced expression of CCL7/MCP-3, CC11/eotaxin-1, and CCL24/eotaxin-2. Transferring eosinophils into these eosinophil-deficient mice and, more importantly, delivery of CCL11/eotaxin-1 into the lung during the development of this disease rescued lung T cell infiltration and airway inflammation when delivered together with allergen. These studies indicate that on the C57BL/6 background, eosinophils are integral to the development of airway allergic responses by modulating chemokine and/or cytokine production in the lung, leading to T cell recruitment.