Development and in vitro-in vivo relationship of controlled-release microparticles loaded with tramadol hydrochloride

In conclusion, the controlled-release microparticles of TmH can be developed via phase separation method. The development and optimization of controlled-release microparticles of tramadol hydrochloride (TmH) for the oral delivery and their in vitro and in vivo correlation was prime objective of the present study. Four formulations of controlled-released microparticles were developed and optimized in terms of encapsulation efficiency, dissolution study and release kinetics. Among all formulated microparticles F-3 (ratio of TmH:EC 1:2) and F-4 (ratio of TmH:EC 1:3) presented the better characteristics in reference to entrapment efficiency, release kinetics and dissolution profile compared to other formulations (F-1, F-2). For in vivo analysis a new HPLC analytical method was developed and validated. The optimized formulations were subjected to in vivo studies to calculate various pharmacokinetic parameters, i.e., C(max), t(max), AUC(0-∞) and MRT. The in vitro dissolution and in vivo absorption data was correlated with the help of Wagner-Nelson method. F-3 showed a good in vitro-in vivo correlation with a correlation determination of 0.9957. Moreover, lower T(max), t(1/2) and MRT, and higher values of C(max) and K(e) were observed for F-3. The control formulation (immediate-release) presented lowest values of t(1/2), MRT and T(max) but the highest values of C(max) and K(e). The controlled-release microparticles (F-3 and F-4) could sustain the drug release within therapeutic level up to 24 h and good IVIVC is expected from them.     

Increased transforming growth factor beta 1 expression mediates ozone-induced airway fibrosis in mice

Ozone (O?), a commonly encountered environmental pollutant, has been shown to induce pulmonary fibrosis in different animal models; the underlying mechanism, however, remains elusive. To investigate the molecular mechanism underlying O?-induced pulmonary fibrosis, 6- to 8-week-old C57BL/6 male mice were exposed to a cyclic O? exposure protocol consisting of 2 days of filtered air and 5 days of O? exposure (0.5 ppm, 8 h/day) for 5 and 10 cycles with or without intraperitoneal injection of IN-1233, a specific inhibitor of the type 1 receptor of transforming growth factor beta (TGF-β), the most potent profibrogenic cytokine. The results showed that O? exposure for 5 or 10 cycles increased the TGF-β protein level in the epithelial lining fluid (ELF), associated with an increase in the expression of plasminogen activator inhibitor 1 (PAI-1), a TGF-β-responsive gene that plays a critical role in the development of fibrosis under various pathological conditions. Cyclic O? exposure also increased the deposition of collagens and alpha smooth muscle actin (α-SMA) in airway walls. However, these fibrotic changes were not overt until after 10 cycles of O? exposure. Importantly, blockage of the TGF-β signaling pathway with IN-1233 suppressed O?-induced Smad2/3 phosphorylation, PAI-1 expression, as well as collagens and α-SMA deposition in the lung. Our data demonstrate for the first time that O? exposure increases TGF-β expression and activates TGF-β signaling pathways, which mediates O?-induced lung fibrotic responses in vivo.     

Seroprevalence of Hepatitis B, Hepatitis C, HIV Infections in Blood Donors of Khulna, Bangladesh

To determine changes (Trends) in infection rates of Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV) and Human immunodeficiency virus (HIV) in blood donors of Khulna Population. Specimens of 34953 voluntary blood donors & party or relative donors in Transfusion Medicine Department of Khulna Medical College Hospital from 2007 to 2009 were screened for HBsAg, anti-HCV, anti-HIV 1 & 2 reactivity in a cross-sectional survey by rapid test method. Reactive samples were verified using a recognized confirmatory test which consisted of a second generation enzyme immune assay (HBsAg), anti-HCV antibodies by anti-HCV EIA & for HIV by western Blot, respectively. The seroprevalence of HBsAg, Anti-HCV, HIV antibody 1 & 2 was 1.4%, 0.09% & 0.03% respectively in all blood donors. Prevalence of confirmed positivity was 0.62% for HBsAg, 0.04 % for Anti-HCV, 0.02% for HIV Western Blot. Between 2007 to 2009 a decreasing trend was observed in HBsAg frequency, HCV frequency decreased in 2009 compared to 2007. One HIV positivity found in 2009. Although the frequency of transfusion transmitted infections is low, party or relative donors have some risk factors than voluntary blood donors. Through more scrutiny in donor selection, improved serological test & reevaluation of infections routes in donor, infection reduction can be achieved.     

Comparative study on methotrexate and hydroxychloroquine in the treatment of rheumatoid arthritis

This study was done to see the efficacy and tolerability of methotrexate and hydroxychloroquine in the Treatment of Rheumatoid Arthritis. It was an open label controlled clinical trial, done in Mymensingh Medical college hospital. Fifty six patients were selected by random sampling method, 28 were included in methotrexate group and another 28 for hydroxychloroquine group using inclusion & exclusion criteria. Primary efficacy variables (DAS28, daily naproxen), secondary efficacy variables, and safety measurement variables studied both clinically & laboratory investigations. The data were analyzed by computer with the help of SPSS. The student's t test was used as test of significant. The mean age of the patients at diagnosis was almost identically distributed between methotrexate and hydroxychloroquine group (41.7±12.2 vs. 42.9±9.2 years, p=0.659). Disease activity at baseline was found to be almost homogeneous to each group except CRP which was observed to be significantly higher in methotrexate group than hydroxychloroquine group (p<0.001). Disease activity at 1 month of treatment reduced in the methotrexate group than those in hydroxychloroquine group (p<0.05 in each case). After 3 and 6 months of treatment, disease activity decreased significantly in both groups (p<0.001 and p<0.05 respectively). The average daily dose of NSAID (Naproxen) decreased significantly (p<0.001). Safety variables at 6 month were within normal physiological ranges and did not differ in groups (p>0.05) indicating that both methotrexate and hydroxychloroquine were effective and safe to use in rheumatoid arthritis. The difference in the incidence of adverse effects, total or individual, was almost nil.     

Classical to current approach for treatment of psoriasis: a review

Psoriasis is a genetic predisposition with T-cell mediated autoimmune inflammatory skin disorder, characterized by cutaneous inflammation, increased epidermal proliferation, hyperkeratosis, angiogenesis, and abnormal keratinization that affects up to 2 - 3% of the population worldwide. Common therapies that are used for the treatment of psoriasis include topical, systemic, phototherapy, combination, herbal therapy and novel molecules. Topically used agents include Vit D, calcipotriol, corticosteroids, dithranol and retinoids etc. Systemically used agents include methotrexate and cyclosporine etc. Phototherapy includes UV-B, Psoralen plus ultraviolet therapy and excimer laser etc. These therapies have a number of potential problems, such as limited in efficacy, inconvenience, organ toxicity, carcinogenic and broadband immunosuppression. In natural treatment a variety of natural agents such as methanolic extracts of duzhong (Eucommia ulmoides Oliv.), yerba mate (Ilex paraguariensis,) linseed oil, fish oil, and Indigo naturalis etc., that modulates T cell and cytokine action at various steps along with the pathogenic sequence have been developed. But till now there is no more in vivo, dose and its efficacy data has been established. Current therapy includes biologicals, small molecules inhibitor and enzyme inhibitors etc, which serve as novel therapeutic options for psoriasis treatment. All these avoid the side effects of the prebiologically developed systemic agents including hepatotoxicity, nephrotoxicity, and bone marrow suppression. Currently, Denilukin diftitox, Efalizumab, Alefacept, Ustekinumab and Etanercept are approved by the FDA, and others molecules are at clinical stage. Patents issued by the US office are also included in current psoriasis treatment scenario. In the United States, biologicals are widely used for moderate-to-severe psoriasis. But because of the high cost of medication and their availability in injection form, it remains to be seen how widely these agents will be utilized worldwide. Still, developing countries prefer conventional drugs.     

Clinicopathologic characteristics and steroid response of IgM nephropathy in children presenting with idiopathic nephrotic syndrome

There is no detailed information on clinical and immunopathologic features of immunoglobulin M nephropathy (IgMN) in children with idiopathic nephrotic syndrome (INS) in Pakistan. We reviewed our native renal biopsies over 15 years (July 1995-July 2010) and identified 135 cases of IgMN in nephrotic children (≤17 years). Their demographic, clinical and immunopathologic data were retrieved from biopsy reports and case notes. Mean age of this cohort was 7.6 ± 4.2 years. Males were 92 (68.1%) and females were 43 (31.9%). Steroid-dependent NS was seen in 88 (65.2%) cases and steroid-resistant NS in 47 (34.2%). Hematuria was found in 42 cases (31.2%) and hypertension in 27 (19.5%). The most common morphologic change was glomerular mesangial proliferation, found in 89 (65.9%) biopsies. Minor changes were seen in 46 (34.1%) cases and focal segmental glomerulosclerosis (FSGS) in 37 (27.4%). Immunofluorescence microscopy showed diffuse mesangial positivity of IgM in all cases. C3 and C1q were found in 72 (53.3%) and 40 (29.7%) cases, respectively. Our results show that IgMN is a fairly common cause of INS in children in Pakistan. It shows a spectrum of morphologic changes ranging from minor changes to FSGS.     

Delayed fixation of the transcervical fracture of the neck of the femur in the pediatric population: results and complications

Purpose  

To determine the impact of a substantial delay in providing surgical treatment on the final outcome in transcervical femoral neck fractures in children.     

Infective endocarditis in patients with congenitally malformed hearts: characterization of the syndrome in a developing country

OBJECTIVE: Cardiac surgery for correction or palliation of congenital cardiac disease in infancy and childhood remains a privilege that is rarely accessible to two-thirds of the world's population. This imbalance has created a unique spectrum of illness in patients with underlying congenital cardiac disease and complicating infective endocarditis in developing countries, including Pakistan. In this study, we characterize endocarditis as seen in such patients presenting in Karachi. PATIENTS AND SETTINGS: We reviewed retrospectively patients admitted to Aga Khan University with underlying congenitally malformed hearts and endocarditis between 1991 and 2004. RESULTS: We identified 48 patients with endocarditis according to the modified Duke Criterions, with just over half the cases (54%) classified as definite endocarditis. Of the patients, 23 (49%) patients were more than 16 years old. Uncorrected left-to-right-shunts, tetralogy of Fallot, and congenital mitral valvar disease were the most common underlying defects. Patients with cyanotic defects, particularly of the complex type, were underrepresented (4%). Only 11 (22.9%) of the patients had a previous palliative or corrective surgery. In one-third of the patients (16), streptococcal species were identified as the microbiologic cause of endocarditis, and 22 (45.8%) had culture-negative endocarditis. In contrast, Staphylococcus aureus and enterococci caused endocarditis in only one patient each. There were no differences in mortality or complications between cyanotic and acyanotic congenital defects. Surgery was performed in nine (18.7%) patients with endocarditis, and of these, 13 (27.1%) died. CONCLUSIONS: In contrast to the developed world, endocarditis in the developing countries, such as Pakistan, complicates uncorrected left-to-right shunts and tetralogy of Fallot, probably because patients with complex cyanotic defects fail to survive long after birth due to the lack of available surgery. Almost half of patients had culture-negative endocarditis, likely related to several factors.     

The Structural and Functional Role of the B‐chain C‐terminal Arginine in the Relaxin‐3 Peptide Antagonist,R3(BΔ23‐27)R/I5

Relaxin‐3, a member of the insulin superfamily, is involved in regulating stress and feeding behavior. It is highly expressed in the brain and is the endogenous ligand for the receptor RXFP3. As relaxin‐3 also interacts with the relaxin receptor RXFP1, selective agonists and antagonists are crucial for studying the physiological function(s) of the relaxin‐3/RXFP3 pair. The analog R3(BΔ23‐27)R/I5, in which a C‐terminally truncated human relaxin‐3 (H3) B‐chain is combined with the INSL5 A‐chain, is a potent selective RXFP3 antagonist and has an Arg residue remaining on the B‐chain C‐terminus as a consequence of the recombinant protein production process. To investigate the role of this residue in the RXFP3 receptor binding and activation, the analogs R3(BΔ23‐27)R/I5 and R3(BΔ23‐27)R containing the B‐chain C‐terminal Arg as well as R3(BΔ23‐27)/I5 and R3(BΔ23‐27), both lacking the Arg, were chemically assembled and their secondary structure and receptor activity assessed. The peptides generally had a similar conformation but those with the extra Arg residue displayed a significantly increased affinity for the RXFP3. Interestingly, in contrast to R3(BΔ23‐27)R and R3(BΔ23‐27)R/I5, the peptide R3(BΔ23‐27) is a weak agonist. This suggests that the C‐terminal Arg, although increasing the affinity, alters the manner in which the peptide binds to the receptor and thereby prevents activation, giving R3(BΔ23‐27)R/I5 its potent antagonistic activity.