S. Shrivastava

Use of dopamine in prevention of contrast induced acute renal failure — A randomised study

We report the use of dopamine in renal doses (5 micrograms/kg/min) to prevent contrast induced nephropathy (CIN). Forty patients with diabetes mellitus who were undergoing coronary angiography were randomly divided into two groups. Gr I (20 patients) was infused with dopamine starting 30 min before cardiac catheterization and continued for 6 h thereafter. Gr II (20 patients) did not receive dopamine. Baseline blood chemistry was performed before catheterization and then repeated 24 h after the procedure. The mean age and sex distribution were similar in both the groups. Urograffin (76%; 120-150 ml) was used in all the cases. The mean serum creatinine and blood urea nitrogen (BUN) levels in Gr I patients before catheterization were 1.5 +/- 0.32 mg % and 16.3 +/- 8.05 mg %, respectively. The corresponding values for Gr II were 1.52 +/- 0.68 mg % and 19.6 +/- 13.4 mg %, respectively. After angiography, Gr I patients did not show significant changes in renal parameters (serum creatinine, 1.37 +/- 0.25 mg % and BUN, 14.7 +/- 5.5 mg %) while Gr II patients showed a significant rise (serum creatinine, 1.96 +/- 1.2 mg % and BUN, 23.25 +/- 12.7 mg %; P = 0.01 and P = 0.05, respectively). Ten patients in Gr II (50%) developed a 25% rise in serum creatinine levels within 24 h of injection of the contrast. None of the patients developed renal failure severe enough to warrant dialysis. Hence alterations of renal function are common after cardiac catheterization. Dopamine in renal doses appears to be an effective means to prevent deterioration in renal function induced by contrast.

Myocardial involvement and its response to immunosuppressive therapy in nonspecific aortoarteritis (Takayasu's disease) - a study by endomyocardial biopsy

Myocardial involvement in nonspecific aortoarteritis was evaluated in 16 patients (age 7-37 years, 2 males, 14 females) with the help of endomyocardial biopsy obtained from the right ventricle using the Cordis bioptome introduced from the right femoral vein. Morphological features of myocarditis were present in 8, endocardial thickening in 2, mild to moderate myofibre hypertrophy in 11, and a normal biopsy in 3 patients. Myocarditis was present in 8/11 cases with active disease and in none with inactive disease. Five of the 8 patients with myocarditis presented with congestive cardiac failure with 3 of them having no associated hypertension or valvar involvement to account for it. Immunosuppressive therapy was given to all patients with myocarditis. Serial studies (ongoing) showed clinical, haemodynamic and morphological improvement. Myocarditis appears to occur commonly in nonspecific aortoarteritis during the acute phase of the disease and may precipitate congestive cardiac failure in some patients. Immunosuppressive therapy shows promise and merits further evaluation.

Anticancer effect of celastrol on human triple negative breast cancer: Possible involvement of oxidative stress, mitochondrial dysfunction, apoptosis and PI3K/Akt pathways

Signaling via the phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) is crucial for divergent physiological processes including transcription, translation, cell-cycle progression and apoptosis. The aim of work was to elucidate the anti-cancer effect of celastrol and the signal transduction pathways involved. Cytotoxic effect of celastrol was assessed by MTT assay on human triple negative breast cancer cells (TNBCs) and compared with that of MCF-7. Apoptosis induction was determined by AO/EtBr staining, mitochondrial membrane potential by JC-1, Annexin binding assays and modulation of apoptotic proteins and its effect on PI3K/Akt/mTOR pathway by western blotting. Celastrol induced apoptosis in TNBC cells, were supported by DNA fragmentation, caspase-3 activation and PARP cleavage. Meanwhile, celastrol triggered reactive oxygen species production with collapse of mitochondrial membrane potential, down-regulation of Bcl-2 and up-regulation of Bax expression. Celastrol effectively decreased PI3K 110α/85α enzyme activity, phosphorylation of Akt(ser473) and p70S6K1 and 4E-BP1. Although insulin treatment increased the phosphorylation of Akt(ser473), p70S6K1, 4E-BP1, celastrol abolished the insulin mediated phosphorylation. It clearly indicates that celastrol acts through PI3k/Akt/mTOR axis. We also found that celastrol inhibited the Akt/GSK3β and Akt/NFkB survival pathway. PI3K/Akt/mTOR inhibitor, PF-04691502 and mTOR inhibitor rapamycin enhanced the apoptosis-inducing effect of celastrol. These data demonstrated that celastrol induces apoptosis in TNBC cells and indicated that apoptosis might be mediated through mitochondrial dysfunction and PI3K/Akt signaling pathway.

Thymoquinone prevents RANKL-induced osteoclastogenesis activation and osteolysis in an in vivo model of inflammation by suppressing NF-KB and MAPK Signalling

Osteoclasts are multinuclear giant cells responsible for bone resorption in inflammatory bone diseases such as osteoporosis, rheumatoid arthritis and periodontitis. Because of deleterious side effects with currently available drugs the search continues for novel effective and safe therapies. Thymoquinone (TQ), the major bioactive component of Nigella sativa has been investigated for its anti-inflammatory, antioxidant and anticancer activities. However, its effects in osteoclastogenesis have not been reported. In the present study we show for the first time that TQ inhibits nuclear factor-KB ligand (RANKL) induced osteoclastogenesis in RAW 264.7 and primary bone marrow derived macrophages (BMMs) cells. RANKL induced osteoclastogenesis is associated with increased expression of multiple transcription factors via activation of NF-KB, MAPKs signalling and reactive oxygen species (ROS). Mechanistically TQ blocked the RANKL induced NF-KB activation by attenuating the phosphorylation of IkB kinase (IKKα/β). Interestingly, in RAW 264.7 cells TQ inhibited the RANKL induced phosphorylation of MAPKs and mRNA expression of osteoclastic specific genes such as TRAP, DC-STAMP, NFATc1 and c-Fos. In addition, TQ also decreased the RANKL stimulated ROS generation in macropahges (RAW 264.7) and H2O2 induced ROS generation in osteoblasts (MC-3T3-E1). Consistent with in vitro results, TQ inhibited lipopolysaccharide (LPS) induced bone resorption by suppressing the osteoclastogenesis. Indeed, micro-CT analysis showed that bone mineral density (BMD) and bone architecture parameters were positively modulated by TQ. Taken together our data demonstrate that TQ has antiosteoclastogenic effect by inhibiting inflammation induced activation of MAPKs, NF-KB and ROS generation followed by suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.

Peptide conjugated polymeric nanoparticles as a carrier for targeted delivery of docetaxel

The aim of this research work was to develop Bombesin peptide (BBN) conjugated, docetaxel loaded nanocarrier for the treatment of breast cancer. Docetaxel loaded nanoparticles (DNP) were prepared by solvent evaporation method using sodium cholate as surfactant. BBN was conjugated to DNP surface through covalent bonding. Both DNP and BBN conjugated DNP (BDNP) were characterized by various techniques such as dynamic light scattering, Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetric analysis. The particle diameter and zeta potential of BDNP were 136±3.95 nm and -10.8±2.7 mV, respectively. The change in surface charge and FTIR studies confirmed the formation of amide linkage between BBN and DNP. AFM analysis showed that nanoparticles were spherical in shapes. In nanoparticles, docetaxel was present in its amorphous form as confirmed by DSC and PXRD analysis and was stable during the thermal studies. The formulations showed the sustained release of DTX over the period of 120 h. During cellular toxicity assay in gastrin releasing peptide receptor positive breast cancer cells (MDA-MB-231), BDNP were found to be 12 times more toxic than pure DTX and Taxotere. The IC50 value for DTX, Taxotere, DNP and BDNP was >375, >375, 142.23 and 35.53 ng/ml, respectively. The above studies showed that Bombesin conjugated nanocarrier system could be a promising carrier for active targeting of anticancer drugs in GRP receptor over expressing cancer cells.

Cardiac involvement in nonspecific aortoarteritis (Takayasu's arteritis)

Fifty-four patients (18 males and 36 females, ages 2 to 37 years) with nonspecific aortoarteritis (NSAA) were studied. Evaluation revealed hypertension in 35, congestive heart failure (CHF) in 24, mild to moderate mitral regurgitation in six, and mild aortic regurgitation in two. Erythrocyte sedimentation rate was raised (greater than 35 mm in the first hour) in 38 patients. The arterial lesions included type I in seven, type II in eight, and type III in 34. Pulmonary artery involvement was present in 4 (type IV) of the 20 patients in whom it was studied. Selective coronary angiography was done in 11 patients and revealed 90% left main stenosis in one patient. Hemodynamic data revealed raised (greater than 7 mm Hg) mean right atrial pressure in nine, raised mean pulmonary artery pressure (greater than 20 mm Hg) in 29, and raised left ventricular filling pressure (greater than 12 mm Hg) in 27 patients. Radionuclide ventriculography revealed reduced (less than 45%) left ventricular ejection fraction (LVEF) in 27 patients. The myocardial morphology as evaluated on right ventricular endomyocardial biopsy revealed normal histology in nine, features of inflammatory myocarditis in 24, and nonspecific changes suggestive of dilated cardiomyopathy in six patients. Marked right ventricular endocardial thickening was present in three. All patients with CHF had some histologic abnormality. We emphasize that myocardial involvement including myocarditis is common in NSAA and may precipitate CHF in these patients.

Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer

Approximately 20% of breast cancer cases are human epidermal growth factor receptor 2 (HER2)-positive. This type of breast cancer is more aggressive and tends to reoccur more often than HER2-negative breast cancer. In this study, we synthesized trastuzumab (TZ)-grafted dendrimers to improve delivery of docetaxel (DTX) to HER2-positive breast cancer cells. Bioconjugation of TZ on the surface of dendrimers was performed using a heterocrosslinker, MAL-PEG-NHS. For imaging of cancer cells, dendrimers were also conjugated to fluorescein isothiocyanate. Comparative in vitro studies revealed that these targeted dendrimers were more selective, and had higher antiproliferation activity, towards HER2-positive MDA-MB-453 human breast cancer cells than HER2-negative MDA-MB-231 human breast cancer cells. When compared with unconjugated dendrimers, TZ-conjugated dendrimers also displayed higher cellular internalization and induction of apoptosis against MDA-MB-453 cells. Binding of TZ to the dendrimer surface could help site-specific delivery of DTX and reduce systemic toxicity resulting from its lack of specificity. In addition, in vivo studies revealed that the pharmacokinetic profile of DTX was significantly improved by the conjugated nanosystem.

Cyclic-RGDfK peptide conjugated succinoyl-TPGS nanomicelles for targeted delivery of docetaxel to integrin receptor over-expressing angiogenic tumours

UNLABELLED Docetaxel (DTX) is an anticancer drug that is used alone and in combination with other drugs to treat tumours. However, it suffers from the drawback of non-specific cytotoxicity. To improve the therapeutic potential of DTX, we report the synthesis of cRGDfK peptide-conjugated succinoyl-TPGS (tocopheryl polyethylene glycol succinate) nanomicelles for targeted delivery of DTX. Among RGD (Arg-Gly-Asp) peptides, cRGDfK peptide shows specificity towards αvβ3 integrin receptors that are most commonly over-expressed in tumour cells. To cRGDfK peptide, succinoylated TPGS was synthesised and conjugated to cRGDfK peptide using a carbodiimide reaction. Peptide-conjugated DTX loaded nanomicelles (PDNM) displayed small particle size with a narrow distribution, controlled drug release and high physicochemical stability. Cytotoxicity, cellular uptake, apoptosis and anti-angiogenic comparisons of unconjugated nanomicelles to PDNM in DU145 human prostate cancer cells and HUVECs (Human Umblical Vein Endothelial Cells) clearly revealed the importance of the cRGDfK peptide in enhancing the drug delivery performance of nanomicelles. FROM THE CLINICAL EDITOR Common to many chemotherapeutic agents for cancer, systemic toxicity remains a big concern. In this article, the authors attempted to address this issue by conjugating RGD based peptides to Docetaxel, which would target integrins expressed on tumor cell surface. The experimental data revealed enhanced drug delivery.

Clinical profile of biopsy proven idiopathic myocarditis

We studied 20 patients in detail (age: 27 months to 45 years, mean 22 years; 15 males, 5 females) of idiopathic myocarditis histologically confirmed by endomyocardial biopsy. None of these patients had evidence of active or previous rheumatic fever. The commonest mode of presentation was congestive heart failure (16 patients) followed by arrhythmias (seven patients--five of whom had associated congestive heart failure) and chest pain resembling myocardial infarction (two patients). Ten patients had a history of preceding upper respiratory infection. Only one of these patients had a significant rising serum titre for Coxsackie B3 virus. Throat and rectal swabs for virus culture were negative in all patients. The electrocardiogram was abnormal in all patients, with a prolonged corrected QT-interval being the commonest abnormality (14 patients). Serial electrocardiographic patterns of evolving myocardial infarction occurred in three patients. Echocardiographic left ventricular end diastolic dimension (4.15 +/- 1.01 cm/m2) and end systolic dimension (3.37 +/- 1.03 cm/m2) were increased in 15 of the 18 patients studied. Pericardial involvement occurred in only one patient. Radionuclide ventriculography showed a reduced left ventricular ejection fraction (< 50%) in 17 patients, global hypokinesia in 12 patients and regional wall motion abnormalities in five patients. Left ventricular and right ventricular end diastolic pressures were elevated in 15 and 11 patients, respectively.

Review on emu products for use as complementary and alternative medicine

Emu (Dromaius novaehallandiae), the flightless bird native to Australia and found in many countries, is receiving much attention for its nutritional benefits as well as its medicinal value. Emu oil contains high amounts of polyunsaturated fatty acids and antioxidants. It has potent anti-inflammatory actions and thus can be used topically and orally to treat conditions such as mucositis, inflammatory bowel syndrome, and auricular inflammation, and to prevent chemotherapy-induced bone loss. Emu oil also has a hypocholesterolemic effect, transdermal penetration-enhancing activity, cosmetic and insect repellent activity, and so on. However, its mechanism(s) of actions are unclear and have not, to our knowledge, been studied to date. Previous studies suggest that the fatty acids of the ω-9, ω-6, and ω-3 series, which are present in emu oil, may act on cyclooxygenase, lipoxygenase, and lipoxin pathways to bring about its anti-inflammatory and other beneficial actions. The aim of this review was to provide a brief summary of the current knowledge of research on emu products, mainly emu oil, for the possible use as a complementary and alternative natural medicine for various chronic diseases. In this review we also highlighted the future research scope of emu oil for its possible antidiabetic activity. Thus, emu oil is an attractive pharmacologic agent to further explore for its therapeutic activity to treat various ailments.