A Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Effect of Topical Urea for Secondary Prophylaxis of Hand Foot Skin Reaction in Renal Cell Cancer Patients on Sunitinib Therapy.

INTRODUCTION: Hand foot skin reaction (HFSR) is a common dose-limiting adverse effect of multi kinase inhibitors (MKI) whose mechanism is not fully understood, and the prophylaxis is inadequate. OBJECTIVE: In this pilot study, a double-blind, randomized placebo-controlled trial was conducted to evaluate the effect of topical urea in secondary prevention of sunitinib-induced HFSR in renal cell cancer patients. METHODS: Out of 55 screened patients, 14 were randomized to receive topical urea or placebo for four weeks. The association of HFSR with drug levels of sunitinib and its metabolite (n-desethyl sunitinib), genetic polymorphism of VEGFR2 gene, quality of life (QOL) and biochemical markers was also assessed. RESULTS: The results showed that urea-based cream was not superior to placebo (P = .075). There was no change in the QOL in both the groups. Single nucleotide polymorphism was checked for two nucleotides rs1870377 and rs2305948 located in VEGFR2 gene on chromosome 4. SNP (variant T > A) at rs1870377 was associated with appearance of new HFSR as compared to the wild type, although the association was not statistically significant (OR 0.714). There was no statistically significant difference between mean plasma levels of sunitinib and N-desethyl sunitinib in urea arm as compared to placebo arm as compared to placebo. The best fit population pharmacokinetic model for sunitinib was one compartment model with first order absorption and linear elimination. The median (IQR) of population parameters calculated from the population pharmacokinetics model for Ka, V and Cl was 0.22 (0.21-0.24) h-1, 4.4 (4.09-4.47) L, 0.049 (0.042-0.12) L/hr, respectively. CONCLUSION: The study suggested that the urea-based cream was not superior to placebo in decreasing the appearance of new HFSR in renal cancer patients receiving 4:2 regimen of sunitinib.

Protective effect of proteins derived from Calotropis procera latex against acute inflammation in rat.

The non-dialysable proteins present in the latex of plant Calotropis procera possess anti-inflammatory and analgesic properties. The aim of this study was to evaluate the effect of latex proteins (LP) on the level of inflammatory mediators, oxidative stress markers and tissue histology in the rat model of carrageenan-induced acute inflammation. This study also aimed at evaluating the anti-inflammatory efficacy of LP against different mediators and comparing it with their respective antagonists. Paw inflammation was induced by subplantar injection of carrageenan, and the effect of LP was evaluated on oedema volume, level of TNF-α, PGE(2), myeloperoxidase, nitric oxide, reduced glutathione, thiobarbituric acid-reactive substances and tissue histology at the time of peak inflammation. Paw inflammation was also induced by histamine, serotonin, bradykinin and PGE(2), and the inhibitory effect of LP against these mediators was compared with their respective antagonists at the time of peak effect. Treatment with LP produced a dose-dependent inhibition of oedema formation, and its anti-inflammatory effect against carrageenan-induced paw inflammation was accompanied by reduction in the levels of inflammatory mediators, oxidative stress markers and normalization of tissue architecture. LP also produced a dose-dependent inhibition of oedema formation induced by different inflammatory mediators, and its efficacy was comparable to their respective antagonists and more pronounced than that of diclofenac. Thus, our study shows that LP has a potential to be used for the treatment of various inflammatory conditions where the role of these mediators is well established.

Protective effect of aqueous suspension of dried latex of Calotropis procera against oxidative stress and renal damage in diabetic rats

Calotropis species have been used in the traditional medicinal system for the treatment of diseases of the liver and abdomen. In view of the antioxidant and anti-hyperglycemic properties of an aqueous suspension obtained from the dried latex of Calotropis procera, the present study was carried out to evaluate its efficacy in affording protection against alloxan induced changes in rat kidney. A single intraperitoneal injection of alloxan (150 mg/kg) in rats produced hyperglycemia within 3 days and altered kidney functions over a period of 90 days. Daily oral administration of the aqueous suspension (100 and 400 mg/kg) in diabetic rats produced anti-hyperglycemic effect that was comparable to that of glibenclamide (10 mg/kg). Unlike glibenclamide, the aqueous suspension did not increase the serum insulin levels in diabetic rats. However, it produced a marked reduction in the levels of urinary glucose and protein and normalized the renal tissue levels of thiobarbituric acid-reactive substances (TBARS) and glutathione (GSH) in diabetic rats and the effect was comparable to that of glibenclamide. The protection afforded by the aqueous suspension was also evident from the histological analysis of the renal tissue. Our study shows that by exhibiting antioxidant and anti-hyperglycemic property the aqueous suspension of dried latex of C. procera affords protection against the complications associated with diabetes.

Protective effect of aqueous suspension of dried latex of Calotropis procera against oxidative stress and renal damage in diabetic rats

Calotropis species have been used in the traditional medicinal system for the treatment of diseases of the liver and abdomen. In view of the antioxidant and anti-hyperglycemic properties of an aqueous suspension obtained from the dried latex of Calotropis procera, the present study was carried out to evaluate its efficacy in affording protection against alloxan induced changes in rat kidney. A single intraperitoneal injection of alloxan (150 mg/kg) in rats produced hyperglycemia within 3 days and altered kidney functions over a period of 90 days. Daily oral administration of the aqueous suspension (100 and 400 mg/kg) in diabetic rats produced anti-hyperglycemic effect that was comparable to that of glibenclamide (10 mg/kg). Unlike glibenclamide, the aqueous suspension did not increase the serum insulin levels in diabetic rats. However, it produced a marked reduction in the levels of urinary glucose and protein and normalized the renal tissue levels of thiobarbituric acid-reactive substances (TBARS) and glutathione (GSH) in diabetic rats and the effect was comparable to that of glibenclamide. The protection afforded by the aqueous suspension was also evident from the histological analysis of the renal tissue. Our study shows that by exhibiting antioxidant and anti-hyperglycemic property the aqueous suspension of dried latex of C. procera affords protection against the complications associated with diabetes

Protective effect of aqueous suspension of dried latex of Calotropis procera against oxidative stress and renal damage in diabetic rats

Calotropis species have been used in the traditional medicinal system for the treatment of diseases of the liver and abdomen. In view of the antioxidant and anti-hyperglycemic properties of an aqueous suspension obtained from the dried latex of Calotropis procera, the present study was carried out to evaluate its efficacy in affording protection against alloxan induced changes in rat kidney. A single intraperitoneal injection of alloxan (150 mg/kg) in rats produced hyperglycemia within 3 days and altered kidney functions over a period of 90 days. Daily oral administration of the aqueous suspension (100 and 400 mg/kg) in diabetic rats produced anti-hyperglycemic effect that was comparable to that of glibenclamide (10 mg/kg). Unlike glibenclamide, the aqueous suspension did not increase the serum insulin levels in diabetic rats. However, it produced a marked reduction in the levels of urinary glucose and protein and normalized the renal tissue levels of thiobarbituric acid-reactive substances (TBARS) and glutathione (GSH) in diabetic rats and the effect was comparable to that of glibenclamide. The protection afforded by the aqueous suspension was also evident from the histological analysis of the renal tissue. Our study shows that by exhibiting antioxidant and anti-hyperglycemic property the aqueous suspension of dried latex of C. procera affords protection against the complications associated with diabetes

Chemoprevention with aqueous extract of Butea monosperma flowers results in normalization of nuclear morphometry and inhibition of a proliferation marker in liver tumors.

Butea monosperma (Lam.) (family: Fabaceae) popularly known as 'Palas' or 'fire of forest' has been used traditionally as a hepatoprotective agent. This study evaluated the hepatoprotective and antitumorigenic properties of the aqueous extract and butanol fractions of B. monosperma flowers in animal models. Dried flowers of B. monosperma were extracted with water and fractionated further using n-butanol. The hepatoprotective activity of the aqueous extract was initially confirmed in a carbon tetrachloride-induced liver damage model of rats. Oral administration of the aqueous extract produced a strong hepatoprotective effect similar to silymarin and normalized the serum levels of ALT, AST, bilirubin and triglyceride in rats. However, it did not affect the levels of glutathione and malondialdehyde which are oxidative stress markers in liver. Intraperitoneal administration of the aqueous extract in the X15-myc oncomice not only maintained liver architecture and nuclear morphometry but also down-regulated the serum VEGF levels. Immunohistochemical staining of liver sections with anti-Ribosomal protein S27a antibody showed post-treatment abolition of this proliferation marker from the tumor tissue. The butanol fractions, however, did not show antitumorigenic activity. Thus, the aqueous extract of B. monosperma flowers is not only hepatoprotective but also antitumorigenic by preserving the nuclear morphometry of the liver.

Atorvastatin exhibits anti-inflammatory and anti-oxidant properties in adjuvant-induced monoarthritis.

Arthritis is a joint disorder where the joint damage is associated with elevated levels of inflammatory mediators and reactive oxygen species (ROS). The inflammatory hyperalgesia associated with arthritis has been shown to be attenuated by anti-hyperlipidemic drug, atorvastatin. The present study was carried out to evaluate the effect of atorvastatin on joint inflammation and associated oxidative stress markers in a rat model where arthritis was induced by intra-articular injection of 0.1 ml of 0.1% Freund's Complete Adjuvant (FCA). Atorvastatin (10 mg and 50 mg/kg) and diclofenac (5 mg/kg) were administered orally, daily during the study period of 4 days and their effect on joint inflammation was evaluated by measuring joint diameter, levels of glutathione (GSH), thiobarbituric acid reactive substances (TBARS), activity of super oxide dismutase (SOD) and tissue histology. Atorvastatin produced a dose-dependent reduction in joint inflammation that was associated with normalization of levels of oxidative stress markers and tissue histology and its effect was found to be comparable to that of diclofenac.

Atorvastatin ameliorates inflammatory hyperalgesia in rat model of monoarticular arthritis.

Statins, the cholesterol lowering drugs, have been shown to exhibit anti-inflammatory properties. The aim of the present study was to evaluate the efficacy of atorvastatin in ameliorating joint dysfunction associated with arthritis. Monoarticular arthritis was induced by the intra-articular injection of FCA (0.1mL of 0.1%). The effect of atorvastatin (10 and 50mg/kg, A10 and A50) following oral administration was evaluated on joint inflammation, locomotor function and hyperalgesia daily for first 4 days and every 4th day till 28 days. The effect of atorvastatin was compared with that of diclofenac (5mg/kg, D5). Daily oral administration of atorvastatin produced a significant reduction in joint inflammation (21% in A10 and 33% in A50) and associated hyperalgesia. Atorvastatin also produced a marked improvement in the stair climbing ability and motility of the arthritic rats. The beneficial effect of atorvastatin was also evident from the histological analysis of joint carried out on day 28. Our results show that atorvastatin is more effective in decreasing the joint inflammation and hyperalgesia as compared to diclofenac while the efficacy of both the drugs in ameliorating functional disability was comparable.

Protective effect of Calotropis procera latex extracts on experimentally induced gastric ulcers in rat.

AIM OF THE STUDY: Calotropis procera is a wild growing plant with multifarious medicinal properties. The present study was carried out to evaluate the effect of dried latex (DL) of Calotropis procera and its methanol extract (MeDL) against gastric ulcers induced in rats. MATERIALS AND METHODS: Aqueous suspension of DL (20 and 100mg/kg) and MeDL (10 and 50mg/kg) were given orally to 36h fasted rats and ulcers were induced by ethanol, pyloric ligation and aspirin. Parameters like ulcer score and levels of oxidative stress markers were measured in all the models. The effect on gastric hemorrhage and tissue histology was studied in ethanol model and on acidity, pH and volume of gastric secretion was evaluated in pyloric ligation model. The protective effect of DL and MeDL was compared with that of standard anti-ulcer drug famotidine (20 mg/kg). RESULTS: DL and MeDL produced 85-95% inhibition of gastric mucosal damage in ethanol model and 70-80% inhibition in aspirin model. The protective effect of these extracts was associated with marked reduction in gastric hemorrhage, maintenance of tissue integrity and normalization of levels of oxidative stress markers like glutathione, thiobarbituric acid reactive substances and superoxide dismutase. Like famotidine, DL and MeDL decreased the gastric acidity from 376.17+/-21.47 mequiv./l to 163.88+/-6.86 and 201.48+/-8.86 mequiv./l respectively in pyloric ligation model. These extracts increased the gastric pH without affording any protection to gastric mucosa in this model. CONCLUSION: The latex of Calotropis procera has the therapeutic potential to relieve gastric hyperacidity and to prevent gastric ulceration induced by necrotizing agents.

Protective effect of latex of Calotropis procera in Freund's Complete Adjuvant induced monoarthritis.

The protective effect of latex of Calotropis procera in Freund's Complete Adjuvant (FCA) induced monoarticular arthritis was evaluated in rats. Arthritis was induced by a single intra-articular injection of 0.1 mL of 0.1% FCA in the right ankle joint. The effect of dried latex (DL, 200 and 400 mg/kg) and its methanol extract (MeDL, 50 and 500 mg/kg) following oral administration was evaluated on joint inflammation, hyperalgesia, locomotor function and histology at the time of peak inflammation. The effects of DL and MeDL were compared with antiinflammatory drugs phenylbutazone (100 mg/kg), prednisolone (20 mg/kg), rofecoxib (20 and 100 mg/kg) and immuno-suppressant methotrexate (0.3 mg/kg). Daily oral administration of DL and its methanol extract (MeDL) produced a significant reduction in joint inflammation (about 50% and 80% inhibition) and associated hyperalgesia. The antihyperalgesic effect of MeDL was comparable to that of rofecoxib. Both DL and MeDL produced a marked improvement in the motility and stair climbing ability of the rats. The histological analysis of the arthritic joint also revealed significant reduction in oedema and cellular infiltration by MeDL that was comparable to that of rofecoxib. Thus, our study suggests that the latex of C. procera has the potential to be used as an antiarthritic agent.

Effect of aqueous suspension of dried latex of Calotropis procera on hepatorenal functions in rat.

AIM OF THE STUDY: The present study was carried out to evaluate the effect of dry latex (DL) of Calotropis procera, a plant of the family Asclepiadaceae, on the functions of liver and kidney in normal rats. MATERIALS AND METHODS: Aqueous suspension of DL was orally administered to rats at doses of 10, 100 and 400 mg/kg for a period of 45 days and the effect on various parameters reflecting liver and kidney functions was compared with that of normal controls. RESULTS: Treatment with DL did not alter the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), creatinine, urea and urinary levels of glucose and protein as compared to the normal rats. It exhibited a modulatory role in maintaining the levels of blood glucose and serum insulin. The liver and kidney of DL treated and normal rats were also comparable with regard to the tissue levels of oxidative stress markers and histology. Further, no signs of toxicity were observed in the DL treated rats over the study period. CONCLUSION: Our study reveals that aqueous suspension of Calotropis procera latex does not produce any toxicity and could be safely used for therapeutic purpose at the doses studied.

The effect of casein phosphopeptide-amorphous calcium phosphate on remineralization of artificial caries-like lesions: an in vitro study.

BACKGROUND: The aims of this study were to investigate the efficacy of CPP-ACP containing Tooth Mousse on the remineralization of enamel lesions and to compare its efficacy to that of a fluoride-containing toothpaste. METHODS: Permanent teeth were placed in demineralizing solution for 96 hours to produce artificial caries-like lesions 120-200 microm in depth. They were sectioned into 100-150 microm thick samples and randomly assigned to five groups: for Group A, a fluoridated toothpaste (1100 ppm) was used as a positive control and in Group B, a non-fluoridated toothpaste was used as a negative control. Tooth Mousse containing CPP-ACP was tested by three different means: as a toothpaste (Group C); as a topical coating (Group D); and (Group E) as a topical coating after treating the sections with the same fluoridated toothpaste as in Group A. RESULTS: The lesion depth decreased significantly by 7 per cent in Group A, 10.1 per cent in Groups C and D, and 13.1 per cent in Group E (Paired t- test, p < 0.05), while in Group B the lesion depth increased significantly by 23 per cent. CONCLUSIONS: Based on the data obtained, CPP-ACP containing Tooth Mousse remineralized initial enamel lesions and it showed a higher remineralizing potential when applied as a topical coating after the use of a fluoridated toothpaste.

Calotropis procera latex affords protection against carbon tetrachloride induced hepatotoxicity in rats.

In the present study, latex of Calotropis procera possessing potent antioxidant and anti-inflammatory properties was evaluated for its hepatoprotective effect against carbon tetrachloride (CCl(4)) induced hepatotoxicity in rats. Subcutaneous injection of CCl(4,) administered twice a week, produced a marked elevation in the serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and tumor necrosis factor alpha (TNF-alpha). Histological analysis of the liver of these rats revealed marked necro-inflammatory changes that were associated with increase in the levels of TBARS, PGE(2) and catalase and decrease in the levels of glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GPx). Daily oral administration of aqueous suspension of dried latex (DL) of Calotropis procera at 5, 50 and 100mg/kg doses produced a dose-dependent reduction in the serum levels of liver enzymes and inflammatory mediators and attenuated the necro-inflammatory changes in the liver. The DL treatment also normalized various biochemical parameters of oxidative stress. Our study shows that the antioxidant and anti-inflammatory effects of DL and silymarin were comparable and suggests that DL could be used as a hepatoprotective agent.

Evaluation of cytotoxic potential of latex of Calotropis procera and podophyllotoxin in Allium cepa root model.

In the present study we have utilized the Allium cepa root tip meristem model to evaluate the cytotoxic and anti-mitotic activities of latex of Calotropis procera (DL) and podophyllotoxin. Standard cytotoxic drug cyclophosphamide and non-cytotoxic drugs cyprohcptadine and aspirin served as controls. Like cyclophosphamide, both DL and podophyllotoxin significantly inhibited the growth of roots and mitotic activity in a dose-dependent manner. However, podophyllotoxin was more potent in this regard and produced root decay. Cyproheptadine and aspirin, on the other hand, showed a marginal effect on the root growth and mitotic activity at much higher concentrations.

A comparative study on the efficacy of rofecoxib in monoarticular arthritis induced by latex of Calotropis procera and Freund's complete adjuvant.

The role of prostaglandins in Calotropis procera latex induced inflammation and hyperalgesia has been well established. The acute inflammation induced by the dried latex (DL) of this plant could be effectively ameliorated by standard anti-inflammatory drugs. In present study we have evaluated the efficacy of rofecoxib, a COX-2 inhibitor in monoarthritis induced by intra-articular injection of DL and compared it with that against Freund's Complete Adjuvant (FCA). DL and FCA were injected into the right ankle joint of the rat and the joint diameter was measured by a micrometer screw gauge on day 0, 4, 8, 12, 20 and 28. Concomitantly the hyperalgesic response was also evaluated by motility test, stair climbing ability test, dorsal flexion pain test and compression test. The effect of rofecoxib was evaluated on these parameters in both the models. Both DL and FCA produced peak inflammation on day 4 that was associated with decreased pain threshold and functional impairment. Although rofecoxib was more effective in improving motility in the DL model, its effect on joint inflammation, hyperalgesia and stair climbing ability was comparable in both the models. Thus, our study indicates that DL induced monoarthritis could be used as a model for the screening and evaluation of anti-inflammatory and anti-arthritic drugs.

Evaluation of cytotoxic potential of latex of Calotropis procera and Podophyllotoxin in Allum cepa root model

In the present study we have utilized the Allium cepa root tip meristem model to evaluate the cytotoxic and anti-mitotic activities of latex of Calotropis procera (DL) and podophyllotoxin. Standard cyto-toxic drug cyclophosphamide and non-cytotoxic drugs cyproheptadine and aspirin served as controls. Like cyclophosphamide, both DL and podophyllotoxin significantly inhibited the growth of roots and mitotic activity in a dose-dependent manner. However, podophyllotoxin was more potent in this regard and produced root decay. Cyproheptadine and aspirin, on the other hand, showed a marginal effect on the root growth and mitotic activity at much higher concentrations

Evaluation of cytotoxic potential of latex of Calotropis procera and Podophyllotoxin in Allum cepa root model

In the present study we have utilized the Allium cepa root tip meristem model to evaluate the cytotoxic and anti-mitotic activities of latex of Calotropis procera (DL) and podophyllotoxin. Standard cyto-toxic drug cyclophosphamide and non-cytotoxic drugs cyproheptadine and aspirin served as controls. Like cyclophosphamide, both DL and podophyllotoxin significantly inhibited the growth of roots and mitotic activity in a dose-dependent manner. However, podophyllotoxin was more potent in this regard and produced root decay. Cyproheptadine and aspirin, on the other hand, showed a marginal effect on the root growth and mitotic activity at much higher concentrations(AU)

Evaluation of cytotoxic potential of latex of Calotropis procera and Podophyllotoxin in Allum cepa root model

In the present study we have utilized the Allium cepa root tip meristem model to evaluate the cytotoxic and anti-mitotic activities of latex of Calotropis procera (DL) and podophyllotoxin. Standard cyto-toxic drug cyclophosphamide and non-cytotoxic drugs cyproheptadine and aspirin served as controls. Like cyclophosphamide, both DL and podophyllotoxin significantly inhibited the growth of roots and mitotic activity in a dose-dependent manner. However, podophyllotoxin was more potent in this regard and produced root decay. Cyproheptadine and aspirin, on the other hand, showed a marginal effect on the root growth and mitotic activity at much higher concentrations(AU)

Antioxidant and protective effect of latex of Calotropis procera against alloxan-induced diabetes in rats.

In the present study, dry latex (DL) of Calotropis procera possessing potent anti-inflammatory activity was evaluated for its antioxidant and anti-hyperglycemic effects against alloxan-induced diabetes in rats. Daily oral administration of DL at 100 and 400 mg/kg doses produced a dose-dependent decrease in the blood glucose and increase in the hepatic glycogen content. DL also prevented the loss of body weight in diabetic rats and brought down the daily water consumption to values comparable to normal rats. DL also produced an increase in the hepatic levels of the endogenous antioxidants, namely superoxide dismutase (SOD), catalase and glutathione, while it brought down the levels of thiobarbituric acid-reactive substances (TBARS) in alloxan-induced diabetic rats. The efficacy of DL as an antioxidant and as an anti-diabetic agent was comparable to the standard anti-diabetic drug, glibenclamide.