A combination therapy with copper nicotinate complex reduces the adverse effects of 5-fluorouracil on patients with hepatocellular carcinoma.

5-Fluorouracil (5-FU) as chemotherapy in cases of hepatocellular carcinoma (HCC), was found to initiate hepatotoxic injuries, ascites, leucopenia, thrombocytopenia and myelosupression that limit its use. Therefore, this work was conducted to investigate whether the combination of copper (I)-nicotinate complex [CuCl (HNA)2] with 5-FU may overcome such a drug resistance. Forty-eight patients with HCC were therapy-naïve and treated with 5-FU (12 mg/kg/day) for 5 days in 2 cycles with 4 weeks in between. Twenty-four of them were simultaneously given oral doses of copper (I)-nicotinate complex (0.8 mg/kg/day) started with the 5-FU treatment. The combined therapy of CuCl (HNA)2 with 5-FU could improve the prognosis of HCC-patients. Improvement of liver function was presented by significant reduction of serum bilirubin (p<0.001), transaminases and alkaline phoshatase (p<0.05). The copper complex prevented hypoproteinaemic and hypoalbuminaemic effects of 5-FU and rendered the prothrombin time to its normal value (p<0.001). Superoxide dismutase, ceruloplasmin and immunoglobulins IgG showed significant increases (p<0.001), while serum copper and lipid peroxides were reduced (p<0.001). Thrombocytopenia, leucopenia and other myelosuppressive effects of 5-FU were reduced by the co-administration of CuCl (HNA)2. In conclusion the combination with CuCl (HNA)2 given in such a dosage schedule mitigated the most frequent toxicities associating 5-FU administration and enhanced defense mechanisms against oxidative stress.

A scorpion venom peptide fraction induced prostaglandin biosynthesis in guinea pig kidneys: incorporation of 14C-linoleic acid.

A peptide fraction isolated from the venom of the Egyptian scorpion Buthus occitanus was proved to have a bradykinin- potentiating activity. In vivo and in vitro modes of action of the isolated bradykinin-potentiating peptide (BPP) on kidneys of guinea pigs were investigated. Animals received five successive i.p. doses of the scorpion BPP (1 microg/g body weight) at one-week intervals. The control animals were i.p. injected with saline solution only. In vivo experiments showed a significant increase in renal tissue PGE(2) content and lipid peroxides of the treated guinea pigs compared to the control animals (p < 0.05). Nonsignificant changes were detected in the levels of tissue c-AMP and 5-nucleotidase activity (p > 0.05) of the treated animals, while the changes in c-GMP and c-AMP/c-GMP ratio were both significant (p < 0.05). In vitro experiments demonstrated enhanced capacity of guinea pig-renal tissue to convert (14)C-linoleic acid to its metabolites, 6-keto-PGF(1)alpha, PGF(2)alpha, PGE(2), TxB(2), PGD(2), and arachidonic acid, in response to the added PBP (1 microg/ml) and bradykinin (1 microg/ml). This enhanced response was abolished upon the addition of 1 microg/ml of BK-inhibitor (D-Arg- [Hyp(3), Thi(5,6), Phe(7)]). The capacity for labeled metabolites recovery in BPP treated renal tissue was 19.78%, while it was 13.00% in the basal control. The total increase that evoked by BPP was 62.78%. The results clearly indicate that the isolated BPP induced prostaglandin biosynthesis, which may trigger enhanced glomerular filtration in guinea pigs.

A bradykinin potentiating peptide from Egyptian cobra venom strongly affects rat atrium contractile force and cellular calcium regulation.

Peptide fractions were isolated from venoms of the Egyptian snake Naja haje haje (cobra BPP) and the scorpions Buthus occitanus (BPP(B)) and Leirus quenquestriatus (BPP(L)). The pharmacological effects of these peptides were bioassayed and showed bradykinin potentiating activities. Amino acid analysis revealed that 14 amino acids contribute to the structure of BPP(B) and 16 for BPP(L), while cobra BPP was composed of 15 amino acids. Treatment of rat atrial preparations with 50 microg/ml of cobra BPP caused a significant reduction (P<0.001) in myocardial force. Elevation of extracellular calcium concentration from 1.25 to 5 mM antagonized the effect of cobra BPP in a way that restored the atrial force development. Na(+)-channel blockers did not change the force development at 5 mM Ca(2+). Experiments with (45)Ca revealed that Ca(2+) uptake of cobra BPP treated atria was 0.52+/-0.07 microM/g wet mass and the force at the end of the uptake period was 55.0+/-2.0%. The corresponding values for non-treated preparations were 0.56+/-0.04 microM/g and 92.0%+/-3.0%, respectively. Our results revealed that cobra BPP did not exhibit any effect on Ca(2+) uptake by rat atrial preparations, but strongly affected cellular Ca(2+) regulation.