The interactions of cephalosporins on polyol pathway enzymes from sheep kidney.

CONTEXT: Cephalosporins are derived from the fungus Acremonium. Due to their strong bactericidal ability, these drugs have to a wide usage in medicine. OBJECTIVE: An investigation of the effects on sheep renal aldose reductase (AR) and sorbitol dehydrogenase (SDH) of cefoperazone, cefazolin, cefuroxime, ceftazidime and ceftriaxone as cephalosporin drugs was carried out in the present study. METHODS: AR and SDH were purified from sheep kidney by ion exchange, gel filtration and affinity methods with approximately 219- and 484-fold, respectively. Some kinetic properties of the enzymes were determined such as optimal pH, optimal ionic strength, optimal temperature, stable pH, Km and Vmax. IC50 values of the drugs were found for each enzyme. RESULTS: While the AR was inhibited by all drugs, SDH enzyme was inhibited by only CXM (IC50 8.10 mM). Interestingly, CZO activated SDH enzyme. This result was evaluated as important for the flow of the polyol reactions. Ki values and inhibition types were determined for AR. However, these values could not have determined for SDH, due to insufficient inhibition. CONCLUSIONS: From these results, it was concluded that cephalosporins may have an important effect on flow of the polyol metabolism.

Mechanism of capsaicin inhibition of aldose reductase activity.

Aldose reductase (AR) inhibitors play a vital importance as a potential therapeutic and preventive medicine when it comes to hyperglycemia associated diabetic complications. Additionally, capsaicin is used as a food additive and a drug in a number of diverse clinical trials. The aim of this study is to determine the in vitro inhibition behavior of capsaicin on AR enzyme activity, which was obtained from different rat tissues (heart, kidney, liver, and brain). We showed that AR was inhibited by capsaicin in the micromolar range and noncompetitive manner in all of the tissues. Ki values of capsaicin were found to be 8.87, 264, 535, and 597, respectively, in heart AR, kidney AR, liver AR, and brain AR. In conclusion, capsaicin may be an effective molecule when used in low concentrations to prevent diabetic complications associated with the polyol pathway.

Inhibition behaviours of some phenolic acids on rat kidney aldose reductase enzyme: an in vitro study.

Aldose reductase (AR) inhibitors have vital importance in the treatment and prevention of diabetic complications. In this study, rat kidney AR was purified 19.34-fold with a yield of 3.49% and a specific activity of 0.88 U/mg using DE-52 Cellulose anion exchange chromatography, gel filtration chromatography and 2'5' ADP Sepharose-4B affinity chromatography, respectively. After purification, the in vitro inhibition effects of some phenolic acids (tannic acid, chlorogenic acid, sinapic acid, protocatechuic acid, 4-hydroxybenzoic acid, p-coumaric acid, ferulic acid, vanillic acid, syringic acid, α-resorcylic acid, 3-hydroxybenzoic acid and gallic acid) were investigated on purified enzyme. We determined IC50, Ki values and inhibition types of these phenolic acids. As a result, tannic and chlorogenic acid had a strong inhibition effect. On the other hand, gallic acid had a weak inhibition effect. In this study, all phenolic acids except for chlorogenic acid and p-coumaric acid showed non-competitive inhibition effects on rat kidney AR.

Some Anti-Inflammatory Agents Inhibit Esterase Activities of Human Carbonic Anhydrase Isoforms I and II: An In Vitro Study.

Carbonic anhydrases (CAs) are known as a drug-target enzymes. The inhibitors of the enzyme are important compounds for discovering new therapeutic agents and understanding in detail protein-drug interactions at the molecular level. For this purpose, the in vitro effects of some anti-inflammatory agents such as tenoxicam, fluorometholone acetate, and dexamethasone were investigated on esterase activity of human erythrocyte CA-I and CA-II in this study. hCA-I and hCA-II were purified by affinity chromatography with a yield of 47.25% and 87%, and a specific activity of 642.8 EU/mg proteins and 5576.9 EU/mg proteins, respectively. SDS-PAGE was performed to determine the purity of the enzymes. Inhibitory effects of the drugs on hCA-I and hCA-II were determined by spectrophotometric method. IC50 values for hCA-I and hCA-II were 0.198, 2.18, 11.7, 0.11, 17.5 and 14 µm using tenoxicam, fluorometholone acetate, and dexamethasone, respectively. For fluorometholone acetate and dexamethasone, Ki values from Lineweaver-Burk plots were obtained as 1.044 and 21.2 µm (noncompetitive) for hCA-I and 9.98 and 8.66 µm (non-competitive) for hCA-II. In conclusion, tenoxicam, fluorometholone acetate, and dexamethasone showed potent inhibitory effects on esterase activity of hCA-I and hCA-II isozymes under in vitro conditions.

Influence of pesticide exposure on carbonic anhydrase II from sheep stomach.

Carbonic anhydrase (CA) is a widely distributed enzyme and has a crucial role in the cells, tissues and organs of living organisms. It is found that CA-II is one of the most abundant CA isoenzymes in the gastrointestinal system. It plays an important role in the gastric acid secretion in stomach. In this study, we purified CA-II isoenzyme from sheep stomach with a 615.2 purification fold, 78% purification yield and 5562.02 specific activity. Moreover, the in vitro effects of some commonly used pesticides including chlorpyrifos, cypermethrin, dichlorvos, glyphosate isopropylamine and lambda cyhalomethrin on the enzyme activity were investigated. Of these compounds, glyphosate isopropylamine and dichlorvos showed an inhibition on CA-II esterase activity. They have IC50 values of 0.155 µM and 2.690 µM and Ki values of 0.329 µM and 3.654 µM, respectively. Both glyphosate isopropylamine and dichlorvos inhibited CA-II isoenzyme in a noncompetitive manner.

Rapid tumor lysis syndrome in a patient with metastatic colon cancer as a complication of treatment with 5-fluorouracil/leucoverin and irinotecan.

Tumor lysis syndrome is a potentially fatal complication of anti-cancer therapy that is usually seen in patients with bulky, rapidly proliferating, treatment-sensitive tumors such as hematological malignancies, but it rarely occurs in a variety of solid tumors such as colorectal carcinoma. Combination chemotherapy with infusional 5-fluorouracil/leucoverin and irinotecan has been recently accepted as the first treatment option for metastatic colorectal cancer. We present a case of tumor lysis syndrome in a patient with metastatic colon carcinoma that occurred 72 hrs after the initial course of a combination chemotherapy with irinotecan and 5-fluorouracil/leucoverin. Despite the immediate treatment with aggressive hydration by a sodium bicarbonate infusion, followed by forced diuresis and uricolytic therapy, he died of a sudden cardiac arrest complicated by acute renal failure. Our case indicates that administration of 5-fluorouracil/leucoverin and irinotecan for bulky tumors of colorectal origin with a rapid doubling time may induce an acute tumor lysis syndrome, which necessitates frequent laboratory monitoring and a close follow-up of the patient as well as prompt initiation of appropriate therapeutic measures.

The significance of paired MEFV mutations in individuals without symptoms of familial Mediterranean fever.

The majority of patients with familial Mediterranean fever (FMF) have identifiable mutations in both alleles of the MEFV gene, while some individuals with paired MEFV mutations do not have clinical symptoms of the disease. During family studies we identified nine such individuals from six kindreds, most of whom either subsequently developed FMF or had other clinically significant inflammatory disease; one case benefiting substantially from colchicine therapy. Four individuals remained asymptomatic. Two further asymptomatic subjects with paired MEFV mutations were identified among 49 healthy controls from western Turkey, of whom a further 18.4 per cent were simple heterozygotes. This carrier rate was higher than would be expected from prevalence of FMF in this region, suggesting that penetrance of paired recognised pathogenic MEFV mutations may frequently be incomplete. MEFV genotyping results must be interpreted with due caution, and follow-up of apparently asymptomatic subjects with paired mutations is advisable.