1-n-methyl-5-thiotetrazole and Vitamin-K-Deficiency

The mechanism of hypoprothrombinemia induced by cephalosporins containing the N-methylthiotetrazole (NMTT) side chain has been investigated in a randomized clinical, trial (pilot study) with 14 hospitalized patients (main inclusion criteria: age greater than or equal to 50 years, urinary tract infection, normal prothrombin time. Therapy groups: latamoxef (n = 5), cefoperazone (n = 5), cefotaxime (control, n = 4). Duration of treatment: 7 days). Two patients under cefoperazone exhibited a significant increase of prothrombin time, accompanied by the appearance of PIVKA II (prothrombin induced in vitamin K absence). Both cefoperazone (in 4 patients) and latamoxef (in 3 patients) caused the appearance of endogenous vitamin K1 2,3-epoxide, whereas cefotaxime did not. This confirms the hypothesis that NMTT-cephalosporins are inhibitors of hepatic vitamin K epoxide reductase, and that this is at least partly responsible for the clinically observed hypoprothrombinemia. In older patients treated with these antibiotics, prothrombin time should be controlled before as well as under therapy. Unexpectedly, the patients displaying an appearance of vitamin K1 2,3-epoxide showed a statistically significant increase of endogenous plasma vitamin K levels. This effect needs further investigation.

Topics: Aged; Aged, 80 and over; Azoles; Blood Coagulation Disorders; Cefoperazone; Cefotaxime; Cephalosporins; Female; Humans; Male; Moxalactam; Pilot Projects; Protein C; Prothrombin Time; Random Allocation; Tetrazoles; Urinary Tract Infections; Vitamin K Deficiency

We experienced a case of epidural hematoma caused by coagulopathy 3 days after surgery. A 72-year-old man, who had undergone a total gastrectomy, suffered from nausea and vomiting by ileus. He underwent repair of ileus under general anesthesia with thoracic epidural anesthesia. Three days after surgery, abnormal bleeding followed by disorder of prothrombin activity (PT) and activated partial thromboplastin time (aPTT) and paralysis due to thoracic epidural hematoma developed. It was suspected that these coagulopathies were the results of vitamin K deficiency. Vitamin K deficiency in this patient was considered to have been caused by cephem antibiotics containing N-methyl-thiotetrazole (NMTT) side chain and no oral intake of food for a few days preoperatively. The patient was treated with fresh frozen plasma and intravenous menatetrenon, which improved abnormal bleeding and disorder of PT and aPTT within 24hr. After a discussion with orthopedic consultants, we selected a conservative therapy rather than surgical removal of the hematoma. Thoracic epidural hematoma disappeared two months after surgery, but motor paralysis requiring rehabilitation remained. In conclusion, when patients have not eaten anything for a few days and antibiotics with an NMTT sidechain has been administered, care must be taken to prevent vitamin K deficiency and coagulopathy.

Topics: Aged; Anesthesia, Epidural; Anesthesia, General; Carbapenems; Gastrectomy; Hematoma, Epidural, Spinal; Humans; Ileus; Infusions, Intravenous; Male; Plasma; Postoperative Complications; Stomach Neoplasms; Tetrazoles; Vitamin K 2; Vitamin K Deficiency

Latamoxef (daily 100 and 300 mg/kg, i.v.) was injected once a day for 8 days to 75% and 90% nephrectomized rats kept on a vitamin K-sufficient diet (500-600 ng/g) or a vitamin K-deficient diet (30-50 ng/g), and changes in ADP-induced platelet aggregation and prothrombin time were examined. The half-life of latamoxef was markedly prolonged and plasma latamoxef and N-methyltetrazolethiol (NMTT) concentrations increased, resulting in a delay of the total body clearance of the compounds. The ADP-induced platelet aggregation increased after nephrectomy, and latamoxef slightly but inconsistently decreased the aggregation. Prothrombin time did not change even in the 90% nephrectomized rats kept on an ordinary diet, but increased dose-dependently in the vitamin K-deficient nephrectomized rats, with the 90% nephrectomized animals showing larger increases of prothrombin time. These data suggest that NMTT or NMTT-containing antibiotics cause no hypoprothrombinemia even in partially nephrectomized rats when they are fed an ordinary diet containing vitamin K, but these compounds enhance the manifestation of hypoprothrombinemia in vitamin K deficiency. Further renal failure promotes the manifestation by increasing drug concentration in the blood. However, platelet aggregation in these animals is not significantly affected at the doses examined.

Topics: Adenosine Diphosphate; Animals; Blood Platelets; Creatinine; Glomerular Filtration Rate; Male; Moxalactam; Nephrectomy; Prothrombin Time; Rats; Rats, Inbred Strains; Tetrazoles; Vitamin K Deficiency

Decreased concentrations of vitamin K-dependent plasma clotting factors are a well-documented response of vitamin K-deprived patients administered broad-spectrum antibiotics. It has recently been claimed that antibiotics containing a N-methylthiotetrazole (NMTT) side chain cause this response through a direct effect of NMTT on the vitamin K-dependent posttranslational carboxylation of these clotting factors. To further study these relationships, 11 groups of three volunteers were fed a synthetic vitamin K-free diet for 2 weeks. During the last 10 days of vitamin K restriction, seven of the volunteer groups received a therapeutic dose of antibiotics not containing NMTT: ampicillin, sulfamethoxazole-trimethoprim (Bactrim), cefoxitin, cefotaxime, ceftazidime, clindamycin, and piperacillin, and three groups received NMTT-containing antibiotics: moxalactam, cefamandole, and cefoperazone. Serum phylloquinone (vitamin K1) concentrations reflected dietary intake and fell from 1.4 +/- 0.9 ng/ml after 3 days of hospital diet to 0.4 +/- 0.3 ng/ml after 13 days of vitamin K-free diet. Median stool excretion of phylloquinone was 19 micrograms/day while subjects consumed the hospital diet, and fell to 3 micrograms/day by day 6 on vitamin K-free diet. Prothrombin times remained within the normal range throughout the study. Suppression of vitamin K-dependent clotting factor biosynthesis was evident by decreased factor VII levels in seven of the volunteers and by an increased concentration of des-gamma-carboxy (abnormal) prothrombin in 21 of the volunteers. The changes occurred in the control subjects and in subjects receiving all nine of the 10 antibiotics with no consistent pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Anti-Bacterial Agents; Blood Coagulation Factors; Humans; Male; Middle Aged; Prothrombin Time; Tetrazoles; Vitamin K 1; Vitamin K Deficiency

N-Methyltetrazolethiol (NMTT) increased prothrombin time (PT) and decreased plasma factor VII and prothrombin levels only in vitamin K-deficient male rats. In female rats identical treatment with NMTT did not produce hypoprothrombinemia. Conventional and germ-free rats displayed no significant difference in the manifestation of hypoprothrombinemia, but the increase of PT in NMTT-treated vitamin K-deficient rats was greater in the germ-free males. Estradiol administration or castration of male rats retarded manifestation of vitamin K deficient syndromes such as increases of PT and activated partial thromboplastin time (APTT), decreases of plasma factor VII and prothrombin levels, and increases of plasma and liver descarboxyprothrombin (PIVKA) levels, and testosterone injection to the castrated rats restored these changes. In female rats testosterone treatment or castration enhanced the manifestation of hypoprothrombinemia and estradiol treatment to the castrated females retarded it. Gamma-glutamyl-carboxylase activity was increased by vitamin K-deficiency but not inhibited by testosterone or NMTT. These data suggest that estrogen protects the rat against manifestation of hypoprothrombinemia even with NMTT treatment, while androgen enhances vitamin K deficiency, and supplementation of vitamin K prevents its deficiency in NMTT-treated rats.

Topics: Animals; Azoles; Estradiol; Factor VII; Female; Germ-Free Life; Gonadal Steroid Hormones; Hypoprothrombinemias; Male; Orchiectomy; Partial Thromboplastin Time; Prothrombin; Rats; Rats, Inbred Strains; Testosterone; Tetrazoles; Vitamin K Deficiency

To determine whether the hypoprothrombinemia associated with antibiotics containing a 1-methyl-5-thiotetrazole (MTT) group is a result of the presence of the MTT group, rats were maintained on a vitamin K-deficient diet for 10 days and then received either intravenous moxalactam or cefotaxime or oral MTT for two additional days. MTT and moxalactam, which contains the MTT group, prolonged prothrombin time. Cefotaxime, which lacks the MTT group, had no effect.

Topics: Administration, Oral; Animals; Azoles; Cefotaxime; Female; Hypoprothrombinemias; Injections, Intravenous; Moxalactam; Prothrombin Time; Rats; Rats, Inbred Strains; Tetrazoles; Vitamin K Deficiency

Topics: Animals; Azoles; Carbon-Carbon Ligases; Ligases; Male; Microsomes, Liver; Moxalactam; Rats; Rats, Inbred Strains; Tetrazoles; Vitamin K Deficiency