Effects of 5-fluorouracil Co-administration on Blood Pressure in Patients Maintained on Antihypertensives: a Retrospective Case Series.

This study aimed to investigate the possible drug-drug interactions (DDIs) of 5-FU with antihypertensives metabolised by CYP3A4 and 2C9, using blood pressure (BP) as a pharmacodynamic (PD) parameter. Patients who received 5-FU in combination with antihypertensives metabolised by CYP3A4 or 2C9, specifically, a) amlodipine, nifedipine, or amlodipine + nifedipine, b) candesartan or valsartan, or c) amlodipine + candesartan, amlodipine + losartan, or nifedipine + valsartan, (Group A, n = 20) were identified. Patients who received 5-FU with WF and antihypertensives, specifically, a) amlodipine or b) amlodipine + telmisartan, amlodipine + candesartan, or amlodipine + valsartan, (Group B, n = 5) or 5-FU alone (Group C, n = 25) were also identified and analysed as a comparator and control group, respectively. Regarding the peak BP levels during chemotherapy, there was a significant increase in both SBP (P < 0.0002 and 0.0013) and DBP (P = 0.0243 and 0.0032) in Groups A and C, respectively (Tukey-Kramer test). In contrast, although SBP also increased in Group B during chemotherapy, the change was not statistically significant and there was a decrease in DBP. The significant increase in SBP can be attributed to chemotherapy-induced hypertension by 5-FU or other drugs in the chemotherapeutic regimens. However, when comparing the lowest BP levels during chemotherapy, there was a decrease in SBP and DBP in all groups from the baseline values. The median time to peak and lowest BP was at least 2 weeks and 3 weeks, respectively, for all groups, suggesting that a BP lowering effect was observed following the offset of the initial chemotherapy-induced hypertension. At least 1 month after 5-FU chemotherapy, the SBP and DBP returned to baseline values in all groups. Since Group B also showed a significant increase in PT-INR, possibly demonstrating 5-FU inhibition of CYP activity and, consequently, of WF metabolism, it is likely that 5-FU also inhibited the metabolism of the antihypertensive drugs. The findings suggest possible DDIs between 5-FU and antihypertensives metabolised by CYP3A4.

[Six-month intraperitoneal toxicity study of cefpirome sulfate in rats].

A six-month intraperitoneal chronic toxicity study of cefpirome sulfate (CPR) in rats as well as a two-month recovery study were carried out at dose levels of 51.2, 128, 320 and 800 mg/kg/day. The results are as follows. 1. CPR caused no remarkable clinical signs in the general condition of the animals. 2. Body weight gain was depressed in males and females given 800 mg/kg/day. Food consumption, however, was not afected at any dose level. Water consumption increased in males and females at dose of greater than or equal to 320 mg/kg/day. 3. Except an increase in urine volume in males at 800 mg/kg/day, no abnormalities in urinary parameters were found. 4. Frequent decreases in erythrocyte count, hematocrit and hemoglobin concentration were seen in males and females of the 800 mg/kg/day group. At this dose, certain males and females also showed an increase in the reticulocyte count. 5. The serum-biochemical examinations showed a very slight or slight decrease in total cholesterol in males and females given 320 mg/kg/day or more, and increases in uric acid and inorganic phosphorus concentration in some males and females given 800 mg/kg/day. 6. Very slight or slight increases in spleen weight in males and females at a dose of greater than or equal to 320 mg/kg/day, in thyroid weight in females at a dose of greater than or equal to 320 mg/kg/day and in kidney weight in males given 320 mg/kg/day or more as well as in females at 800 mg/kg/day were measured. Further, a decrease in thymus weight was seen in females of the 800 mg/kg/day group. 7. At autopsy, very slight or slight reddish browning of the thyroid was seen in males given 320 mg/kg/day or more and in females given 800 mg/kg/day.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacological investigations of the new antiinflammatory agent 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid. 1st communication: inhibitory effects of rat paw edema.

In the development process of a new nonsteroidal antiinflammatory drug (NSAID) with less toxicity and side-effects, 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepein-2-yl) propionic acid (CN-100) was chosen as the most excellent NSAID from synthetic tricyclic compounds after screening test. For the series of studies on antiinflammatory effects of this compound in detail, its effect on rat paw edema induced by various phlogists was first investigated. The inhibitory effect of CN-100 on carrageenin-induced edema was remarkable and nearly equal to that of indometacin. The effect was not affected by continuous administration for 2 weeks or adrenalectomy. Similarly to indometacin, CN-100 had no significant effect on yeast-induced edema mediated by 5-hydroxytryptamine and concanavalin-A-induced edema unrelated with prostaglandins. However, CN-100 displayed a weaker inhibitory effect on nystatin-induced edema than indometacin, suggesting that CN-100 has a low membrane stabilizing action and a strong blocking action on synthesis of prostaglandins. CN-100 inhibited the sustained edema induced by mustard, but the drug did not interfere with the increase in body weight of rats. Indometacin in the same dose caused decrease in body weight and death. The toxicity of CN-100 was definitely less than that of indometacin, although both drugs were similar in antiinflammatory activity and mode of action on rat paw edema. Results suggest that CN-100 is an effective drug on not only acute but also subacute and chronic inflammation.

Pharmacological investigations of the new antiinflammatory agent 2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl]propionic acid. 4th communication: inhibitory effects on rat adjuvant arthritis.

The preventive and therapeutic effects of 2-(10,11-dihydro-10-oxodibenzo [b,f]thiepin-2-yl)propionic acid (CN-100) on local and systemic changes of rats with adjuvant arthritis being used frequently as experimental model of rheumatoid arthritis were investigated in comparison with those of reference drugs, indometacin and pranoprofen. Preventively and therapeutically CN-100 showed potent inhibitory effects on adjuvant primary inflammation and secondary lesion. CN-100 also exerted an evident preventive effect on destruction of foot bone, improved the changes in organ weight, and stimulated weight gain. These effects were dose-dependent, and the effects at 5.0 mg/kg were almost the same as those of indometacin and pranoprofen at 1.25 and 2.5 mg/kg, respectively. The mode of action of CN-100 resembled that of reference compounds. Although CN-100 improved the change in albumin/globulin ratio, which was a parameter of systemic inflammatory reactions, the effect was more remarkable in therapeutic administration than in preventive one. This suggests that CN-100 is suitable for clinical application.

[Effect of alpha-(p-thenoylphenyl)-propionic acid (TN-762) on acute inflammatory reactions and prostaglandin biosynthesis].

A series of compounds with the general structure of phenylpropionic acid was originally synthesized for anti-inflammatory screening. The title compound, TN-762, showed marked anti-inflammatory and analgesic activities and was less toxic. This compound was the same as suprofen which was reported by Janssen to have potent anti-inflammatory and anti-writhing activities. Effects of TN-762 on acute inflammatory reactions and prostaglandin biosynthesis were investigated in animal models and findings compared to those of ketoprofen and indomethacin. TN-762 showed a dose-dependent inhibition at low doses of 5-20 mg/kg, p.o. on an increased vascular permeability induced by histamine in rats and by acetic acid in mice and carrageenin-induced paw edema in rats. The anti-inflammatory activity of TN-762 was much the same as that of ketoprofen and indomethacin. The inhibitory effect of TN-762 on carrageenin-induced paw edema was not affected by successive administration for 14 days and/or by adrenalectomy. The compound was more active than the two reference compounds in inhibiting ultraviolet erythema in guinea pigs. TN-762 inhibited markedly the arachidonic acid potentiation of carrageenin-induced edema in rat paw, the sudden death following intraveneous administration of arachidonic acid to rabbits and the diarrhea produced by endotoxin in mice, all considered to be induced by biosynthetic prostaglandins. The activities of TN-762 were the same or were more potent than those of ketoprofen and indomethacin. On the contrary, the ulcerogenic activity of TN-762 on the gastrointestinal tract in rats was significantly less than that of ketoprofen and indomethacin. From the above results, TN-762 proved to be a potent inhibitor of acutely-induced inflammation and of prostaglandin biosynthesis, however, the ulcerogenic effects were comparatively diminished.