Subjective adverse reactions to metronidazole in patients with amebiasis

Subjective adverse reactions to metronidazole were analyzed in 111 patients with amebiasis. Metronidazole was administered to 36 patients at a daily dose of 2250 mg and 75 patients at daily doses lower than 2250 mg. The reactions reported included nausea without vomiting in 11 (9.9%) patients, nausea with vomiting in 2 (1.8%), dysgeusia in 2 (1.8%), diarrhea in 1 (0.9%), headache in 1 (0.9%), numbness in 1 (0.9%), dizziness in 1 (0.9%), urticaria in 1 (0.9%), exanthema in 1 (0.9%), and discomfort in 1 (0.9%). Nausea was reported by 28% (10/36) of the patients receiving metronidazole at a daily dose of 2250 mg and 4% (3/75) of the patients receiving lower daily doses. The duration of the metronidazole administration in days was not associated with the appearance of nausea. No life-threatening adverse reactions were identified, and good clinical therapeutic effects were observed in 96% (107/111) of the patients. While metronidazole appears to be a safe anti-protozoal agent for patients with amebiasis, our results indicate that a daily metronidazole dose of 2250 mg is excessive for amebiasis, as it often induces nausea.     

Combined treatment of advanced malignant melanoma with coumarin and cimetidine

Summary Immunostimulant therapy with coumarin and cimetidine was evaluated in 17 patients with advanced malignant melanoma. Induction therapy with coumarin 100 mg daily was given for 8 weeks, whereupon cimetidine 1000 mg daily was added. No patients had been previously treated with cytotoxic drugs, and all patients had a good performance status. In 16 patients progressive disease was observed, and only 1 patient experienced no change in condition, lasting 30 weeks. We conclude that treatment with this schedule of coumarin and cimetidine is without effect in advanced malignant melanoma.     

Controlled comparison of cimetidine and carbenoxolone sodium in gastric ulcer.

Fifty-four outpatients with endoscopically diagnosed benign gastric ulcer were allocated at random to treatment with either cimetidine 800 mg daily for six weeks or carbenoxolone sodium 300 mg daily for one week then 150 mg daily for five weeks. Ulcers were reassessed by endoscopy at the end of the trial. The endoscopist was unaware of the treatment and did not take part in the clinical care of the patients. Twenty-one of the 27 patients (78%) given cimetidine and 14 of the 27 (52%) given carbenoxolone had healed ulcers. Symptomatic response occurred earlier with cimetidine but was not significantly better. Unwanted effects were more common in the carbenoxolone group: 12 patients developed hypokalaemia, four of whom needed oral potassium supplements. The results suggest that histamine H2-receptor blockade is at least as effective as carbenoxolone sodium for benign gastric ulcer and produces fewer side effects.     

Cimetidine and ranitidine in duodenal ulcer.

Two histamine H2 antagonists, cimetidine and ranitidine, given in doses of 1 g daily and 200 mg daily to 18 and 20 patients respectively proved equivalent in promoting healing of duodenal ulcer. No adverse effects occurred during the trial, though serum urea and creatinine concentrations tended to rise slightly during treatment with cimetidine but not ranitidine. Choice between the two drugs is likely to be influenced by overall patterns of adverse effects rather than considerations of individual potency.     

NXX-066 in patients with Alzheimer's disease: a bridging study

Reduced cholinergic transmission is a key neurotransmitter dysfunction in Alzheimer's Disease (AD). NXX-066, a physostigmine analog and acetylcholinesterase (AChE) inhibitor, has demonstrated activity in animal models of memory function, and was well tolerated in healthy subjects up to a single dose of 64 mg and multiple doses of 60 mg QD for seven days. Since AChE inhibitors are often tolerated differently in AD patients than in healthy volunteers, a randomized, placebo-controlled, double-blind, single-center, inpatient bridging study was conducted to determine the maximum tolerated dose (MTD) of NXX-066 in the target patient population. Seven consecutive panels of eight AD patients each (6 active, 2 placebo) received fixed oral doses of NXX-066 (20, 30, 40, 50, 60, 70, or 80 mg BID) for seven days. Initiation of each subsequent panel (dose group) was contingent upon the tolerability of lower dose levels. The MTD was determined to be 70 mg BID when four of six patients receiving 80 mg BID were prematurely discontinued from the study due to nausea and/or vomiting, accompanied in some patients by mild to moderate dizziness, headache, asthenia, and gastric symptoms. Wide variability in plasma levels of NXX-066 was observed in all dose panels. AChE inhibition in whole blood correlated with both maximum plasma concentration and dose; however, AChE inhibition was not predictive of adverse events. In this study, AD patients tolerated larger daily doses of NXX-066 on a BID regimen than healthy normal subjects had tolerated with QD dosing. Further studies are warranted to examine whether differing tolerability between patients and healthy subjects or the reduced dosing interval explains these findings.     

Serious renal transplant rejection and adrenal hypofunction after gradual withdrawal of prednisolone two years after transplantation.

Ten patients with stable renal function two years after transplantation had their sole immunosuppressive treatment (oral prednisolone 10 mg daily) withdrawn by reducing the daily dose by 1 mg at monthly intervals. Plasma prednisolone concentration, cortisol concentration, creatinine clearance, and serum creatinine concentration were measured in all patients, and the adrenal response to corticotrophin was determined in five by measuring plasma cortisol concentrations before and after tetracosactrin injection. No episodes of rejection occurred in patients taking over 7 mg prednisolone daily. Although three patients apparently required only minimal immunosuppressive treatment (less than 5 mg daily) the remainder suffered episodes of rejection at daily doses below 7 mg. There was a tenuous association between rejection and low plasma cortisol concentration, but neither the pattern of plasma prednisolone concentrations nor the response to tetracosactrin were related to episodes of rejection. Reducing the daily dose of oral prednisolone to under 7 mg should not be attempted in patients with renal transplants unless there are extenuating circumstances.     

Treatment of nonspecific diarrhea with metronidazole in rhesus macaques

Nonspecific diarrhea was successfully treated with metronidazole in 76% (13/17) of cases in adult rhesus macaques (Macaca mulatta). Effective treatment was achieved by oral administration of metronidazole daily at a low dose of 250 mg for at least eight days or at high daily doses of 500-1,500 mg for one to four days. Minimal effective total dose was 1500 mg. Apart from occasional vomiting, no side effects were observed.     

Evaluation of anti-emetic action of domperidone in patients treated with cytostatics]

Domperidone was administered to 40 patients with various neoplastic syndromes to prevent nausea and vomiting observed during previous courses of chemotherapy. It was found, that daily dose of 30 mg completely prevents nausea and vomiting in 30% of patients and significantly lowers such symptoms in further 58% of patients. An increase in a daily dose of 60 mg abolishes nausea and vomiting in 60%, and decrease their intensity in 35% of patients. Domperidone was administered orally during the whole period of chemotherapy without any adverse reactions related to its anti-dopamine actions.     

Radiopharmaceutical therapy of malignant pheochromocytoma with [131I]metaiodobenzylguanidine: results from ten years of experience.

Twenty-eight patients with histologically proven metastatic or invasive, unresectable pheochromocytomas, which were shown to concentrate and retain tracer doses of [131I]metaiodobenzylguanidine (131I-MIBG), were treated with therapeutic quantities of this radiopharmaceutical. Between one and six doses ranging from 97 to 301 mCi (cumulative dose 111-916 mCi) were administered. Partial response in tumor size was achieved in 8/28 patients and partial biochemical responses in 12/28 patients. No pharmacological toxicity was observed. Mild radiation sickness (nausea, vomiting, anorexia) occurred in 21/28. Minor degrees of leukopenia and thrombocytopenia were observed in 3/28. There were three cases of hypothyroidism but no significant hepatic, renal, adrenocortical or autonomic nervous dysfunction. We conclude that therapeutic 131I-MIBG can achieve significant therapeutic responses in some cases of malignant pheochromocytoma without pharmacological toxicity and only mild radiotoxicity.     

Low-dose subcutaneous recombinant interleukin-2 in advanced human malignancy: a phase II outpatient study

Recombinant interleukin-2 (rIL-2; EuroCetus, Amsterdam, Netherlands) was studied in an outpatient phase II trial in 14 patients with progressive metastatic renal carcinoma, malignant melanoma, and colorectal cancer. Escalating doses of rIL-2 were administered as subcutaneous bolus every 12 hours, starting at 0.3 million U/m2/d. A 100% dose increase occurred at weekly intervals, up to a maximum of 2.4 million U/m2/d. Responding patients or patients with stable disease after 4 weeks of rIL-2 (n = 9) were continued on maintenance therapy at 1.8 million U/m2 of rIL-2 administered once weekly. After 12 weeks of therapy, one renal cell cancer patient had a partial regression in lung metastases. Bolus injection of rIL-2 (1.2 million U/m2) resulted in peak serum levels of 25 to 30 U/ml. Toxicity of this regimen was moderate, with local inflammation at the injection sites, grade I-II (World Health Organization) malaise, nausea and/or vomiting, and fevers in 70% to 100% of patients treated. Thyroid dysfunction was observed in 10 patients receiving subcutaneous rIL-2; four of these patients had laboratory evidence of hyperthyroidism, and one had hypothyroidism. rIL-2-induced toxicity reversed spontaneously after cessation of treatment. In all patients receiving rIL-2, a dose-dependent increase in peripheral blood lymphocyte and eosinophil counts was noted, with a mean of 2.6 and 3.8 x 1,000/microliters after 4 weeks of therapy; mean lymphocyte and eosinophil counts were measured at 2.0 and 2.4 x 1,000/microliters in patients who received prior high-dose chemotherapy, compared with 3.2 and 5.1 x 1,000/microliters in those who did not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prophylactic effect of cimetidine in duodenal ulcer disease.

Fifty-seven symptom-free patients with duodenal ulcer entered a double-blind trial to assess the prophylactic effect of cimetidine. Patients were randomly allocated to receive cimetidine 400 mg twice daily (29 patients) or placebo (28 patients). The trial was designed to imitate daily clinical practice, so duodenal ulcer disease was diagnosed by means of x-ray examination. Three patients from each group withdrew from the trial. All remaining patients continued to receive treatment for 12 months or until symptoms recurred. Three out of 26 patients suffered relapses during cimetidine treatment, compared with 20 out of 25 receiving placebo. No side effects were attributable to cimetidine. Long-term cimetidine treatment had no curative effect as relapses occurred soon after treatment was stopped. The estimated chance (cumulative remission rate +/- 2 SE) of remaining symptom-free 13 weeks after one year''s cimetidine treatment had been completed was 47 +/- 21%. Maintenance treatment with cimetidine is a suitable alternative to elective in surgery in patients with duodenal ulcer subjects frequent relapses. Further study is needed to establish the optimal duration and safety of prolonged cimetidine treatment.     

两性霉素B治疗侵袭性肺部真菌感染的临床分析

目的 分析两性霉素B治疗ICU内侵袭性真菌感染的疗效与不良反应.方法 回顾性分析98例合并侵袭性肺部真菌感染的重症患者接受两性霉素B微泵静脉给药的临床资料.结果 两性霉素B的临床有效率77.55％,真菌清除率75.51％.不良反应包括寒战发热（9.18％）、皮疹（4.08％）、静脉炎（1.02％）、恶心呕吐（6.12％）、低钾血症（16.32％）、肝损害（1.02％）和肾损害（4.08％）.结论 国产两性霉素B对于重症患者侵袭性真菌感染疗效确定,采用持续微泵静脉给药不良反应发生率低.     

Long-term results of [131I]metaiodobenzylguanidine treatment of refractory advanced neuroblastoma.

Fourteen patients with advanced neuroblastoma, which was unresponsive to or had relapsed despite conventional therapy, were entered into a phase I/II trial of [131I]metaiodobenzylguanidine (131I-MIBG). Doses ranged from 1.85-8.14 GBq each (50-220 mCi), with cumulative doses of 1.85-24.20 GBq (50-654 mCi) in one to three doses. Side effects included mild nausea and vomiting and moderate myelosuppression which occurred in nine patients. Subjective responses occurred in five patients. Four patients had objective responses (one partial, two minor and one mixed). Two of these patients remain alive 80 and 60 months after beginning 131I-MIBG therapy. Comparison of the 131I-MIBG treated patients with 11 carefully matched control patients treated with an advanced current chemotherapy protocol (CCG 8605) was performed by means of Kaplan-Meier life table analysis. The 14% four-year survival with 131I-MIBG compared favorably with the 6% achieved by salvage chemotherapy. We thus believe 131I-MIBG may have a role in the management of neuroblastoma.     

Acute Toxicity of Ochratoxins A and B in Chicks

Ochratoxins A and B were given to 1-day-old Babcock B-300 cockerels to evaluate acute toxic effects. Two trials with ochratoxin A gave 7-day oral median lethal dose estimates of 116 mug (3.3 mg/kg) and 135 mug (3.9 mg/kg) per chick. Chicks given daily oral doses of 100 mug of ochratoxin A died on the second day. Single subcutaneous doses of 400 mug of ochratoxin A were also lethal. The 7-day oral median lethal dose of B was estimated at 1,890 mug (54 mg/kg) per chick. Chicks given oral doses of 100 mug of ochratoxin B daily for 10 days survived. Sublethal doses of both ochratoxins A and B resulted in growth suppression which was proportional to the amount of ochratoxin given. Visceral gout was the principal gross finding. Microscopic examinations revealed acute nephrosis, hepatic degeneration or focal necrosis, and enteritis. Suppression of hematopoiesis in the bone marrow and depletion of lymphoid elements from the spleen and bursa of Fabricius were frequently seen. Both ochratoxins appeared to have similar pathological effects. This is the first report on the toxicity of ochratoxin B.     

Embryo‐Fetal Developmental Toxicity Studies with Pregabalin in Mice and Rabbits

Pregabalin was evaluated for potential developmental toxicity in mice and rabbits. Pregabalin was administered once daily by oral gavage to female albino mice (500, 1250, or 2500 mg/kg) and New Zealand White rabbits (250, 500, or 1250 mg/kg) during organogenesis (gestation day 6 through 15 [mice] or 6 through 20 [rabbits]). Fetuses were evaluated for viability, growth, and morphological development. Pregabalin administration to mice did not induce maternal or developmental toxicity at doses up to 2500 mg/kg, which was associated with a maternal plasma exposure (AUC_0–24) of 3790 μg?hr/ml, ≥30 times the expected human exposure at the maximum recommended daily dose (MRD; 600 mg/day). In rabbits, treatment‐related clinical signs occurred at all doses (AUC_0–24 of 1397, 2023, and 4803 μg?hr/ml at 250, 500, and 1250 mg/kg, respectively). Maternal toxicity was evident at all doses and included ataxia, hypoactivity, and cool to touch. In addition, abortion and females euthanized moribund with total resorption occurred at 1250 mg/kg. There were no treatment‐related malformations at any dose. At 1250 mg/kg, compared with study and historical controls, the percentage of fetuses with retarded ossification was significantly increased and the mean number of ossification sites was decreased, which correlated with decreased fetal and placental weights, consistent with in utero growth retardation. Therefore, the no‐effect dose for developmental toxicity in rabbits was 500 mg/kg, which produced systemic exposure approximately 16‐times human exposure at the MRD. These findings indicate that pregabalin, at the highest dose tested, was not teratogenic in mice or rabbits     

Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one.

The main iron chelator used for transfusional iron overload is desferrioxamine, which is expensive, has toxic side effects, and has to be given subcutaneously. An orally active iron chelator is therefore required. The effects of oral 1,2-dimethyl-3-hydroxypyrid-4-one on urinary iron excretion were studied in eight patients who had received multiple transfusions: four had myelodysplasia and four beta thalassaemia major. Different daily doses of the drug up to 100 mg/kg/day, alone or in combination with ascorbic acid, were used. In three patients with thalassaemia the effect of the drug was compared with that of subcutaneous desferrioxamine at the same daily dose. In all eight patients a single dose of oral 1,2-dimethyl-3-hydroxypyrid-4-one resulted in substantial urinary iron excretion, mainly in the first 12 hours. Urinary iron excretion increased with the dose and with the degree of iron loading of the patient. Giving two or three divided doses over 24 hours resulted in higher urinary iron excretion than a single dose of the same amount over the same time. In most patients coadministration of oral ascorbic acid further increased urinary iron excretion. 1,2-Dimethyl-3-hydroxypyrid-4-one caused similar iron excretion to that achieved with subcutaneous desferrioxamine at a comparable dose. In some cases the iron excretion was sufficiently high (maximum 99 mg/day) to suggest that a negative iron balance could be easily achieved with these protocols in patients receiving regular transfusions. No evidence of toxicity was observed on thorough clinical examination or haematological and biochemical testing in any of the patients. None of the patients had any symptoms that could be ascribed to the drug. These results suggest that the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one is as effective as subcutaneous desferrioxamine in increasing urinary iron excretion in patients loaded with iron. Its cheap synthesis, oral activity, and lack of obvious toxicity at effective doses suggest that it should be developed quickly and thoroughly tested for the management of transfusional iron overload.     

Single or multiple daily doses of aminoglycosides: a meta-analysis.

OBJECTIVE--To assess relative efficacy and toxicity of aminoglycosides given by single daily dose compared with multiple daily doses. DESIGN--Meta-analysis of 21 randomised trials identified through MEDLARS (1966 to January 1995). Data were overviewed with fixed effects and random effects models and with meta-regression analysis. SUBJECTS--Total of 3091 patients with bacterial infection, most without pre-existing renal disease. INTERVENTIONS--Patients were randomized to receive aminoglycosides once daily or multiple times daily with similar total daily dose. MAIN OUTCOME MEASURES--Clinical failure of treatment, nephrotoxicity, ototoxicity, and mortality. RESULTS--Single daily dose regimen produced a non-significant decrease in risk of antibiotic failures (random effects risk ratio 0.83 (95% confidence interval 0.57 to 1.21)). Benefit of once daily dosing was greater when the percentage of pseudomonas isolates in a trial was larger. Once daily administration reduced risk of nephrotoxicity (fixed effects risk ratio 0.74 (0.54 to 1.00)). Similar trends were noted for patients with febrile neutropenia and for children. There was no significant difference in ototoxicity between the two dosing regimens, but the power of the pooled trials to detect a meaningful difference was low. There was no significant difference in mortality. CONCLUSIONS--Once daily administration of aminoglycosides in patients without pre-existing renal impairment is as effective as multiple daily dosing, has a lower risk of nephrotoxicity, and no greater risk of ototoxicity. Given the additional convenience and reduced cost, once daily dosing should be the preferred mode of administration.     

Comparison of the results of the treatment with pirenzepine combined with cimetidine and sucralfate of stomach ulcer resistant to cimetidine

Increased inhibition of gastric acid release through simultaneous blockade of H2-receptors and muscarine-receptors or administration of gastroprotective agent is theoretically justified in patients with peptic ulcer unresponsive to cimetidine. The study involved 70 patients with peptic ulcer previously treated with cimetidine in daily dose 1000 mg for 6 weeks without an effect. Patients were divided into two groups: group 1 treated with cimetidine plus pirenzepine, and group 2 given sucralfate in daily dose 4.0 g. Pirenzepine to patients of group 1 was given in a single dose of 50 mg before bedtime. Both groups were comparable in age, sex, disease onset, smoking, gastric acid secretion, and ulcer size. Healing was evaluated with endoscopic technique following 2 and weeks of therapy. Ulceration healed up within 2 weeks in 40% of patients treated with cimetidine combined with pirenzepine and in 31.4% patients treated with sucralfate. After 4 weeks, healing of ulceration was 71.4% and 68.6%, respectively. Large ulcers (over 1 cm in diameter) and previous partial gastrectomy did not affect healing rate. The obtained results suggest that administered therapies enable recovery in over 2/3 of patients with peptic ulcer unresponsive to a 6-week therapy with cimetidine alone.     

Radiotherapy in combination with low-dose chemotherapy in locally advanced head and neck cancer

A previous preclinical study revealed that the maximal additive effect between chemotherapy (CT) and irradiation (RT) occurred at a low level of CT. Therapy was therefore designed with an oral drug daily given in combination with RT in order to determine the efficacy and toxicity. Locoregionally advanced head and neck tumor patients were treated with simultaneous RT and CT. RT was administered 5 times per week at 2 Gy per fraction in a total dose of 70 Gy. Throughout the treatment 30 mg/kg Tegafur was given daily orally. In the period between 2000 and 2002, 50 patients were enrolled. Complete remission was attained in 60%, with an overall response rate of 94%. Acute mucositis of grade 2 or 3 was observed in 56% (28 patients), and gastrointestinal and hematologic toxicity of grade 2 or 3 occurred in 8% (4 patients). Because of side-effects, the duration of treatment was at most 2 weeks longer. Toxicity was eliminated quickly by careful supportive therapy. In conclusion, it is considered that oral low-dose CT in combination with RT is an efficient and simple mode of treatment for locally advanced head and neck tumor patients with a poor prognosis.     

The pharmacokinetics of H2 receptor blocking agents in compensated liver cirrhosis

The bioavailability of oral and intravenous cimetidine and ranitidine was studied in patients with compensated liver cirrhosis. Single doses of 200 and 400 mg cimetidine were used for both administration routes, while ranitidine was administered in doses of 150 mg orally or 50 mg i.v. Plasma concentrations and urinary recovery were determined by the HPLC method. The pharmacokinetics of both of these drugs in the cirrhotic patients did not differ from those found in normal subjects. The two doses of cimetidine given i.v. gave rise to the same plasma concentrations, while after oral administration, 400 mg produced higher plasma concentrations than 200 mg. As to the pharmacokinetic parameters, neither cimetidine nor ranitidine administered i.v. offered any further advantages compared to the oral route. The urinary recovery of both cimetidine and ranitidine was higher after intravenous than after oral administration. It is concluded therefore that the pharmacokinetics of cimetidine and ranitidine is not altered in compensated liver cirrhosis.