Phase II Study of Mitoxantrone in Patients With Non-Small Cell Lung Cancer

A phase II study of mitoxantrone was performed in 24 patientswith non-small cell lung cancer (NSCLC). Mitoxantrone was administeredby intravenous drip infusion of 12 mg/m² every three weeks.There were no responders among the 21 evaluable patients includingfive patients without prior therapy. The major hematologicaltoxic effect was leukocytopenia. Thrombocytopenia and decreasein hemoglobin were slight. A change in the electrocardiogramwas observed in one patient and one patient experienced cardiogenicshock. Mitoxantrone is not acceptable for the treatment of NSCLC becauseof its low antitumor activity, and careful observation is neededfor administration of this agent to patients with pre-existingrisk factors, such as prior anthracycline exposure, mediastinalradiation or underlying cardiovascular disease.     

The Protective Effect of 2-Mercapto-Ethane Sulfonate (MESNA) on Hemorrhagic Cystitis Induced by High-Dose Ifosfamide Treatment Tested by a Randomized Crossover Trial

High-dose ifosfamide (one or two courses of 6 g/m²) with orwithout mesna was administered to 13 patients with advancednon-small cell lung cancer. The protective effect of 2-mercapto-ethanesulfonate (mesna) against the urotoxic side effects inducedby ifosfamide was examined by a randomized crossover trial.A significant reduction in the incidence of hematuria was observedin the patients receiving mesna. Macroscopic hematuria was observedin only one patient who received treatment with mesna versusseven patients treated with ifosfamide alone. Other symptoms,such as frequency and dysuria, tended to be diminished in thepatients receiving mesna, although the difference was not statisticallysignificant. Our results suggest that mesna is effective inpreventing or diminishing ifosfamide-induced hemorrhagic cystitis.Concomitant use of mesna should allow the administration ofa high dose of ifosfamide although more extensive studies areneeded to define the optimal dose and schedule of administrationof mesna to prevent or attenuate the hemorrhagic cystitis.     

Risks of antipyretics in young children with fever due to infectious disease

The objective of this study was to determine whether paracetamol (acetaminophen) affects the outcome of children with fever due to bacterial infectious disease. A total of 208 outpatients aged 6 months to 15 years with pyrexia due to bacterial infection who had been examined at the Fujimoto Children's Hospital from March 1992 to May 1992. The number of antipyretic doses of paracetamol (10 mg/kg) a day received within 3 days of illness in the patients with acute fever (≥ = 38°C) was investigated. In this study, the patients were divided into two groups: (i) the pneumonia group, which consisted of 101 patients who were subsequently diagnosed as having pneumonia during their illness and (ii) the control group, which consisted of 107 patients who were subsequently diagnosed as having illness with fever that did not progress to pneumonia. The mean number of daily doses was significantly higher for the pneumonia group (2.52 ± 0.80) than for the control group (1.37 ± 0.72, P < 0.001). There was no significant difference between the pneumonia group and the control group in body temperature during acute fever (38.7 ± 0.65 vs 38.8 ± 0.54°C). The data suggest that frequent administration of antipyretics to children with infectious disease may lead to a worsening of their illness.     

Evaluation of biological activities of new LH-RH antagonists (T-series) in male and female rats

A series of new highly potent LH-RH antagonists (T-series) has been synthesized in our laboratory. Among these analogs, antagonists [Ac-d -Nal(2), d -Phe(4Cl)². d -Pal(3)³, d -Lys(A₂pr(Car)₂)⁶, d -Ala¹⁰LH-RH (T-140); [Ac-d -Nal(2)¹, d -Phe(4Cl)², d -Pal(3)³, d -Lys(A₂pr(Ac)₂)⁶, d -Ala¹⁰]LH-RH (T-148); [Ac-d -Nal(2)¹, d -Phe(4Cl)², d -Pal(3)³, d -Lys(A₂pr(For)₂)⁶, d -Ala¹⁰)]LH-RH (T-151) and [Ac-d -Nal(2)¹, d -Phe(4cl)², d -Pal(3)³, d -Lys(A₂bu(For)₂)⁶, d -Ala¹⁰]LH-RH (T-159) were the most powerful. Antagonists T-140, T-148 and T-151 produced a complete blockade of ovulation in normal cycling rats at a dose of 1.5 μg/rat and antagonist T-159 at a dose of only 0.75 μg/rat. The inhibitory effects of compounds T-148, T-151 and T-159 on gonadotropin and sex steroid secretion were investigated in male and female rats. To determine their effect on LH levels in castrated male and ovariectomized female rats, T-148, T-151 and T-159 were injected subcutaneously in doses of 0.625 and 2.5 μg/rat. Blood samples were taken at different intervals for 48 h. All three compounds at either dose caused a significant (P< 0.01) decrease in LH levels for more than 6 h. Significant (P <0.01) inhibition of LH lasted for more than 24 h following a dose of 2.5 μg sc of all 3 antagonists in both male and female rats. Serum FSH levels were also suppressed significantly for more than 48 h in castrated male rats by all three antagonists at a dose of 5 μg/rat sc. Serum testosterone levels were measured in intact male rates injected with antagonists T-148, T-151 and T-159 in doses of 50 and 100 pg sc. Both doses produced a dramatic fall in testosterone (P<0.01) to castration levels 6 h after injection. The inhibition of serum testosterone lasted for more than 48 h, but only 100 μg of T-148 maintained testosterone in the castration range for more than 48 h. Antagonists T-148, T-151 and T-159 injected at a dose of 100 μg to intact female rats reduced serum estradiol levels significantly (P<0.01) for more than 48 h, as compared to control animals. In the cutaneous anaphylactoid test (CAT), T-148, T-151 and T-159 proved to have very low histamine releasing activities. These data demonstrate a high efficacy of these new LH-RH antagonists in suppressing the pituitary-gonadal axis in male and female rats. These LH-RH antagonists could possibly be used for treatment of sex-hormone sensitive cancers and other disorders and conditions, in which a reduction in circulating sex steroids would be beneficial.     

Selective high dose gamma-globulin treatment in Kawasaki disease: Assessment of clinical aspects and cost effectiveness

BACKGROUND: High-dose intravenous gamma-globulin (IVGG) plus aspirin (ASA) treatment is effective in preventing coronary artery complications in acute Kawasaki disease (KD). However, gamma-globulin is very expensive, especially in Japan. Furthermore the indication for IVGG treatment and the optimal dose of gamma-globulin remain controversial. OBJECTIVES: To examine these two issues, we used Harada's scoring system to investigate whether a single 2 g/kg dose therapy has any advantage over the 5 day 400 mg/kg per day therapy. METHODS: We studied 203 patients with KD who had no coronary artery complications on admission. Of these, 145 patients scored 4 or more on Harada score within the first 9 days of illness and were treated with IVGG treatment. Using a random number table, 72 patients were selected to receive a single 2 g/kg dose (2 g group), while the remaining 73 patients were treated with 400 mg/kg per day for 5 consecutive days (400 mg group). Those who had a Harada score of three or less received no IVGG (non-IVGG group) treatment (58 patients). RESULTS: The incidence rate of coronary artery complications in the 2 g group was significantly lower than in the 400 mg group. The duration of high fever, positive duration of C-reactive protein and the number of hospital days in the 2 g group were each significantly shorter than in the 400 mg group. The total medical expense in the 2 g group was significantly lower than in the 400 mg group. There were no coronary artery complications in the non-IVGG group. CONCLUSIONS: It was found to be clinically more effective and more cost effective to select a patient by Harada's scoring system and, where a score of four or more was obtained, to administer a single 2 g/kg intravenous dose of gamma-globulin for acute KD.     

Preliminary Phase II Study of Adriamycin (ADM) in Patients with Non-Small Cell Lung Cancer (NSCLC)

A phase II study of adriamycin (ADM) (60 mg/m² was performedin 22 patients with non-small cell lung carcinoma (NSCLC). Therewere no responders in the 19 evaluable patients (16 with adenocarcinoma,two with squamous cell carcinoma and one with large cell carcinoma).The major side effects were alopecia (89%), leukocytopenia (73%),thrombocytopenia (58%) and upper gastrointestinal symptoms. Although ADM at 60 mg/m² did not appear to have sufficient antitumoractivity against NSCLC in this study, it is necessary to evaluatefurther the efficacy of ADM against NSCLC with another treatmentschedule.     

Phase II Study of UFT in Patients With Advanced Non-Small Cell Lung Cancer

A phase II study of UFT (a mixture of uracil and tegafur; molarratio of uracil to tegafur = 4) was undertaken in 21 patientswith advanced non-small cell lung cancer (NSCLC). UFT was administeredorally at a dose of 400 mg/m² every day, for more than fourweeks. Of 16 adequately treated patients, one (6.3%) showed a partialresponse. Toxic effects included minimal myelosuppression, anorexia,nausea, vomiting and epigastralgia. Gastrointestinal toxicitywas well tolerated. Considering the poor response and mild toxicity,a further phase II study of higher-dose UFT is necessary forpatients without prior therapy.     

Antiemetic Efficacy of High-Dose Intravenous Metoclopramide and Dexamethasone in Patients Receiving Cisplatin-Based Chemotherapy: A Randomized Controlled Trial

High-dose intravenous (IV) metoclopramide has shown efficacywith few side effects for the treatment of nausea and vomitingon the day of cisplatin administration. From November 1984 toJanuary 1986, two randomized trials in an antiemetic study wereconducted. In trial I, the antiemetic effect of a short courseof high-dose dexamethasone was compared with that of high-dosemetoclopramide in 29 patients with lung cancer receiving chemotherapycon taining cisplatin (80 mg/m² IV) in a randomized controlledtrial. Dexamethasone was given IV at a dose of 16 mg 1/2 hrbefore and 8 mg, 1 1/2, 3 1/2 and 5 1/2 hr after cisplatin.Metoclopramide was given IV at a dose of 2 mg/kg, 1/2 hr beforeand 1 1/2, 3 1/2 and 5 1/2 hr after cisplatin. Major emeticcontrol (0–2 episodes of vomiting) during the 24 hr aftercisplatin administration was achieved in 55% (6/11) and 67%(12/18) of the patients receiving dexa methasone and metoclopramide,respectively, without serious toxicity. The dura tion of nauseaor anorexia was similar for the two treatment groups. In trial11, the combination of metoclopramide and dexamethasone wascompared with metoclopramide alone to assess the additive antiemeticeffect of the two drugs in 23 patients with lung cancer receivingcisplatin at a dose of 120 mg/m IV in a randomized cross-overstudy. A major antiemetic response was observed in 27% (3/11)and 92% (11/12) of the patients receiving metoclopramide aloneand metoclopramide plus dexamethasone, respectively (p <0.005). The duration of nausea and anorexia was similar forthe two treatment groups. Pa tients tended to prefer the combinationof metoclopramide and dexamethasone; however, the differencewas not statistically significant (p = 0.14) in the small numberof patients entered in this study. Despite excellent controlof acute chemotherapy-induced emesis, 45% of 52 patients experienceddelayed nausea and vomiting more than 24 hr after cisplatinadministration even among those who had had an excellent short-termresponse to the antiemetic agents.