Hughes W T, Smith B L
Antimicrob Agents Chemother. 1984 Oct;26(4):436-40. doi: 10.1128/AAC.26.4.436.
The purpose of this study was to identify new drugs for the prevention and treatment of Pneumocystis carinii pneumonitis (PCP) induced in rats by continuous daily dosage with dexamethasone. Initially, test drugs were administered prophylactically as a screen for efficacy. Drugs were selected because of their known activity against certain protozoa and their tolerance in human usage. Doses were based on previous studies in rats or estimated from usage in humans and lower animals. Allopurinol (50 mg/kg per day), ketoconazole (25 mg/kg per day), difluoromethylornithine (2.5 g/kg per day), diloxanide (125 mg/kg per day, nifurtimox (100 mg/kg per day), suramin (20 mg/kg per day), melarsoprol (20 mg/kg per day), gentian violet (0.5 mg/kg per week, 5 and 50 mg/kg per day), primaquine (5.6 mg/kg per day) and chloroquine (37.5 mg/kg per day) were ineffective, whereas diaminodiphenylsulfone (daspone) (25 mg/kg per day) was totally effective in preventing the infection. Diaminodiphenylsulfone was then evaluated at dose levels of 5, 25, and 125 mg/kg per day and compared with trimethoprim-sulfamethoxazole (TMP-SMZ), given at 50 per 250 mg/kg per day orally. The two highest dose levels of diaminodiphenylsulfone and TMP-SMZ prevented the infection in all of the animals, and the lowest dose of diaminodiphenylsulfone prevented it in 40% of the rats. All of the untreated controls developed PCP. To determine therapeutic efficacy, animals with extensive PCP were treated for 2.5 weeks with diaminodiphenylsulfone or TMP-SMZ. Based on residual extensive pneumonitis at the completion of treatment, the pneumonitis was reduced to 50% by TMP-SMZ and to 25% by diaminodiphenylsulfone, whereas 100% of untreated controls had extensive PCP. When treatment was begun earlier in the course of the pneumonitis, diaminodiphenylsulfone was totally effective in eradicating the infection. These results suggest that diaminodiphenylsulfone is an effective drug for the treatment and prevention of murine PCP and that it is at least as effective as TMP-SMZ.
本研究的目的是确定用于预防和治疗因每日连续给予地塞米松诱导大鼠发生卡氏肺孢子虫肺炎（PCP）的新药。最初，预防性给予受试药物以筛选其疗效。选择这些药物是因为它们对某些原生动物具有已知活性且在人体使用中具有耐受性。剂量基于先前在大鼠中的研究或根据人体及低等动物的使用情况估算。别嘌醇（每日50毫克/千克）、酮康唑（每日25毫克/千克）、二氟甲基鸟氨酸（每日2.5克/千克）、双碘喹啉（每日125毫克/千克）、硝呋替莫（每日100毫克/千克）、苏拉明（每日20毫克/千克）、美拉胂醇（每日20毫克/千克）、龙胆紫（每周0.5毫克/千克，每日5毫克和50毫克/千克）、伯氨喹（每日5.6毫克/千克）和氯喹（每日37.5毫克/千克）均无效，而氨苯砜（每日25毫克/千克）在预防感染方面完全有效。然后对氨苯砜在每日5、25和125毫克/千克的剂量水平进行评估，并与口服给予的甲氧苄啶-磺胺甲恶唑（TMP-SMZ）（每日50比250毫克/千克）进行比较。氨苯砜和TMP-SMZ的两个最高剂量水平可预防所有动物感染，氨苯砜的最低剂量可预防40%的大鼠感染。所有未治疗的对照均发生PCP。为确定治疗效果，对患有广泛PCP的动物用氨苯砜或TMP-SMZ治疗2.5周。根据治疗结束时残留的广泛肺炎情况，TMP-SMZ可将肺炎减少至50%，氨苯砜可将其减少至25%，而100%未治疗的对照患有广泛PCP。当在肺炎病程中更早开始治疗时，氨苯砜在根除感染方面完全有效。这些结果表明氨苯砜是治疗和预防小鼠PCP的有效药物，且其疗效至少与TMP-SMZ相同。
