Safety evaluation of NK 631. Antigenicity, effect on delated hypersensitivity, irritative effect on eye mucous membrane and mutangenicity of pepleomycin (NK 631) (author's transl)]

1. Whether NK 631 is antigenic to guinea pigs and rabbits was studied by the methods of active and passive anaphylactic shock tests, Schultz-Dale reaction, passive cutaneous anaphylaxis, Ouchterlony, tanned red cell haemagglutination test and test according to the U.S. Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. However, none of the tests proved NK 631 to be antigenic. 2. The immunosuppressive effect of NK 631 was studied by delayed hypersensitivity to picryl chloride in normal and L-1210 tumor bearing mice. Therapeutic dosis of NK 631 was no immunosuppressed but toxic dosis of NK 631 was slightly decreased in ear thickness of delayed hypersensitivity. 3. The acute irritative effect of NK 631 and of bleomycin was studied by single instillation to the rabbit eye mucous membrane with 0.1 ml of either of 10, 33 and 100 mg/ml solution of the drugs in physiological saline. The irritative effect of NK 631 on the eye mucous membrane at each concentration was slightly severe than that of bleomycin at the same concentration. However, the manifestations were only mild to moderate dilatation of the conjunctival and nictating membrane blood vessels and eye mucous, and recovered or were mitigated 48 hours after the instillation. No severe changes such as corneal opacity, corneal desquamation, swelling and deaquamation of the conjunctival and nictating membrane were observed. The histopathological examination revealed no striking changes. 4. Mutagenicity of NK 631 and of bleomycin on Salmonella typhimurium strain TA 100 and TA 98 was studied. It was definitely shown that neither NK 631 nor bleomycin exerted any mutagenic action on either test strains.     

经尿道膀胱肿瘤电切术后立即腔内灌注及定期灌注吡柔比星预防复发的疗效观察

目的探讨经尿道膀胱肿瘤电切（TURBt）术后吡柔比星立即腔内灌注＋定期灌注预防复发的疗效。方法浅表性膀胱癌TURBt术后患者140例完全随机分为2组,A组（70例）术后立即灌注吡柔比星30mg,以后行常规定期灌注,即术后1周开始每周1次,灌注8次,再改为每月1次,总疗程1年;B组（70例）TURBt术后行常规定期灌注;2组均随访2年,观察肿瘤复发率和不良反应发生情况。结果A组5例复发,复发率7．1％;B组复发13例,复发率18．6％,2组比较差异有统计学意义（X2=4．08,P〈0．05）。随访期内均无死亡病例。2组均未见全身不良反应发生,A组16例出现短期尿路刺激症状,发生率22．8％;B组14例出现短期尿路刺激症状,发生率20．0％,差异无统计学意义呼=0．16,P〉0．05）。结论吡柔比星术后立即腔内灌注＋定期灌注预防术后复发的效果优于单纯常规定期灌注,且无明显增加不良反应的发生率。     

Ocular pharmacokinetics of thiamphenicol in rabbits.

The ocular pharmacokinetics of thiamphenicol (TAP, CAS 15318-45-3) was studied in rabbits by means of the assessment of its ocular and systemic absorption, and urinary excretion after instillation of 0.5% TAP eye drops. TAP concentrations in aqueous humor, plasma and urine were evaluated by a coupled LC/GC method (detection limit = 0.1 ng/ml), because the necessity to have a technique much more sensitive than the traditional chromatographic ones available in order to quantify the very low drug concentrations in biological fluids produced by the ocular treatment, and generally by a topical administration. The intravenous route was chosen as reference and allowed the absolute bioavailability to be estimated. TAP proved to be well absorbed through the cornea with the peak aqueous humor concentration of 110 ng/ml at 45 min following the instillation. The good ocular absorption of TAP was confirmed by the plasma concentrations observed after instillation of 0.5% eye drops. In any case, these concentrations were more than 1000 times lower than those observed after the intravenous treatment at the dose normally used for infectious diseases, allowing to exclude any systemic toxicity of TAP eye drops. The absolute ocular bioavailability was 16.2% when estimated from the AUC values and 34.0% from the cumulative urinary excretion values.     

Pupillometry study of brimonidine tartrate 0.2% and apraclonidine 0.5%

This study investigated possible effects of brimonidine tartrate 0.2% and apraclonidine 0.5% on pupil diameter. Ten subjects between 20 and 40 years of age participated. A Colvard pupillometer (Oasis Medical) was used to measure pupil diameter. Baseline and serial measurements were obtained at 3 luminance levels (>6.4, <0.82-0.4, and <0.2-0.02 cd/m(2)) during a 4-hour interval following instillation of 1 drop of brimonidine tartrate 0.2% or apraclonidine 0.5% in one eye versus a placebo in the contralateral eye. The measurements for each drug were obtained on different days. A nested random effects model controlling for subject's age, race, and sex was used for statistical analysis. A maximum reduction in pupil diameter was observed at 90 minutes from instillation (1.40 mm at >6.4 cd/m(2), 1.69 mm at <0.82-0.4 cd/m(2), and 1.55 mm at <0.2-0.02 cd/m(2)) for brimonidine tartrate 0.2%. At all time intervals and illumination levels, miosis (P < .01) occurred. Apraclonidine 0.5% did not produce a significant effect on pupil diameter. Brimonidine tartrate 0.2% produced a moderate miotic effect. No effect was observed for apraclonidine 0.5%. A predominant agonistic effect on α-2 receptors of the iris dilator may explain this behavior.     

吡柔比星及卡介苗膀胱灌注预防膀胱癌术后复发的临床观察

目的评价吡柔比星(THP)膀胱灌注及卡介苗(BCG)膀胱灌注预防膀胱癌术后复发的效果.方法患者随机分成两组,一组患者膀胱灌注THP(52例),另一组膀胱灌注卡介苗(47例),各组均灌注6～48个月,期间观察复发情况及不良反应.结果THP膀胱灌注组复发率为11.5%,无全身不良反应例子;卡介苗膀胱灌注组复发率为21.2%,68.1%患者出现膀胱刺激症状,两组比较THP组略好于.结论THP及卡介苗均是有效的预防膀胱癌术后复发的药物,THP膀胱灌注操作简单,全身不良反应小,是一种安全有效的膀胱局部化疗药物.     

Intramuscular prednisolone pretreatment does not influence the dermal lesions induced by topical sulfur mustard

The effect of a single intramuscular injection of prednisolone sodium phosphate (14.3 mg/kg) on the development and severity of dermal lesions induced by topical sulfur mustard was investigated in guinea pigs. Control animals received sulfur mustard alone, topical sulfur mustard and intramuscular saline, intramuscular prednisolone alone, or intramuscular saline alone. With topical sulfur mustard alone there were typical mustard lesions consisting of epidermal necrosis and hyalinization, with acute inflammation and necrosis in the dermis, the severity and extent of which were dose-related. Systemic prednisolone therapy had no influence on the nature, severity or progression of the dermal histopathologic response to topical sulfur mustard.     

Toxicological studies on a new cephamycin, MT-141. VII. Its locally-irritating activity in rabbits

The local irritation of MT-141 was compared with that of cefmetazole (CMZ) in rabbits to obtain following results. Microscopic observations revealed that the irritative activity of 10% solution of MT-141 in blood vessels was not so much different from that of saline and 10% solution of CMZ when they were injected twice a day into vein retroauricularis of rabbits for 7 days. The histopathological changes induced by 10% solution of MT-141 were similar to those by 10% solution of CMZ but somewhat different from those by saline, because both compounds caused slight necrosis in the tissue around vessels. Histopathological observations suggested that the occurrence of necrosis was due to the leakage of them during injections. The local irritation of MT-141 by an injection of 1 ml of its solution into muscle vastus lateralis was compared with that of CMZ in rabbits. The potencies of irritative activity of the test solutions were summarized in the following order; saline less than 5% MT-141 less than 10% MT-141 not equal to 10% CMZ much less than 0.75% acetic acid less than 6.0% acetic acid. The above-mentioned results suggest that MT-141 has low irritating activity when injected through intravenous or intramuscular route for clinical practice as 5% or 10% solution.     

Ophthalmic use of clindamycin-2-phosphate (author's transl)]

Bacterial and clinical experiments for ophthalmic use of clindamycin-2-phosphate (CLDM-2-P) were performed and the results were summarized as follows. 1. The distribution of sensitivity for 100 strains of Staphylococcus aureus isolated in 1975 was in the range of less than or equal to 0.19 approximately greater than or equal to 100 mug/ml, and majority of them (96.0%) were in less than or equal to 0.39 mug/ml. 2. The serum concentration by intramuscular injection of 300 mg and 600 mg CLDM-2-P in a single dose respecitvely reached the peak level after 2 hours and decreased gradually until 12 hours in both of them. 3. Ocular penetrations were examined in rabbit eyes. (1) After instillation of 1% CLDM-2-P solution, the aqueous level reached the highest after 1 hour and measurable after 6 hours. (2) After subconjunctival injection of 5 mg/0.5 ml CLDM-2-P, the aqueous level reached the highest after 2 hours and decreased until 6 hours. (3) After intramuscular injection of 100 mg/kg, the aqueous concentration was recognized from 1 to 8 hours, and peak was reached after 1 hour. 1 to 8 hours, and peak was reached after 1 hour. Aqueous-serum ratio in 1 hour was 37.13%. The ocular tissue concentrations at 2 hours showed relatively high levels in both of outer and inner parts of the eye. 4. The intramuscular injection of CLDM-2-P, 300 approximately 1800 mg daily, against suppurative ocular infections revealed excellent effects on cases of external hordeolum, acute chalazion, lid abscess, orbital phlegmone, corneal infiltration, corneal ulcer, and iridocyclitis purulenta. 5. Side effects: Two cases out of 22 cases complained of diarrhoea and bitter taste after injection, and able to be treated continuously by the drug. No abnormal findings in hepatic and renal tests were observed and no servere side effects like allergic reactions were recognized.     

吡柔比星与丝裂霉素膀胱灌注预防浅表性膀胱癌术后复发的疗效对比

目的 评价吡柔比星、丝裂霉素膀胱灌注预防浅表性膀胱癌术后复发的临床疗效.方法 将145例浅表性膀胱癌按病理分级和临床分期完全随机分为吡柔比星组75例和丝裂霉素组70例,分别用吡柔比星、丝裂霉素作为膀胱灌注治疗药物.观察2组疗效.结果 所有患者随访3～36个月,平均19.5个月;吡柔比星组有效率89.3%,复发率10.7%,丝裂霉素组有效率78.6%,复发率21.4%,2组差异有统计学意义(P＜0.05).结论 丝裂霉素耐受性较好,吡柔比星疗效优于丝裂霉素,对预防浅表性膀胱癌术后复发的疗效满意,可作为临床一线药物.     

两种灌注药物预防膀胱癌术后复发的疗效观察

目的探讨吡柔比星（pirarubicin,THP）、表柔比星（epirubicin,EPI）两种不同药物膀胱灌注化疗,预防膀胱癌术后复发的疗效和安全性。方法对42例行膀胱癌手术后患者,随机分为2组：Ⅰ组THP（24例）、Ⅱ组EPI（18例）,分别于术后1～2周开始规律膀胱灌注,比较2组肿瘤复发率。结果随访14—24个月,平均20个月;Ⅰ组和Ⅱ组2年复发率分别为16．67％、22．22％,2组比较统计学无差异（P〉0．05）。Ⅰ组和Ⅱ组不良反应发生率分别为25．00％和61．11％,两组比较统计学有差异（P〈0．05）。结论THP、EPI膀胱灌注预防膀胱癌术后复发疗效满意,不良反应轻,耐受性良好。     

Gross and microscopic characteristics of liver lesions induced by direct injection of pentobarbital sodium into rats

The hepatotoxic effects of anesthetics brought about by their faulty intraperitoneal application was investigated. Using a syringe with a 26G needle, we injected 0.05 ml/rat of a 50 mg/ml solution of pentobarbital sodium directly into the livers of Sprague-Dawley rats. The animals were killed at 15, 30, or 45 minutes after injection. Massive hemorrhagic necrosis of the liver was seen in all animals injected, while focal necrosis accompanied by inflammatory cell infiltration was observed in the rats killed at 30 and 45 minutes after injection. The histological characteristics of these liver lesions were composed of three types, namely, massive hemorrhagic necrosis, focal cell infiltration separate from the necrosis, and focal necrosis with inflammatory cell infiltration. The infiltrates were composed of both neutrophils and lymphocytes. The characteristic liver lesions closely resembled the hepatic lesions produced by captopril (Helliwel et al., 1985), cyclopiazonic acid (Morrissey et al., 1985), as well as spontaneous liver lesions. The study of serum transaminase levels showed that the elevation of both SGPT and SGOT activities was correlated with the time after injection. Also, a significant increase in the total bilirubin level was noted in all animals treated.     

棘阿米巴角膜炎6例治疗分析

目的总结6例因配戴角膜接触镜(CL)引起的棘阿米巴角膜炎的临床资料,并探讨其成功治疗经验。方法回顾性分析6例棘阿米巴角膜炎的临床资料和治疗经过。结果 6例患者(平均年龄25岁)均配戴CL(1例硬性CL,5例软性CL)。其中5例以角膜剧烈疼痛为主诉就诊。4例初次眼科检查时确诊假树枝状角膜炎,2例表现为放射状角膜神经炎和环状基质混浊。所有病例进行角膜刮片培养并确诊棘阿米巴感染。5例立即开始0.02%氯己定联合抗真菌滴眼液滴眼治疗,最终矫正视力获得不同程度的提高,范围为0.5～1.5。另外1例未能及时治疗,角膜炎症状恶化,视力下降为手动,施行穿透性角膜移植+白内障手术,术后矫正视力提高到0.6。结论棘阿米巴角膜炎病例早期阶段及时应用0.02%氯己定联合抗真菌药物滴眼可提高疗效,避免不必要手术,并产生相对较好的最终视力。     

Biochemical, hematological, and histological changes in B6C3F1 mice after intramuscular administration of PROven

Repeated intramuscular administration of PROven to B6C3F1 mice has a potential cardiotoxic effect, an immunogenic effect, and a hematological effect. A significant decrease in two lactic dehydrogenase isoenzymes of myocardial origin was a result of chronic administration of PROven. The immunological effect was observed as a significant increase in beta- and gamma-globulins. The hematological effect of PROven was to increase the number of circulating neutrophils. Both the immunogenic and hematological effect should be anticipated due to the foreign protein nature of PROven. Following intramuscular injections of PROven, severe inflammatory changes including necrosis of skeletal muscle tissue were seen histologically.     

Antinociceptive effect of amygdalin isolated from Prunus armeniaca on formalin-induced pain in rats

Amygdalin is a plant glucoside isolated from the stones of rosaceous fruits, such as apricots, peaches, almond, cherries, and plums. To investigate the pain-relieving activity of amygdalin, we induced pain in rats through intraplantar injection of formalin, and evaluated the antinociceptive effect of amygdalin at doses of 0.1, 0.5, 1.0, and 10.0 mg/kg-body weight by observing nociceptive behavior such as licking, biting and shaking, the number of Fos-immunoreactive neurons in the spinal cord, and the mRNA expression of inflammatory cytokines in the plantar skin. The intramuscular injection of amygdalin significantly reduced the formalin-induced tonic pain in both early (the initial 10 min after formalin injection) and late phases (10-30 min following the initial formalin injection). During the late phase, amygdalin did reduce the formalin-induced pain in a dose-dependent manner in a dose range less than 1 mg/kg. Molecular analysis targeting c-Fos and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) also showed a significant effect of amygdalin, which matched the results of the behavioral pain analysis. These results suggest that amygdalin is effective at alleviating inflammatory pain and that it can be used as an analgesic with anti-nociceptive and anti-inflammatory activities.     

吡柔比星与羟基喜树碱对浅表性膀胱癌的预防及安全性的meta分析

目的 比较吡柔比星(THP)与羟基喜树碱（HCPT）膀胱灌注对膀胱癌复发的预防作用及治疗毒性。方法 收集关于THP与HCPT 膀胱灌注治疗膀胱癌的比较性研究文献,进行系统分析。采用相对危险度(RR)及95%可信区间(CI)作为评价比较疗效及毒性差异的指标。统计软件为 RevMan 5.3。结果 共入选18项临床研究包括1597名患者,其中822例接受THP治疗,775例接受HCPT治疗。Meta分析结果提示,THP组与HCPT组6个月复发率无统计学差异[ RR =0.69,95% CI (0.47,1.02), P >0.05],9个月复发率无统计学差异[ 0R =0.80,95% CI (0.42,1.54), P>0.05],而THP组1年内复发率低于 HCPT 组 [ RR =0.74,95% CI (0.56,0.99), P <0.05] ,2年内复发率也低于HCPT组[ RR =0.74,95% CI (0.61,0.92), P <0. 01]。两组间的膀胱刺激症状、血象无显著性差异 ( P 均>0.5);两组膀胱灌注预防血尿发生率的差异有统计学意义[ RR =1.74,95% CI (1.11,2.72) P =0.02],羟基喜树碱组血尿发生率低于吡柔比星组。 结论： 吡柔比星与羟基喜树碱对肿瘤的复发率的控制灌注后约6、9个月无明显差异,而长期来看1年和2年THP的复发率小于HCPT,因此THP的控制效果优于HCPT：两者的不良反应中的膀胱刺激症状、血象异常（白细胞降低）无明显差异,而羟基喜树碱组血尿发生率低于吡柔比星组。在可以耐住不良反应的前提下,优选THP。     

L-662,583 is a topically effective ocular hypotensive carbonic anhydrase inhibitor in experimental animals.

1. L-662,583 was a potent inhibitor in vitro of purified, human erythrocyte carbonic anhydrase II, possessing an IC50 of 0.7 nM. The IC50 values for MK-927, acetazolamide and methazolamide were 13.0 nM, 10.8 nM and 21.2 nM, respectively. 2. A 1 h pretreatment with one 50 microliters drop of a 0.1% solution of L-662,583 blocked carbonic anhydrase activity in a homogenate of the iris + ciliary body of albino rabbits by 63%. Similar treatment with 0.1% suspensions of acetazolamide and methazolamide elicited inhibitions of 30% and 20%, respectively. This ex vivo model indirectly assesses the ability of an agent to enter the rabbit eye. 3. Concentrations of L-662,583 in the cornea, aqueous humour and iris + ciliary body of albino rabbits were determined by h.p.l.c. at predetermined times after the instillation (one drop of 50 microliters) of a 2% solution of L-662,583. Peak levels for cornea (47.4 micrograms g-1), aqueous humour (4.51 micrograms ml-1) and iris + ciliary body (9.61 micrograms g-1) occurred at 0.5, 2 and 1 h after instillation, respectively. 4. The experimentally elevated intraocular pressure of the right eye of rabbits, induced by prior intraocular injection of alpha-chymotrypsin, was maximally decreased by 4.5 mmHg, 6.2 mmHg and 9.8 mmHg after the instillation (one drop of 50 microliters) of 0.01%, 0.1% and 0.5% solutions of L-662,583, respectively. All three concentrations lowered intraocular pressure at all time points from 1 h up to and including 5 h, the last recorded time point.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ocular tolerance of preservatives on the murine cornea.

We investigated the effects of instilling 13 commonly used preservatives on the murine cornea in vivo. Due to the instillation of preservatives, micro-lesions are formed on the cornea and can be selectively marked by fluorescein. The sum of the resulting fluorescent areas was measured using an episcopic microscope coupled to an image processing system. All the tested preservatives proved to be well-tolerated by the eye at commonly used concentrations. However, in some cases, increased concentrations of preservatives or combinations resulted in significant increase of the amount of corneal damage. With increasing the concentration, corneal lesion increased the most in the case of cetylpyridinium. While a combination of chlorobutanol 0.5% and phenylethylalcohol 0.5% did not result in an increase in corneal damage (when compared to the use of each separately), the associations of thiomersal 0.02% and phenylethylalcohol 0.4% on one hand and of edetate disodium (EDTA) 0.1% and benzalkonium 0.01% on the other, resulted in significant increases in the amount of corneal damage. However, in none of the tested combinations, the increase in the observed damage exceed the limit of ocular intolerance we had defined beforehand: thus, they were all deemed relatively well-tolerated. In the last part of the study, we investigated the effects of combining several preservatives, at usual concentrations, with an anesthetic solution of oxybuprocaine and found no notable increase in ocular damage.     

紫杉醇注射液对血管刺激性与溶血性试验研究

目的:观察紫杉醇注射液是否具有血管刺激性、溶血反应。方法:家兔耳缘静脉注射紫杉醇注射液高、低剂量组,每日一次,连续5次,每天给药前及最后给药后48h、96h对动物和注射部位进行肉眼观察耳局部血管刺激情况,停药96 h后对注射部位做病理组织学检查;体外不同浓度的紫杉醇注射液0.1～0.5 ml在2%兔红细胞混悬液中放置15min～4 h,观察对兔红细胞悬液的溶血作用及有无红细胞凝聚作用。结果紫杉醇注射液对家兔血管内皮没有损伤和刺激作用;对兔红细胞没有致溶血作用和凝聚作用。结论:紫杉醇注射液用药血管没有刺激性反应,无溶血及红细胞凝聚现象。结果:符合新药申报要求。     

Local tissue damage after intramuscular injections in rabbits and pigs: quantitation by determination of creatine kinase activity at injection sites

The creatine kinase (CK) method, which is based on difference in CK activity at injection sites and in control tissue, was used for quantitation of local tissue damage after intramuscular injection of varying volumes and preparations in rabbits and pigs. Injections were given in the central part of the longissimus dorsi muscle. Three days after the injections the animals were killed and the arbitrary amounts of tissue without CK were calculated from the CK activity in muscle tissue at the injection sites and in control tissue. Determination of tissue damage by the CK method was in good agreement with macroscopic and microscopic changes, whether a well demarcated necrotic area or little or no necrosis was found at the injection site. Tissue damage was proportional to injection volumes between 0.25 and 1 ml in rabbits and 0.5 and 3 ml in pigs. In rabbits tissue damage per injected ml was found to be more than twice the damage seen in pigs. It is concluded that the CK method is a reliable method for quantitation of local tissue damage after intramuscular injections and that injection of even small volumes of 0.25-0.5 ml in the longissimus dorsi muscle of rabbits is a sensitive test of the local toxicity of drugs.     

长托宁对冠状动脉搭桥术心肺转流期间炎性细胞因子的影响

目的 观察长托宁对冠状动脉脉搭桥术(CABG)心肺转流(CPB)炎性细胞因子的影响.方法 39例接受CABG手术的患者完全随机分为长托宁1组、长托宁2组和对照组,各13例.长托宁1组和长托宁2组术前30 min肌内注射长托宁0.02～0.03 mg/kg;长托宁2组术后第24、48小时各静脉追加一次长托宁0.02～0.03 mg/kg;对照组术前30 min肌内注射阿托品0.01 mg/kg.观察3组患者注药前及注药30 min后体温及心率,分别于麻醉诱导前、CPB开始30 min、术后即刻、术后24、48 h采动脉血检测肿瘤坏死因子a(TNF-ct)、白细胞介素6(IL-6)和IL-8的浓度;观察术后胸部X线片肺炎发生率、呼吸机支持时间及ICU停留时间.结果 注药30 min后对照组患者的心率较注药前明显升高[(78.2±3.4) 次/min比(61.1±3.2)次/min;P＜0.05],且明显高于长托宁1组和长托宁2组同时间心率[分别为(56.7±1.4)、(58.9±5.3)次/min,均P＜0.05];与麻醉诱导前相比,CPB后对照组炎性细胞因子的浓度均明显升高,CPB结束时达到最高值,术后缓慢下降,术后24、48 h均高于术前[TNF-a(12.2±2.1)ng/L比(19.4±1.7)ng/L、(26.3±2.5) ng/L、(19.1±1.7)ng/L、(16.3±1.3)ng/L,P＜0.05].组间比较,长托宁1组和长托宁2组最高值明显低于对照组(P＜0.05);长托宁2组术后第24、48小时TNF-a、IL-6、IL-8值明显低于对照组,长托宁1组和长托宁2组术后呼吸机支持时间和ICU停留时间明显少于对照组[(10.6±3.7)h、(9.6±7.7)h,(11.8±7.7)h,(3.5±1.9)h、(3.0±1.8)h比(3.9±1.8)h,均P＜0.05].结论 CABG患者术前及术后应用长托宁能有效抑制炎症细胞因子TNF-a、IL-6、IL-8的释放,减轻CPB后的肺部炎症,缩短机械通气和ICU停留时间,比单纯术前应用长托宁效果更好.