Activated carbon particles as anti-cancer drug carrier into regional lymph nodes

The effect of a new dosage form for anti-cancer agents was studied on tissue distribution and compared with the aqueous solution form. The new dosage form, developed in order to distribute a greater amount of the agent to regional lymph nodes, comprises polyvinylpyrrolidone and small activated carbon particles adsorbing pepleomycin (PEP-CH) or mitomycin C (MMC-CH) in saline. Pepleomycin at 500 micrograms/kg or mitomycin C at 250 micrograms/kg were injected into the gastric wall of dogs in the new dosage form or the aqueous solution form. The activity level of the agents in tissues was bioassayed within 24 h after injection by the thin agar plate method. Statistically, the new dosage form maintained an activity level in lymph nodes that was significantly higher than the aqueous solution form (ratio of PEP-CH to solution form, 6-32 times in 24 h; MMC-CH, 100-1000 times in 6 h; p less than 0.05-0.01), and a concentration in blood that was significantly lower (PEP-CH, about 1/2 times in 2 h; MMC-CH, 1/10-1/5 times in 1 h; p less than 0.05).     

Pharmacokinetics of mitomycin C in patients after bolus injection and chemobolisation of the hepatic artery with Spherex starch particles.

The pharmacokinetics of mitomycin C after chemobolisation of the common hepatic artery by micronized Spherex starch particles (mean particle size 30 microns) were investigated in 5 cancer patients. Bolus injection and simultaneous occlusion of the artery lead to a significantly lower systemic circulation of mitomycin C in the blood vessel system than after bolus injection without chemobolisation. The plasma concentration-time curves showed lower values in the alpha-phase in the presence of Spherex (co = 743 ng/ml) than without starch particles (co = 987 ng/ml). Accordingly, the AUC values were significantly lower too (AUC = 28.6 micrograms/ml.h with Spherex and 39.7 micrograms/ml.h without Spherex), thus leading to a lower systemic bioavailability of the drug and a higher local bioavailability in the tumor region. Elimination of mitomycin from the central compartment was similar for both administrations (t1/2 = 27 min with Spherex and 28 min without Spherex) and showed the characteristic profile of the substance. The clinical picture showed a milder toxicity with a certain loss of side effects. These results indicate a significant and desirable change in the pharmacokinetics of mitomycin C during the distribution phase into the tissue of patients.     

"Methamphetamine-stereotypies" and brain dopamine levels of rats treated with single or repeated doses of alpha-methyl-para-tyrosine (author's transl)

Male albino Wistar rats were injected intraperitoneally with saline solution (1.0 ml/kg) or a-methyl-paratyrosine (50 mg/kg) once or daily X 7 and methamphetamine (10 mg/kg) was injected 3 hr or 24 hr after the last injection of these drugs. Stereotyped licking and biting activity were scored during 120 min after methamphetamine injection and, in parallel brain dopamine levels were measured. Methamphetamine given 3 hr after single or repeated administrations of alpha-methyl-para-tyrosine was not effective for stereotyped behavior and brain dopamine levels in similarly treated rats decreased markedly in comparison with saline-treated rats. Methamphetamine 24 hr after repeated administration of alpha-methyl-para-tyrosine clearly induced stereotypies and brain dopamine levels in these rats did not differ from saline-treated rats. The results suggest a possible role of brain dopamine on "methamphetamine-stereotypies".     

长春花生物碱部分之一 AC-875的抗肿瘤作用及毒性

木文对长春花(Catharanthus roseus Linn.G.Don)中分离提出的生物碱AC-875进行了毒性及抗癌作用的实验研究.试验结果表明AC-875在20-42毫克/公斤时,对小鼠Ehrlich腹水癌及腹水型肝癌均有明显的抑制作用.当剂量为10毫克/公斤时,对大鼠腹水型吉田肉瘤也有较好的疗效.在实体瘤的治疗中,注射35毫克/公斤,对小鼠S-180仅有轻度抑制作用,且不太稳定.对小鼠网织细胞瘤、Ehrlich腹水癌实体瘤、大鼠Jensen肉瘤及Walker癌等则无抑制作用.给小鼠腹腔注射AC-875的急性LD₅₀为170毫克/公斤,亚急性LD₅₀为61毫克/公斤.给大白鼠腹腔注射AC-875的意性及亚急性LD₅₀分别为122毫克/公斤及18毫克/公斤.给家兔静脉注射8毫克/公斤AC-875时,心电图无明显变化.静脉注射AC-875 1毫克/公斤、2.5毫克/公斤或皮下注射5毫克/公斤,对狗的肝、肾功能、尿常规、红血细胞、血红蛋白及体重均无明显影响,但2.5和5毫克/公斤组,狗的白细胞有下降现象.     

Effect of HI-6, applied into the cerebral ventricles, on the inhibition of brain acetylcholinesterase by soman in rats

When applied to rats (intraperitoneally) immediately after subcutaneous injection of soman (120 micrograms/kg) HI-6 (100 mg/kg) protected about 40% of the activity of acetylcholinesterase (AChE) in the motor end plate region of the diaphragm but did not protect AChE in the brain. However, a partial protection of AChE in brain against inhibition by soman was obtained in anaesthetized, atropinized rats by the oxime injected into the cerebral ventricle 5 min before parenteral exposure to soman. The AChE activity in brain of rats pretreated with HI-6, analyzed 60 min after the injection of soman was between 10 and 19%, while that in non-protected animals did not exceed 1% of the control. The degree of protection of AChE in brain was dose-dependent. Large doses of HI-6 (greater than or equal to 100 micrograms) were tolerated by animals because of the pentobarbital anaesthesia which counteracted the lethal action of HI-6. The rate of "aging" of AChE in brain inhibited by soman was analyzed by intracerebroventricular injection of 200 micrograms of HI-6 at different time intervals after the subcutaneous injection of soman. A statistically-significant reactivation of inhibited AChE activity in brain was demonstrated when HI-6 was applied up to 20 min after soman. The protection and reactivation by HI-6 of both AChE in brain and AChE in muscle end plates in poisoning with soman appear to be quite similar.     

Ochratoxin A: plasma concentration and excretion into bile and urine in albumin-deficient rats

The fate of ochratoxin A (OA) injected iv was studied in both albumin-deficient and normal rats. The OA concentration in plasma decreased to a level below 0.5 micrograms/ml within 10 min of the injection in albumin-deficient rats, but remained above 50 micrograms/ml for 90 min in normal rats. The OA concentrations in bile and urine, and the rate of OA excretion in these fluids were 20-70-fold higher in albumin-deficient than in normal rats. The results demonstrate that a primary effect of albumin binding on OA is to retard its elimination by restricting the entry of OA into the hepatic and renal cells.     

In vivo ability of antimyotoxin a serum plus polyvalent (Crotalidae) antivenom to neutralize prairie rattlesnake (Crotalus viridis viridis) venom

A mixture of antimyotoxin a serum and polyvalent (Crotalidae) antivenom was injected i.v. in mice either 5 min before or 5 min, 30 min, 1 hr or 3 hr after i.m. injection of venom. Neutralization of the local myotoxicity of a sublethal dose (1.5 micrograms/g) of C. v. viridis venom occurred if the antisera were injected 5 min before or 5 or 30 min after venom, but not if injected 1 or 3 hr after the venom. Hemorrhage was neutralized when the mixture was injected either 5 min before or 5 min after injection of venom, but not when injected 30 min after injection of venom. Previous results showed that the mixture of antisera neutralized the same amount of venom (1.5 micrograms/g) when mixed with the venom prior to injection. Thus it is not possible with these two antisera to neutralize myonecrosis if the time interval between injections is greater than 30 min.     

Pharmacokinetics of m-nisoldipine in rabbits and rats

A reverse phase HPLC method was devised for determination of m-Nis in plasma. A mobile phase of methanol-KH2PO4 with a flow rate of 1 ml/min was used. Diazepam was used as the internal standard. A two-compartment model featured the pharmacokinetic process of m-Nis after its iv injection to rats (30 micrograms/kg) and rabbits (50 micrograms/kg). The pharmacokinetic parameters were: T 1/2 alpha = 4.3 min, T 1/2 beta = 63.6 min, Vd = 0.805 L/kg, Cl = 9 ml/(min.kg) in rats; T 1/2 alpha = 5.0 min, T 1/2 beta = 78.3 min, Vd = 1.191 L/kg, Cl = 11 ml/(min.kg) in rabbits. The pharmacokinetics for m-Nis after ig 200 micrograms/kg to rats described one-compartment model with parameters: T 1/2 = 84.8 min, Tmax = 31.2 min, Cmax = 49.97 micrograms/L, Vd = 0.792 L/kg and Cl = 25 ml/(min.kg).     

Enhanced gentamicin nephrotoxicity after experimental biliary obstruction in rats

To explore whether bile duct ligation increased the risk for gentamicin nephrotoxicity, male Wistar rats were subjected to bile duct ligation or sham surgery and given either gentamicin 20 mg/kg or saline twice daily intraperitoneally for 8 days. Bile duct ligated and gentamicin injected rats elicited a decline in renal function and tubular cell necrosis after 8 days of treatment whereas equal dosage regimen in sham operated rats exhibited no evidence of renal dysfunction. In addition, though serum and kidney gentamicin levels were higher in bile duct ligated rats (1.84 +/- 0.11 micrograms/ml versus 0.20 +/- 0.03 microgram/ml, and 1453 +/- 164 micrograms/g versus 698 +/- 138 micrograms/g of cortex, respectively, P less than 0.05). The data indicate that complete biliary obstruction enhances renal sensitivity to gentamicin.     

右美托咪啶对胃穿孔修补术大鼠血流动力学及苏醒时间的影响

目的探讨右美托咪啶对胃穿孔修补术大鼠血流动力学及恢复翻正反射时间的影响。方法选择右侧颈动脉置管成功的雄性SD大鼠20只,随机分成实验组(D组)和对照组(C组),每组10只。大鼠平均动脉压(MAP)监测建立后,实验组经腹腔注射右美托嘧啶30μg/kg(浓度4μg/ml),对照组注射同容量的生理盐水,腹腔注药15min后实施胃穿孔修补术。全程记录大鼠腹腔注药前(基础值)、注药后15min、以及整个手术过程的平均动脉压(MAP)变化,记录大鼠恢复翻正反射的时间。结果与C组比较,D组大鼠腹腔注药后5min和10minMAP的差异无统计学意义(P>0.05),注药后15minMAP下降,D组为(60.58±13.13)mmHg,C组为(81.82±18.75)mmHg,差异有统计学意义(P>0.05)。两组大鼠翻正反射恢复的时间,D组为(200.38±40.82)min,C组为(171.50±33.10)min,差异无统计学意义(P>0.05)。结论大鼠腹腔注射右美托嘧啶(30μg/kg)15min后MAP开始降低,其对大鼠恢复翻正反射的时间无影响。     

Increase of plasma corticosterone induced by loperamide in rats

Loperamide given intracerebroventricularly and intraperitoneally to rats provoked, like morphine, a plasma corticosterone increase 60 min after injection. Loperamide intracerebroventricularly was 3.73 times less active than morphine, while intraperitoneally it was 10.13 times more potent. This increase, associated with a significant elevation in the plasma ACTH concentration, was antagonized by naloxone (10 mg/kg i.p.) injected 30 min before loperamide. In hypophysectomized rats loperamide intraperitoneally did not affect the plasma corticosterone levels. We conclude that loperamide can stimulate corticosterone secretin from the adrenal gland via the opiate receptors and that this effect is mediated by a direct or indirect induction of ACTH release.     

Antitumor activity and pharmacokinetics of 7-N-(p-hydroxyphenyl)mitomycin C in human tumor xenografts transplanted into nude mice

The effects of 7-N-(p-hydroxyphenyl)mitomycin C (M-83), a derivative of mitomycin C, against eight human tumor xenografts serially transplanted into male BALB/c nude mice were evaluated. M-83 showed positive antitumor effect against six out of eight tumor strains. The antitumor spectrum of this agent was similar to that of mitomycin C except for two strains. The serum level of M-83 detected by bioassay was biphasic, elimination half-life T1/2 beta was 10.9 minutes and the area under curve AUC60(0) was 112.4 micrograms . minute/ml when 15 mg/kg of the agent was administered. In the tumor, the peak concentration and AUC60(0) detected by radioassay correlated well with the value of drug efficacy TRW/CRW. The ratio of the concentrations detected by bioassay to radioassay in the tumor was approximately 10%, which was thought to be affected by inactivation of the agent in the tumor.     

Acrylic microspheres in vivo VI: antitumor effect of microparticles with immobilized L-asparaginase against 6C3HED lymphoma

The antitumor effect of immobilized L-asparaginase was tested against lymphoid leukemia in mice with concomitant scanning of the L-asparagine level in serum. L-Asparaginase was immobilized in microspheres of polyacrylamide or polyacryldextran. These particles were used in C3H mice bearing the L-asparagine-dependent lymphoma (6C3HED). The tumor was maintained as an ascites tumor, 1 X 10(6) cells were injected intraperitoneally and on day 4 after inoculation, L-asparaginase was injected intramuscularly or intraperitoneally in microparticles. After injection of 5.0 IU ip of L-asparaginase in microparticles, partial remission was induced, generally, however, the cancer relapsed and killed the mice within 2-3 weeks. To obtain complete regression, it was necessary to inject 20 IU of L-asparaginase in microparticles intraperitoneally. The best therapeutic effect was obtained when the particles were administered intramuscularly. After injection of 5 IU the survival time was prolonged, but complete regression was not achieved. The best effect was obtained when the particles were given intramuscularly in two small doses (2.5 IU) at a 3-day interval. Such treatment induced complete regression; 10 out of 12 treated mice were completely cured and lived for several months. It is concluded that the L-asparagine level in serum has to be depressed to less than 20% of the normal level for at least 6-7 days to obtain complete regression of the tumor.     

Behavioral assessment of the toxicity of aspartame

Six experiments with rats assessed the toxicity of aspartame with behavioral measures. The first three experiments used a conditioned taste aversion procedure since taste aversions are typically observed after a taste is followed by a toxin. Thirty min after thirsty rats drank a sweet solution they were intraperitoneally injected (Experiment 1) or intragastrically intubated (Experiment 2) with saline or 176, 352, or 704 mg/kg of aspartame. Relative to rats given saline, rats injected with 704 and 352 mg/kg aspartame showed strong and mild aversions, respectively. Rats injected with 176 mg/kg of aspartame or intubated with any dose of aspartame did not show taste aversions. In Experiment 3, rats voluntarily consumed an aspartame solution sweetened with saccharin for 7 hr each day. Consumption of the taste paired with aspartame was not reduced. When 352 mg/kg aspartame was injected (Experiment 4), but not when intubated (Experiment 5), 5 min prior to access to a running wheel, running was reduced. Wheel running was not affected by the voluntary consumption of aspartame (Experiment 6). The route of administration effect (intraperitoneal vs. intragastric) on behavior corresponded with the amino acid levels in blood plasma (Experiment 7). Aspartate, phenylalanine, tyrosine and glutamate levels increased more after the injection, than the intubation, of aspartame (176 mg/kg). Overall, the results suggest that aspartame may have adverse effects when intraperitoneally injected but not when the route of administration is oral.     

Characteristics of bombesin-induced inhibition of intake of ethanol

The temporal and neural dependencies of the inhibitory effect of the administration of bombesin tetradecapeptide (BBS) on the intake of ethanol were assessed in the water-deprived rat. Variation of the intraperitoneal (i.p.) injection of neuropeptide--5% ethanol access interval (0-20 min), revealed that suppression induced by bombesin (0.5-4.0 micrograms/kg) was significantly greater and more potent at shorter intervals. The intake of ethanol was less in rats with subdiaphragmatic vagotomies, but bombesin equivalently suppressed the intake. Intracerebroventricular injection of bombesin more potently and completely inhibited the intake of ethanol but bombesin injected intraventricularly, unlike that given intraperitoneally, elicited excessive grooming and scratching behavior. The suppressant effect of bombesin, given intraperitoneally, requires close temporal contiguity of administration and caloric solution access, which is consistent with a satiety action of a neuropeptide. This satiation effect to ethanol of peripherally administered bombesin appears to reflect a non-vagal, extra-ventricular neural action.     

The diffusion of cefazedone into heart muscle, prostatic and skin tissue and into bile

The diffusion of cefazedone into human heart muscle, prostatic and skin tissue as well as bile fluid was investigated. 40 to 80 min after a single injection of 100 mg/kg (n = 14) the concentration in the heart muscle was between 10.8 and 85.5 micrograms/g. The respective serum levels were between 117 and 168.1 micrograms/ml. The single i.v. injection of 2 g cefazedone resulted within 30 min in a mean concentration of 34.63 +/- 9.75 micrograms/g in the prostatic tissue and in serum levels of 139.07 +/- 39.68 micrograms/ml (n = 14). In 5 patients additional values were estimated after 60 min. At this time the antibiotic concentrations were 24.92 +/- 1.31 micrograms/g in the tissue, with simultaneous serum levels of 87.25 +/- 20.86 micrograms/ml. 1 h after a 500 mg i.v. dose, concentrations in bile taken from T-tube were between 71.4 and 210 micrograms/ml. After 2 h there was a mean level of 83.2 micrograms/ml which was significantly above the serum concentrations at the same time (1 h = 35.25 +/- 7.17; and 2 h = 20.5 micrograms/ml). The bile concentration of 2 patients taken 5 h after cefazedone injection was 4.95 and 11.6 micrograms/ml. The cefazedone concentrations in the skin were estimated mainly in biopsies from granulating leg ulcer tissues. The mean concentrations in 4 cases were 120 +/- 28.7 micrograms/g 3 h after i.v. injection of 2 g cefazedone. The simultaneous serum levels were between 14.85 and 68.2 micrograms/ml, in one patient with extreme venous stasis the tissue concentration was only 8.1 micrograms/g. Cefazedone should be regarded as an antibiotic with excellent penetration into tissues.     

Effect of sex-hormone on composition of rat skin surface lipid

The optimum analytical conditions for studying the composition of skin surface lipid were examined by high-performance liquid chromatography equipped with a photo-diode array detector. Optimum conditions were as follows: ULTRON N-C18 (150 x 4.6 mm) as stationary phase, acetonitrile/tetrahydrofuran/water (55/35/10, V/V) as eluent at the flow rate of 1.0 ml/min, and column temperature of 40 degrees C. The peaks were detected by monitoring the absorbance at 210 nm. Effect of sex-hormone on composition of skin surface lipids was examined. Gonadectomized Sprague-Dawley rats were injected with either testosterone (50 mg/kg, s.c.) or estradiol (5 mg/kg, s.c.) for 12 days. Amount of crude lipid from the skin surface was decreased at 8 days after castration; estradiol dosing to castrated rats also decreased the amount. The other hand, in ovariectomized rats, testosterone injection increased skin surface lipids. It is recognized that sex-hormone dosing after gonadectomy changes the percentage composition of squalene and cholesterol in male rats, but does not charge them in females.     

Cytostatic and antitumour properties of a new series of Pt (II) complexes with cyclopentylamine

Ten new Pt (II) complexes were synthesized and tested as potential antitumor drugs in vitro on KB human tumour cell line, and in vivo against four experimental tumour systems (P388, L1210, ADJ/PC6A and Yoshida sarcoma). The complexes contained two primary amine ligands (cyclopentylamine) with bidentate leaving ligands consisting of nitro-, dinitro- and sulfo-derivatives of phthalic and isophthalic anions. Various complexes showed a good cytostatic effect in vitro with ID50 from 0.29 and 0.99 mcg/ml. The Pt(cpa)2 (5-sulfo-IPA) appeared to be the most effective compound against P388 and L1210 (T/C% 310 and 250 respectively after three 50 mg/Kg i.p. injections) as well as against ADJ/PC6A (ID90 2.8 mg/kg after a single i.p. injection) and Yoshida sarcoma (T/C% 17.5 after a single 50 mg/kg i.p. injection), but the phthalic acid nitro-derivatives were also quite effective. As far as antileukemic effect was concerned, there was a fairly good correlation between the results in vitro and in vivo. Relationships between antitumour activity and pi electronic charge localization on O- atoms of leaving ligands (M.O. Huckel's Calculations) are also discussed.     

Effects of lead on sialic acid content and survival of rat erythrocytes

The anemia frequently observed in lead poisoning is thought to result from a shortening of erythrocyte survival in combination with inhibition of hemoglobin synthesis. However, the exact mechanism by which lead shortens erythrocyte survival remains unclear. In the present study, the effects of lead, injected intraperitoneally, on sialic acid content and survival of rat erythrocytes were investigated in order to study the relationship between them. As indices of lead exposure, hemoglobin (Hb) levels, hematocrits (Ht) and blood lead (blood Pb) levels in the injected rats were also examined. Exposure to lead significantly decreased the sialic acid content of the erythrocyte membrane. The decreases in sialic acid content were evident to some extent below a blood Pb level of 100 micrograms/100 ml and generally present at a level of 100 micrograms/100 ml and higher. In the rats exposed to lead a significant negative correlation was found between sialic acid content and the logarithm of blood Pb level. A shortening of erythrocyte survival was also observed in the rats exposed to lead.