Effects of dimethyl sulphoxide (DMSO) on aggregation of human blood platelets

The effects were examined of the universal solvent dimethyl sulphoxide (DMSO) on human platelet aggregatory activity, in-vitro, of the endogenous mediators ADP, adrenaline, arachidonic acid, collagen and PAF-acether which are believed to play important roles in cardiovascular diseases in man. DMSO inhibited aggregation induced by all of the mediators in the order ADP greater than adrenaline = arachidonic acid = PAF-acether greater than collagen. Since DMSO is widely used as a solvent for drug substances, an awareness of its intrinsic activity in any such evaluations is essential.     

Some effects of dimethyl sulphoxide (DMSO) on the frog neuromuscular junction

1. Dimethyl sulphoxide (DMSO) partially reversed neuromuscular blockade brought about by the action of (+)-tubocurarine or Mg(2+) on the frog sartorius nerve-muscle preparation.2. The amplitude and duration of the endplate potential (e.p.p.) were increased by DMSO at concentrations of 70 mM or greater.3. Miniature endplate potentials were raised in frequency, prolonged in duration and increased in amplitude by DMSO at concentrations of 141 mM or greater, but the increase in amplitude was generally less than in the case of the e.p.p.4. The resting muscle membrane potential was significantly depolarized by DMSO at 70 mM or greater concentrations, both at the endplate and remote from an endplate.5. The reversal of neurmuscular blockade by DMSO can be explained in terms of its previously reported ability to inhibit cholinesterase activity, together with the depolarizing action on muscle.     

New insights of dimethyl sulphoxide effects (DMSO) on experimental in vivo models of nociception and inflammation

DMSO is one of the most common solvents used experimentally to dissolve hydrophobic substances for in vivo and in vitro purposes. A wide range of pharmacological effects exerted by DMSO has been documented in both animal and human experimental models. However, only a few and sometimes contrasting data about the effects of DMSO in animal models of nociception and inflammation are presently available. In this study, we evaluated the effects induced by DMSO and a DMSO-containing saline on thermal and chemical nociception, inflammation and locomotor activity in CD1 mice. We demonstrated that centrally or orally administered DMSO displayed anti-nociceptive effects to thermal (hot plate and tail-flick test) and chemical (formalin test) stimuli. Conversely, DMSO was able to increase both nociceptive phases in the formalin test when applied subcutaneously in the dorsal surface of the mouse hind paws 10 min before formalin administration. Oral administration of DMSO produced anti-inflammatory effects on zymosan-induced edema in the mouse paw, whereas local administration potentiated the inflammatory action exerted by zymosan. Oral and central, but not local, administration of DMSO improved the mouse locomotor activity. These results suggest that DMSO displayed opposite effects on nociception and inflammation, depending on the route of administration. New and helpful evidence about DMSO laboratory applications need to be considered in the in vivo studies to assess correctly the pharmacological properties of investigated drugs.     

A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours

AIMS

This trial was conducted to evaluate the safety and pharmacokinetics of combretastatin A4 phosphate (CA4P) given intravenously as a single dose to Chinese patients with refractory solid tumours.

METHODS

Twenty-five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85 mg m⁻² infused intravenously over 30 min.

RESULTS

CA4P was generally well tolerated at ≤65 mg m⁻². Transient, moderate increases in the heart rate-corrected QT interval occurred at all doses. CA4P produced a transient dose-dependent increase in neural and gastrointestinal toxicities. Acute renal failure occurred in one dehydrated patient who had also taken paracetamol. There were seven episodes of dose-limiting toxicity at doses ≥65 mg m⁻², including two episodes of reversible ataxia at 85 mg m⁻². For CA4P, at 50 mg m⁻², mean (SD) peak plasma concentration (C_max) was 0.99 (0.33) µm, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) µm h and terminal elimination half-life (t_1/2) was 1.81 (0.61) h. At 65 mg m⁻², C_max was 1.73 (0.62) µm, AUC(0,t) was 3.19 (1.47) µm h and t_1/2 was 1.90 (0.61) h. One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass.

CONCLUSION

Doses ≤65 mg m⁻² given as 30 min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50–65 mg m⁻² have been selected for further studies.     

A multicentre trial of Zostrum (5 percent idoxuridine in dimethyl sulphoxide) in herpes zoster

Forty-six patients with herpes zoster were randomised into two groups treated with DMSO alone and 5 percent IDU in DMSO, provided that treatment started within 48 hours of the appearance of a rash. In the IDU group the interval before pain improved was significantly shorter than in the control DMSO group, and significantly fewer new vesicles developed at the three day follow up in the active group compared with the control group. These findings are in agreement with previously published work and confirm the usefulness of Zostrum (5 percent IDU in DMSO) in the treatment of herpes zoster.     

Effects of the Ru(III) complexes [mer-RuCl3(DMSO)2Im]degrees and Na[trans-RuCl4(DMSO)Im] on solid mouse tumors.

The effects of two new Ru(III) complexes, [mer-RuCl3(DMSO)2Im] degrees and Na[trans-RuCl4(DMSO)Im], were investigated on primary tumor growth and on the survival time using three solid metastasizing tumors of the mouse: Lewis lung carcinoma, B16 melanoma and MCa mammary carcinoma. Na[trans-RuCl4(DMSO)Im] appears to be the most promising compound, in that: (1) it is soluble in water and therefore easy to handle in comparison with the neutral species [mer-RuCl3(DMSO)2Im]degrees or to the already described BBR2382; (2) similarly to cisplatin, though at a lower level, it reduces tumor growth in its primary site in each tumor model employed; (3) unlike cisplatin, it increases the life span of tumor-bearing hosts in all tumors used, independently of the effects on primary tumor growth; and (4) it is also effective in reducing spontaneous metastasis formation when the effects on primary tumor growth are completely absent. Dimethylsulfoxide (DMSO), used for solubilizing poorly water-soluble compounds (i.e. [mer-RuCl3(DMSO)2Im]degrees) or for stabilizing the compound in the solution before injection (i.e. Na[trans-RuCl4(DMSO)Im]), reduces the anti-tumor potency. Conversely, the antitumor effects of Na[trans-RuCl4(DMSO)Im] are more pronounced in mice hydrated with isotonic saline. We conclude that Na[trans-RuCl4(DMSO)Im] is a good candidate for further investigations aimed at ascertaining the mechanism of the anti-metastatic activity and of the positive effects on survival time of mice bearing solid metastasizing tumors.     

Cefepime (diHCl/L-arginine blend): intravenous continuous infusion and/or single dose subcutaneous toxicity study in rats and dogs]

To investigate single dose toxicity of cefepime (CFPM diHCl/L-arginine blend), the test drug was administered to rats [Crj: CD (SD)] of both sexes at dose levels of 500, 1,000 and 2,000 mg/kg using intravenous continuous infusion or subcutaneous injection, and to male beagle dogs at 1,000 and 2,000 mg/kg using intravenous continuous infusion. As the control, two additional groups of each animals were given either saline or L-arginine alone which was used in the test formulation to adjust pH values of CFPM diHCl solutions. The obtained results are summarized as follows: 1. Rats dosed with 2,000 mg/kg CFPM through intravenous continuous infusion showed slightly decreased spontaneous physical activity. One male rat dosed with L-arginine alone via continuous infusion also showed slightly decreased activity. Slight to severe inflammatory reactions at injection sites including sloughing of the tail were prominent at doses of 1,000 or 2,000 mg/kg of CFPM, or L-arginine alone. Average body weights of rats in the test groups of either sex were comparable to the controls in all of the dose groups of the same sex during the 14-day test period. 2. Rats receiving 2,000 mg/kg CFPM in single subcutaneous injection showed slightly diminished activities. Slight to moderate reactions occurred around the injection site (viz., hardening, depilation, scab-formation and necrosis) in rats injected any of the 3 doses of CFPM. Though body weight gains were slightly retarded in male rats receiving 2,000 mg/kg CFPM during the last half of the observation period, such weight gain retardation was not observed in rats of other dose groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quinoxaline chemistry. Part XVII. Methyl [4-(substituted 2-quinoxalinyloxy) phenyl] acetates and ethyl N-([4-(substituted 2-quinoxalinyloxy) phenyl] acetyl) glutamates analogs of methotrexate: synthesis and evaluation of in vitro anticancer activity

Fourteen out of 21 quinoxaline derivatives described in the present paper were selected at NCI for evaluation of their in vitro anticancer activity. Preliminary screening showed that some derivatives exhibited a moderate to strong growth inhibition activity on various tumor panel cell lines between 10(-5) and 10(-4) M concentrations. Interesting selectivities were also recorded between 10(-8) and 10(-6) M for the compounds 9 and 13.     

海南哥纳香醇甲(GHM-10)对体外L1210细胞的抗肿瘤活性

用体外培养法研究GHM-10对L1210细胞生长的抑制作用和作用机制。结果表明,L1210细胞在用GHM-10处理1h,24h和7d后,IC₅₀依次为6.85,3.32和1.59μg·ml^-1,提示GHM-10有非时相特异性细胞毒药物的特性。在用GHM-10 1～2μg·ml^-1作用24h后,L1210细胞的增长率和有丝分裂指数下降,细胞核形态发生变化,但活细胞率仍保持在96%以上,提示GHM-10主要抑制细胞的增殖。用流式细胞计对L1210细胞进行细胞周期动力学的分析表明,GHM-10可在一定程度上阻断G₁期细胞向S期移行,还可增加L1210细胞的膜流动性。     

Poly [N -(2-hydroxypropyl)methacrylamide] Conjugates of Bovine Pancreatic Ribonuclease (RNase A) Inhibit Growth of Human Melanoma in Nude Mice

Recently hydrophilic poly [N -(2-hydroxypropyl)methacrylamide] (PHPMA) was used for BS-RNase modification to prevent its degradation in bloodstream or fast elimination. Polymer-conjugated BS-RNase preparations proved to be cytotoxic after intravenous or intraperitoneal application, whereas native BS-RNase was ineffective. Here RNase A unimer was conjugated with two HPMA polymers (classic and star) and their antitumor effects both in vitro and in vivo were compared with those of BS-RNase polymers. Surprisingly, the antitumor effect of RNase A conjugates was also pronounced. The RNase A conjugates (classic and star) injected intravenously to mice bearing melanoma tumor caused a significant reduction in tumor volume following ten doses of 5 and 1 mg/kg, respectively. Despite the antitumor activity observed in vivo, the in vitro tested cytotoxic activity of RNase A did not differ from that caused by native RNase A while native BS-RNase (50 μ g/ml) totally inhibited DNA synthesis in treated cells. The experiments with 125 I-labeled preparations demonstrated concentration-dependent internalization of native BS-RNase by tumor cells within an hour, whereas the polymer conjugate (S-BS) was not internalized. On the contrary, the in vivo experiments showed that whereas 40% of S-BS conjugate persisted in bloodstream for 24 h after administration, 98% of the native BS-RNase was already eliminated. Improved antitumor activities of PHPMA-modified RNases in vivo might be ascribed to their prolonged retention in bloodstream, better proteolytic stability and resistance to the action of the ribonuclease inhibitor.     

Effect of dimethyl sulfoxide (DMSO) on the electrocardiogram (ECG) in freely moving male Balb/c mice

• 1.1. Since dimethyl sulfoxide (DMSO) is a solvent which is often used for drugs in animal studies, we investigated the effect of a daily administration of DMSO on the telemetrically obtained electrocardiogram (ECG) in freely moving male Balb/c mice.
• 2.2. During treatment with 4.5 ml 100% DMSO/kg i.p. 5 days per week during 3 weeks, DMSO caused substantial cardiotoxicity. The ST-interval increased significantly after 1 week by 2.2 ± 1.3 msec and also the ECG wave form changed completely in time.
• 3.3. During treatment with 4.5 ml 50% DMSO/kg i.p. 5 days per week during 3 weeks, no significant difference was observed compared with the control animals.
• 4.4. During the entire study the maximal heart rate and body weight remained constant in all treated groups.
• 5.5. The data indicate that DMSO can not be used in a 100% concentration to dissolve compounds that are tested for protection against the cardiotoxicity of cytostatics.

     

Disposition of styrene-acrylonitrile (SAN) trimer in female rats: single dose intravenous and gavage studies

Styrene-acrylonitrile trimer (SAN Trimer), a mixture of six isomers (four isomers of 4-cyano-1,2,3,4-tetrahydro-alpha-methyl-1-naphthaleneacetonitrile [THAN] and two isomers of 4-cyano-1,2,3,4-tetrahydro-1-naphthaleneproprionitrile [THNP]), is a by-product of a specific production process of styrene-acrylonitrile polymer. Disposition studies in female rats were conducted to evaluate the pharmacokinetic behavior of [3H]SAN Trimer following a single intravenous administration (26 mg/kg) to nonpregnant rats; a single gavage administration (nominal doses of 25 mg/kg, 75 mg/kg, or 200 mg/kg in corn oil) to nonpregnant rats; and a single gavage administration (nominal dose of 200 mg/kg in corn oil) to pregnant and lactating rats. SAN Trimer was rapidly eliminated from blood (T1/2 approximately 1h) following a single intravenous dose and following single oral doses (T1/2 approximately 3-4h). SAN Trimer was also rapidly excreted in the urine and feces following single oral doses, while total radioactivity was cleared more slowly. In pregnant rats, the concentrations of both radioactivity and SAN Trimer 2h after dosing were highest in the blood, followed by the placenta, with the lowest levels in the fetus. In lactating rats, the concentrations of both radioactivity and SAN Trimer were higher in milk than in maternal blood. Total radioactivity and SAN Trimer blood concentrations in nonpregnant, pregnant, and lactating rats were both higher in lactating rats compared to nonpregnant and pregnant rats.     

静脉治疗质控小组在提高儿科病房静脉留置针输液安全管理中的应用与效果观察

目的 探讨静脉治疗质控小组(简称静脉治疗QC小组)在提高儿科病房静脉留置针输液安全管理中的效果.方法 成立静脉治疗QC小组,根据相关标准和文献制定静脉留置针穿刺、维护标准以及并发症预防和处理,并进行专项督查与管理,将实施前使用静脉留置针输液的患儿210例与实施后使用静脉留置针输液的患儿232例,在静脉留置针穿刺成功率、平均留置时间、相关并发症等几个方面进行比较与分析.结果 实施静脉治疗QC小组输液安全管理后,科室护理人员的静脉穿刺成功率提高,留置针平均留置时间延长,相关并发症发生率、非计划拔管率降低,患儿家长满意度提高,两组比较差异有统计学意义(P<0.05).结论 开展静脉治疗QC小组输液安全管理能够有效的提高静脉穿刺成功率,延长静脉留置针使用时间,降低非计划拔管率,减少留置针相关并发症的发生,具有临床工作指导意义.     

A comparative study of the hemodynamic effects of single intravenous doses of 3-hydrazino-6-[N,N-bis-(2-hydroxyethyl)-amino]-pyridazine-dihydrochloride and hydralazine.

The new pyridazine derivative 3-hydrazino-6-[N,N-bis(2-hydroxyethyl)-amino]-pyridazine-dihydrochloride (DL 150 IT) was administered to five hypertensive patients at the dose of 50 mug/kg by i.v. bolus injection. A parallel group of five patiens received 250 mug/kg of hydralazine. Hemodynamic measurements were obtained before treatment, and then after 30--60 and 80-120 min. Cardiac output was evaluated by radiocardiography and myocardial perfusion by clearance of 86Rb. The antihypertensive effect of DL 150 IT was most pronounced 2 h after the injection, whereas by this time the increased heart rate and cardiac output tended to revert to the baseline values. On the contrary, the magnitude of these effects did not change during the observation period after hydralazine treatment. Both drugs increased myocardial perfusion. The new compound appears at least five times more potent than hydralazine and, possibly, has a longer duration of action.     

Design, Synthesis and Evaluation of Novel 1-(Substituted Acetyl)-4-(10-Bromo-8-Chloro-5,6-Dihydro-11H-Benzo[5,6]Cyclohepta[1,2-B]Pyridine-11-Ylidene)piperidines as Antitumor Agents and Farnesyl Protein Transferase Inhibitors

Eight novel 1-(substituted acetyl)-4-(10-bromo-8-chloro-5,6-dihydro-11H-benzo[5,6] cyclohepta [1,2-b] pyridine-11-ylidene)piperidines were designed by incorporating zinc binding groups to enhance activity. The designed molecules were synthesized and were evaluated for antitumor activity in vitro in five cell lines and for farnesyl protein transferase inhibition. Test compounds (6a-h) exhibited antitumor activity in most of the cell lines but were less potent than adriamycin. Compound 6e was most active with IC(50) values of <15 μM in two cell lines tested. Test compounds also exhibited potent FPT inhibitory activity and 6c was most potent with IC(50) value of <30 μM.     

General toxicity study of gadobenate dimeglumine formulation (E7155) (2)--Single dose intravenous toxicity study in dogs

Gadobenate dimeglumine formulation (E7155) was given by single intravenous injection to 4-5 month-old beagle dogs at doses of 2 or 6 mmol/kg. Treatment was followed by a 14-day observation period in order to evaluate the test article's toxicity. The male and female dogs at 6 mmol/kg vomited and showed reddened gums and ears as clinical signs. One male dog at 6 mmol/kg was euthanized approximately 23 hr after administration due to its very poor clinical condition, which included an unwillingness to move, pale gums and weak pulse. Body weight was decreased at 6 mmol/kg, and also slightly at 2 mmol/kg. Decreased food consumption was noted both at 2 and 6 mmol/kg. Hematology for the euthanized male at 6 mmol/kg showed increases in the total white blood cell count, packed cell volume, hemoglobin and red cell count and a decrease in the platelet count. Biochemistry showed a dose-related increase in alkaline phosphatase, GPT and GOT at 2 and 6 mmol/kg. Males and females at 6 mmol/kg showed increases in bilirubin, calcium and urea, and a reduction in glucose. Females at 6 mmol/kg also showed a reduction in total protein. Urinalysis showed an increase in pH at 2 mmol/kg and above. For females at 6 mmol/kg, an increase in urine volume and a decrease in specific gravity and osmolality were noted. An increase in relative liver and kidney weights was recorded for males and females dosed at 6 mmol/kg. For the euthanized male at 6 mmol/kg, postmortem examination revealed a pale liver with rounded edges and an accentuated lobular pattern, and dark material on the gastro-intestinal mucosal surface. In macroscopic pathology, the male at 6 mmol/kg revealed single liver cell necrosis, minimal early hyperplasia in small biliary ductules, inflammatory cells in the sinusoidal and portal tracts, centrilobular inflammatory cells, diffuse vacuolation of the hepatocytes and sinusoidal dilatation in the liver, and cortical tubular vacuolation in the kidneys. In the female dog treated at 6 mmol/kg, hyperplasia in the small biliary ductules, inflammatory cells in the portal tracts, diffuse vacuolation of hepatocytes and sinusoidal dilatation were seen in the liver, and increases in the severity of cortical tubular basophilia, cortical tubular dilatation and cortical tubular casts were detected in the kidney. Based on these results, the lethal dose of E7155 was set at 6 mmol/kg. It is also concluded that a dose of 2 mmol/kg was tolerated in the beagle dog after a single injection followed by a 14-day observation period.