Behavioural effects of d-amphetamine alone and in combination with antidepressants,antihistamines or other psychotropic drugs in young chicks

Antidepressants, antihistamines or other psychotropic drugs were administered before injection of d-amphetamine in 3–5 day old chicks. This pretreatment completely protected some animals against the characteristic behavioural changes seen after d-amphetamine 6 mg/kg i.p. In addition chlorpheniramine, chlorimipramine, imipramine, cocaine and diphenhydramine were also able to antagonize a dose of 10 mg/kg i.p. It was further noticed that well developed d-amphetamine symptoms were interrupted by subsequent treatment with imipramine.     

Interaction of cisplatin with other cytotoxics and non-steroidal anti-inflammatory drugs

This study investigated a possible interaction between cisplatin, other cytotoxics and non-steroidal anti-inflammatory drugs. Experiments were performed in quadruplicate. Plasma was spiked with cisplatin with or without another cytotoxic or non-steroidal anti-inflammatory drug. The results were analysed by Student's t-test and a p value of less than 0.05 was accepted as statistically significant. No interaction between cisplatin and the other cytotoxics was demonstrated. However, an increase in free cisplatin was noted when mixed with indomethacin (p = 0.019). No interaction with the other non-steroidal anti-inflammatory drugs was demonstrated.     

Clinical pharmacokinetics of commonly used anticancer drugs

The quantitative aspects of drug disposition in man of the commonly used antineoplastic agents, including cyclophosphamide, the nitrosoureas, cisplatin, methotrexate, cytarabine, 5-fluorouracil, doxorubicin, daunorubicin, bleomycin, vincristine, vinblastine, and vindesine are reviewed. Although the pharmacokinetic behaviour of these drugs has been adequately described in man, the chemical reactivity, the complexity of metabolism and disposition, the lack of simple, rapid and sensitive assays to measure plasma concentration, and the lack of defined therapeutic and toxic plasma concentrations have limited the application of routine drug monitoring in clinical oncology. With the exception of high dose methotrexate, drug doses and administration schedules remain empirical with a standard starting dose and subsequent dosage modifications determined by ensuing drug toxicities. However, many of the pharmacological characteristics of the drugs, such as their low therapeutic index, potentially life-threatening toxicities and wide individual variability in drug disposition, necessitate pharmacological monitoring. Comprehensive pharmacokinetic analysis of new and established antineoplastic agents does play a role in defining dosage, administration schedule, route of administration, and dosage modification in the presence of organ dysfunction. Consideration of the kinetics of these drugs in planning treatment regimens could lead to more rational, safer and possibly more efficacious use.     

替加环素联合用药的研究进展

替加环素与其他抗菌药物联合使用已经成为抗感染领域研究的热点之一,近年来在体外实验、动物模型、病例报道、临床应用等研究中有相关报道。例如:体外实验研究中,替加环素与其他药物如利福平、阿米卡星、多黏菌素等联用时,表现出协同作用;动物实验研究结果也显示,替加环素与多黏菌素合用可以治疗肺炎克雷伯菌感染引起的菌血症和绿脓杆菌感染引起的骨髓炎等。本文通过查阅近年来替加环素联合用药的国内外相关文献,对其研究进展进行综述,以便更好地了解替加环素联合用药情况,为临床合理用药提供理论基础。     

Activation of programmed cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and hyperthermia

Cell death induced by cisplatin was studied in Chinese hamster ovary cell lines, one proficient and the other deficient (100-fold sensitive) in DNA excision repair. Previous experiments demonstrated that cells progressed to and arrested in the G2 phase of the cell cycle before dying. DNA double-strand breaks were detected following G2 arrest and prior to loss of membrane integrity. These DNA breaks have been studied in more detail. DNA fragments were observed consisting of multimers of approximately 180 base pairs. These fragments are consistent with internucleosomal cleavage of chromatin by an endonuclease. At LC90 concentrations, DNA digestion began 48 hr cisplatin treatment followed by loss of membrane integrity and cell shrinkage 24 hr later. High concentrations of cisplatin (170 logs of kill) induced DNA digestion 12 hr after drug treatment but loss of membrane integrity occurred 12 hr later. Both cell death and DNA fragmentation were inhibited by cycloheximide, suggesting the requirement for new protein synthesis. Cells incubated with many other agents demonstrated the same characteristic pattern of DNA degradation. At 90% lethal conditions, DNA digestion was induced within 30 min by hyperthermia, 18 hr by methotrexate, and 48-72 hr by all other agents tested. DNA digestion always preceded loss of membrane integrity and cell shrinkage. These observations are consistent with cell death occurring by the process of apoptosis, or prorammed cell death, and demonstrate the importance of DNA digestion as an early and presumably essential step in cell death. The results suggest that, irrespective of the primary site of action of a drug, cell death by most pharmacologic agents is mediated by activation of the signal transduction pathway for apoptosis. The results also suggest two signal pathways for apoptosis, one directly associated with drug action and a second that requires cell cycle-related events.     

The effects of alcohol alone or in combination with other drugs on information processing,task performance and subjective responses

This paper reviews the effects of alcohol on human psychomotor performance and cognitive function. It concentrates particularly on effects on reaction time and on skills related to car driving. The effects of alcohol on performance are very variable at low doses (under 1 g per kg body weight). The variability is due to the different measures and methods employed by the researchers and to the large interindividual and interoccasional differences in the effects of alcohol. That is, alcohol affects different people in different ways and it affects the same person differently on separate occasions. Greater performance deficits are observed as the dose increases and as the tasks become more complex. Although results vary, both nicotine and caffeine appear to antagonize the detrimental effects of alcohol on performance. Many other drugs interact with alcohol, the most important of which are sedative agents that can combine synergistically with alcohol to produce profound psychomotor and cognitive impairment. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetic drug interactions of commonly used anticancer drugs

With the use of combination chemotherapy as well as a wide range of symptomatic therapies (e.g. analgesics and antiemetics) for the treatment of patients with cancer, the field of oncology practises polypharmacy to an extreme degree. The risk for a drug interaction under these conditions is high, and the pharmacological characteristics of the anti-cancer drugs, such as steep dose-response curves, low therapeutic indices and severe toxicities, suggest that even small changes in the pharmacokinetic profile of the affected drug could significantly alter its toxicity or efficacy. In this review, drug interactions which quantitatively affect the absorption, distribution, biotransformation or excretion of the commonly used anticancer drugs are described. Most of the significant drug interactions involving this class of drugs occur at the level of biotransformation and excretion. For example, the renal excretion of methotrexate by glomerular filtration and tubular secretion is affected by a number of weak organic acids, such as probenecid, salicylates and penicillin, which compete for tubular secretion, resulting in delayed clearance of methotrexate. The best described example of an interaction at the level of biotransformation is the effect of allopurinol on the catabolism of 6-mercaptopurine. By inhibiting xanthine oxidase, allopurinol blocks the first-pass metabolism of 6-mercaptopurine following its oral administration, leading to a 4- to 5-fold increase in plasma concentrations. Known drug interactions may potentially be used to enhance the antitumour activity of a drug--for instance, the administration of tetrahydrouridine (a cytidine deaminase inhibitor) with cytarabine in an attempt to block its rapid inactivation to uridine arabinoside. Overall, little information is available concerning the pharmacokinetic interactions of anticancer drugs with each other and with other classes of drugs in man, in part because the high incidence of toxicity and treatment failure, and empirical dosing methods, obscure the recognition of possible interactions. Awareness on the part of the clinician and more extensive pharmacokinetic investigation will be needed to recognise, document and avoid potentially harmful pharmacokinetic drug interactions involving this class of drugs.     

比较顺铂与卡铂联合紫杉醇同步化疗在宫颈癌患者中的价值

目的比较顺铂与卡铂联合紫杉醇同步化疗在宫颈癌患者中的价值。方法前瞻性收集我院2011年1月至2013年1月收治的宫颈癌患者86例,随机分为研究组和对照组,每组43例,研究组采用卡铂联合紫杉醇同步化疗,对照组采用顺铂联合紫杉醇同步化疗。主要观察指标为3年生存率、复发率、无进展生存期、实体瘤疗效评价等级、健康相关的生存质量(SF-36)和相关并发症。结果两组患者3年生存率、无进展生存期、术后1年实体瘤疗效评价等级和有效率比较差异均无统计学意义(P>0.05)。研究组患者复发率低于对照组(32.56%vs.55.81%,P=0.030);术后1年健康相关的生存质量(SF-36)高于对照组(77.30±6.72 vs.73.42±6.15,P=0.006)。两组患者化疗期间相关并发症发生率比较差异无统计学意义(P>0.05)。结论卡铂联合紫杉醇同步化疗有助于降低宫颈癌患者术后复发率,改善患者生存质量。     

氟康唑与常用药物的配伍及稳定性

氟康唑与常用药物的配伍及稳定性徐蜀远（四川省自贡市三医院６４３０２０）ＳｔａｂｉｌｉｔｙａｎｄｃｏｍｐａｔｉｂｉｌｉｔｙｏｆｆｌｕｃｏｎａｚｏｌｅｗｉｔｈｏｔｈｅｒｃｏｍｍｏｎｌｙｕｓｅｄｄｒｕｇｓＸｕＳｈｕｙｕａｎ（ＴｈｅＴｈｉｒｄＰｅｏｐｌｅ′ｓ...     

Beta-lactamase stability and antibacterial activity of cefpirome alone and in combination with other antibiotics

The antibacterial activity of cefpirome (HR810), a new cephalosporin, was compared with that of other "third-generation" cephalosporins, as well as cefuroxime, piperacillin and gentamicin. Cefpirome was the most active beta-lactam antibiotic against Gram-negative bacteria. The MIC90 for Enterobacteriaceae was always less than 0.5 ml/l except for Enterobacter species. The MIC90 against Pseudomonas species was 2 mg/l, which was equal to that of ceftazidime and gentamicin. Cefpirome was also more active than the other beta-lactam antibiotics against Staphylococcus aureus. A relatively high frequency of synergy was observed when cefpirome was combined with aminoglycosides against both Gram-positive and Gram-negative bacteria. No antagonism was detected. This antibiotic was very stable to both plasmid- and chromosomally-mediated beta-lactamases. It was more resistant to Enterobacter cloacae P99 enzyme than ceftazidime, cefotaxime and cefotetan. Its stability to the Klebsiella K1 beta-lactamase was more than that of cefotaxime and ceftriaxone but slightly less than that of ceftazidime and latamoxef. MBC90 values for cefpirome were generally less than twice the corresponding MIC values.     

In vitro anti-HIV potency of stampidine alone and in combination with standard anti-HIV drugs

The purpose of the present study was compare the in vitro anti-HIV potency stampidine (CAS 217178-62-6), a novel aryl phosphate derivative of stavudine (CAS 3056-17-5), and drug combinations containing stampidine to the anti-HIV tency of the standard drugs zidovudine (CAS 30516-87-1), stavudine, lamivudine (CAS 134678-17-4), nelfinavir (CAS 159989-65-8), and nevirapine (CAS 129618-40-2) as well as their combinations. Stampidine inhibited the laboratory HIV-1 strain HTLV(IIIB) (B-envelope subtype) as well as the primary clinical HIV-1 isolates BR/92/025 (C-envelope subtype) and BR/93/20 (F-envelope sub-type) with subnanomolar IC50 values. Stampidine was as effective as zidovudine against HTLV(IIIB) and BR/92/025 and 3-logs more effective than zidovudine against BR/93/20. Stampidine was more effective than stavudine, lamivudine, nelfinavir, and nevirapine against all three HIV-1 isolates. The combination of stampidine with zidovudine + lamivudine was more effective than the combination of nelfinavir or nevirapine with zidovudine lamivudine against all three HIV-1 isolates. The combination of stampidine with nelfinavir was more effective than zidovudine + lamivudine as well as the combination of zidovudine + lamivudine with nelfinavir. The combination of stampidine with lamivudine + nelfinavir was more effective than the combination of zidovudine with lamivudine + nelfinavir. The combination of stampidine with lamivudine + nevirapine was more effective than the combination of stavudine with lamivudine + nevirapine. These findings demonstrate that (a) stampidine, as well as its combinations with the standard anti-HIV drugs zidovudine, lamivudine, nelfinavir or nevirapine, are potent inhibitors of HIV-1 replication in human peripheral blood mononuclear cells, and (b) replacement of either zidcovudine, zidovudine+lamivudine or stavudine in 3-drug cocktails with stampidine resulted in greater anti-HIV potency in vitro.     

Stability of cisplatin, iproplatin, carboplatin, and tetraplatin in commonly used intravenous solutions

The stability of cisplatin, iproplatin, carboplatin, and tetraplatin in common intravenous solutions was studied. Admixtures of each drug in each of the following vehicles were prepared in glass containers: 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose and 0.45% sodium chloride injection (admixtures were prepared in plastic bags also), and 5% dextrose and 0.225% sodium chloride injection. Drug concentrations were monitored for 24 hours using stability-indicating high-performance liquid chromatographic methods. The stability of cisplatin and tetraplatin was related to the chloride ion content of the infusion fluid; when the infusion fluid contained 0.9% sodium chloride, each of these drugs was present at greater than 90% of the original concentration after six hours. The stability of iproplatin was not related to chloride concentration. A slight increase in the decomposition rate of carboplatin was observed in the presence of chloride ion. Carboplatin and iproplatin are stable for 24 hours in all the infusion fluids studied, but carboplatin should not be diluted with solutions containing chloride ions because of possible conversion to cisplatin. Cisplatin is stable for 24 hours in admixtures containing sodium chloride concentrations of 0.3% or greater. Tetraplatin is stable for six hours in admixtures containing sodium chloride concentrations of at least 0.018%.     

氟尿嘧啶、顺铂、阿霉素动脉联合用药的药物动力学研究

目的：研究氟尿嘧啶、阿霉素、顺铂三种抗肿瘤药物对肺癌患者不同给药方案的药物动力学。方法：以高效液相色谱法测定氟尿嘧啶、阿霉素，以原子吸收分光光度法测定顺铂，应用３Ｐ８７实用药物动力学软件处理数据，以半衰期（Ｔ１／２）及生物利用度（ＡＵＣ）为评价指标。结果：所建立的方法能快速、准确、有效地测定血清中氟尿嘧啶、阿霉素及顺铂的浓度。结论：三种药物联合动脉给药优于单一动脉给药，单一动脉给药优于三种药物联合静脉给药     

Activity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice

The non-steroidal anti-inflammatory drug diclofenac (DCL) shows noteworthy in vitro and in vivo antimycobacterial activity. The aim of this study was to ascertain whether DCL used in combination with the first-line antitubercular antibiotic streptomycin (STM) synergistically augments its efficacy in vitro as well as in a murine tuberculosis infection model. In vitro minimum inhibitory concentrations (MICs) and synergistic activities of the drugs with respect to standard strains and clinical isolates of Mycobacterium tuberculosis were determined. Swiss albino male mice were intravenously infected with 2.3x10(7) M. tuberculosis H37Rv. Mice were treated with DCL or STM alone as well as in combination for 4 weeks to determine the survival rate, spleen weight and colony-forming unit (CFU) counts in the lungs and spleen. DCL was bactericidal at 40 microg/mL (4xMIC) against M. tuberculosis H37Rv and was synergistic with STM in vitro (fractional inhibitory concentration index 0.37). A dose of 10 microg/g/day DCL or 150 microg/g/day STM for 4 weeks, administered from 1 day post infection, significantly (P<0.05) lowered bacterial counts and reduced mean spleen weight of mice compared with untreated animals. Simultaneous administration of both agents further decreased CFU counts (P<0.05) in the lungs and spleen compared with mice receiving STM alone. Thus, the ability of extended antibiotic therapy may be improved with the help of this synergistic drug pair in murine tuberculosis, and further investigations may throw light on new directions to combat multidrug-resistant tuberculosis infections in humans.     

Effects of heroin,alone or in combination with other drugs,on the locomotor activity in two inbred strains of mice

The locomotor activity of C57B1/6J and DBA/2J mice was studied, under the influences of heroin, amphetamine, strychnine, or ethanol, and of combinations of the opiate with each one of the other drugs. Heroin treatment was followed by the typical running fit in the C57 mice, while the DBA strain was unaffected. Amphetamine enhanced the activity in the C57 strain only. The combination of heroin with amphetamine or ethanol increased the locomotor activity only in the DBA strain, while heroin + strychnine exerted a clear stimulating effect on the activity of the C57 mice. The strychnine + heroin mixture was more toxic than heroin alone when the lethal doses (LD50) were determined in the 2 strains.     

新铂类药物双环铂与顺铂、卡铂体内毒性的比较研究

目的:比较新铂类药物双环铂与顺铂、卡铂的体内毒性.方法:大鼠重复静脉注射双环铂、顺铂与卡铂,分别于给药结束以及恢复期末收集标本,进行血液学、血尿生化指标及病理切片的检测.结果:与溶剂对照组比较,重复静脉注射后,双环铂的高剂量组(13.89 mg·kg-1)全血网织红细胞以及红细胞明显降低(P＜0.01),骨髓切片示有核细胞显著减少;恢复期末网织红细胞和骨髓切片基本恢复至正常,而红细胞仍维持较低水平(P＜0.05).而双环铂各组尿酶、血尿素氮和肌苷以及肾脏病理切片在给药结束和恢复期均未见明显改变.结论:双环铂对SD大鼠的肾毒性明显低于顺铂,其骨髓抑制作用与卡铂相近,暗示肾毒性可能不会成为限制双环铂临床应用的主要毒副反应,临床应用需密切观察其对造血组织的损伤.     

In vitro antibacterial and antimalarial activity of dehydrophenylalanine-containing undecapeptides alone and in combination with drugs

A set of three cationic undecapeptides, analogous to the previously reported peptide VS2 (KWΔFWKΔFVKΔFVK), was created by alanine substitution in order to probe the effect of hydrophobicity on peptide activity. The activities of these peptides were determined against Escherichia coli, Staphylococcus aureus and the malaria parasite Plasmodium falciparum. VA1, the closest analogue of VS2, showed five-fold augmented activity [minimum inhibitory concentration (MIC)=10 μM] against the Gram-positive bacterium S. aureus. The designed analogues were non-haemolytic and non-cytotoxic at their MICs and clinically relevant concentrations. By alanine substitution, it was also possible to probe the critical role of tryptophan residues in determining peptide potency. Circular dichroism studies of the peptides in a membrane-mimetic system showed a correlation between peptide helicity and antimicrobial activity. The peptides were also tested in combination with sublethal concentrations of antibiotic drugs (rifampicin and kanamycin) and the antimalarial drug chloroquine. In combination with these drugs, the effect of the peptides was synergistic or additive. These results provide insight into basic design principles for generating new clinically relevant lead peptides. It also provides an alternative strategy where a peptide and a non-peptide drug can be used in combination to battle increasingly drug-resistant microbes.     

Anti-tumor effect of honokiol alone and in combination with other anti-cancer agents in breast cancer

Honokiol, an active component isolated and purified from Chinese traditional herb magnolia, was demonstrated to inhibit growth and induce apoptosis of different cancer cell lines such as human leukaemia, colon, and lung cancer cell lines; to attenuate the angiogenic activities of human endothelial cells in vitro; and to efficiently suppress the growth of angiosarcoma in nude mice. In this study, we have demonstrated that treatment of different human breast cancer cell lines with honokiol resulted in a time- and concentration-dependent growth inhibition in both estrogen receptor-positive and -negative breast cancer cell lines, as well as in drug-resistant breast cancer cell lines such as adriamycin-resistant and tamoxifen-resistant cell lines. The inhibition of growth was associated with a G1-phase cell cycle arrest and induction of caspase-dependent apoptosis. The effects of honokiol might be reversely related to the expression level of human epidermal growth receptor 2, (HER-2, also known as erbB2, c-erbB2) since knockdown of her-2 expression by siRNA significantly enhanced the sensitivity of the her-2 over-expressed BT-474 cells to the honokiol-induced apoptosis. Furthermore, inhibition of HER-2 signalling by specific human epidermal growth receptor 1/HER-2 (EGFR/HER-2) kinase inhibitor lapatinib synergistically enhanced the anti-cancer effects of honokiol in her-2 over-expressed breast cancer cells. Finally, we showed that honokiol was able to attenuate the PI3K/Akt/mTOR (Phosphoinositide 3-kinases/Akt/mammalian target of rapamycin) signalling by down-regulation of Akt phosphorylation and upregulation of PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) expression. Combination of honokiol with the mTOR inhibitor rapamycin presented synergistic effects on induction of apoptosis of breast cancer cells. In conclusion, honokiol, either alone or in combination with other therapeutics, could serve as a new, promising approach for breast cancer treatment.     

Economic evaluation of gemcitabine alone and in combination with cisplatin in the treatment of nonsmall cell lung cancer

OBJECTIVE: To evaluate the cost effectiveness of gemcitabine in the treatment of nonsmall cell lung cancer (NSCLC). METHODS: Gemcitabine was compared with best supportive care and gemcitabine/cisplatin was compared with three standard chemotherapies and four other novel chemotherapy combinations. Costs and effectiveness measures were based on resource and outcome data from previously reported clinical trials. All direct costs associated with NSCLC treatment were included and adjusted to year 2000 values. PERSPECTIVE: UK National Health Service. RESULTS: Gemcitabine plus best supportive care was associated with an incremental cost per progression-free life year gained of pound sterling5228 compared with best supportive care alone. In comparison with standard chemotherapies, gemcitabine/cisplatin was associated with an incremental cost per progression-free life year gained of pound sterling1751 versus etoposide/cisplatin and cost per 1-year survival gain of pound sterling5681 versus mitomycin/vinblastine/platinum. Incremental cost per tumour response was pound sterling2032 relative to etoposide/cisplatin, pound sterling5169 relative to mitomycin/ifosfamide/cisplatin and pound sterling6240 relative to mitomycin/vinblastine/platinum. Compared with four novel (newer) combination chemotherapies gemcitabine/ cisplatin showed cost savings in each case, with the same or better outcome. Thus, gemcitabine/cisplatin showed improved cost effectiveness and dominance. Sensitivity analyses showed the results were robust to variations to the values of key parameters. CONCLUSION: Gemcitabine alone or in combination with cisplatin was assessed to be a cost-effective or cost-saving therapy when compared with best supportive care, standard chemotherapy regimens and novel chemotherapy combinations. Chemotherapy regimens containing gemcitabine therefore represent good value for money and efficient use of healthcare resources in the treatment of advanced NSCLC.