Potentiation of the cytotoxic action of melphalan and "activated" cyclophosphamide against cultured tumor cells by centrophenoxine.

Centrophenoxine, without antitumor activity itself, enhanced the cytotoxic action of melphalan and "activated" cyclophosphamide against mouse P388 lymphoma and rat W256 carcinosarcoma cells growing in static suspension culture. The concentration of alkylating agent required for 99% cell-kill was approximately halved when centrophenoxine was also present during exposure to the antitumor drug. Maximum potentiation by centrophenoxine of the cytotoxic action of melphalan occurred when cells were exposed to the two agents simultaneously; little or no potentiation was observed when cells were exposed to centrophenoxine before or after exposure to the alkylating agent.     

Potentiation of an antimalarial oxidant drug.

In a previous report we described the synergistic antimalarial interaction between two structurally similar compounds, rufigallol and exifone. To explain this phenomenon, we proposed that exifone is transformed inside the parasitized erythrocyte into a xanthone with potent antimalarial properties. We speculated that the transformation process was induced by the prooxidant activity of rufigallol. On the basis of this model we hypothesized that exifone would act synergistically with other oxidant drugs. In the present study we have found a similar synergistic interaction between exifone and ascorbic acid (vitamin C) against both chloroquine-susceptible and multidrug-resistant strains of Plasmodium falciparum. The prooxidant activity of ascorbic acid against Plasmodium-infected erythrocytes is believed to result from an intraerythrocytic Fenton reaction occurring in the acidic food vacuole of the parasite. The hydroxyl radicals produced during this process are believed to attack exifone, which undergoes cyclodehydration to become 2,3,4,5,6-pentahydroxyxanthone (X5). Evidence presented to support this "xanthone hypothesis" includes the demonstration that the exifone ==> X5 transformation occurs readily in vitro under mildly acidic conditions in the presence of iron, ascorbic acid, and oxygen.     

Potentiation of radioresponse by polymer-drug conjugates.

Although combined chemotherapy and radiotherapy has produced significantly improved response and survival rates among cancer patients, there is still a compelling need to establish the most effective way to deliver these agents. We hypothesize that the radiosensitizing effect of a chemotherapeutic agent can be further enhanced if the drug is delivered at an optimal concentration and is maintained in the tumor for a prolonged period. Using a water-soluble poly(L-glutamic acid)-conjugated paclitaxel (PG-TXL) as a model compound, we investigated whether paclitaxel delivered by means of polymeric carrier could increase the tumor's response to radiation. Mice bearing 8-mm syngeneic ovarian carcinoma OCa-1 tumors implanted intramuscularly were treated with i.v. injected PG-TXL alone or in combination with single doses of local radiation. The enhancement factors at 24 h interval, as measured by incremental tumor growth delay compared with radiation alone, ranged from 2.48 to 4.28. The values varied as a function of radiation dose. The enhancement of radioresponse is also a function of time interval between injection of PG-TXL and tumor irradiation. The enhancement factor increased with decreasing interval, suggesting that radiation may in turn mediate the sensitivity of tumor toward PG-TXL. Thus, the mechanism of PG-TXL's radiopotentiation activity is probably multifactorial. Remarkably, while combined radiation and TXL produced additive or even sub-additive interaction when radiation preceded TXL injection, combined radiation and PG-TXL produced synergistic interaction in a mammary MCa-4 tumor model. Radiation significantly increased tumor uptake of PG-TXL, suggesting a potential role of radiation-modulated antitumor activity of polymeric drugs. Our data support a treatment strategy combining radiation and polymeric chemotherapy that may have important clinical implications in terms of scheduling and optimization of the therapeutic ratio.     

Potentiation of enkephalin action by peptidase inhibitors in rat locus ceruleus in vitro

Intracellular recordings were made from locus ceruleus (LC) neurons in slices of rat pons. It has been shown previously that opioids inhibit firing and hyperpolarize LC neurons by activating mu-opioid receptors. Concentration-response curves were constructed by measuring the hyperpolarization, or outward current at -60 mV, caused by various opioid agonists added to the superfusing solution. Peptidase inhibitors (kelatorphan, bestatin and thiorphan) each increased the potency of Met-enkephalin, Leu-enkephalin and metorphamide but had no effect of their own on the LC neurons. Kelatorphan (20 microM) produced a 7-fold shift to the left of the Met-enkephalin dose-response curve. Higher concentrations produced no further shift. Thiorphan (3 microM) and bestatin (20 microM) each had a smaller potentiating effect on the Met-enkephalin hyperpolarization. The effects of Tyr-D-Ala-Gly-MePhe-Gly-ol and noradrenaline were not potentiated by these peptidase inhibitors. Electrical stimulation produced an inhibitory synaptic potential that was prolonged by cocaine (10 microM) and blocked by the alpha-2 adrenoceptor antagonist idazoxan (1 microM). After addition of idazoxan, hyperpolarizing synaptic potentials could be evoked even in the presence of kelatorphan (20 microM). These results indicate that peptide metabolism in the intact brain slice can account for a substantial decrease in the sensitivity of LC neurons to exogenously applied opioid peptides; even after peptidase inhibition, no evidence could be obtained for hyperpolarizing synaptic potentials due to the release of endogenous opioids.     

Potentiation of N-methyl-D-aspartate-induced currents by the nootropic drug nefiracetam in rat cortical neurons

Nefiracetam is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and post-stroke vascular-type dementia. In the brain of Alzheimer's disease patients, down-regulation of both cholinergic and glutamatergic systems has been found and is thought to play an important role in impairment of cognition, learning and memory. We have previously shown that the activity of neuronal nicotinic acetylcholine receptors is potently augmented by nefiracetam. The present study was undertaken to elucidate the mechanism of action of nefiracetam on glutamatergic receptors. Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell patch-clamp technique at a holding potential of -70 mV in Mg2+-free solutions. N-Methyl-D-aspartate (NMDA)-evoked currents were greatly and reversibly potentiated by bath application of nefiracetam resulting in a bell-shaped dose-response curve. The minimum effective nefiracetam concentration was 1 nM, and the maximum potentiation to 170% of the control was produced at 10 nM. Nefiracetam potentiation occurred at high NMDA concentrations that evoked the saturated response, and in a manner independent of NMDA concentrations ranging from 3 to 1,000 microM. Glycine at 3 microM potentiated NMDA currents but this effect was attenuated with an increasing concentration of nefiracetam from 1 to 10,000 nM. 7-Chlorokynurenic acid at 1 microM prevented nefiracetam from potentiating NMDA currents. Nefiracetam at 10 nM shifted the dose-response relationship for the 7-chlorokynurenic acid inhibition of NMDA currents in the direction of higher concentrations. Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid- and kainate-induced currents were not significantly affected by application of 10 nM nefiracetam. It was concluded that nefiracetam potentiated NMDA currents through interactions with the glycine binding site of the NMDA receptor.     

Potentiation of erythropoiesis in vitro by dexamethasone.

The effect of dexamethasone on erythropoiesis was examined in vitro. Hematopoietic cells from 13-day mouse fetal livers were cultured for 48 h in the presence or absence of erythropoietin and erythroid colonies enumerated. Colony formation occurring in cultures containing no added erythropoietin was inhibited by the incorporation of antierythropoietin antibody, suggesting that these colonies formed in response to endogenous hepatic erythropoietin. Maximal colony formation was observed with 0.5 U/ml of sheep erythropoietin. Dexamethasone increased erythroid colony formation with peak stimulation at 10(-9) M. Dexamethasone potentiation was most marked in cultures containing less than maximally stimulating concentrations of erythropoietin. The cells required only a brief exposure to glucocorticosteroid to exhibit the augmented cloning capacity, and dexamethasone stimulation was inhibited by progesterone (10(-6) M). A comparable response to dexamethasone was observed in cultures of adult murine and human bone marrow erythroid progenitors, implying that the phenomenon is not peculiar to fetal cells and is not dependent on the presence of fetal hepatocytes. These data suggest that erythroid progenitor cells possess a glucocorticoid receptor mechanism that can modulate the response to erythropoietin in vitro.     

Potentiation of pentazocine analgesia by low-dose naloxone.

The analgesia produced by combinations of low-dose naloxone with pentazocine or morphine was studied in 105 patients with moderately severe postoperative pain after standardized surgery for removal of impacted third molars. Pain intensity was quantified using a visual-analogue scale. To eliminate the release of endogenous opioids produced by the placebo component of open drug administration, all injections were made by a preprogrammed infusion pump. The analgesia produced by pentazocine, an agonist-antagonist opiate-analgesic acting predominantly at the kappa opiate receptor, was potentiated by low-dose naloxone, whereas the analgesia produced by morphine, a mu-agonist, was attenuated by low-dose naloxone. To evaluate whether similar potentiation would be present in an animal model, and specifically, in the absence of diazepam, which patients receive, we performed an analogous experiment in rats in which nociceptive threshold was determined using the Randall-Selitto paw-withdrawal test. The results were completely analogous to the clinical results: pentazocine analgesia was potentiated by low-dose naloxone, whereas morphine analgesia was attenuated by low-dose naloxone. These data demonstrate a novel interaction between opiates, and suggest a rationale for opiate combinations to produce potent analgesia with fewer autonomic side effects and less abuse potential than presently available analgesics.     

抗肿瘤药物载体的主动靶向策略

背景:抗肿瘤药物给药后,在机体内往往非特异性分布,毒副作用大,生物利用度低,具有主动靶向功能的药物载体可成功解决这一问题。目的:综合论述了近年来国内外制备主动靶向药物载体应用于抗肿瘤药物输送的最新研究,归纳总结出药物载体的各类主动靶向策略。方法:应用计算机检索平台ISI Web of Knowledge检索2004/2011各英文数据库,检索词采用与抗肿瘤药物载体靶向给药密切相关的关键词,如"tumor,drug carrier,active targeting"等,共检索到文献58篇,最终纳入符合标注的文献26篇。结果与结论:主动靶向策略是设计抗肿瘤药物载体时首先需要考虑也是最为重要的环节,它决定了药物载体实际的药物输送效果以及药物的生物利用度。具有主动靶向策略的药物载体可携带抗肿瘤药物到达肿瘤部位,显著减少机体内其他部位药物的非特异性分布,从而降低其毒副作用,提高生物利用度。     

Potentiation by previous nutrients of glibenclamide-induced insulin release in man. An effect which is counteracted by meal-induced retardation of drug absorption

We have studied the impact of a previous meal on insulin and glucose responses to the subsequent administration of glibenclamide. Healthy volunteers and NIDDM patients ingested a standard low-carbohydrate breakfast, and glibenclamide was administered 110-120 min later either as an intravenous bolus (12.5 micrograms/kg body wt), or as a tablet (5 mg HB 419). When glibenclamide was administered i.v. the drug raised insulin and lowered blood glucose levels, and previous breakfast potentiated these effects both in healthy volunteers and in NIDDM patients. Conversely when glibenclamide was given as a tablet the drug per se raised C-peptide and lowered blood glucose levels under fasting conditions, whereas the drug had no effect when ingested after breakfast. Measurements of glibenclamide in plasma revealed that previous breakfast delayed the systemic appearance of ingested glibenclamide. We conclude that nutrients sensitize insulin-releasing cells to subsequent stimulation by glibenclamide, thereby aggravate a blood-glucose-lowering effect of the drug. However this effect, which could potentially induce undesirable hypoglycaemia in sulphonylurea-treated diabetics, is counteracted when glibenclamide is taken orally because of a meal-induced decrease in drug absorption.     

Modulation of HERG potassium channel function by drug action

Repolarization of cardiomyocytes is mainly performed by the rapid component of the delayed rectifier potassium current, I(Kr), which is encoded by the human ether-a-go-go-related gene (HERG). Inhibition of HERG potassium currents by class III antiarrhythmic drugs causes lengthening of the cardiac action potential, which produces a beneficial antiarrhythmic effect. Conversely, excessive prolongation of the action potential by a wide variety of antiarrhythmic and non-antiarrhythmic drugs may lead to acquired long-QT syndrome, which is associated with a risk for 'torsade de pointes'-arrhythmias and sudden cardiac death. As a result, this undesirable side effect has prompted the withdrawal of several drugs from the market. Recent studies on HERG channel inhibition provide significant insights into the molecular factors that determine state-, voltage-, and use-dependency of HERG current block. In addition, crucial properties of the putative drug binding site in HERG have been identified. The broad diversity in response to pharmacologic treatment among individuals is likely to depend on a combination of multiple factors from the fields of arrhythmia genetics, physiology and pharmacology. In conclusion, the increasing understanding of the molecular mechanisms that underlie HERG channel block by antiarrhythmic and non-antiarrhythmic drugs may improve prevention and treatment of drug-induced long-QT syndrome.     

Circadian rhythms in drug action and drug metabolism in the mouse.

The relationship between circadian rhythms in the pharmacological actions of meperidine and hexobarbital and similar rhythms in the hepatic metabolism of these drugs was examined in mice under a variety of environmental alterations to determine whether such rhythms may be causally related. The rate of metabolism of p-nitroanisole and hexobarbital by hepatic 9000 X g supernatant fractions was found to be higher at 2400 hours (middark phase) compared to 1200 hours (midlight phase). The rhythms in in vitro hexobarbital and in vivo merperidine metabolism were inversely related in time with similar rhythms in duration of hexobarbital sleep time and meperidine analgesia. Exposure of mice to continuous lighting abolished the rhythms in metabolism and response to meperidine and hexobarbital. Reversal of the usual lighting cycle inverted the rhythm in hexobarbital metablism while abolishing the rhythm in pharmacological response to hexobarbital; meperidine was similarly affected. Adrenalectomy abolished the rhythm in hexobarbital metabolism, diminished the amplitude of the circadian variation in meperidine metabolism and abolished the rhythm in hexobarbital hypnosis and meperidine analgesia. These results indicate that circadian rhythms in the action of hexobarbital and meperidine are well correlated with similar rhythms in the disposition of these drugs.     

In vitro effects of a sulfonylurea on insulin action in adipocytes. Potentiation of insulin-stimulated hexose transport.

The mechanism(s) by which the oral sulfonylurea, tolazamide, exerts its extrapancreatic hypoglycemic effects was studied using rat epididymal adipose tissue maintained 20-44 h in the presence or absence of the drug. Insulin binding, hexose transport and glucose metabolism were compared in adipocytes isolated from the cultured tissue. In contrast to earlier reports that suggested that sulfonylureas alter the binding of insulin, neither receptor number nor affinity were changed by tolazamide treatment. The uptake of the glucose analogs 2-deoxyglucose and 3-0-methylglucose in the absence of insulin (i.e., basal) was also unchanged. However, exposure to tolazamide resulted in a potentiation of the stimulatory effects of insulin by approximately 30% at each hormone concentration assayed (0.4-40 ng/ml). This potentiation was dependent on the tolazamide concentration (0.003-0.30 mg/ml), with a maximal effect observed at therapeutic levels. A tolazamide analog hypoglycemic activity in vivo was found not to enhance either basal or insulin-stimulated uptake in vitro. Conversion of 0.1-5.0 mM glucose to CO2 and total lipids in the presence of insulin was also potentiated by tolazamide treatment. The inability of the drug to directly stimulate basal glucose uptake was paralleled by its lack of effect on glucose metabolism. At 50 mM glucose, where transport is no longer rate-limiting, tolazamide did not potentiate metabolism in the absence or the presence of insulin. These studies demonstrate that tolazamide in vitro alters postreceptor insulin action without influencing the receptor, and suggests insulin-stimulated hexose transport as the cellular process responsible for the hypoglycemic effect of sulfonyureas in adipose tissue.     

Caffeine drug discrimination in humans: acquisition, specificity and correlation with self-reports.

This study evaluated the discriminative stimulus effects of caffeine in humans. Nine normal male and female volunteers (ages 18-28) were trained to discriminate between the methylxanthine central nervous system stimulant caffeine (320 mg/70 kg, p.o.) and placebo. Monetary reinforcers were earned for identifying correctly the letter code associated with each substance. After four training sessions, the ability to discriminate between the two training conditions was tested for 20 sessions (test-of-acquisition). In subjects who met the criterion for discrimination (i.e., greater than or equal to 85% correct responding on greater than or equal to 4 consecutive sessions during the last 10 test-of-acquisition sessions) dose-effect curves for caffeine (0, 56, 100, 180, 240 and 320 mg/70 kg) and for the benzodiazepine triazolam (0, 0.10, 0.32 and 0.56 mg/70 kg) were determined. Seven of the nine subjects learned the caffeine-placebo discrimination and their performance improved across the 20 test-of-acquisition sessions. The training dose of caffeine (320 mg/70 kg) produced stimulant-like self-reports that differed from placebo when the letter codes were identified correctly, but not when the letter codes were identified incorrectly. Novel caffeine doses produced dose-related increases in caffeine-appropriate responding (N = 4), whereas triazolam produced predominantly placebo-appropriate responding (N = 3) and self-reports that differed from both caffeine and placebo. Throughout dose-effect curve determinations, the training dose of caffeine and placebo continued to be identified correctly (range: 84-100% correct responding). These results suggest that a caffeine (320 mg/70 kg)-placebo discrimination 1) can be acquired and maintained, 2) is related to self-reported drug effects if the training conditions are correctly identified and 3) has some pharmacological specificity.     

Genotoxic action of cycloplatam,a new platinum antitumor drug,on mammalian cells in vivo and in vitro

Cycloplatam (CP), a new antitumor platinum compound of the second generation, was first synthesized in Russia. This drug shows less toxicity in vivo than the widely used cisplatin and carboplatin and a higher antitumor activity than carboplatin. CP is not nephrotoxic with respect to the platinum-based antitumor agents. CP is actually studied in clinical phase II trials in Russia and Armenia. Promising results were obtained in patients with lung, ovary, and prostate cancers. The aim of this work was to study the micronuclei (MN) inducing effect of CP in vivo in murine bone marrow cells and in human lymphocytes in vitro. The mutagenic activity of CP in bone marrow of mice was significantly lower than that of cisplatin at equitoxic doses. In human lymphocytes CP induced a dose-dependent increase of MN, beginning at a very low dose (0.1 micro M). Our results showed that CP is much less toxic and MN inducing in vivo in murine bone marrow than cisplatin. In vitro data evidenced that CP is more toxic and genotoxic to human cells than cisplatin. The evidence of a MN-induced activity of an antitumor drug suggests a potential risk for long-time survivors.