Antiproliferative activity induced by the somatostatin analogue, TT-232, in human pancreatic cancer cells.

Somatostatin analogues have been developed as antiproliferative agents, but their administration as general antitumour agents is limited, mainly because of the wide distribution of somatostatin receptors throughout the human body. TT-232, a new somatostatin structural analogue, was reported to have tumour-selective antiproliferative activity without an antisecretory action. We examined whether TT-232 had antiproliferative activity in human pancreatic cancer cell lines, and compared its antiproliferative activity with that of RC-160 and other TT-232 derivatives. TT-232 inhibited the growth of all of the cell lines used in this study and induced apoptotic cell death. RC-160 showed no such growth inhibition. TT-232 also inhibited tumour formation in a xenograft model. A competitive binding assay was performed using the cell membrane fraction and 111In-DTPA-TT-232 in order to show the existence of a specific binding site on the cells. A specific binding site was detected in MIAPaCa-2 cells. It has been shown that the activation of protein tyrosine phosphatase (PTPase) is one of the main intracellular pathways responsible for somatostatinergic inhibition of cell growth. We found a significant PTPase stimulation after TT-232 administration using an immunoblot analysis assessing the level of protein tyrosine phosphorylation, and also a direct measurement of the PTPase activity. We also demonstrated that PTPase stimulation by TT-232 was involved in its antiproliferative activity as this activity was reversed by the addition of sodium orthovanadate, a PTPase inhibitor. Our results indicate that TT-232 could be a potentially useful therapeutic agent if these data are translated into clinical practice.

Changes in DNA 8-hydroxyguanine levels, 8-hydroxyguanine repair activity, and hOGG1 and hMTH1 mRNA expression in human lung alveolar epithelial cells induced by crocidolite asbestos.

We examined 8-hydroxyguanine (8-OH-Gua) formation and 8-OH-Gua repair enzyme activity in pulmonary type-II-like epithelial cells to determine whether oxidative stress induced by asbestos plays a role in its carcinogenic mechanism. A549 cells were incubated with crocidolite asbestos at concentrations of 0, 10, 50 and 100 microg/ml over 27 h. We then evaluated 8-OH-Gua formation, 8-OH-Gua repair enzyme activity and gene expression of 8-oxoguanine-DNA glycosylase 1 (hOGG1) and human MUtT homologue (hMTH1). This was done using a high-performance liquid chromatography system equipped with an electrochemical detector, endonuclease nicking assay and reverse transcription polymerase chain reaction, respectively. Crocidolite induced the formation of 8-OH-Gua in DNA at concentrations of 50 and 100 microg/ml. 8-OH-Gua levels increased at 9 h and had declined to near baseline at 27 h, whereas 8-OH-Gua repair enzyme activity peaked at 18 h post-crocidolite exposure. hOGG1 and hMTH1 mRNA levels were also increased by crocidolite exposure. These data suggest that crocidolite asbestos is associated with epithelial cell injury in the process of carcinogenesis through oxidative stress.

Involvement of central opioid systems in human interferon-alpha induced immobility in the mouse forced swimming test.

1. We investigated the mechanism by which human interferon-alpha (IFN-alpha) increases the immobility time in a forced swimming test, an animal model of depression. 2. Central administration of IFN-alpha (0.05 - 50 IU per mouse, i.cist.) increased the immobility time in the forced swimming test in mice in a dose-dependent manner. 3. Neither IFN-beta nor -gamma possessed any effect under the same experimental conditions. 4. Pre-treatment with an opioid receptor antagonist, naloxone (1 mg kg(-1), s.c.) inhibited the prolonged immobility time induced by IFN-alpha (60 KIU kg(-1), i.v. or 50 IU per mouse. i.cist. ). 5. Peripheral administration of naloxone methiodide (1 mg kg(-1), s. c.), which does not pass the blood - brain barrier, failed to block the effect of IFN-alpha, while intracisternal administration of naloxone methiodide (1 nmol per mouse) completely blocked. 6. The effect of IFN-alpha was inhibited by a mu(1)-specific opioid receptor antagonist, naloxonazine (35 mg kg(-1), s.c.) and a mu(1)/mu(2) receptor antagonist, beta-FNA (40 mg kg(-1), s.c.). A selective delta-opioid receptor antagonist, naltrindole (3 mg kg(-1), s.c.) and a kappa-opioid receptor antagonist, nor-binaltorphimine (20 mg kg(-1), s.c.), both failed to inhibit the increasing effect of IFN-alpha. 7. These results suggest that the activator of the central opioid receptors of the mu(1)-subtype might be related to the prolonged immobility time of IFN-alpha, but delta and kappa-opioid receptors most likely are not involved.

Human interferon-alpha induces immobility in the mouse forced swimming test: involvement of the opioid system.

In a previous study, we indicated that human interferon (IFN)-alpha (IFN-alpha, 6 x 10(4) IU/kg, i.v.), but not human IFN-beta or -gamma, prolonged the immobility time of the forced swimming test in mice. In this study, we investigated the mechanism of the effect of human IFN-alpha. None of the mouse IFNs tested (IFN-alpha/beta, IFN-beta, and IFN-gamma, 3 x 10(5) U/kg, i.v.) changed the immobility time or the spontaneous locomotor activity in mice. Indomethacin (10 mg/kg, s.c.), a cyclooxygenase inhibitor, did not affect the increase in the immobility time induced by human IFN-alpha (6 x 10(4) IU/kg, i.v.). However, naloxone (1 mg/kg, s.c.), an opioid receptor antagonist, blocked the increasing caused by human IFN-alpha in the forced swimming test. These results suggest that the increase in the immobility time caused by human IFN-alpha in the forced swimming test might be mediated through opioid receptors, but not mouse IFN receptors.

Effects of mineral fibers on the gene expression of proinflammatory cytokines and inducible nitric-oxide synthase in alveolar macrophages.

To determine which parameters are useful for the risk assessment of man-made mineral fibers (MMMFs), we examined the gene expression of interleukin-1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6) and inducible nitric-oxide synthase (iNOS) in mineral fiber-exposed alveolar macrophages (AMs). Male Wistar rats were intratracheally exposed to saline or mineral fibers suspended in saline (2 mg of crocidolite, chrysotile, alumina silicate refractory fiber (RF1) or potassium octatitanate whisker (TW)). Bronchoalveolar lavage was performed 4 weeks after the fiber-instillation, and the recovered AMs were stimulated by lipopolysaccharide for 2 or 6 hours. Expression of IL-1 alpha, TNF alpha, IL-6 and iNOS from AMs was observed using reverse transcription-polymerase chain reaction (RT-PCR). The levels of IL-1 alpha and IL-6 mRNA induced by mineral fiber exposure were greatest in AMs exposed to TW, crocidolite, chrysotile and RF1 in that order. However, both gene expression of iNOS and TNF alpha were not elevated in both crocidolite and TW exposure, despite their high pathological potential. These data suggested that IL-1 alpha and IL-6 may be useful indicators for the risk assessment of MMMFs.

Enhancement of immobility in mouse forced swimming test by treatment with human interferon.

We investigated the depression induced by human interferons using the forced swimming test in mice. Intravenous (i.v.) administration of interferon-alpha s (natural interferon-alpha, recombinant interferon-alpha-2a and recombinant interferon-alpha-2b, 600-60000 IU/kg) increased the immobility time in the forced swimming test in a dose-dependent manner, but natural interferon-beta and recombinant interferon-gamma-1a did not affect the immobility time. The increase in the immobility time induced by recombinant interferon-alpha-2b peaked at 15 min after dosing. Administration of recombinant interferon-alpha-2b (6000 IU/kg, i.v.) once daily for 7 consecutive days increased the immobility time, but natural interferon-beta and recombinant interferon-gamma-la did not. Recombinant interferon-alpha-2b in combination with the anti-depressants imipramine (10 mg/kg, i.p.) and mianserin (20 mg/kg, i.p.) did not increase the immobility time. These results suggest that interferon-alpha has a greater potential for inducing depression than interferon-beta and -gamma, and that anti-depressants are effective against interferon-alpha-induced depression.

Inhibition of intestinal microflora beta-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats.

PURPOSE: SN-38, a metabolite of irinotecan hydrochloride (CPT-11), is considered to play a key role in the development of diarrhea as well as in the antitumor activity of CPT-11. We have previously found that the inhibition of beta-glucuronidase, which hydrolyzes detoxified SN-38 (SN-38 glucuronide) to reform SN-38, in the lumen by eliminating the intestinal microflora with antibiotics, markedly ameliorates the intestinal toxicity of CPT-11 in rats. In this study we compared the disposition of CPT-11 and its metabolites in rats treated with and without antibiotics. METHODS: Rats were given drinking water containing 1 mg/ml penicillin and 2 mg/ml streptomycin from 5 days before the administration of CPT-11 (60 mg/kg i.v.) and throughout the experiment. CPT-11, SN-38 glucuronide and SN-38 concentrations in the blood, intestinal tissues and intestinal luminal contents were determined by HPLC. RESULTS: Antibiotics had little or no effect on the pharmacokinetics of CPT-11, SN-38 glucuronide or SN-38 in the blood, or in the tissues or contents of the small intestine, which has less beta-glucuronidase activity in its luminal contents. In contrast, antibiotics markedly reduced the AUC1-24 h of SN-38 (by about 85%) in the large intestine tissue without changing that of CPT-11, and this was accompanied by a complete inhibition of the deconjugation of SN-38 glucuronide in the luminal contents. CONCLUSIONS: These results suggest that SN-38, which results from the hydrolysis of SN-38 glucuronide by beta-glucuronidase in the intestinal microflora, contributes considerably to the distribution of SN-38 in the large intestine tissue, and that inhibition of the beta-glucuronidase activity by antibiotics results in decreased accumulation of SN-38 in the large intestine.

Oral vehicle administration before radiation causes radioprotection of murine SCCVII tumors.

The effect of administering various vehicles on the response to radiation of SCCVII tumors in C3H mice was investigated. When saline, 0.5% carboxymethyl cellulose solution, or 1% hydroxypropylmethyl cellulose (HPMC) solution was given orally 30 min before single 15 Gy irradiation, the tumor regrowth was significantly faster than that seen after 15 Gy treatment alone. There was no difference in this radioprotective response due to the type of vehicle. On the other hand, the tumor regrowth was similar to that seen after 15 Gy alone when saline was given intravenously 20 min before irradiation or intraperitoneally 30 min beforehand, or when 1% HPMC was given orally 2 h beforehand. Oral vehicle administration shortly before irradiation can cause radioprotection of murine tumors, probably by increasing the hypoxic fraction.

Combined effect of clinically relevant doses of emitefur, a new 5-fluorouracil derivative, and radiation in murine tumours.

We investigated the combined effect of radiation and clinically relevant doses of emitefur (BOF-A2), a newly developed anti-cancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor of 5-FU degradation, in two types of murine tumours. In preliminary pharmacokinetic studies, the area under the curve for 5-FU in plasma, after administration of 12.5 mg kg-1 and 25 mg kg-1 emitefur in mice, appeared to be similar to that obtained on the first day and that on the seventh day, respectively, after starting administration of 400-600 mg day-1 in humans. These doses (12.5 and 25 mg kg-1) of emitefur were evaluated either alone or in combination with single (15 Gy), five-fraction (4 Gy each) or ten-fraction (2.8 Gy each) irradiation using a tumour growth delay assay for SCCVII tumours and in combination with four-fraction (5 Gy each) irradiation using an in vivo-in vitro assay for EMT6 tumours. The anti-tumour and radiation-enhancing effects of 12.5 mg kg-1 emitefur were not significant in any except the ten-fraction experiment. On the other hand, multiple doses of 25 mg kg-1 emitefur given either alone or in combination with radiation produced marked effects. The mean tumour growth delay time (the time to double in volume for treated tumours minus that for untreated tumours) was 8.1 days for five administrations of 25 mg kg-1 emitefur. 10.4 days for five fractions of 4 Gy and 22.1 days for five treatments with the combination of the two. Thus, the increase in growth delay afforded by this combination was at least additive. The effect of four fractions of 5 Gy with 25 mg kg-1 emitefur in EMT6 tumours was lower than that of four fractions of 7.5 Gy, but the effect of five fractions of 4 Gy with this dose of emitefur in SCCVII tumours was similar to the effect of five fractions of 6 Gy, and the effect of ten fractions of 2.8 Gy with 25 mg kg-1 emitefur was much higher than that of ten fractions of 4.2 Gy. In conclusion, emitefur given either alone or in combination with radiation appears to have a significant anti-tumour effect even at clinically relevant dose levels, although a threshold dose exists between 12.5 and 25 mg kg-1. Further clinical studies of this compound are warranted.

Involvement of beta-glucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats.

Irinotecan hydrochloride (CPT-11), an antitumor camptothecin derivative, causes severe forms of diarrhea clinically. We characterized CPT-11-induced diarrhea histologically and enzymologically and assessed the relationships between intestinal toxicity and the activity of the enzymes that play a key role in the major metabolic pathway of CPT-11 in rats. CPT-11 (60 mg/kg i.v. for 4 days) induced intestinal toxicity characterized by severe chronic diarrhea, loss of body weight, and anorexia. Histological damage was most severe in the cecum. The segmental difference in the degree of the damage showed good correlation with the beta-glucuronidase activity in the contents of the lumen in each case, but not with the intestinal tissue carboxylesterase activity, which converts CPT-11 to its active form (7-ethyl-10-hydroxycamptothecin). Inhibition of the beta-glucuronidase activity in the intestinal microflora by antibiotics (1 mg penicillin and 2 mg streptomycin per ml of drinking water) markedly ameliorated the diarrhea and reduced cecal damage. Analysis of CPT-11 and its metabolites in the feces indicated that antibiotics completely inhibited the deconjugation of the glucuronic conjugate of 7-ethyl-10-hydroxycamptothecin by beta-glucuronidase. It is suggested that CPT-11-induced diarrhea would be attributable to the damage to the cecum, and that the inhibition of the beta-glucuronidase activity in the intestinal microflora is a major protective effect of antibiotics.

The combined antitumour effect of a new 5-fluorouracil derivative, BOF-A2, and radiation in vivo.

We examined the combined effect of radiation and BOF-A2, a newly developed anti-cancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor of 5-FU degradation in the liver, on murine tumors. Subcutaneous 8-mm-diameter SCCVII tumours grown in the right thigh of C3H/He mice were used. The mice were locally irradiated with single doses of 10-30 Gy or five fractions of 4 Gy for 5 days, alone or in combination with BOF-A2. BOF-A2 at doses of 30, 75 and 150 mg kg-1 was orally administered 2 h before or immediately after single doses of irradiation, while 15 or 30 mg kg-1 of BOF-A2 was given 1 h prior to each fraction of 4 Gy. The effect of BOF-A2 alone was also examined. The antitumour effect was evaluated by a tumour growth delay assay. BOF-A2 alone showed significant tumour growth delay at all doses used in this study. Combination of BOF-A2 and single or fractionated doses of radiation appeared to produce an additive tumour response, which occurred independently of sequence of the two treatments. The combined effect became greater with the dose of radiation and BOF-A2. In conclusion, BOF-A2 and radiation may be efficiently combined.

Increasing-current electroshock seizure test: a new method for assessment of anti- and pro-convulsant activities of drugs in mice.

We developed the increasing-current electroshock seizure (ICES) test, a new method for assessment of anti- and pro-convulsant activities of drugs in mice. In this method, a single train of pulses (square wave, 5 msec, 20 Hz) of linearly increasing intensity from 5 to 30 mA (increment of 0.1 mA/0.1 sec, i.e., 5-30 mA in 25 sec) was applied via ear electrodes. The current at which tonic hindlimb extension occurred was recorded as the seizure threshold. Thus, this method allows determination of the seizure threshold current for individual animals. Carbamazepine, phenytoin, valproate, phenobarbital, diazepam, and morphine all increased the seizure threshold current in a dose-dependent manner, whereas ethosuximide was not effective. The seizure threshold current decreased after treatment with reserpine, chlorpromazine, aminophylline, strychnine, pentylenetetrazol, bicuculline, picrotoxin, and ethyl-beta-carboline-3-carboxylate (beta-CCE). These results indicate that the ICES test, like the maximal electroshock seizure test, is a model of grand mal-type seizure and is useful for evaluation of both the anti- and pro-convulsant activities of drugs.

Protective effects of kampo medicines and baicalin against intestinal toxicity of a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats.

In clinical use, irinotecan hydrochloride (CPT-11; 7-ethyl-10-[4-(piperidino)-1-piperidino]carbonyloxycamptothecin), a novel antitumor agent, causes a relatively high incidence of severe forms of diarrhea. We investigated whether baicalin, an inhibitor of beta-glucuronidase, which deconjugates the glucuronide of the active metabolite of CPT-11, SN-38 (7-ethyl-10-hydorxycamptothecin), and Japanese herbal medicines (Kampo medicines) which contain baicalin can ameliorate CPT-11-induced intestinal toxicity in rats. CPT-11 (60 mg/kg i.v. once daily for 4 consecutive days) induced intestinal toxicity characterized by diarrhea, loss of body weight, anorexia and disruption of intestinal epithelium. Treatment with baicalin (25 mg/kg p.o. twice daily) or Kampo medicines (TJ-14 and TJ-114; 1 g/kg p.o. twice daily) from the day before to 4 or 10 days after the start of CPT-11 administration resulted in significantly decreased weight loss, improved anorexia and delayed onset of diarrheal symptoms. Histological examination revealed that Kampo medicine-treated animals had less damage to the intestinal epithelium and that damage was repaired more rapidly than in control rats. These results suggest that the prophylactic use of Kampo medicines (TJ-14 and TJ-114) may be of value against CPT-11-induced intestinal toxicity.

[General pharmacological study of iodixanol, a new non-ionic isotonic contrast medium].

The general pharmacological study of iodixanol, a non-ionic isotonic contrast medium, was conducted. 1) Iodixanol administered intravenously over a dose range of 320 to 3,200 mgI/kg had little or no effect on the general behavior, spontaneous locomotor activity, hexobarbital sleeping time, pain response, electroshock- or pentylenetetrazol-induced convulsion (mouse), EEG or body temperature (rabbit), gastrointestinal propulsion (mouse) or skeletal muscle contraction (rabbit). Iodixanol had no specific interaction with acetylcholine, histamine, serotonin, nicotin, BaCl2 (ileum), methacholine (trachea), isoprenaline (atrium) or oxytocin (pregnant uterus), nor had any effect on spontaneous contractility (atrium and uterus), or transmural electrostimulation-induced contractility (vas deferens) at concentrations of < or = 3.2 x 10(-3) gI/ml in vitro. Iodixanol had no effect on the cardiovascular system of dog, except that it increased femoral blood flow and respiratory rate at doses of > or = 1,000 mgI/kg. Iodixanol at 3,200 mgI/kg i.v. reduced urine output with a decrease in Na+ and Cl- excretion, whereas at 320 mgI/kg i.v., it slightly increased urine output (rat). 2) Injections of iodixanol into the cerebroventricular (0.96, 9.6 mgI/mouse and 3.2, 32 mgI/rat), left ventricular (1,920, 6,400 mgI/dog) or coronary artery (640, 1,920 mgI/dog) had no conspicuous effect on the central nervous system or the cardiovascular system, respectively. There was no marked difference among iodixanol, iohexol and iopamidol in this respect. Vascular pain during injection into the femoral artery (300-320 mgI/guinea pig) appeared to be less intense with iodixanol, compared with the other contrast media iohexol and iopamidol. These results suggest that intravenous injection of iodixanol is relatively free from pharmacological activity, and effects of iodixanol on the central nervous system (intracerebroventricular injection) and cardiovascular system (intra-left ventricular and -coronary injections) are comparable to those of iohexol and iopamidol. Furthermore, intra-femoral injection of iodixanol has less of a tendency to produce vascular pain than those of iohexol and iopamidol.

[Study on the mechanisms of diarrhea induced by a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats].

We investigated the mechanisms of CPT-11-induced diarrhea. 1) CPT-11 (80 mg/kg, i.v.) induced watery diarrhea within 1 hr after dosing in saline-loaded (10 ml/kg, p.o.) rats. This was partially inhibited by subcutaneous injection of atropine (1 mg/kg) or ondansetron (1 mg/kg) and almost completely inhibited by a combination of atropine and ondansetron or by clonidine (0.3 mg/kg) or morphine (10 mg/kg) alone. 2) CPT-11 at the same dose reduced intestinal fluid absorption, which was blocked by the anti-diarrheal agents mentioned above. Intraluminal injection of CPT-11 (20 mg/2 ml) inhibited fluid absorption and induced fluid secretion. 3) CPT-11, 60 mg/kg, by single intravenous injection induced fewer enzymological and histological changes in the small intestine than 5-FU at 270 mg/kg, while 4 consecutive dosings of CPT-11 induced delayed diarrhea (days 5-7) associated with disruption of intestinal integrity. Co-administration with anti-diarrheal agents, except for ondansetron, protected against watery diarrhea appearing within 1 hr after CPT-11 on days 3 and 4, but worsened delayed diarrhea. These results suggest that single injection of higher doses of CPT-11 causes watery diarrhea at an acute phase at least partly by reducing fluid absorption or increasing secretion, and that while conventional anti-diarrheal agents protect against watery diarrhea, their co-administration in repeated CPT-11 administration has no ameliorative effect on CPT-11-induced delayed diarrhea.

Toxicity of quinolone antimicrobial agents.

An approach to minimization of toxicity of a new compound is to elucidate the mechanisms of toxicity of analogous compounds and to clarify their structure-toxicity relationships. A problem with this approach, however, is that such elucidation remains difficult. For quinolones, some improvements in this mechanistic approach have been achieved in the central nervous system (CNS), particularly with regard to their interaction with non-steroidal anti-inflammatory drugs (NSAIDs), and in genotoxicity and phototoxicity studies, particularly in comparison with other toxicities, such as to the cardiovascular, gastrointestinal, bone, reproductive, and developmental systems. This review concentrates on a description of the known effects of quinolones on various organ systems in experimental animals and humans. Given the logarithmic increase in the synthesis of new quinolones, it is questionable whether these drugs share similar safety and efficacy. Nevertheless, this mechanistic approach to the investigation and minimization of toxicity has produced satisfactory results to date and deserves to be continued.

General pharmacological profile of the new cognition-enhancing agent nefiracetam.

The general pharmacological properties of a novel cognition-enhancing agent, nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide, DM-9384, CAS 77191-36-7) were investigated, and the following results were obtained. 1. Central nervous system: Nefiracetam showed depressant activities (such as ataxia) on general behavior (mice), and inhibited spontaneous locomotor activity, rota-rod and traction performances (mice) and polysynaptic potential of the spinal reflex (rats), and potentiated pentobarbital anesthesia (mice). The drug inhibited electroshock-induced seizure at relatively low doses, but did not affect chemoshock-induced seizure (mice). Nefiracetam failed to show analgesic activity in the tail pinch test, but inhibited the acetic acid-induced writhing syndrome (mice). An inhibitory pattern in the electroencephalogram was observed (cats). Nefiracetam had little or no effect on body temperature (rats). 2. Respiratory and cardiovascular systems: Nefiracetam induced transient decreases in blood pressure, left ventricular pressure and LV dp/dt max at higher doses (dogs). 3. Autonomic nervous system: Nefiracetam had no influence on pupil size (rabbits). The drug induced no significant effect on the pressor response to norepinephrine or depressor response to acetylcholine, but inhibited the contractile response of the nictitating membrane to preganglionic cervical sympathetic nerve stimulation at the highest dose (dogs). 4. Gastrointestinal system: Nefiracetam inhibited gastrointestinal propulsion (mice), gastric emptying rate and gastric secretion (rats) at higher doses. Nefiracetam produced no apparent damage in the gastric mucosa, and had no effect on bile secretion (rats). 5. Isolated smooth muscle: Nefiracetam had no effect on the resting tonus of isolated ileum, whereas it inhibited the contractile response to acetylcholine, histamine, serotonin, nicotine and BaCl2 at higher concentrations (guinea pigs). Nefiracetam had no effect on the resting tonus or the serotonin-induced contraction of stomach fundus (rats). The drug had no effect on the resting tonus or the norepinephrine-induced contraction of vas deferens, but tended to inhibit the contraction induced by nerve stimulation (guinea pigs). Nefiracetam had little or no effect on the resting tonus or oxytocin-induced contraction of virgin uterus, or on spontaneous contraction of pregnant uterus (rats). Nefiracetam did not affect the resting tonus of trachea, whereas it inhibited isoproterenol-induced relaxation at the highest concentration (guinea pigs). Nefiracetam had no chronotropic effect in isolated atria, but showed a slight negative inotropic effect at the highest concentration (guinea pigs). 6. Miscellaneous: Nefiracetam slightly decreased urinary volume, whereas it did not affect urinary electrolyte excretion (rats).(ABSTRACT TRUNCATED AT 400 WORDS)

General pharmacological profile of the new anti-ulcer drug 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl]-amino-N -methylbenzamide.

Pharmacological properties of the anti-ulcer drug 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl] methyl]-amino-N-methylbenzamide (DQ-2511, CAS 104775-36-2) on the central and autonomic nervous systems, smooth muscle, gastrointestinal system, and other miscellaneous systems were investigated. 1. DQ-2511 showed little or no influence on general behavior, spontaneous motor activity, hexobarbital sleeping time (mouse), conditioned avoidance response (rat), body temperature (rabbit), EEG or spinal reflex (cat) after oral administration (300-1000 mg/kg) or intravenous injection (15, 50 mg/kg). It also had no anticonvulsant or analgesic activities (mouse). 2. DQ-2511 had no influence on pupil size (rabbit). It reduced or tended to reduce contractile responses of the nictitating membrane induced by electrical stimulation of pre- and post-ganglionic sympathetic nerve (cat) at the highest dose. The drug inhibited the pressor response to norepinephrine, but had little or no inhibitory effect on the depressor response to acetylcholine at the highest dose (dog). 3. DQ-2511 reduced contractile responses to nicotine, BaCl2, acetylcholine, histamine and serotonin (isolated guinea pig ileum), to acetylcholine and histamine (trachea), and to norepinephrine (vas deferens) at high concentrations. It also inhibited spontaneous and oxytocin-induced motility (isolated rat uterus). 4. DQ-2511 decreased gastric motility in a dose-related manner at intravenous doses of 5-50 mg/kg (dog). It also reduced gastric emptying rate at oral doses of 100-1000 mg/kg, and gastric secretion at intraperitoneal doses of 100-300 mg/kg (rat). On the other hand, it induced no definite changes in intestinal motility (dog) or gastrointestinal transit (mouse).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular properties of the new anti-ulcer drug 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl]-amino-N- methylbenzamide.

Cardiovascular activities of 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl]-amino-N- methylbenzamide (DQ-2511, CAS 104775-36-2), an anti-ulcer drug, were investigated in anesthetized dogs and conscious rats. In anesthetized and laparotomized dogs, DQ-2511 at intravenous doses of 5-50 mg/kg dose-relatedly induced an increase in celiac and mesenteric arterial blood flow, and a decrease in their resistance, whereas the drug had little or no effect on carotid and renal blood flow. DQ-2511 increased cardiac contractility in anesthetized dogs at an intravenous dose of 15 mg/kg. In addition to this effect, it produced an increase in respiratory rate, a decrease in blood pressure and a slight increase in heart rate after dosing at 50 mg/kg. The drug had little or no effect on femoral blood flow and produced no significant changes in the electrocardiogram. In conscious rats, blood flow in gastrointestinal organs was compared with flow in other organs using the microsphere method. Blood flow in the stomach, duodenum, ileum, pancreas, spleen, and kidney tended to decrease in the vehicle-treated control group. DQ-2511, at an oral dose of 100 mg/kg, significantly increased blood flow in the stomach, duodenum and spleen, and tended to increase flow in the pancreas, testis and fat in comparison with the vehicle-treated control group. Blood flow in the liver, heart and skeletal muscle tended to decrease, whereas the other regional blood flows did not differ from those in the control group. DQ-2511 at this oral dose had little or no effect on blood pressure, heart rate, cardiac output and total peripheral resistance in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

General pharmacology of the new quinolone antibacterial agent levofloxacin.

The general pharmacological properties of (-)-(S)-9-fluoro-2,3-dihydro-3- methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4] benzoxazine-6-carboxylic acid hemihydrate (levofloxacin, DR-3355, CAS 100986-85-4), an optically active isomer of ofloxacin, were examined. 1. Central nervous system (CNS): DR-3355 at 200-600 mg/kg p.o. showed depressant activity on the CNS, as was indicated by the depressant syndrome (mice), decreased spontaneous motor activity (mice) and hypothermia (mice and rabbits). In the cat behavior and EEG experiments, it had both stimulant and depressant effects at 30-100 mg/kg i.p., and caused transient slow waves followed by seizures at 20-30 mg/kg i.v. DR-3355 had no effect on convulsion, hexobarbital anesthesia, pain reaction to a tail pinch, or conditioned avoidance response, except that it showed mild analgesic activity in acetic acid writhing at 600 mg/kg p.o. 2. Respiratory and cardiovascular system: DR-3355 produced a hypotensive and a bradycardiac effect after the rapid i.v. injection of 6 mg/kg or more in anesthetized dogs, accompanied by an increase in plasma histamine concentration. Both changes were markedly reduced when the test drug was administered by continuous i.v. infusion. 3. Autonomic nervous system: DR-3355 inhibited nictitating membrane contraction induced by both pre- and post-ganglionic stimulation, and inhibited the depressor response to acetylcholine at 20 mg/kg i.v. It had no influence on pupil size or on pressor response to norepinephrine. 4. Gastrointestinal system: DR-3355 at 600 mg/kg p.o. inhibited gastric secretion. Dog gastrointestinal motility was slightly inhibited, and was then stimulated over the dose range of 2-20 mg/kg i.v. It had no influence on gastrointestinal propulsion, the gastric emptying rate or the gastric mucosa. 5. Isolated smooth muscle: At a concentration of 5 x 10(-4) g/ml, DR-3355 was devoid of spasmogenic or smasmolytic activity, except for showing a slight relaxation effect (trachea), inhibition of nicotine-induced contraction (ileum) and spontaneous or oxytocin-induced motility (pregnant uterus). 6. Miscellaneous: DR-3355 inhibited the urine output and carrageenin-induced paw edema at 600 mg/kg p.o. It had no effect on skeletal muscle contraction or the corneal reflex.