Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors.

BACKGROUND: Lucitanib is a potent, oral inhibitor fibroblast growth factor receptor types 1 and 2 (FGFR), vascular endothelial growth factor receptor types 1, 2, and 3 (VEGFR), platelet-derived growth factor receptor types α and ß (PGFRα/ß), which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of fibroblast growth factor (FGF)-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1- or FGF3/4/19-amplified) tumors. METHODS: This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). RESULTS: Doses from 5 to 30 mg were evaluated with dose-limiting toxic effects dominated by vascular endothelial growth factor (VEGF) inhibition-related toxic effects at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t½ was 31-40 h, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were assessable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria In Solid Tumors (RECIST) partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response + partial response) was 26% (7 of 27) and progression-free survival (PFS) was 25 weeks. In assessable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. CONCLUSION: Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.

Enterococcus faecalis resistant to vancomycin and teicoplanin (VanA phenotype) isolated from a bone marrow transplanted patient in Brazil.

We report for the first time in Brazil, a patient from whom an Enterococcus faecalis VanA phenotype was isolated. Glycopeptide resistance is not commonly observed in Enterococcus faecalis, so this finding is of great concern since this species is responsible for 90% of enterococcal infections in Brazil. The isolate was recovered from a surveillance rectal swab culture from a patient with acute lymphocytic leukemia (ALL). Identification to the species level was performed by conventional biochemical tests and Vitek GPI cards. Antimicrobial susceptibility testing was evaluated by use of broth microdilution and Etest (AB BIODISK, Solna, Sweden) methods. The isolate was identified as E. faecalis and was considered resistant to both vancomycin (MIC, > 256 microg/mL) and teicoplanin (MIC, 256 microg/mL). The isolate also showed high level resistance to gentamicin and streptomycin (MICs, > 1024 microg/mL), but was considered susceptible to ampicillin (MIC, 4 microg/mL). Although the frequency of enterococcal infections is very low in most Latin America countries, the finding of glycopeptide (VanA) resistance in E. faecalis increases concern about apreading antimicrobial resistance in this region.

Antimicrobial susceptibility of coagulase-negative staphylococci and characterization of isolates with reduced susceptibility to glycopeptides.

The antimicrobial susceptibility of 239 coagulase-negative staphylococci (CNS) isolates consecutively collected from blood culture in patients admitted in a 600-bed teaching hospital was evaluated. The isolates were identified to the species level by conventional methods and the MicroScan Positive Combo Panel type 6 system, and their susceptibility to vancomycin, teicoplanin, and oxacillin were tested by agar dilution, disk diffusion, and MicroScan-WalkAway system. The species distribution was as follows: Staphylococcus epidermidis 120 (50.2%), S. hominis 29 (12.1%), S. haemolyticus 24 (10.0%), S. cohnii 14 (5.9%), and isolates from other CNS species 52 (21.8%). The percentage of resistance to oxacillin was 74.5% by agar dilution. The highest percentages of oxacillin resistance were found among S. haemolyticus (95.8%) and S. epidermidis (80.8%). Teicoplanin resistance (MIC > or = 32 micrograms/mL) was detected in five S. haemolyticus isolates, whereas intermediate resistance (MIC = 16 micrograms/mL) was detected in nine strains. These isolates with reduced susceptibility to teicoplanin were resistant to oxacillin, but remained susceptible to vancomycin (MIC < or = 4 micrograms/mL). Two isolates, one S. haemolyticus and one S. epidermidis, showed a vancomycin MIC of 8 micrograms/mL, and both MicroScan and disk diffusion methods classified these isolates as susceptible. Our results showed that glycopeptide resistance is emerging among CNS isolates in our institution and the disk diffusion method may not detect isolates with decreased susceptibility to these antimicrobial agents.

Evaluation of the in vitro Activity of Cefprozil Relative to Other Oral Antimicrobial Agents Against Bacteria in Clinical Specimens from Patients in São Paulo With Respiratory Tract Infections.

Cefprozil is a new oral second generation cephalosporin. Its in vitro antimicrobial activity was evaluated against 371 recent clinical isolates from patients with respiratory infections. We tested the susceptibility of 244 streptococci (96 Streptococcus pneumoniae, 105 group viridans streptococci, 32 Streptococcus agalactiae, and 11 group A beta-hemolitic streptococci) 107 Haemophilus influenzae, and 20 oxacillin-susceptible S.aureus (OSSA). The isolates were susceptibility tested against cefprozil, cefaclor and amoxicillin/clavulanic acid by the E-test method; and against cefadroxil, cefuroxime, cefetamet, erythromycin, and azythromycin by disk diffusion. The methods and the susceptibility categorization followed the National Committee for Clinical Laboratory Standards (NCCLS) procedures. Amoxicillin/clavulanic acid was slightly more active againstH.influenzae (MICs(90) 0.5µg/mL) than cefprozil or cefaclor (MICs(90) 4 and 2µg/mL respectively). Cefprozil demonstrated potent activity against streptococci. Against S.pneumoniae, cefprozil was 2-4 fold more active than cefaclor (MICs(90)0.125 and 0.38µg/mL, respectively). S. pneumoniae susceptibility was 84% to penicillin, 95% to erythromycin and 97% to azithromycin by disk diffusion. Viridans streptococci showed higher MICs for cefprozil and cefaclor (MICs(90) 4µg/mL and 8µg/mL, respectively) and only 50% susceptibility to the macrolides. Cefprozil was four times more active than cefaclor and as active as amoxieillin/clavulanic acid against group A beta-hemolytic streptococci and S.agalactiae. These three compounds showed similar activity against OSSA. In conclusion, cefprozil demonstrated excellent in vitro activity against bacterial species responsible for respiratory infections in São Paulo.

In Vitro Antimicrobial Activity Against Enterococci Isolated in a University Hospital in São Paulo, Brazil.

The prevalence of multiresistant enterococci (MRE) is rapidly increasing and becoming an important problem in several countries. São Paulo Hospital is a 600-bed tertiary hospital located in São Paulo, Brazil. The use of vancomycin is very high in the hospital due to the high prevalence of multi-resistant S. aureus (around 70%). We susceptibility tested 250 isolates of Enterococci consecutively collected between March, 1994 and June, 1995. Isolates were susceptibility tested using agar dilution disc diffusion BHI screen plating, and E test. In addition to vancomycin and teicoplanin, the isolates were tested against ampicillin, gentamicin, streptomycin and RP 59-500. Methods used for susceptibility testing were compared. None of the isolates showed high-level resistance to vancomycin or teicoplanin. The MIC90s for teicoplanin were <e;1µg/mL for E. faecalis (EF, n=216), E. faecium (EFM, n=23) and for the non-faecalis-non-faecium (NFNF, n=11) species. The MlC90s for vancomycin were 2µg/mL, 4µg/mL and 4µg/mL for EF, EFM and NFNF respectively. Eight isolates (3.2%), 5 E. faecalis, 2 E. casseliflavus and 1 E. gallinarum presented intermediate MICs for vancomycin (6 - 12µg/mL), but they were highly susceptible to teicoplanin (MIC 0.19 - 1µg/mL). The percentage of resistance to ampicillin and high-level resistance to gentamicin and streptomycin were, respectively: 4.8%, 26.4%, and 24.8%. In spite of the high usage of vancomycin in our hospital, the prevalence of glycopeptide resistance among enterococci seems to be low. Teicoplanin appears to be more potent than vancomycin, RP 59-500, gentamicin, streptomycin and ampicilin against this genus, especially EFM and NFNF species.

Avaliaçäo da sensibilidade in vitro de 446 amostras clínicas de bactérias gram-positivas testadas para novos antimicrobianos da classe das quinolonas, carbapenens e cefalosporinas / In vitro susceptibility testing of 446 clinical isolates of gram-positive bacteria against new quinolones, carbapenems and cephalosporins

Objetivo. Avaliar a sensibilidade in vitro de amostras clínicas de bactérias gram-positivas, hospitalares contra cinco fluoroquinolonas, três carbapenens e três cefalosporinas. Material e Método. Foram analisadas 67 amostras de estreptococos, 38 de enterococos, 250 de S. aureus e 91 de S. epidermidis. As amostras foram isoladas no Hospital Sao Paulo durante os meses de junho e julho de 1992. Os valores de concentraçao inibitória mínima (MIC) foram determinados por microdiluiçao em caldo seguindo a padronizaçao do National Commitee for Clinical Laboratory Standards (NCCLS). Os antimicrobianos testados foram: ciprofloxacina, ofloxacina, levofloxacina, grepafloxacina, DU-6859, imipenem, meropenem, biapenem, ceftazidima, cefepime e FK-037. Resultados. As novas fluoroquinolonas, especialmente o DU-6859, foram os antimicrobianos que demonstraram maior atividade contra as bactérias testadas. Entre as drogas disponíveis comercialmente, as fluoroquinolonas ciprofloxacina e ofloxacina (81 por cento de sensibilidade) e o carbapenem imipenem (74 por cento de sensibilidade) foram as mais ativas. Os enterococos e os estafilococos resistentes à oxacilina foram as bactérias que demonstraram maior resistência antimicrobiana. Conclusao. Os resultados do presente estudo mostraram que os novos carbapenens apresentam potência semelhante àquela apresentada pelo imipenem, enquanto que as cefalosporina de quarta geraçao apresentam atividade superior àquela mostrada pela ceftazidima. Por outro lado, as novas fluoroquinolonas demonstraram espectro e potência superiores às fluoroquinolonas disponíveis comercialmente, especialmente contra enterococos e estafilococos resistentes à oxacilina e à ciprofloxacina, indicando que essas novas drogas merecem ser avaliadas em ensaios clínicos.

[In vitro susceptibility testing of 446 clinical isolates of gram-positive bacteria to new quinolones, carbapenems and cephalosporins]. / Avaliação da sensibilidade in vitro de 446 amostras clínicas de bactérias gram-positivas testadas para novos antimicrobianos da classe das quinolonas, carbapenens e cefalosporinas.

OBJECTIVE: To assess the in vitro susceptibility of gram-positive bacteria isolated in the São Paulo Hospital against five fluoroquinolones, three carbapenems and three cephalosporins. MATERIALS AND METHOD: Susceptibility was tested in 77 isolates of streptococci, 38 enterococci, 25 S. aureus and 91 S. epidermidis. The strains were isolated in the São Paulo Hospital in June and July of 1992. The susceptibility testing was performed by broth microdilution according to the procedure described by the national committee for Clinical Laboratory Standards (NCCLS). The antimicrobial agents tested were: ciprofloxacin, ofloxacin, levofloxacin, grepafloxacin (formerly OPC 17116), DU-6859, imipenem, meropenem, biapenem, ceftazidime, cefepime and FK-037. RESULTS: The best in vitro activity was demonstrated by the new fluoroquinolones, especially DU 6859. Among the commercially available compounds, the fluoroquinolones ciprofloxacin and ofloxacin (81% susceptibility) and the carbapenem imipenem (74% susceptible) were the most active compounds. The highest resistance rates were shown by enterococci and oxacillin-resistant staphylococci. CONCLUSIONS: The results of the present study showed that the in vitro activities of the new carbapenems are similar to that of imipenem and the fourth generation cephalosporins are more active than ceftazidime against gram-positive bacteria. In addition, the newer fluoroquinolones were four to sixteen-fold more active than that showed by the commercially available compounds of this class, especially against enterococci and oxacillin-resistant staphylococci. These results indicate that these newer fluoroquinolones should be further evaluated in clinical trials.

New antianginal nitro esters with reduced hypotensive activity. Synthesis and pharmacological evaluation of 3-[(nitrooxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones.

New nitro ester 3-[(nitrooxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones show marked inhibitory activity against ischemia-induced electrocardiographic changes, with only limited systemic hemodynamic effects, and are reported in the present study. These new nitro vasodilators are potent inhibitors of the electrocardiographic T-wave and S-T segment elevation induced by intravenous or intracoronary administration of Arg-vasopressin or methacholine in the anesthetized rat. The most active compounds are up to 300- and 600-fold more potent than glyceryl trinitrate or Nicorandil, respectively. These nitro esters relax in a concentration-dependent manner the isolated rabbit aorta, at higher concentrations (2-40-fold) than glyceryl trinitrate, and reduce the mean arterial blood pressure at doses 7-300-fold higher than those required by glyceryl trinitrate to exert a similar hypotensive effect. Remarkably, these compounds retain their anti-ischemic and hemodynamic profile after oral (po) administration. These new nitro ester derivatives, endowed with a marked antianginal activity, which is not associated with concurrent and pronounced falls in systemic blood pressure, represent the leads of a new class of selective nitrovasodilators having a preferential action on large coronary vessels, which could be clinically relevant in the treatment of coronary artery diseases.

Effect of ITF 296 on total effective vascular compliance in the anesthetized dog under autonomic blockade.

The effects of ITF 296 on venous tone, estimated as changes in total effective vascular compliance (TEVC), were investigated in the anesthetized, spontaneously breathing dog under autonomic blockade. TEVC was calculated from the correlation between the observed changes in central venous pressure (CVP) and the experimentally induced changes in blood volume during an 11-min cycle of whole blood infusion (2 ml/kg/min), withdrawal, and reinfusion. Stepwise increasing doses (short steady-state infusions) of ITF 296 (3, 10, and 30 micrograms/kg/min) resulted in a dose-dependent increase in TEVC (+27, +54, and +67%), whereas mean blood pressure (MBP) was reduced (-12, -23, and -33%, respectively). SIN-1 (10 micrograms/kg/min), administered at the end of the experiment as the reference NO-releasing compound, induced a rather complete venodilation (TEVC +182%) and a marked reduction in MBP (-47%). When nitroglycerin (NTG) was used as the reference compound at 1.5 micrograms/kg/min, a 67% increase in TEVC was observed. These results suggest that ITF 296 exerts a venodilator action but that this effect, and therefore the reduction in venous return, is less than that in response to nitrovasodilators such as SIN-1 or NTG. Furthermore, the vasodilator spectrum of ITF 296 compared to other nitrovasodilators is shifted somewhat more toward the arteriolar bed, with less pronounced venodilator effects, as indicated by the fall in MBP.

The new nitroderivative ITF 296 improves collateral blood flow in a canine model of coronary thrombosis.

The actions of ITF 296 and isosorbide dinitrate (ISDN), 20, 70, and 200 g/kg/min, on myocardial transmural blood flow distribution during acute thrombotic occlusion of the left circumflex coronary artery (LCX) have been evaluated in seven and three anesthetized open-chest dogs, respectively, and compared with four animals receiving vehicle. Occlusion of LCX was achieved in 14 +/- 2 min by the insertion of a copper coil. This caused transmural myocardial ischemia in the LCX area, while leaving blood flow in the left anterior descending coronary artery (control area) unaffected. Infusion of ITF 296 (200 g/kg/min) increased transmural coronary flow in the border zone and in the control area without affecting blood flow in the central ischemic area. ISDN, given in the same dose, reduced systemic blood pressure but did not affect LCX blood flow. In three dogs with residual perfusion in the LCX central area ITF 296 also increased blood flow. These results confirm that ITF 296 promotes an increase of flow to the border zone, thus possibly reducing the area of myocardial infarction.

Effects of ITF 296 on epicardial coronary artery diameter during acute and long-term treatment in the conscious dog.

The action of the newly developed organic nitrate ITF 296 on large coronary arteries was investigated during acute and long-term treatment in the conscious dog, chronically instrumented for recording of large coronary artery diameter (CD), mean arterial blood pressure (MBP), and heart rate (HR). Short-term steady-state infusion of ITF 296 at doses of 0.1-30 micrograms/kg/min induced a dose-dependent increase in CD. Maximal coronary artery dilation (+11%) was reached at 10 micrograms/kg/min and no further increase was observed at 30 micrograms/kg/min. At the same doses no significant variations of MBP or HR were observed. Long-term administration (5-day infusion) of ITF 296 at 20 micrograms/kg/min resulted in a 10% increase in CD, and the effect was well maintained over the entire infusion period. MBP did not change significantly, whereas HR rose by 21% by the second day of infusion and remained elevated until the end of the treatment. These results confirm that ITF 296 is an effective dilator of large coronary arteries at doses devoid of peripheral hemodynamic effects. Moreover, the vasodilating effect on coronary arteries is well maintained during long-term administration, suggesting a reduced tolerance development.

Protective effect of the nitrate ester ITF 296 against methacholine-induced myocardial ischemia in the anesthetized rat.

The activity of ITF 296 against methacholine-induced myocardial ischemia was investigated in anesthetized rats in comparison with the organic nitrates nitroglycerin (NTG) and isosorbide dinitrate (ISDN), the K(+)-channel openers nicorandil and cromakalim, the Ca(2+)-channel blocker amlodipine, and the vasodilator dipyridamole. Given as i.v. boluses, ITF 296 (0.1-100 micrograms/kg) dose-dependently prevented methacholine-induced ST-segment elevation without affecting mean arterial blood pressure or heart rate to a significant extent. In this situation, ITF 296 was 10- to 30-fold more potent than the other coronary vasodilators tested. The protective effect of ITF 296 and ISDN against myocardial ischemia was also observed after oral administration, demonstrating good absorption and a limited first-pass metabolism of the two drugs. The anti-ischemic action of ITF 296 at 1 and 10 micrograms/kg/min was well maintained during 2 h of continuous i.v. infusion, whereas the effect of NTG and ISDN was attenuated or abolished by the end of the infusion. The new nitrate ester ITF 296 has a potent and long-lasting cardioprotective action in the anesthetized rat. The anti-ischemic effect displayed by this compound is probably mediated by an improvement of myocardial blood supply caused by pronounced coronary dilatation, whereas the contribution of systemic vasodilation is not important. Moreover, the maintenance of the anti-ischemic action during continuous i.v. infusion suggests a reduced "tolerance" development for ITF 296 compared with other nitrovasodilators.

Protective effects of ITF 296 in the isolated rabbit heart subjected to global ischemia.

The anti-ischemic action of ITF 296 was evaluated in isovolumic, electrically driven rabbit heart preparations subjected to temporary ischemia and reperfusion. Reduction of perfusion rate from 20 to 0.2 ml/min produced a sharp decrease of peak systolic pressure, left ventricular (LV)-developed pressure, and LV dP/dt, which culminated in complete ventricular arrest within 3-4 min. Thereafter, LV end-diastolic pressure (LVEDP) progressively increased, suggesting a severe ischemic episode. Reperfusion with 20 ml Krebs solution/min after 40 min of low-flow perfusion produced only minimal recovery from the rhythm disturbances associated with cardiac mechanical activity. During reperfusion, loss of myocardial elasticity was associated with a significant increase in coronary vascular resistance, as indicated by the augmentation of coronary perfusion pressure. Injection of ITF 296 (0.3-10 microM) into the perfusion system dose-dependently inhibited the increase in LVEDP that took place during ischemia and progressively improved the recovery of a regular rhythm in the isolated heart. Isosorbide dinitrate (ISDN) at a concentration of 10 microM exerted a protective action on the myocardium similar to that obtained with ITF 296 (3 microM). Treatment with ITF 296 (1 and 10 microM) resulted in a dose-dependent increase in the rate of 6-keto-PGF1 alpha biosynthesis during both the ischemia and the reperfusion period (+157% over basal values). Similar results were obtained when hearts were pretreated with ISDN (10 microM). Infusion of a buffer containing NG-monomethyl-L-arginine (L-NMMA; NO synthase inhibitor at 10 microM) just before reduction of flow, markedly exacerbated the effects of ischemia and reperfusion on the myocardium and increased coronary perfusion pressure. The effects of L-NMMA were clearly antagonized by ITF 296 (10 microM) or L-arginine (100 microM). Mechanical activity and sinus rhythm during reperfusion were rapidly and completely restored, and coronary resistance values were close to the preischemic values. As with ISDN, ITF 296 significantly increased the rate of synthesis of 6-keto-PGF1 alpha both under basal conditions and during reperfusion.

Antireactive properties of glucosamine sulfate.

Glucosamine (CAS 3416-24-8) is an aminomonosaccharide naturally occurring in the human body. It was tested for antiinflammatory activities and it showed to protect against the edema provoked in the rat paw by carrageenin, dextran, formalin, but not against the edema provoked by specific inflammation mediators, such as bradykinin, serotonin, histamine. Glucosamine protected against pleurities provoked in the rat by carrageenin, but not against that provoked by bradykinin. Furthermore glucosamine protected against peritonitis provoked in the rat by formalin and in the mouse by acetic acid. Glucosamine did not show antinoceptive properties against writings provoked by i.p. phenylquinone in the mouse. Glucosamine did not show inhibiting activities on cyclooxygenase or on the proteolytic enzymes in the inflamed paw of the rat, but it was able to inhibit in vitro superoxide generation and lysosomial enzymes of the liver. The potency of glucosamine on the antiinflammatory tests was lower than that of acetylsalicylic acid and much lower than that of indomethacin. Its acute toxicity, however, and notably the toxicity on the gastrointestinal tract is very low, practically absent. The pharmacological therapeutic index of glucosamine with regard to the antiinflammatory activities seems therefore comparable or superior to that of the known non-steroidal anti-inflammatories.

Antispasmodic activity of tiropramide.

Tiropramide hydrochloride and some of its metabolites were studied in vivo for their antispasmodic activities on the following models: gastric emptying in the mouse retarded by cholecystokinin octapeptide (CCK-8) or morphine, progression of intestinal contents in the mouse, spontaneous motility of the colon in the anesthetized rabbit, diarrhea induced by castor oil in the rat, spasm of the sphincter of Oddi provoked by morphine in the guinea pig, contractions of the urinary bladder in the anesthetized rat. On these models tiropramide had an antispasmodic activity at doses of 4-40 mg/kg i.p. or i.v. and of 50-90 mg/kg orally. The potency was greater on "pathological" contractions or spasms and smaller on "physiological" movements. Tiropramide may therefore be regarded as a "eukinetic" antispasmodic agent. Tiropramide in general was more potent than reference agents such as papaverine or flavoxate and was active also after oral administration. The metabolites of tiropramide, i.e. CR 1034, CR 1098 and CR 1166 showed similar pharmacodynamic effects, but their potency was smaller than that of tiropramide. Large doses of tiropramide have depressive actions on the cardiovascular system, which can be seen especially if tiropramide is administered i.v. and are less pronounced after oral administration. The circulatory effects are therefore probably the limiting factor for increasing the parenteral doses of tiropramide in human therapy. Tiropramide was found less toxic than papaverine (LD50). The metabolites of tiropramide were less toxic than the parent compound. The toxicity of the chiralic forms of tiropramide does not differ significantly from that of the racemic substance.

Pharmacological characterisation of the smooth muscle antispasmodic agent tiropramide.

(+/-) Tiropramide hydrochloride, its D and L optical isomers and some of its metabolites were characterized in a number of in vitro pharmacological tests. Tiropramide showed broad spectrum antispasmodic activities on the isolated stomach of guinea pig electrically stimulated; on the longitudinal muscles of the ileum of guinea pig stimulated by electrical impulses, BaCl2, acetylcholine, histamine, serotonin, substance P and cholecystokinin octapeptide (CCK-8); on the spontaneous contractions and on the electrical inhibition of the jejunum of rabbit; on the spontaneous contractions and on the contractions provoked by BaCl2 and acetylcholine of the ascending colon of the rat; on the contractions provoked by BaCl2, acetylcholine, histamine and cerulein of the circular muscles of the gall bladder of the guinea pig; on the spontaneous contractions of the pyel-ureter preparation of the guinea pig; on the contractions of the uterus of the rat provoked by oxitocin, serotonin, acetylcholine, PGF2; on the spontaneous contraction of the portal vein of the rat; on the constriction of the tail artery of the rat provoked by electrical stimulation, epinephrine and ergotamine; on the contractions of the aortic strip of the rabbit stimulated by norepinephrine; on the contractions of the strip of bovine coronary artery depolarized by HCl. In general tiropramide had antispasmodic effect at 5-60 mumol/l concentration. It was more potent than papaverine on contractions provoked by electrical or chemical stimuli, and was less potent or ineffective on spontaneous and "physiological" contractions of the different smooth muscle preparations. Tiropramide had small effects on vascular smooth muscles and showed very small calcium channel blocking activity.

Pharmacological properties of lorglumide as a member of a new class of cholecystokinin antagonists.

Derivatives of 5-(dipentylamino)-5-oxo-pentanoic acid are a new class of non-peptide cholecystokinin (CCK) antagonists. The most potent compound, D,L-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxo-pen tanoic acid (lorglumide, CR 1409), has a great affinity for the pancreatic CCK receptors and is a competitive, specific and potent CCK antagonist on the smooth muscles of the gall bladder and ileum of the guinea pig and on the CCK-induced amylase secretion of isolated pancreatic acini. In vivo lorglumide antagonizes the contraction of the gall bladder of the guinea pig and of the dog provoked by i.v. CCK-8 or ceruletide (caerulein). It antagonizes the satiety effect of CCK-8 in the rat and is protective against ceruletide-, taurocholate- and diet-induced pancreatitis. Lorglumide is therefore a useful pharmacological tool to study the functions of CCK. For its pharmacological properties, its relatively low toxicity and because it is active also after oral administration, lorglumide is a candidate for diagnostic or therapeutic use in man when an involvement of CCK is suspected.

Anticholecystokinin activities of loxiglumide.

The anticholecystokinin activities of loxiglumide, (D,L-4-(3,4-dichloro-benzoylamino)-5-(N-3-methoxypropyl-pentylamino++ +)-5-oxo- pentanoic acid, CR 1505) are described. Loxiglumide antagonizes in vivo the contractions of the gall bladder of guinea pig induced or mediated by cholecystokinin-8 (CCK-8) (i.v. ED50 = 0.24 mumol/kg), the emptying of the gall bladder of the mouse induced by CCK-8 (i.v. ED50 = 29 mumol/kg, oral ED50 = 42 mumol/kg), the retardation of gastric emptying of the rat induced by CCK-8 (i.p. ED50 = 13 mumol/kg), the retardation of the pyloric transit in the mouse induced by CCK-8 (i.v. ED50 = 3.7 mumol/kg, oral ED50 = 11 mumol/kg), the hypermotility of the ileum of the rabbit induced by CCK-8 (i.v. ED50 = 1.2 mumol/kg) and the contractions of the gall bladder of the non-anesthetized dog induced by caerulein (i.v. ED50 ca. 11 mumol/kg). Loxiglumide also antagonizes the satiety behaviour of the rat elicited by CCK-8 (i.p. ED50 = 0.65 mumol/kg) and the exocrine pancreatic hypersecretion in the anaesthetized dog induced by CCK-8 (i.v. ED50 ca. 0.35 mumol/kg). Loxiglumide has a simple, non-polypeptidic chemical structure and is active after parenteral and after oral administration.

Loxiglumide protects against experimental pancreatitis.

Loxiglumide (D,L-4-(3,4-dichloro-benzoylamino)- 5-(N-3-methoxypropyl-pentylamino)-5-oxo-pentanoic acid, CR 1505) is a derivative of pentanoic acid and belongs to a newly discovered class of agents with cholecystokinin antagonistic activities. Loxiglumide has preventive effects on different types of experimental pancreatitis, induced e.g. by ceruletide (i.p. ED50 ca. 9 mumol/kg), by intrapancreatic taurocholate (i.p. ED50 ca. 80 mumol/kg) or by choline-deficient ethionine-supplemented diet (i.p. ED50 ca. 45 mumol/kg). Loxiglumide has a simple, non-polypeptidic chemical structure and may be a candidate for clinical investigations in man, e.g. for pancreatitis.