The emerging role of sunitinib in the treatment of advanced epithelial thyroid cancer: our experience and review of literature.

Tyrosine kinase receptors have been shown to play an important role in epithelial thyroid tumor growth and angiogenesis. Thyroid cancers commonly present oncogene mutations involved in MAPK kinase pathway like BRAF and RET; they are also frequently dependent on VEGF stimuli. Preliminary clinical experiences suggest a promising role of sunitinib (a tyrosine kinase inhibitor) for the treatment of advanced thyroid cancers. This review deals with the available data on the effect of sunitinib in the treatment of metastatic, radioiodine refractory thyroid cancers. We also report our experience with the off-label use of sunitinib in such patients.

Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer.

BACKGROUND: AZD1152, the prodrug for AZD1152-hydroxyquinazoline pyrazol anilide (HQPA), is a selective inhibitor of Aurora B kinase activity. Preclinical evaluation of AZD1152 has been reported in several human cancer models. The potentiality of this compound in combination therapy warrants further investigation in solid tumours. EXPERIMENTAL DESIGN: This study explored the effects of AZD1152-HQPA in colon and pancreatic tumour cells. The antitumour properties of AZD1152, either as single agent or in combination with chemotherapeutics, were evaluated in each study model. The efficacy and the toxicity of AZD1152 alone and in combination with gemcitabine were validated in pancreatic tumour xenograft model. RESULTS: AZD1152-HQPA treatment resulted in a dramatic increase of chromosome number, modification of cell cycle and induction of apoptosis. The most effective combination was that with chemotherapeutics given soon after AZD1152 in both tumour cell types. The effectiveness of the sequential schedule of AZD1152 with gemcitabine was confirmed in nude mice bearing MiaPaCa-2 tumours, showing inhibition of tumour volumes and delaying of tumour growth after the interruption of the treatments. Here we show that AZD1152-HQPA enhances oxaliplatin and gemcitabine effectiveness in colon and pancreatic cancer, respectively. First, we provide advances into administration schedules and dosing regimens for the combination treatment in in vivo pancreatic tumour.

Three-times weekly teicoplanin as outpatient treatment of chronic osteoarticular infections.

Treatment of difficult-to-treat infections such as osteomyelitis or infections related to indwelling medical devices requires lengthy antibiotic therapy and adequate surgical debridement. Teicoplanin, a glycopeptide antibiotic with a long half-life, was used three-times weekly in the treatment of these infections. After a period of daily dosing with teicoplanin, patients were treated with an intravenous dose of 12 mg on mondays, wednesdays and fridays. A control group of patients were treated with teicoplanin daily. Teicoplanin levels were measured during the study. Thirty-six patients were enrolled in the study: 14 with vertebral osteomyelitis, 12 with infected orthopedic implants, 7 with osteomyelitis and 3 with arterial prosthetic infections. The duration of treatment ranged from 60 to 360 days. Cure was obtained in 21 (58%) patients and improvement in 15 (42%) patients. Trough and peak serum concentrations in three-time weekly patients were 16.2+/-7.2 mg/l and 58.7+/-14.4 mg/l. In the control group trough and peak serum concentrations were 18.9+/-13.6 mg/l and 52.2+/-27 mg/l. Adverse events occurred in 6 patients: mainly mild liver toxicity. Three times weekly teicoplanin seems to be a valuable option in the treatment of chronic infections.

Genetic polymorphisms of thiopurine S-methyltransferase in a cohort of patients with systemic autoimmune diseases.

OBJECTIVES: Azathioprine (AZA) is a purine antimetabolite, prodrug widely used as a disease modifying drug in several rheumatic conditions. The aim of the present study was to evaluate the prevalence of TPMT genetic polymorphisms in a cohort of Italian Caucasian patients affected by rheumatic diseases and treated with AZA, and to establish correlations with the tolerability of AZA treatment. RESULTS: Seventy-eight Caucasian patients, 16 males and 62 females, median age 41 years (min-max: 24-76) were enrolled. At the time of evaluation, the median duration of treatment with AZA was 8 months (min-max: 2-150 months); the median dose of AZA per kg of body weight was 1.42 mg (min-max: 0.5-2). Among the 78 patients evaluated, 76 presented a wild type genotype (TPMT *1), while polymorphic alleles were identified in 2 patients (2.6%). Twenty-five patients (32%) experienced different types of adverse events (AE) under AZA treatment. Eighteen patients (23.1%) discontinued AZA because of AE. No correlation was observed between polymorphic TPMT alleles and the development of AE. CONCLUSIONS: Our analysis supports the view that TPMT genotyping alone is not sufficient to adequately personalize the AZA dosage in rheumatic patients. Further studies based on phenotypic analysis of TPMT enzyme and assay of AZA metabolite appear to be required.

Characterization of mechanisms underlying the effects of esomeprazole on the impairment of gastric ulcer healing with addition of NSAID treatment.

BACKGROUND: The efficacy of proton pump inhibitors in patients at high risk of gastrointestinal injury receiving non-steroidal anti-inflammatory drugs is currently debated. AIMS: To evaluate the effects of esomeprazole on the impairment of gastric ulcer healing associated with non-steroidal anti-inflammatory drug treatment. METHODS: Gastric ulcers were induced in rats by acetic acid. Four days later, animals were treated daily with equivalent acid-inhibiting doses of esomeprazole or famotidine, alone or in combination with indomethacin. At day 3 or 7 of treatment, ulcerated tissues were processed to assess: ulcer area; malondialdehyde; prostaglandin E(2); nuclear factor-kB; proliferating cell nuclear antigen and caspase-3 (Western blot). RESULTS: In indomethacin-treated animals, esomeprazole was more effective than famotidine or the antioxidant melatonin in promoting ulcer healing. Malondialdehyde levels were increased by indomethacin, and this effect was counteracted by esomeprazole, but not famotidine. Esomeprazole and famotidine, given alone or in combination with indomethacin, increased proliferating cell nuclear antigen expression. Increased levels of prostaglandin E(2) were detected in ulcerated tissues. Ulcer prostaglandin E(2) production was reduced by indomethacin, alone or in combination with esomeprazole or famotidine, while it was enhanced when esomeprazole or famotidine were tested alone. The activation of caspase-3 was induced by indomethacin, and this effect was prevented by esomeprazole, but not famotidine. In the presence of indomethacin, esomeprazole, but not famotidine, enhanced nuclear factor-kB activation in gastric ulcers. CONCLUSIONS: Esomeprazole counteracts the detrimental action of indomethacin on ulcer repair through both acid-dependent and acid-independent effects. The acid-independent actions are related to decrease in tissue oxidation and apoptosis and to enhancement of nuclear factor-kB activation.

A1 and A2a receptors mediate inhibitory effects of adenosine on the motor activity of human colon.

Experimental evidence in animal models suggests that adenosine is involved in the regulation of digestive functions. This study examines the influence of adenosine on the contractile activity of human colon. Reverse transcription-polymerase chain reaction revealed A(1) and A(2a) receptor expression in colonic neuromuscular layers. Circular muscle preparations were connected to isotonic transducers to determine the effects of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; A(1) receptor antagonist), ZM 241385 (A(2a) receptor antagonist), CCPA (A(1) receptor agonist) and 2-[(p-2-carboxyethyl)-phenethylamino]-5'-N-ethyl-carboxamide-adenosine (CGS 21680; A(2a) receptor agonist) on motor responses evoked by electrical stimulation or carbachol. Electrically evoked contractions were enhanced by DPCPX and ZM 241385, and reduced by CCPA and CGS 21680. Similar effects were observed when colonic preparations were incubated with guanethidine (noradrenergic blocker), L-732,138, GR-159897 and SB-218795 (NK receptor antagonists). However, in the presence of guanethidine, NK receptor antagonists and N(omega)-propyl-L-arginine (NPA; neuronal nitric oxide synthase inhibitor), the effects of DPCPX and CCPA were still evident, while those of ZM 241385 and CGS 21680 no longer occurred. Carbachol-induced contractions were unaffected by A(2a) receptor ligands, but they were enhanced or reduced by DPCPX and CCPA, respectively. When colonic preparations were incubated with guanethidine, NK antagonists and atropine, electrically induced relaxations were partly reduced by ZM 241385 or NPA, but unaffected by DPCPX. Dipyridamole or application of exogenous adenosine reduced electrically and carbachol-evoked contractions, whereas adenosine deaminase enhanced such motor responses. In conclusion, adenosine exerts an inhibitory control on human colonic motility. A(1) receptors mediate direct modulating actions on smooth muscle, whereas A(2a) receptors operate through inhibitory nitrergic nerve pathways.

A dose finding and pharmacokinetic study of capecitabine in combination with oxaliplatin and irinotecan in metastatic colorectal cancer.

PURPOSE: The GONO-FOLFOXIRI regimen demonstrated higher activity and efficacy than FOLFIRI in metastatic colorectal cancer patients. The aim of this study was to determine the maximum tolerated dose of capecitabine, in substitution of 5-fluorouracil, combined with oxaliplatin and irinotecan and to evaluate the pharmacokinetics of the drugs. PATIENTS AND METHODS: We treated 15 patients with escalating doses of capecitabine (from day 1 to 7) and fixed doses of oxaliplatin (85 mg/m(2)) plus irinotecan (165 mg/m(2)) (both administered on day 1), repeated every 2 weeks. Pharmacokinetic analysis was performed on plasma samples collected at the first cycle of treatment. RESULTS: The maximum tolerated dose of capecitabine resulted 2,000 mg/m(2)/day, with diarrhea being the only dose-limiting toxicity. Large interpatient variability in the pharmacokinetic parameters of investigated drugs was observed. Results in terms of activity are promising. CONCLUSIONS: At the maximum tolerated dose of capecitabine of 2,000 mg/m(2)/day the combination is feasible with promising activity and deserves further investigations.

Effects of a bicarbonate-alkaline mineral water on digestive motility in experimental models of functional and inflammatory gastrointestinal disorders.

This study investigates the effects of Uliveto, a bicarbonate-alkaline mineral water, in experimental models of diarrhea, constipation and colitis. Rats were allowed to drink Uliveto or oligomineral water (control) for 30 days. Diarrhea and constipation were evoked by 16,16-dimethyl-prostaglandin E(2) (dmPGE(2)) or loperamide, respectively. Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS) or acetic acid. Gastric emptying, small-intestinal and colonic transit were evaluated. dmPGE(2)-induced diarrhea reduced gastric emptying and increased small-intestinal and colonic transit. In this setting, Uliveto water enhanced gastric emptying, and this effect was prevented by L-365,260 (gastrin receptor antagonist). Loperamide-induced constipation reduced gastric emptying, small-intestinal and colonic transit, and these effects were prevented by Uliveto water. L-365,260 counteracted the effects of Uliveto on gastric emptying, while alosetron (serotonin 5-HT(3) receptor antagonist) blunted the effect of Uliveto on colonic transit. Gastric emptying, small-intestinal and colonic transit were reduced in DNBS-induced colitis, and Uliveto water enhanced gastric emptying and normalized small-intestinal and colonic transit. Gastric emptying, small-intestinal and colonic transit were also reduced in acetic acid-induced colitis, and Uliveto increased both gastric emptying and small-intestinal transit. In conclusion, Uliveto water exerts beneficial effects on gastrointestinal motility in the presence of bowel motor dysfunctions. The effects of Uliveto water on gastric emptying depend on gastrin-mediated mechanisms, whereas the activation of serotonergic pathways accounts for the modulation of colonic functions.

Somatostatin inhibits colon cancer cell growth through cyclooxygenase-2 downregulation.

BACKGROUND AND PURPOSE: Cyclooxygenase-2 (COX-2) is expressed in colonic neoplasms, where it supports cell proliferation via prostaglandin E(2) (PGE(2)) production. This study investigated the effects of somatostatin-14 on COX-2 expression, PGE(2) production and proliferation in colon cancer cells. EXPERIMENTAL APPROACH: Human colon adenocarcinoma cell lines Caco-2, HT-29 and HCT116 were used. The following techniques were employed: colourimetric assay for cell growth; 5-bromo-2'-deoxyuridine assay for DNA synthesis; enzyme immunoassay for PGE(2); COX-2 mRNA silencing; RT-PCR or Western blot for somatostatin receptor subtypes, cyclooxygenase isoforms, phosphorylated-ERK-1/ERK-2 and phosphorylated-Akt. KEY RESULTS: HT-29 and Caco-2 cells expressed COX-2 and somatostatin receptors (sst(3/4/5) and sst(3/5), respectively). HCT116 cells did express somatostatin receptors (sst(2/3/5)), but not COX-2. Somatostatin-14 inhibited basal COX-2 expression, PGE(2) production, DNA synthesis and growth in Caco-2 cells and these effects were prevented by BN81658 (sst(3) receptor antagonist). Basal proliferation of HT-29, HCT116 and COX-2-silenced Caco-2 cells was not affected by somatostatin-14. Stimulation of HT-29 cells with gastrin-17 elicited increments of ERK-1/ERK-2 and Akt phosphorylation, COX-2 expression, PGE(2) production, DNA synthesis and cell growth, which were all counteracted by somatostatin-14. Somatostatin-14-induced inhibition of COX-2 expression, PGE(2) production and DNA synthesis were blocked by BIM23056 (sst(5) receptor antagonist). CONCLUSIONS AND IMPLICATIONS: Somatostatin decreases COX-2 expression and function in colon cancer cells via activation of sst(3) or sst(5) receptors, and these effects contribute to the inhibitory action of somatostatin on cell proliferation. These findings can be relevant to the development of therapeutic strategies based on the modulation of the COX-2 pathway.

The beta3-adrenoceptor agonist SR58611A ameliorates experimental colitis in rats.

Beta(3)-adrenoceptor agonists protect against experimental gastric ulcers. We investigated the effects of the beta(3)-adrenoceptor agonist SR58611A on 2,4-dinitrobenzene sulphonic acid-induced colitis in rats and analysed the expression of beta(3)-adrenoceptors in the colonic wall. SR58611A was administered orally (1-10 mg kg(-1)) for 7 days, starting the day before induction of colitis. Colitis was assessed by macroscopic and histological scores, tissue myeloperoxidase activity, interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) levels. Reverse transcription-polymerase chain reaction and immunohistochemical analysis were used to examine the expression of beta(3)-adrenoceptors. SR58611A significantly reduced the severity of colitis as well as the tissue levels of TNF-alpha, IL-1beta and IL-6. Colitis was associated with a decreased expression of beta(3)-adrenoceptor mRNA in the mucosal/submucosal layer of distal colon and this reduction was not affected by SR58611A. Immunohistochemical analysis revealed beta(3)-adrenoceptors within the muscularis externa, in myenteric neurons and nerve fibres and in the submucosa. beta(3)-Adrenoceptor immunoreactivity was decreased in inflamed tissues compared to controls, particularly in the myenteric plexus; this reduction was counteracted by SR58611A. Amelioration of experimental colitis by the selective beta(3)-adrenoceptor agonist SR58611A suggests that beta(3)-adrenoceptors may represent a therapeutic target in gut inflammation.

Review article: molecular, pathological and therapeutic features of human enteric neuropathies.

BACKGROUND: Considerable information has been gathered on the functional organization of enteric neuronal circuitries regulating gastrointestinal motility. However, little is known about the neuropathophysiological mechanisms underlying gastrointestinal motor disorders. AIM: To analyse the most important pathological findings, clinical implications and therapeutic management of idiopathic enteric neuropathies. METHODS: PubMed searches were used to retrieve the literature inherent to molecular determinants, pathophysiological bases and therapeutics of gastrointestinal dysmotility, such as achalasia, gastroparesis, chronic intestinal pseudo-obstruction, Hirschsprung's disease and slow transit constipation, to unravel advances on digestive disorders resulting from enteric neuropathies. RESULTS: Current data on molecular and pathological features of enteric neuropathies indicate that degenerative and inflammatory abnormalities can compromise the morpho-functional integrity of the enteric nervous system. These alterations lead to a massive impairment in gut transit and result in severe abdominal symptoms with associated high morbidity, poor quality of life for patients and established mortality. Many pathophysiological aspects of these severe conditions remain obscure, and therefore treatment options are quite limited and often unsatisfactory. CONCLUSIONS: This review of enteric nervous system abnormalities provides a framework to better understand the pathological processes underlying gut dysmotility, to translate this knowledge into clinical management and to foster the development of targeted therapeutic strategies.

Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib.

Metronomic chemotherapy refers to the administration of chemotherapy at low, nontoxic doses on a frequent schedule with no prolonged breaks. The aim of the study is to rationally develop a CPT-11 metronomic regimen in preclinical settings of colon cancer. In vitro cell proliferation, apoptosis and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on endothelial (HUVEC, HMVEC-d) and colorectal cancer (HT-29, SW620) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11. HT-29 human colorectal cancer xenograft model was used, and tumour growth, microvessel density and VEGF/TSP-1 quantification was performed in tumours. In vitro and in vivo combination studies with the tyrosine inhibitor semaxinib were also performed. SN-38 preferentially inhibited endothelial cell proliferation alone and interacted synergistically with semaxinib; it induced apoptosis and increased the expression and secretion of TSP-1. Metronomic CPT-11 alone and combined with semaxinib significantly inhibits tumour growth in the absence of toxicity, which was accompanied by decreases in microvessel density and increases in TSP-1 gene expression in tumour tissues. In vitro results show the antiangiogenic properties of low-concentration SN-38, suggesting a key role of TSP-1 in this effect. In vivo, the CPT-11 metronomic schedule is effective against tumour and microvessel growth without toxic effect on mice.

A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients.

The pharmacokinetics (PK) and pharmacodynamics (PD) of metronomic irinotecan have not been studied in cancer patients. The aim of the study is to investigate the PK/PD profile of irinotecan/SN-38 administered by metronomic schedule. Twenty chemotherapy-refractory or chemotherapy-resistant patients with metastatic colorectal carcinoma were enrolled. Irinotecan was infused continuously as follows: irinotecan 1.4 mg m(-2) day(-1) (n=7), 2.8 mg m(-2) day(-1) (n=5) and 4.2 mg m(-2) day(-1) (n=8). Drug levels were examined by HPLC, whereas ELISAs and real-time RT-PCR were used, respectively, for the measurement of plasma levels and gene expression in peripheral blood mononuclear cells of vascular endothelial growth factor/thrombospondin-1. Pharmacokinetic analysis demonstrated that the steady-state levels (C(ss)) of SN-38 were between 1 and 3.3 ng ml(-1). From a PD point of view, higher thrombospondin-1 (TSP-1) plasma levels (153.4+/-30.1 and 130.4+/-9.2% at day 49 vs pretreatment values at 1.4 and 2.8 mg m(-2) day(-1) dose levels, respectively) and increased gene expression in PBMC were found during the metronomic irinotecan infusion, especially at the lower doses. Four patients (20%) obtained a stable disease (median 3.9 months) despite progressing during previous standard irinotecan schedule. Toxicities >grade 1 were not observed. Metronomic irinotecan administration is very well tolerated and induces an increase of gene expression and plasma concentration of TSP-1 at low plasma SN-38 concentrations.

Pharmacokinetics of azithromycin in serum, bronchial washings, alveolar macrophages and lung tissue following a single oral dose of extended or immediate release formulations of azithromycin.

OBJECTIVES: Antibacterial efficacy of azithromycin could be improved by achieving higher concentrations at the sites of infection. Azithromycin extended release (azithromycin-ER) formulation was developed to enable a higher dosage of 2 g to be administered as a single oral dose without decreasing the safety profile. The aim of this study was to compare the pharmacokinetics of azithromycin in serum, epithelial lining fluid (ELF), alveolar macrophages (AMs) and lung tissue following a single oral dose of azithromycin-ER or azithromycin immediate release (azithromycin-IR) formulation. PATIENTS AND METHODS: A total of 64 patients, diagnosed with lung cancer, requiring open-chest surgery for lung resection, completed the study. Subjects were randomized to receive oral administration of either a single 2 g dose of azithromycin-ER (32 subjects) or a single 500 mg dose of azithromycin-IR (32 subjects). Simultaneously, subjects within each treatment group were randomized to one of eight specific nominal post-dose time points for bronchoalveolar lavage and lung tissue sampling. Results For azithromycin-IR formulation, the AUC(0-24) in serum, ELF, AMs and lung tissue was 3.1, 2.3, 1674 mg.h/L and 130 mg.h/kg, respectively. For azithromycin-ER formulation, the AUC(0-24) in serum, ELF, AMs and lung tissue were 10.0, 17.6, 7028 mg.h/L and 505 mg.h/kg, respectively. The AUC(0-24) ratio following administration of azithromycin-ER relative to azithromycin-IR was 3.2, 7.7, 4.2 and 3.9 in serum, ELF, AMs and lung tissue, respectively. CONCLUSIONS: Within the first 24 h, a single 2 g azithromycin-ER dose produced dose-related increase in systemic exposure compared with a single 500 mg azithromycin-IR dose, which resulted in higher levels of azithromycin in ELF, AMs and lung tissue. Both formulations had similar safety profiles. By achieving high azithromycin exposure early in the course of treatment, without compromising tolerability, azithromycin-ER shows the potential for improved antibacterial efficacy compared with azithromycin-IR.

In vitro antiangiogenic activity of selective somatostatin subtype-1 receptor agonists.

BACKGROUND: Endothelial cells of human blood vessels (arteries and veins) show high levels of somatostatin subtype-1 receptor (sst(1)). The aim of the present study is to investigate the inhibitory effects of novel somatostatin analogs, highly selective for human sst(1), on in vitro angiogenesis and their modulation of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) expression. MATERIALS AND METHODS: Somatostatin analogs BIM-23745 and BIM-23926 were tested for their ability to prevent proliferation and migration of human endothelial HMEC-1 cells, to modulate VEGF and VEGFR-2 expression and to inhibit sprouting of microvessels from cultured human placental vessel explants in fibrin matrix for 28 days. RESULTS: The somatostatin sst(1 )receptor-selective agonists, BIM-23745 and BIM-23926 showed a suppression of endothelial proliferation (e.g. 10(-6) M BIM-23475, 40.0 +/- 2.1% vs. 100% of controls; 10(-7) M BIM-23926, 55.3 +/- 3.3% vs. 100% of controls), migration (e.g. 10(-7) M BIM-23475, 35.0 +/- 1.56% vs. 100% of controls; 10(-7) M BIM-23926, 53.7 +/- 1.77% vs. 100% of controls) and microvessel sprouting (e.g. 10(-8) M BIM-23475, 42.8 +/- 5.6% vs. 100% of controls; 10(-7) M BIM-23926, 17.2 +/- 11.8% vs. 100% of controls). A small but significant percentage of cells exposed to BIM-23745 and BIM-23926 for 24 h and for 72 h presented typical apoptotic morphology. Moreover, both the analogs significantly inhibit VEGF and VEGFR-2 gene expression in endothelial cells grown for 144 h in a fibrin matrix and the VEGF secretion in conditioned media. CONCLUSIONS: The inhibition of endothelial activities suggests potential therapeutic utility for administration of somatostatin sst(1 )receptor-selective agonists in the proliferative diseases involving angiogenesis.

Tolerability profiles of leukotriene receptor antagonists and long-acting beta2-adrenoceptor agonists in combination with inhaled corticosteroids for treatment of asthma: a review.

Inhaled corticosteroids, long-acting beta2-adrenoceptor agonists, and leukotriene receptor antagonists are widely used for treatment of asthma. Inhaled corticosteroids are recommended as first-line therapy, whereas long-acting beta2-adrenoceptor agonists and leukotriene receptor antagonists are indicated as add-on therapy in patients not adequately controlled with corticosteroids alone. A number of studies have investigated the efficacy of combinations of these drugs in asthma, but several issues concerning the safety of these treatments are highly debated. This review provides a critical appraisal of the tolerability profiles of long-acting beta2-agonists and leukotriene receptor antagonists used in combination with inhaled corticosteroids for the treatment of asthma.

Cholecystokinin CCK2 receptors mediate the peptide's inhibitory actions on the contractile activity of human distal colon via the nitric oxide pathway.

BACKGROUND AND PURPOSE: Cholecystokinin is known to exert stimulant actions on intestinal motility via activation of type 1 cholecystokinin receptors (CCK(1)). However, the role played by cholecystokinin 2 (CCK(2)) receptors in the regulation of gut motility remains undetermined. This study was designed to examine the influence of CCK(2) receptors on the contractile activity of human distal colon. EXPERIMENTAL APPROACH: The effects of compounds acting on CCK(2) receptors were assessed in vitro on motor activity of longitudinal smooth muscle, under basal conditions as well as in the presence of KCl-induced contractions or transmural electrical stimulation. KEY RESULTS: Cholecystokinin octapeptide sulphate induced concentration-dependent contractions which were enhanced by GV150013 (CCK(2) receptor antagonist; +57% at 0.01 microM). These effects were unaffected by tetrodotoxin. The enhancing actions of GV150013 on contractions evoked by cholecystokinin octapeptide sulphate were unaffected by N(omega)-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor), while they were prevented by N(omega)-nitro-L-arginine methylester (L-NAME, non-selective nitric oxide synthase inhibitor). In the presence of KCl-induced contractions, cholecystokinin octapeptide sulphate elicited concentration-dependent relaxations (-36%), which were unaffected by NPA, but were counteracted by GV150013 or L-NAME. The application of electrical stimuli evoked phasic contractions which were enhanced by GV150013 (+41 % at 0.01 microM). CONCLUSIONS AND IMPLICATIONS: CCK(2) receptors mediate inhibitory actions of cholecystokinin on motor activity of human distal colon. It is suggested that CCK(2) receptors exert their modulating actions through a nitric oxide pathway, independent of the activity of the neuronal nitric oxide synthase isoform.

Linezolid cerebrospinal fluid concentration in central nervous system infection.

We report two cases of central nervous system infection due to methicillin-resistant Staphylococcus epidermidis treated with linezolid. The first case was a 72-year old woman with ventriculitis in the presence of intraventricular catheter: therapeutic effectiveness was documented clinically and microbiologically; serum and cerebrospinal fluid levels were measured after the first and fourth doses: trough linezolid concentrations in cerebrospinal fluid were 1.44 and 2.9 mg/L respectively, higher than the minimum inhibitory concentration (MIC). The second case was a 27-year old man with post-traumatic cerebral abscess; during 5 days linezolid was not found in his cerebrospinal fluid despite very high serum level peak, and the drug was not detectable in cerebral tissue surgically removed after 14 days of therapy. Linezolid may not reach therapeutic concentrations in cerebrospinal fluid, and, when possible, we suggest that drug levels be monitored.