Serum endostatin levels are elevated in colorectal cancer and correlate with invasion and systemic inflammatory markers.

BACKGROUND: Endostatin, a fragment of collagen XVIII, is an endogenous angiogenesis inhibitor with anti-tumour functions. However, elevated circulating endostatin concentrations have been found in several human cancers including colorectal cancer (CRC). METHODS: Serum endostatin levels were measured by enzyme-linked immunoassay from a series of 143 patients with CRC and from 84 controls, and correlated with detailed clinicopathological features of CRC, serum leukocyte differential count and C-reactive protein (CRP) levels. RESULTS: Patients with CRC had higher serum endostatin levels than the controls (P=0.005), and high levels associated with age, tumour invasion through the muscularis propria and poor differentiation, but not with metastases. Endostatin levels showed a positive correlation with the markers of systemic inflammatory response and a negative correlation with the densities of tumour-infiltrating mast cells and dendritic cells. Collagen XVIII was expressed in tumour stroma most strikingly in blood vessels and capillaries, and in the muscle layer of the bowel wall. CONCLUSIONS: Elevated endostatin levels in CRC correlate with systemic inflammation and invasion through the muscularis propria. Increased endostatin level may be a result of invasion-related cleavage of collagen XVIII expressed in the bowel wall. The negative correlations between serum endostatin and intratumoural mast cells and immature dendritic cells may reflect angiogenesis inhibition by endostatin.

Stage-dependent alterations of the serum cytokine pattern in colorectal carcinoma.

BACKGROUND: Inflammation contributes to the pathogenesis of colorectal cancer (CRC), and cytokine levels are altered during colorectal carcinogenesis. METHODS: The serum levels of 13 cytokines and their relation to clinical and pathological parameters, and systemic inflammatory response (mGPS, CRP and neutrophil-lymphocyte ratio), were analysed from a prospective series of 148 CRC patients and 86 healthy age- and sex-matched controls. RESULTS: CRC patients had higher serum platelet-derived growth factor, interleukin (IL)-6, IL-7, and IL-8 levels and lower monocyte chemotactic protein-1 (MCP-1) levels than the controls. A logistic regression model for discriminating the patients from the controls - including the five most predictive cytokines (high IL-8, high IL-6, low MCP-1, low IL-1ra, and low IP-10) - yielded an area under curve value of 0.890 in receiver operating characteristics analysis. Serum cytokines showed distinct correlation with other markers of systemic inflammatory response, and advanced CRCs were associated with higher levels of IL-8, IL-1ra, and IL-6. A metastasised disease was accompanied by an orientation towards Th2 cytokine milieu. CONCLUSION: CRC is associated with extensive alterations in serum cytokine environment, highlighting the importance of studying relative cytokine level alterations. Serum cytokine profile shows promise in separating CRC patients from healthy controls but its clinical value is yet to be confirmed.

Bridging therapies and liver transplantation in acute liver failure, 10 years of MARS experience from Finland.

Acute liver failure is a life-threatening condition in the absence of liver transplantation option. The aetiology of liver failure is the most important factor determining the probability of native liver recovery and prognosis of the patient. Extracorporeal liver assist devices like MARS (Molecular Adsorbent Recirculating System) may buy time for native liver recovery or serve as bridging therapy to liver transplantation, with reduced risk of cerebral complications. MARS treatment may alleviate hepatic encephalopathy even in patients with a completely necrotic liver. Taking this into account, better prognostic markers than hepatic encephalopathy should be used to assess the need for liver transplantation in acute liver failure.

Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors.

Eighteen patients with refractory and progressive solid tumors were treated with a single round of triple modified oncolytic adenovirus (Ad5/3-Cox2L-D24). Ad5/3-Cox2L-D24 is the first non-Coxsackie-adenovirus receptor-binding oncolytic adenovirus used in humans. Grades 1-2 flu-like symptoms, fever, and fatigue were seen in most patients, whereas transaminitis or thrombocytopenia were seen in some. Non-hematological grades 3-5 side effects were seen in one patient with grade 3 ileus. Treatment resulted in high neutralizing antibody titers within 3 weeks. Virus appeared in serum 2-4 days after treatment in 83% of patients and persisted for up to 5 weeks. One out of five radiologically evaluable patients had partial response (PR), one had minor response (MR), and three had progressive disease (PD). Two patients scored as PD had a decrease in tumor density. Tumor reductions not measurable with Response Evaluation Criteria In Solid Tumors (RECIST) were seen in a further four patients. PR, MR, stable disease, and PD were seen in 12, 23.5, 35, and 29.5% of tumor markers analyzed, respectively (N=17). Ad5/3-Cox2L-D24 appears safe for treatment of cancer in humans and extended virus circulation results from a single treatment. Objective evidence of anti-tumor activity was seen in 11/18 (61%) of patients. Clinical trials are needed to extend these findings.

Effect of fluconazole on plasma fluvastatin and pravastatin concentrations.

OBJECTIVE: To study the effects of fluconazole on the pharmacokinetics of fluvastatin and pravastatin, two inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. METHODS: Two separate randomised, double-blind, two-phase, crossover studies with identical study design were carried out. In each study, 12 healthy volunteers were given a 4-day pretreatment with oral fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo, according to a randomisation schedule. On day 4, a single oral dose of 40 mg fluvastatin (study I) or 40 mg pravastatin (study II) was administered orally. Plasma concentrations of fluvastatin, pravastatin and fluconazole were measured over 24 h. RESULTS: In study 1, fluconazole increased the mean area under the plasma fluvastatin concentration-time curve (AUC0-infinity) by 84% (P < 0.01), the mean elimination half-life (t1/2) of fluvastatin by 80% (P < 0.01) and its mean peak plasma concentration (Cmax) by 44% (P < 0.05). In study II, fluconazole had no significant effect on the pharmacokinetics of pravastatin. CONCLUSIONS: Fluconazole has a significant interaction with fluvastatin. The mechanism of the increased plasma concentrations and prolonged elimination of fluvastatin is probably inhibition of the CYP2C9-mediated metabolism of fluvastatin by fluconazole. Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are prescribed to patients using fluvastatin. However, pravastatin is not susceptible to interactions with fluconazole or other potent CYP2C9 inhibitors.

Effect of itraconazole on cerivastatin pharmacokinetics.

OBJECTIVE: To determine the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of cerivastatin, a competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. METHODS: A randomized, double-blind, cross-over study design with two phases, which were separated by a washout period of 4 weeks, was used. In each phase ten healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days according to a randomization schedule. On day 4, 0.3 mg cerivastatin was administered orally. Serum concentrations of cerivastatin, its major metabolites, active and total HMG-CoA reductase inhibitors, itraconazole and hydroxyitraconazole were measured up to 24 h. RESULTS: Itraconazole increased the area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) of the parent cerivastatin by 15% (P < 0.05). The mean peak serum concentration (Cmax) of cerivastatin lactone was increased 1.8-fold (range 1.1-fold to 2.4-fold, P < 0.001) and the AUC(0-24h) 2.6-fold (range 2.0-fold to 3.6-fold, P < 0.001) by itraconazole. The elimination half-life (t1/2) of cerivastatin lactone was increased 3.2-fold (P < 0.001). Itraconazole decreased the AUC(0-24h) of the active M-1 metabolite of cerivastatin by 28% (P < 0.05), whereas the AUC(0- 24h) of the more active metabolite, M-23, was increased by 36% (P < 0.05). The AUC(0-24h) and t1/2 of active HMG-CoA reductase inhibitors were increased by 27% (P < 0.05) and 40% (P < 0.05), respectively, by itraconazole. CONCLUSIONS: Itraconazole has a modest interaction with cerivastatin. Inhibition of the CYP3A4-mediated M-1 metabolic pathway leads to elevated serum concentrations of cerivastatin, cerivastatin lactone and metabolite M-23, resulting in increased concentrations of active HMG-CoA reductase inhibitors.

Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations.

OBJECTIVE: To study the effects of erythromycin and verapamil on the pharmacokinetics of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. METHODS: A randomized, double-blind crossover study was performed with three phases separated by a washout period of 3 weeks. Twelve young, healthy volunteers took orally either 1.5 gm/day erythromycin, 240 mg/day verapamil, or placebo for 2 days. On day 2, 40 mg simvastatin was administered orally. Serum concentrations of simvastatin, simvastatin acid, erythromycin, verapamil, and norverapamil were measured for up to 24 hours. RESULTS: Erythromycin and verapamil increased mean peak serum concentration (Cmax) of unchanged simvastatin 3.4-fold (p < 0.001) and 2.6-fold (p < 0.05) and the area under the serum simvastatin concentration-time curve from time zero to 24 hours [AUC(0-24)] 6.2-fold (p < 0.001) and 4.6-fold (p < 0.01). Erythromycin increased the mean Cmax of active simvastatin acid fivefold (p < 0.001) and the AUC(0-24) 3.9-fold (p < 0.001). Verapamil increased the Cmax of simvastatin acid 3.4-fold (p < 0.001) and the AUC(0-24) 2.8-fold (p < 0.001). There was more than tenfold interindividual variability in the extent of simvastatin interaction with both erythromycin and verapamil. CONCLUSIONS: Both erythromycin and verapamil interact considerably with simvastatin, probably by inhibiting its cytochrome P450 (CYP) 3A4-mediated metabolism. Concomitant administration of erythromycin, verapamil, or other potent inhibitors of CYP3A4 with simvastatin should be avoided. As an alternative, the dosage of simvastatin should be reduced considerably, that is, by about 50% to 80%, at least when a simvastatin dosage higher than 20 mg/day is used. Possible adverse effects, such as elevation of creatine kinase level and muscle tenderness, should be closely monitored when such combinations are used.

Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin.

AIMS: The effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin, two inhibitors of HMG-CoA reductase with different pharmacokinetic properties, were studied. METHODS: Two separate randomized, placebo-controlled, cross-over studies, each involving 10 healthy volunteers, were carried out. The general design was identical in both studies. The subjects took either 100 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg fluvastatin or 40 mg lovastatin was administered orally. Plasma concentrations of fluvastatin, lovastatin, lovastatin acid, itraconazole and hydroxyitraconazole were determined up to 24 h. RESULTS: Itraconazole had no significant effect on the Cmax (190 +/- 124 ng ml(-1) vs 197 +/- 189 ng ml(-1) (mean +/- s.d.)) or total AUC (368 +/- 153 ng ml(-1) h vs 324 +/- 155 ng ml(-1) h) of fluvastatin compared with placebo. However, the t1/2,z of fluvastatin was slightly prolonged by itraconazole (2.8 +/- 0.49 h vs 2.4 +/- 0.51 h; P < 0.05). The Cmax of lovastatin was increased about 15-fold (P < 0.01) and the total AUC more than 15-fold (P < 0.01) by itraconazole. Similarly, the Cmax and total AUC of lovastatin acid were increased about 12-fold (95% CI, 5.3 to 17.7-fold; P < 0.01) and 15-fold (95% CI, 4.6 to 26.2-fold; P < 0.01) by itraconazole, respectively. The t1/2,z of lovastatin averaged 3.7 +/- 3.8 h and that of lovastatin acid 4.7 +/- 4.0 h during the itraconazole phase; these variables could not be determined in all subjects during the placebo phase. CONCLUSIONS: Itraconazole, even at a small dosage of 100 mg daily, greatly elevated plasma concentrations of lovastatin and its active metabolite, lovastatin acid. Lovastatin should therefore not be used concomitantly with itraconazole and other potent CYP3A4 inhibitors, or the dosage of lovastatin should be greatly reduced while using a CYP3A4 inhibitor. In contrast, fluvastatin concentrations were not significantly increased by itraconazole, indicating that fluvastatin has much less potential than lovastatin for clinically significant interactions with itraconazole and other CYP3A4 inhibitors.

Effect of itraconazole on the pharmacokinetics of atorvastatin.

BACKGROUND: Itraconazole, a potent inhibitor of CYP3A4, increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by increasing their serum concentrations. The aim of this study was to characterize the effect of itraconazole on the pharmacokinetics of atorvastatin, a new HMG-CoA reductase inhibitor that is metabolized at least in part by CYP3A4. METHODS: In a randomized, double-blind, two-phase crossover study, 10 healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days. On day 4, 40 mg atorvastatin was administered orally, and a further dose of 200 mg itraconazole or placebo was taken 24 hours after atorvastatin intake. Serum concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxyatorvastatin acid and lactone, 4-hydroxyatorvastatin acid and lactone, active and total HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were measured up to 72 hours. RESULTS: Itraconazole increased the area under the concentration--time curve from time zero to 72 hours [AUC(0-72)] and the elimination half-life of atorvastatin acid about threefold (p < 0.001), whereas the peak serum concentration was not significantly changed. The AUC(0-72) of atorvastatin lactone was increased about fourfold (p < 0.001), and the peak serum concentration and half-life were increased more than twofold (p < 0.01). Itraconazole decreased the peak serum concentration and AUC(0-72) of 2-hydroxyatorvastatin acid (p < 0.01) and 2-hydroxyatorvastatin lactone (p < 0.01). Itraconazole significantly (p < 0.01) increased the half-life of 2 hydroxyatorvastatin lactone. The AUC(0-72) values of active and total HMG-CoA reductase inhibitors were increased 1.6-fold (p < 0.001) and 1.7-fold (p < 0.001), respectively. CONCLUSIONS: Itraconazole has a significant interaction with atorvastatin. The mechanism of increased serum concentrations of atorvastatin and HMG-CoA reductase inhibitors is inhibition of CYP3A4-mediated metabolism of atorvastatin and its metabolites by itraconazole. Concomitant use of itraconazole and other potent inhibitors of CYP3A4 with atorvastatin should be avoided or the dose of atorvastatin should be reduced accordingly.

Grapefruit juice greatly increases serum concentrations of lovastatin and lovastatin acid.

BACKGROUND: Grapefruit juice increases the bioavailability of several drugs known to be metabolized by CYP3A4. We wanted to investigate a possible interaction of grapefruit juice with lovastatin, a cholesterol-lowering agent that is partially metabolized by CY P3A4. METHODS: An open, randomized, two-phase crossover study with an interval of 2 weeks between the phases was carried out. Ten healthy volunteers took either 200 ml double-strength grapefruit juice or water orally three times a day for 2 days. On day 3, each subject ingested 80 mg lovastatin with either 200 ml grapefruit juice or water, and an additional dose of 200 ml was ingested 1/2 and 1 1/2 hours after lovastatin intake. Serum concentrations of lovastatin and lovastatin acid were measured up to 12 hours. RESULTS: Grapefruit juice greatly increased the serum concentrations of both lovastatin and lovastatin acid. The mean peak serum concentration (Cmax) of lovastatin was increased about 12-fold (range, 5.2-fold to 19.7-fold; p < 0.001) and the area under the concentration-time curve [AUC(0-12)] was increased 15-fold (range, 5.7-fold to 26.3-fold; p < 0.001) by grapefruit juice. The mean Cmax and AUC(0-12) of lovastatin acid were increased about fourfold (range, 1.8-fold to 11.5-fold; p < 0.001) and fivefold (range, 2.4-fold to 23.3-fold; p < 0.001) by grapefruit juice, respectively. The half-lives of lovastatin and lovastatin acid remained unchanged. CONCLUSIONS: Grapefruit juice can greatly increase serum concentrations of lovastatin and its active metabolite, lovastatin acid, probably by preventing CYP3A4-mediated first-pass metabolism in the small intestine. The concomitant use of grapefruit juice with lovastatin and simvastatin should be avoided, or the dose of these 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.

Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole.

BACKGROUND: Itraconazole increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A' (HMG-CoA) reductase inhibitors by increasing their serum concentrations. We studied possible interactions of itraconazole with simvastatin and pravastatin. METHODS: Two randomized, double-blind, two-phase crossover studies were performed with use of an identical design, one with simvastatin (study I) and one with pravastatin (study II). In both studies, 10 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of simvastatin (study I) or pravastatin (study II). Serum concentrations of simvastatin, simvastatin acid, pravastatin, HMG-CoA reductase inhibitors, itraconazole, and hydroxyitraconazole were determined. RESULTS: In study I, itraconazole increased the peak serum concentrations (Cmax) and the areas under the serum concentration-time curve [AUC(0-infinity)] of simvastatin and simvastatin acid at least tenfold (p < 0.001). The Cmax and AUC(0-infinity) of total simvastatin acid (naive simvastatin acid plus that derived by hydrolysis of the lactone) were increased 17-fold and 19-fold (p < 0.001), respectively, and the half-life (t1/2) was increased by 25% (p < 0.05). The AUC(0-infinity) of HMG-CoA reductase inhibitors was increased fivefold (p < 0.001) and the Cmax and t1/2 were increased threefold (p < 0.001). In study II, itraconazole slightly increased the AUC(0-infinity) and Cmax of pravastatin, but the changes were statistically nonsignificant (p = 0.052 and 0.172, respectively). The t1/2 was not altered. The AUC(0-infinity) and Cmax of HMG-CoA reductase inhibitors were increased less than twofold (p < 0.05 and p = 0.063, respectively) by itraconazole. There were no differences in the serum concentrations of itraconazole and hydroxyitraconazole between studies I and II. CONCLUSIONS: Itraconazole greatly increased serum concentrations of simvastatin, simvastatin acid, and HMG CoA reductase inhibitors, probably by inhibiting CYP3A-mediated metabolism, but it had only a minor effect on pravastatin. Concomitant use of potent inhibitors of CYP3A with simvastatin should be avoided or its dosage should be greatly reduced.

Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole.

BACKGROUND: The oral bioavailability of buspirone is very low as a result of extensive first-pass metabolism. Erythromycin and itraconazole are potent inhibitors of CYP3A4, and they increase plasma concentrations and effects of certain drugs, for example, oral midazolam and triazolam. The possible interactions of buspirone with erythromycin and itraconazole have not been studied before. METHODS: The pharmacokinetics and pharmacodynamics of buspirone were investigated in a randomized, double-blind, double-dummy crossover study with three phases. Eight young healthy volunteers took either 1.5 gm/day erythromycin, 200 mg/day itraconazole, or placebo orally for 4 days. On day 4, 10 mg buspirone was administered orally. Timed blood samples were collected up to 18 hours, and the effects of buspirone were measured with four psychomotor tests up to 8 hours. RESULTS: Erythromycin and itraconazole increased the mean area under the plasma concentration-time curve from time zero to infinity [AUC(0-infinity] of buspirone about sixfold (p < 0.05) and 19-fold (p < 0.01), respectively, compared with placebo. The mean peak plasma concentration (Cmax) of buspirone was increased about fivefold (p < 0.01) and 13-fold (p < 0.01) by erythromycin and itraconazole, respectively. These interactions were evident in each subject, although a striking interindividual variability in the extent of both interactions was observed. The elimination half-life of buspirone did not seem to be prolonged by either erythromycin or itraconazole. The effect of itraconazole on the Cmax and AUC(0-infinity) of buspirone was significantly (p < 0.01) greater than that of erythromycin. The greatly elevated plasma buspirone concentrations resulted in increased (p < 0.05) pharmacodynamic effects (as measured by the Digit Symbol Substitution test and the Critical Flicker Fusion test) and in side effects of buspirone. CONCLUSIONS: Both erythromycin and itraconazole greatly increased plasma buspirone concentrations, obviously by inhibiting its CYP3A4-mediated first-pass metabolism. These pharmacokinetic interactions were accompanied by impairment of psychomotor performance and side effects of buspirone. The dose of buspirone should be greatly reduced during concomitant treatment with erythromycin, itraconazole, or other potent inhibitors of CYP3A4.

Concentrations and effects of zopiclone are greatly reduced by rifampicin.

AIMS: The effects of rifampicin on the pharmacokinetics and pharmacodynamics of zopiclone, a non-benzodiazepine hypnotic, were studied. METHODS: In a randomized, placebo-controlled cross-over study with two phases, eight young healthy volunteers took either 600 mg rifampicin or placebo once daily for 5 days. On the 6th day, 10 mg zopiclone was administered orally. Plasma zopiclone concentrations and effects of zopiclone were measured for 10 h. RESULTS: The total area under the plasma zopiclone concentration-time curve after rifampicin was 18.0% (95% CI 13.5-22.5%) of that after placebo (86.1 +/- 34.5 ng ml(-1) h vs 473 +/- 114 ng ml(-1) h (mean +/- s.d.); P<0.001). Rifampicin decreased the peak plasma concentration of zopiclone from 76.9 +/- 27.2 ng ml(-1) to 22.5 +/- 6.0 ng ml(-1) (P<0.001) and the half-life from 3.8 +/- 0.6 h to 2.3 +/- 0.9 h (P<0.005). A significant (P<0.02) reduction in the effects of zopiclone was seen in three of the five psychomotor tests used (digit symbol substitution test, critical flicker fusion test and Maddox wing test) after rifampicin pretreatment. CONCLUSIONS: The strong interaction of rifampicin with zopiclone is due to enhanced metabolism of zopiclone. Zopiclone may show a reduced hypnotic effect when used concomitantly with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.