bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transgenic mouse models in carcinogenesis: interaction of c‐myc with transforming growth factor α and hepatocyte growth factor in hepatocarcinogenesis
Authors: THORGEIRSSON SNORRI S. , SANTONI‐RUGIU ERIC 
Published: October 2003

1Overexpression of the c‐myc oncogene is associated with a variety of both human and experimental tumours, and cooperation of other oncogenes and growth factors with the myc family are critical in the evolution of the malignant phenotype. 2Double transgenic mice bearing fusion genes consisting of mouse albumin enhancer/promoter‐mouse c‐myc cDNA and mouse metallothionein 1 promoter‐human transforming growth factor (TGF‐α) cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing the interaction of nuclear oncogenes and growth factors in tumourigenesis. 3Coexpression of c‐myc and TGF‐α as transgenes in the mouse liver resulted in a tremendous acceleration of neoplastic development in this organ as compared to expression of either of these transgenes alone. The two distinct cellular reactions that occurred in the liver of the double transgenic mice prior to the appearance of liver tumours were dysplastic and apoptotic changes in the existing hepatocytes followed by emergence of multiple focal lesions composed of both hyperplastic and dysplastic cell populations. 4These observations suggest that the interaction of c‐myc and TGF‐α, during development of hepatic neoplasia contributes to the selection and expansion of the preneoplastic cell populations which consequently increases the probability of malignant conversion. 5We have now extended these studies and examined the interaction of hepatocyte growth factor (HGF) with c‐myc during hepatocarcinogenesis in the transgenic mouse model. While sustained overexpression of c‐myc in the liver leads to cancer, coexpression of HGF and c‐myc in the liver delayed the appearance of preneoplastic lesions and prevented malignant conversion. Similarly, tumour promotion by phenobarbitone was completely inhibited in the c‐myc/HGF double transgenic mice whereas phenobarbitone was an effective tumour promoter in the c‐myc single transgenic mice. 6The results indicate that HGF may function as a tumour suppressor during early stages of liver carcinogenesis, and suggest the possibility of therapeutic application for this cytokine. Furthermore, we show for the first time that interaction of c‐myc with HGF or TGF‐α results in profoundly different outcomes of the neoplastic process in the liver.
Single‐dose pharmacokinetics of ampicillin and tobramycin administered by hypodermoclysis in young and older healthy volunteers
Authors: CHAMPOUX N. , DU SOUICH P. , RAVAOARINORO M. , PHANEUF D. , LATOUR J. , CUSSON J. R. 
Published: October 2003

1To test the feasibility of administering antibiotics by subcutaneous infusion to the elderly, we compared the pharmacokinetics of tobramycin (single dose of 80 mg) given by hypodermoclysis (HDC) with the kinetics of the antibiotic injected intravenously (i.v.) in 10 young (<50 years old) and 10 elderly (>65 years old) healthy volunteers. Similar studies were performed with ampicillin (single dose of 1 g) in 12 young and 10 older healthy volunteers. 2Compared with the i.v. route, HDC delayed the time to reach the maximal plasma concentration (tmax) of tobramycin in young volunteers: 32±6 (s.d.) min vs 88±46, P<0.005, and older volunteers: 27±4 min vs 89±15, P<0.005. Administration of the antibiotics by HDC was well tolerated. The plasma concentration of tobramycin 30 min after the end of infusion (C60) was lower (P<0.05) following HDC than after the i.v. route in both young, 2.2±0.7 vs 3.5±0.8 μg ml−1, and elderly subjects, 2.2±0.8 vs 3.8±0.9. μg ml−1. 3The area under the curve (AUC) of tobramycin given by HDC was slightly smaller than when given i.v., i.e. in young subjects: 740±225 (s.d.) vs 893±223 μg ml−1 min, NS, and in the elderly: 980±228 vs 1056±315 μg ml−1 min, NS. 4When ampicillin was administered by HDC, the tmax was also delayed in young volunteers: 45±18 vs 23±6 min, and in the elderly: 49±18 vs 27±4 min, P<0.005, the AUC was greater by HDC than i.v. in the young volunteers: 4527±1658 μg ml−1 min vs 3810±1033 μg ml−1 min and in the elderly: 6795±2094 μg ml−1 min vs 4217±1518 μg ml−1 min, and the C60 was higher by HDC in the young: 27±7 vs 24±9 μg ml−1, and in the elderly: 32±9 vs 23±11 μg ml−1, P<0.05. 5In conclusion, HDC delays the entry of the antibiotic into the systemic circulation, but did not affect the amount available. HDC was well tolerated and could become an adequate method for antibiotic administration to the elderly.
Clinical pharmacology of β3‐adrenoceptors
Authors: LIPWORTH BRIAN J. 
Published: October 2003

1An atypical non β1/β2‐adrenoceptor (AR) subtype (β3‐AR) has been identified which is selectively stimulated by a group of ligands which mediate lipolytic and thermic responses in brown and white adipose tissue. 2Molecular studies have shown that β3‐AR in man are mainly expressed in visceral adipocytes, and to a lesser extent in gall‐bladder and colon. In vitro studies with β3‐AR agonists have shown activity at other sites including skeletal muscle and myocardium. 3Regulation of β3‐AR may differ from β1/β2‐AR subtypes in that continuous agonist exposure does not result in receptor down‐regulation. 4A polymorphism of the human β3‐AR gene (Trp64Arg) has been identified which is associated with obesity, insulin resistance and an earlier onset of non‐insulin‐dependent diabetes mellitus (NIDDM). Studies are required to establish whether expression of the mutant gene results in altered metabolic responses to β3‐AR stimulation in man. 5There is accumulating evidence to support a therapeutic role of β3‐AR agonists in NIDDM because of anti‐obesity and anti‐diabetic activity, as a consequence of thermogenic effects as well as increased insulin sensitivity and glucose tolerance. 6Selectivity studies with BRL35135 and isoprenaline in humans have demonstrated a β3‐AR mediated component to thermogenesis which is dissociated from β1/β2‐mediated effects on carbohydrate and fat metabolism. Similar studies have suggested a functional β3‐AR mediating cardiac but not airway responses in humans. An evaluation of β3‐AR agonists in irritable bowel syndrome may be warranted in view of colonic antimotility properties in vitro.
A possible role for mono(ADP‐ribosyl)transferase in the signalling pathway mediating neutrophil chemotaxis
Authors: ALLPORT JENNIFER R. , DONNELLY LOUISE E , KEFALAS PANAGIOTIS , LO GAR , NUNN ALISTAIR , YADOLLAHI‐FARSANI MASOUD , RENDELL NIGEL B. , MURRAY STEPHEN , TAYLOR GRAHAM W. , MACDERMOT JOHN 
Published: October 2003

1Mono(ADP‐ribosyl)transferase activity has been identified on the external surface of human polymorphonuclear neutrophil leucocytes (PMNs). The enzyme is released from the plasma membrane by phosphoinositide‐specific phospholipase C, suggesting a glycosylphosphatidylinositol (GPI) linkage of the enzyme to the plasma membrane. Partial sequence of cDNA encoding the enzyme suggests that it is identical to the GPI‐linked mono(ADP‐ribosyl)transferase identified previously on human skeletal muscle. 2A panel of inhibitors of mono(ADP‐ribosyl)transferase (including vitamins K1 and K3, novobiocin and nicotinamide) showed a rank order of inhibitory potency similar to that described for other mono(ADP‐ribosyl)transferases. Furthermore, the mono(ADP‐ribosyl)ation of agmatine was inhibited also by diethylamino(benzylidineamino)guanidine (DEA‐BAG), another substrate of the enzyme related structurally to arginine. 3There was a close linear correlation between the IC50 values for inhibition of mono(ADP‐ribosyl)ation of agmatine by DEA‐BAG or the enzyme inhibitors and their IC50 values for inhibition of receptor‐dependent polymerization of cytoskeletal actin and chemotaxis. 4These results suggest a role for mono(ADP‐ribosyl)transferase in the transduction pathway involved in receptor‐dependent re‐alignment of the cytoskeleton during neutrophil chemotaxis.
Heterocyclic amines: evaluation of their role in diet associated human cancer
Authors: GOODERHAM N. J. , MURRAY S. , LYNCH A. M. , EDWARDS R. J. , YADOLLAHI‐FARSANI M. , BRATT C. , RICH K. J. , ZHAO K. , MURRAY B. P. , BHADRESA S. , CROSBIE S. J. , BOOBIS A. R. , DAVIES D. S. 
Published: October 2003

1Heterocyclic amines are formed in parts per billion levels when meat is cooked. 2The heterocyclic amines MeIQx and PhIP are efficiently absorbed into the systemic circulation after ingestion of cooked food. 3We have shown that MeIQx and PhIP, both in vitro and in vivo, are substrates for human hepatic CYP1A2, which exclusively and efficiently catalyses their conversion to genotoxic hydroxylamines. 4MeIQx and PhIP are promutagens. MeIQx is a very powerful bacterial mutagen whereas PhIP is a more potent mammalian cell mutagen. Using a mammalian cell target gene, hprt, we have shown that PhIP induces a characteristic mutational ‘fingerprint’. 5MeIQx and PhIP are carcinogenic in bioassays. The PhIP mutational ‘fingerprint’ has been detected in the Apc gene of 5/8 colonic tumours induced by PhIP in rats.
Pharmacokinetics and pharmacodynamics of recombinant human erythropoietin in athletes. Blood sampling and doping control
Authors: SOUILLARD AGNES , AUDRAN MICHEL , BRESSOLLE FRANÇOISE , GAREAU RAYNALD , DUVALLET ALAIN , CHANAL JEAN‐LOUIS 
Published: October 2003

1The pharmacokinetics of recombinant human erythropoietin (rHuEpo) were initially determined in two healthy volunteers after a single subcutaneous dose (50 u kg−1). Twenty subjects then received repeated subcutaneous administrations of high dose (200 u kg−1) rHuEpo and 10 subjects received placebo. An immunoradiometric assay was used to measure the concentrations of erythropoietin (Epo) in serum and urine. 2Serum Epo concentration‐time profiles were best described by a one‐compartment open model with zero‐order input. The mean elimination half‐life (±s.d.) was 42.0±34.2 h. Clearance, uncorrected for bioavailability, was 0.05±0.01 l h−1 kg& minus;1. Erythropoietin concentrations returned to normal values in serum and urine, 7 and 4 days after the last administration, respectively. 3The recombinant hormone was well tolerated. Significant changes in reticulocytes and red blood cells, haemoglobin concentrations and haematocrit were observed after administration of rHuEpo. In the control group, these parameters remained unchanged. 4The change in reticulocytes was used as an index of the therapeutic effect of rHuEpo. The concentration‐effect relationship was best described by an exponential model. 5These data show the limitations of the measurement of Epo concentrations in blood and urine samples, collected in athletes during competition, for antidoping control. Epo doping can be detected only during or within 4 to 7 days of ending, a course of rHuEpo.
Pharmacokinetics of recombinant human interleukin‐11 (rhIL‐11) in healthy male subjects
Authors: Aoyama K. , Uchida T. , Takanuki F. , Usui T. , Watanabe T. , Higuchi S. , Toyoki T. , Mizoguchi H. 
Published: October 2003

Aims To study the pharmacokinetics of recombinant human interleukin‐11 (rhIL‐11) in healthy male volunteers following subcutaneous (s.c.) and intravenous (i.v.) administration.Methods RhIL‐11 was infused intravenously at 10–50 μg kg−1 for 1 or 3 h, or administered subcutaneously at 3–50 μg kg−1 to volunteers. RhIL‐11 was also administered at 3 μg kg−1 s.c. once daily for 7 days. Plasma and urinary concentrations were measured by enzyme‐linked immunosorbent assay (ELISA).Results RhIL‐11 showed linear pharmacokinetics after both intravenous infusion and s.c. administration. Comparison of t1/2 and MRT values after i.v. administration with those after s.c. administration indicated that rhIL‐11 pharmacokinetics after s.c. administration were absorption rate‐limited. Bioavailability after s.c. administration was about 65%. Since RhIL‐11 was not detected in urine after a single 50 μg kg−1 s.c. dose, rhIL‐11 was considered to be eliminated by metabolism. There was no significant change in the pharmacokinetic profile of rhIL‐11 following repeated s.c. administration.Conclusions RhIL‐11 demonstrated linear pharmacokinetics at these dose ranges after single and repeated s.c. administration or constant‐rate i.v. infusion in healthy volunteers.
The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90)
Authors: Seaber E. , On N. , Dixon* R. M. , Gibbens M. , Leavens W. J. , Liptrot J. , Chittick G. , Posner J. , Rolan† P. E. , Peck R. W. 
Published: October 2003

Aims Two open studies in healthy volunteers were conducted to determine the absolute bioavailability and metabolic disposition of zolmitriptan (311C90), a novel 5HT1D agonist for the acute treatment of migraine.Methods After an initial test i.v. infusion, bioavailabilty was assessed by comparison of AUC after an i.v. infusion (3.5 mg) and an oral tablet (10 mg), in six men and six women using a randomised, crossover design. Disposition was studied by administration of a 25 mg capsule, labelled with 100 μCi []>
14C]‐zolmitriptan, to five men and one woman on a single occasion.Results Zolmitriptan was well tolerated by both i.v. and oral routes. Adverse events were mostly mild, consistent with earlier studies and characteristic of this class of drug. Reports were similar in nature and number after both oral and iv dosing. Mean±s.d. oral bioavailability was 0.49±0.24 (0.38±0.16 in men and 0.60±0.28 in women). After oral dosing, Cmax and AUC values in women were approximately double those in men. Relative to zolmitriptan concentrations, metabolite concentrations were higher after oral dosing than after i.v., and higher in men compared with women. Half‐life was significantly longer after oral dosing (mean 22%, 95% CI 6–35%). Mean±s.d. values for CL, Vz and t1/2,z after i.v. dosing (all subjects) were 8.7±1.7 ml min−1 kg−1, 122±32 l and 2.30±0.59 h respectively. Following administration of 25 mg [14C]‐zolmitriptan, 91.5% of the dose was recovered in 7 days, 64.4±6.5% in urine and 27.1±6.0% in faeces. Less than 10% was recovered unchanged in urine, with 31.1±6.4% recovered as the inactive indole acetic acid metabolite. Most of the faecal material was unchanged zolmitriptan, representing unabsorbed drug. Plasma concentrations of [14C] were slightly higher than those of the summed concentrations of known analytes zolmitriptan, the active N‐desmethyl metabolite (183C91), the inactive N‐oxide (1652W92) and indole acetic acid (2161W92) metabolites, which accounted for 86% of total plasma radioactivity. No other significant metabilites were detected in plasma. Some minor additional metabolites were detected in urine, none of which contributed more than 5% of the dose.Conclusions The data suggest that zolmitriptan undergoes first‐pass metabolism and this is more extensive in men than in women. Zolmitriptan has suitable bioavailabilty for an acute oral migraine treatment and there are no significant unidentified metabolites in man.
The comparison of the responsiveness of human isolated internal mammary and gastroepiploic arteries to levcromakalim: an alternative approachto the management of graft spasm
Authors: Akar Fatma , Sönmez Uydeş‐Dogˇan B. , Tufan Hale , Aşlamaci Saı˙t , Köksoy Cüneyt , Kanzik İlker 
Published: October 2003

Aims We studied the effectiveness of levcromakalim, a potassium channel opener (KCO), in the prevention and reversal of spasm in arterial grafts used in coronary artery bypass operations, namely, internal mammary artery (IMA) and gastroepiploic artery (GEA). Methods Spasm was mimicked in vitro in arterial rings from 109 patients by increasing the vascular tension with noradrenaline, the thromboxane analogue U46619, endothelin‐1 and K+. Results GEA displayed considerably higher contractile force to these agents than IMA. Pretreatment with levcromakalim depressed significantly the maximal contractile responses (either absolute or relative) to noradrenaline and U46619 but did not affect those of endothelin‐1 and K+ in both of the arteries. Sensitivities (to all agents, except to endothelin‐1) decreased significantly after levcromakalim. In experiments evaluating the antispasmodic activity of levcromakalim, a higher relaxant capacity was observed in GEA than IMA (for K+ contraction; IMA: 31.32±3.83%, n=13 vs GEA: 98.01±0.71%, n=7, P<0.05). This different activity of levcromakalim between two arterial grafts was apparent even when GEA rings were contracted to higher force (g) than that of IMA (for K+ contraction; GEA: 72.56±4.96%, n=7). Responses to levcromakalim were similar in IMA and GEA when endothelin‐1 was used as the spasmogenic agent (IMA: 80.98±4.85%, n=10 vs GEA: 91.93±3.17%, n=7, P >0.05). Conclusions Our results provide evidence that levcromakalim may have a therapeutic value in the treatment of spasm of coronary artery bypass grafts, especially GEA.
Further evidence that chronic perindopril treatment maintains neurohormonal suppression but does not lower blood pressure in chronic cardiac failure
Authors: MacFadyen Robert J. , Barr Craig S. , Sturrock Nigel D.C. , Fenwick Michael , Struthers Allan D. 
Published: October 2003

Aims Previous studies in heart failure (CHF) after temporary diuretic withdrawal have suggested that perindopril is associated with no first dose hypotension in comparison with other ACE inhibitors (ACEI) or placebo. The aim of this study was to explore further the profile of perindopril during chronic dosing. Methods We report the effects of acute and chronic (8 weeks) treatment with the ACE inhibitor perindopril (Per, 2→4 mg daily) or placebo (P) in a double‐blind parallel group study of 24 diuretic treated patients (17M; 67±8 years, 80±17 kg) with ischaemic cardiomyopathy (fractional shortening, 19±5%; radionuclide ejection fraction, 31±3%). Baseline biochemical, hormonal (ACE, Ang I, Ang II), isotopic renal function (GFR, ERPF, ECFV), pretreatment diuretic dose and heart failure scores were similar between groups. Concomitant cardiac treatments remained unchanged and diuretic withdrawal was not used to introduce treatment. Results There were no significant effects on electrolytes, liver function tests, serum or erythrocyte magnesium. There was no significant first dose fall in SBP over 6 h) (P, baseline 137±18; min 115±16 mmHg; Per, baseline 137±15; min 118±17 mmHg). Neither supine nor erect BP was significantly affected by chronic treatment (P, erect baseline 134±23/76±10 to 124±41/74±10 mmHg; Per, baseline 135±21/76±14 to 128±22/70±12 mmHg, P=NS). Active treatment was associated with significant ACE inhibition (P, baseline 47±17 to 43±17; Per baseline 49±15 to 14±7); aldosterone (P, baseline 337±179 to 375±306; Per, baseline 335±357 to 293±155 pg ml−1 ) and Ang II suppression (P, baseline 9±9 to 20±39; Per baseline 10±9 to 3±3 pm ). Isotopic renal function was unaffected by either treatment. Conclusions At this dose (2–4 mg orally) chronic perindopril therapy has no significant effect on blood pressure or renal function. Sustained neurohormonal suppression of ACE and AII occurred without evidence of AII reactivation. A lack of effect on BP at these doses may make perindopril suitable for study in unstable patients with acute HF or useful in those patients where there are concerns over ACEI induced hypotension.
Improved bioavailability and clinical response in patients with chronic liver disease following the administration of a spironolactone: β‐cyclodextrin complex
Authors: Abosehmah‐Albidy A. Z. M. , York P. , Wong V. , Losowsky M. S. , Chrystyn H. 
Published: October 2003

Aims To compare the absorption and clinical effect of spironolactone from an inclusion complex with β‐cyclodextrin (SP‐COMP) to Aldactone tablets (ALD) in chronic liver disease. Methods Patients, admitted with chronic liver disease, completed a randomized crossover steady state study. They received their spironolactone dose as either daily SP‐COMP or ALD for 7 days. Serial blood samples were drawn over a 24 h period from day 7 of each therapy. Accurate fluid balance was recorded on days 5–7 and 12–14. Thirteen (six females) whose mean (s.d.) age and weight was 58.4(9.3) years and 74.3(19.0) kg completed the study. Results The mean (95% confidence limits) relative bioavailability for SP‐COMP (compared with ALD) from steady state serum concentrations of canrenone, 6β‐hydroxyl 7α‐thiomethyl spironolactone and 7α‐thiomethyl spironolactone was 310.0 (265.4, 336.7), 233.4(212.9, 250.8) and 254.8(230.8, 279.0)%, respectively. Improvements in clinical status and fluid balance occurred over the last 3 days of SP‐COMP with a mean (s.d.) net loss, in fluid balance, of 1370(860)ml compared with a gain of 228(936)ml during ALD. Conclusions Better absorption of spironolactone from the spironolactone: β‐cyclodextrin complex formulation should lead to a reduction in dosage and perhaps a more consistent effect in patients with chronic liver disease.
Investigation of multiple dose citalopram on the pharmacokinetics and pharmacodynamics of racemic warfarin
Authors: Priskorn M. , Sidhu J. S. , Larsen F. , Davis J. D. , Khan A. Z. , Rolan P. E. 
Published: October 2003

Aims An open, controlled, randomized, crossover study was conducted in healthy males to assess the possible occurrence of a pharmacokinetic/pharmacodynamic interaction between warfarin and the selective serotonin re‐uptake inhibitor citalopram.Methods Twelve subjects received a single 25 mg dose of racemic warfarin either alone or on Day 15 of a 21‐day oral dosing regimen of 40 mg citalopram daily. Blood samples for pharmacokinetic analysis were obtained over a 168 h period after warfarin dosing. The degree of anticoagulation was assessed by the prothrombin time.Results Citalopram produced no change in the pharmacokinetics of (R)‐ and (S)‐warfarin, indicating that citalopram does not alter the metabolism of warfarin mediated via CYP1A2, CYP3A4 and CYP2C9. Citalopram coadministration resulted in a statistically significant increase in the maximum prothrombin time (Rmax; by 1.6±3.0 s) and the area under the prothrombin time‐time curve (AUCPT; by 5.0±5.7%). The 90% confidence intervals for Rmax and AUCPT ratios (citalopram+warfarin/warfarin alone) were 1.01–1.10 and 1.03–1.07, respectively.Conclusions The small increase in prothrombin time observed in this study with coadministration of citalopram and warfarin is not considered to be of importance in the clinical setting.