bluuebunny/crossref_metadata_2025 huggingface dataset:
The clinical pharmacologist in drug discovery and development
Authors: LEWIS PETER
Published: October 2003

1Clinical pharmacology is a key activity in drug discovery and drug development with much to contribute to drug innovation.

2However, very few clinical pharmacologists choose the pharmaceutical industry as their ultimate career.

3Medical alumni of the RPMS clinical pharmacology department illustrate this; only four industrial careers vs thirty professors of clinical pharmacology or medicine.
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.
Effect of locally applied prazosin on the kinetics of the pupillary light reflex
Authors: MORTLOCK S.‐A. , LANGLEY R. W. , BRADSHAW C. M. , SZABADI E.
Published: October 2003

The effect of locally applied prazosin on pupillometric measures was studied in healthy volunteers, in an attempt to identify the role of α1‐adrenoceptors in the recovery time of the light reflex. Prazosin antagonized the mydriatic effect of phenylephrine, but did not alter that of tropicamide. Miotic responses to a range of light stimuli were measured under ambient temperature conditions of 22° C and 40° C. The 40° C condition was associated with shorter recovery times of the light reflex; prazosin increased the recovery time under both temperature conditions. Response amplitude was not affected by the temperature condition or prazosin. The results are consistent with the hypothesis that sympathetic neuromuscular transmission is involved in the redilatation of the pupil following a miotic response to light stimulation.
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.
Expression of CYP3A4, CYP3A5 and CYP3A7 in human duodenal tissue
Authors: KIVISTÖ KARI T. , BOOKJANS GERHARD , FROMM MARTIN F. , GRIESE ERNST‐ULRICH , MÜNZEL PETER , KROEMER HEYO K.
Published: October 2003

The essential role of cytochrome P450 3A4 (CYP3A4) in human small intestine is well established, and CYP3A5 seems also to be present in most subjects. However, the role of CYP3A7 in the small intestine remains poorly characterized. We have therefore studied the expression of these CYP3A enzymes in the duodenal tissue from 19 patients, using a specific RT‐PCR (reverse transcriptase‐polymerase chain reaction) method. CYP3A4 and CYP3A5 were present at the mRNA level in the duodenum of 18 and 19 of the 19 patients studied, respectively. In contrast, mRNA for CYP3A7 was not found in the duodenum in any of the patients. These findings strongly suggest that, unlike CYP3A4 and CYP3A5, CYP3A7 is not expressed in human duodenum.
The need for large‐scale randomized evidence
Authors: Baigent C.
Published: October 2003

The reliable detection of moderate differences in major health outcomes that arise as a result of treatment requires large‐scale randomized evidence (and the appropriate interpretation of this evidence once it has been generated). This may take the form of a single mega‐trial or, exceptionally, a meta‐analysis of many smaller randomized trials may provide worthwhile information. Small or non‐randomized studies cannot generally be trusted to distinguish reliably between a moderate benefit, a moderate hazard, and a negligible difference in major outcomes. Simple design, streamlined data collection, and use of the ‘uncertainty principle’ to guide eligibility would all encourage the recruitment of larger samples in randomized trials. Future trials need to adopt these methods in order to detect any moderate improvements in major outcomes that may await discovery.
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.
Consumption of non‐steroidal anti‐inflammatory drugs and the development of functional renal impairment in elderly subjects. Results of a case‐control study
Authors: Henry David , Page John , Whyte Ian , Nanra Ranjit , Hall Christopher
Published: October 2003

Aims The aim of the present study was to explore the level of risk associated with community use of non‐steroidal anti‐inflammatory drugs (NSAIDs).

Methods We carried out a matched case‐control study of the relationship between recent use of NSAIDs and the presence of functional renal impairment present at the time of hospitalisation with a range of clinical problems. Cases (n=110) were consecutive patients admitted acutely to hospital who had serum creatinine levels greater than or equal to 0.15 mmol l−1, which improved by 20% or more within the next 14 days, or prior to discharge from hospital. Controls (n=189) were subjects of the same sex and age (to within 5 years) as the cases, who were admitted to the same hospital, who had normal serum creatinine levels (<0.12 mmol l−1 ) throughout their hospital stay. Information on a number of study factors, including recent use of aspirin and other NSAIDs, was obtained by structured interview.

Results Overall, there was a weak association between consumption of NSAIDs (including non‐prophylactic aspirin) and the development of functional renal impairment—adjusted odds ratios (OR) with use of NSAIDs in the previous week or in the previous month: OR 1.5 (95% CI 0.80, 2.9) and 1.8 (95% CI 0.97, 3.4) respectively. In subjects with a previous history of renal disease the adjusted OR was 6.6 (0.75, 57.8) and in those with a history of gout or hyperuricaemia the OR was 7.2 (1.3, 40.2). There was a weak positive relationship between the dose of drug consumed in the previous week and the odds of functional renal impairment. The relationship between risk and published figures for drug half‐lives (t½ ) was stronger. The odds ratio increased from 1.2 (95% CI 0.61, 2.4) with a t½≤4 h, to 4.8 (1.5, 15.8) with a t½ of ≤12 h (P=0.012, test for trend). This relationship remained statistically significant after adjustment for a number of clinical variables and the dose of drug ingested.

Conclusions NSAIDs are an important cause of functional renal impairment in subjects with renal disease or a history of gout or hyperuricemia. The half‐life of the drug is more important than the ingested dose in determining the risk of this outcome. Long half‐life drugs should be avoided in individuals who are at risk of developing renal impairment.
Cyclosporin pharmacokinetics following administration of capsules and Neoral in paediatric patients with lupus nephritis
Authors: Fu L. W. , Yang L. Y. , Chen W. P. , Lin C. Y.
Published: October 2003

Aims Neoral is a new microemulsion form of cyclosporin. Pharmacokinetic reports in children are scarce. Therefore, we performed a pharmacokinetic study between Cyclosporin A (CsA) capsules and Neoral in paediatric patients with lupus nephritis.

Methods A single 5 mg kg−1 dose orally of either CsA capsules or Neoral was given to 10 paediatric patients (serum creatinine<1.5 mg dl−1 ). CsA whole blood levels were measured for 24 h post‐dose by h.p.l.c.

Results Neoral had a higher Cmax and AUC(Cmax: 943±176 ng ml−1; AUC: 4612±785 ng ml−1 h) than those of the CsA capsules (Cmax: 697±187 ng ml−1; AUC: 3483±873 ng ml−1 h; P<0.05). There was no difference in tmax and t1/2,z between the two groups.

Conclusions CsA Neoral had improved absorption and bioavailability, which is similar to what is reported in adults. However, interpatient variability still existed. Careful drug monitoring and dose adjustment should be performed during treatment to avoid nephrotoxicity, especially in lupus nephritis.
A comparison of the effects of aspirin on bleeding time measured using the Simplate™ method and closure time measured using the PFA‐100™, in healthy volunteers
Authors: Marshall P. W. , Williams A. J. , Dixon R. M. , Growcott J. W. , Warburton S. , Armstrong J. , Moores J.
Published: October 2003

Aims The aim of this study was to compare the effects of aspirin on platelet function as measured by the ‘classical’ template bleeding time with a new ex vivo method measuring closure times using the PFA‐100™ machine. Platelet aggregation in response to arachidonic acid was also measured ex vivo.

Methods The trial was a randomized, double‐blind, placebo‐controlled crossover design, with each volunteer taking 750 mg aspirin (BP) or placebo, three times a day for 5 days, with an 18 day wash‐out period between treatments. Bleeding times and closure times were measured before the first dose on the first day and 0.5 h after the last dose on the fifth day of each treatment period. They were also measured 2 weeks after the last day of the trial.

Results Baseline bleeding times (pre‐placebo) were 415 s using the Simplate, whilst baseline closure times were 115 s using the PFA‐100™. Aspirin treatment caused an increase of both the template bleeding time (61%) and the closure time of the PFA‐100™ (79%) when compared with the effects of placebo. The platelet aggregatory response to arachidonic acid was completely inhibited following aspirin treatment and was unaffected following placebo. Two weeks after the end of the trial, all values had returned to pre‐treatment levels. The template bleeding time was unaltered in 1 of the 12 volunteers during aspirin treatment and was significantly prolonged in 3 of the 12 volunteers during placebo treatment. The PFA‐100™ closure time was unaltered in 1 of the 12 volunteers during aspirin treatment and was prolonged in 1 subject during placebo treatment.

Conclusions The change in closure time using the PFA‐100™ is as sensitive and reproducible to the effects of aspirin on platelet function as is the template bleeding time test. However, the PFA‐100™ produced less variable effects with fewer false positive results.
Non‐puerperal lactation associated with antidepressant drug use
Authors: Egberts Antoine C. G. , Meyboom Ronald H. B. , De Koning Fred H. P. , Bakker Albert , Leufkens Hubert G. M.
Published: October 2003

Aims The aim of the present study was to estimate the relative risk of non‐puerperal lactation in patients using antidepressants in general, and specifically for serotonergic (selective serotonin reuptake inhibitors (SSRIs) and clomipramine) and non‐serotonergic antidepressants.

Methods All suspected adverse drug reactions in women and reported from January 1986 until August 1996 to the Netherlands Pharmacovigilance Foundation, a spontaneous adverse drug reaction reporting programme, were analysed. Adverse drug reaction (ADR) reporting odds ratios, defined as the ratio of the exposure odds among reported cases of non‐puerperal lactation to the exposure odds of reported other ADRs, were calculated adjusted for age and year of reporting.

Results Thirty‐eight cases of non‐puerperal lactation were reported, of which 15 were associated with the use of antidepressant drugs. In general, antidepressants were associated with a higher risk of non‐puerperal lactation in comparison with other drugs (ADR reporting odds ratio 8.3 [ 95%CI: 4.3–16.1]). Serotonergic antidepressants (selective serotonin reuptake inhibitors (SSRIs) and clomipramine) were associated with a higher risk (OR 12.7 [95%CI: 6.4–25.4]), whereas other antidepressants were not (OR 1.6 [95%CI: 0.2–11.6]), compared with all other drugs.

Conclusions Our results indicate that serotonergic antidepressants are associated with an approximately eight times higher risk of non‐puerperal lactation compared with other antidepressants. This effect is probably mediated by an indirect inhibition effect of serotonin on the dopaminergic transmission. This finding is in line with the occurrence of other antidopaminergic effects, such as extrapyramidal symptoms, in patients using serotonergic antidepressants.
A pharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2‐receptor antagonists cimetidine and ranitidine
Authors: Kamali F. , Howes A. , Thomas S. H. L. , Ford G. A. , Snoeck E.
Published: October 2003

Aims The study was designed to investigate the effects of the H2‐receptor antagonists, cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of nebivolol in healthy volunteers.

Methods Twelve healthy volunteers took part in a randomized placebo‐controlled cross‐over study. Each subject received on three separate occasions placebo, cimetidine (400 mg twice daily) or ranitidine (150 mg twice daily) for 24 h before and 48 h after a single oral dose of nebivolol (5 mg). Nebivolol and its individual (+) and (−) enantiomers were determined tby h.p.l.c.

Results Ranitidine had no significant effect on nebivolol pharmacokinetics. Cimetidine, however, resulted in a 21–23% increase in Cmax of unchanged nebivolol and of each enantiomer plus its hydroxylated metabolites. Cimetidine significantly (P<0.05) increased the AUC [mean±s.d. (95% C.I. of differences in mean)] for unchanged (±)‐nebivolol [7.76±3.07 ng ml−1h with placebo; 11.50±5.40 (1.75, 8.76) ng ml−1h with cimetidine], (+)‐nebivolol plus its hydroxylated metabolites [73.0±18.0 ng ml−1h with placebo; 91.5±25.7 (1.0, 23.1) ng ml−1h with cimetidine] and (−)‐nebivolol plus its hydroxylated metabolites [101±32 ng ml−1h with placebo; 123±38 (3.3, 27.0) ng ml−1h with cimetidine]. Statistical analysis of the resting blood pressure and heart rate and exercise data did not suggest any consistent effects of ranitidine or cimetidine upon the pharmacodynamic effects of nebivolol.

Conclusions There was no interaction between ranitidine and nebivolol. Although cimetidine inhibited nebivolol metabolism, it did not have a significant influence on the pharmacodynamics of the drug.
Excretion of citalopram in breast milk
Authors: Spigset Olav , Carleborg Lena , Öhman Robert , Norström Åke
Published: October 2003

Aims The objective of this study was to measure the secretion of the selective serotonin uptake inhibitor citalopram in breast milk.

Methods The excretion of citalopram in breast milk was studied at steady‐state conditions in two patients with depression and in one healthy volunteer after ingestion of a single dose citalopram.

Results Milk/serum concentration ratios based on single pairs of samples from the two patients ranged from 1.16 to 1.88. Based on milk concentration data from the patients, the absolute dose ingested by a suckling infant would be 4.3–17.6 μg kg−1 day−1, and the relative dose 0.7–5.9% of the weight‐adjusted maternal dose. Based on area‐under‐the‐time‐concentration curves from the healthy volunteer, the milk/serum ratio was 1.00, the absolute dose to the infant during steady‐state conditions would be 11.2 μg kg−1 day−1 and the relative dose 1.8% of the weight‐adjusted maternal dose.

Conclusion The study shows that the relative dose to a suckling infant is close to that reported for fluoxetine, and higher than reported for fluvoxamine, paroxetine and sertraline.
Effects of prostacyclin on renal haemodynamics, renal tubular function and vasoactive hormones in healthy humans. A placebo‐controlled dose–response study
Authors: Nielsen C. B. , Bech J. N. , Pedersen E. B.
Published: October 2003

Aims To investigate the acute effects of prostacyclin (Flolan® ) on renal haemodynamics, renal tubular function, plasma concentration of angiotensin II (Ang II), aldosterone (Aldo), atrial natriuretic peptide (ANP), arginine vasopressin (AVP), mean arterial blood pressure (MBP), and heart rate (HR).

Methods Thirteen healthy control subjects were investigated on two separate occasions in a placebo controlled, randomized, dose–response study of the effect of intravenous infusion of prostacyclin (PGI2, Flolan®, 2, 4 and 8 ng kg−1min−1 ). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the use of constant infusion of []>
51Cr]‐EDTA and [125I]‐hippurane. Urinary output, urinary sodium excretion, fractional sodium excretion, fractional lithium excretion were measured and hormones were measured using radioimmunoassay.

Results During prostacyclin (PGI2 ) infusion we observed a significant increase in RPF (PGI2: 4.8%; 6.1% and 5.2%vs Plac: −1.5%; −1.9% and −5.8% for 2,4 and 8 ng kg−1min−1 respectively; P≤0.05 for 4 and 8 ng kg−1min−1 ) in Ang II (PGI2: 20.0%; 42.9% and 88.9%vs Plac: 0.1%; 8.0% and 0.0%, P≤0.01 for 4 and 8 ng kg−1 min−1 ) in ANP (PGI2: 13.6%; 12.7% and 37.5%vs Plac: −10.2%; −6.6% and −2.4%, P≤0.05 for 2 ng kg−1min−1 and P≤0.01 for 4 and 8 ng kg−1min−1 ), and in HR (PGI2: 8.8%; 17.6% and 32.7%vs Plac: 0.8%; 4.1% and 3.5%, P≤0.05 for 2 and P≤0.01 for 4 and 8 ng kg−1min−1.). A significant decrease was observed in MBP (MBP:PGI2: −1.7%; −1.9% and −5.6%vs Plac: −0.4%; −1.6% and +2.1%, P≤0.01 for 8 ng kg−1min−1 ). No significant changes were seen in the other effect variables.

Conclusions Infusion of prostacyclin in healthy control subjects increases renal plasma flow, angiotensin II, atrial natriuretic peptide, and heart rate and decreases mean blood pressure. Furthermore prostacyclin infusion does not change net sodium excretion in healthy controls.
Comparison of myeloma cell contamination of bone marrow and peripheral blood stem cell harvests
Authors: Henry Julianne M. , Sykes Pamela J. , Brisco Michael J. , Bik To Luen , Juttner Christopher A. , Morley Alexander A.
Published: October 2003

It could be speculated for patients with myeloma and other lymphoproliferative disorders that peripheral blood stem cells may be preferable to bone marrow for autologous transplantation because they may be less contaminated by neoplastic cells. To test this possibility, the immunoglobulin heavy chain gene rearrangement and limiting dilution polymerase chain reaction were used to sensitively quantify myeloma cells in bone marrow and peripheral blood stem cell collections, taken at a similar time, from eight patients with multiple myeloma. Levels of residual disease in the peripheral blood stem cell harvests were variable and did not reflect the tumour burden in the marrow. Peripheral blood stem cells contained 1.7 to 23 700‐fold fewer myeloma cells compared with the bone marrow and would have resulted in reinfusion of 0.08 to 59 480‐fold fewer myeloma cells based on total reinfused CFU‐GM and 0.24 to 24 700‐fold fewer myeloma cells based on total reinfused nucleated cells. Assuming that the proportion of clonogenic myeloma cells is equivalent, peripheral blood stem cells may be better than bone marrow as a source of haemopoietic stem cells for transplantation in multiple myeloma. The clinical follow‐up suggested that patients transplanted with peripheral blood stem cells containing a low number of myeloma cells had better disease control than those transplanted with peripheral blood stem cells containing a high number.
The role of plasma D‐dimer concentration in the exclusion of pulmonary embolism
Authors: Van Beek Edwin J. R. , Schenk B. Ed , Michel Bowine C. , Van Den Ende Bram , Brandjes Dees P. M. , Van Der Heide Yvonne T. , Bossuyt Patrick M. M. , Büller Harry R.
Published: October 2003

Objective. To determine the role of four ELISA D‐dimer assays in the exclusion of pulmonary embolism.

Design. Blinded comparison using pulmonary angiography and/or lung scintigraphy as a reference method.

Setting. A secondary and tertiary referral centre.

Patients and methods. Consecutive patients with suspected pulmonary embolism underwent lung scintigraphy, followed by angiography if a non‐diagnostic result was obtained. Comorbid conditions resulting in elevated plasma D‐dimer levels were defined a priori. Cut‐off levels for 100% sensitivity were determined. A decision‐analytic model was used to determine effectiveness and costs in the management pulmonary embolism.

Main outcome measures. The exclusion efficacy of the various assays at a sensitivity of 100%, and cost‐effectiveness.

Results. A total of 179 patients were included (78 inpatients and 101 outpatients; 74 patients had comorbid conditions). Pulmonary embolism could be adequately excluded in between 8% and 18% of all patients, and in between 3% and 7% and 11% and 27% of inpatients and outpatients, respectively, depending on the assay used. D‐dimer assays could exclude pulmonary embolism in <5% of patients with comorbid conditions, whereas this increased to 14–32% in outpatients without comorbid conditions. A cost‐effectiveness analysis showed a cost reduction of 10% at a specificity of 30%, largely due to a 28% decrease in angiography requirements. Furthermore, for every 2% decrease in sensitivity, one per 1000 evaluated patients would die as a result of inadequately treated pulmonary embolism.

Conclusion. D‐dimer ELISA assays may have a role in the exclusion of pulmonary embolism in symptomatic outpatients, where the application may reduce angiography by 30% and costs by 10%.
Deletions of the long arm of chromosome 7 in myeloid disorders: loss of band 7q32 implies worst prognosis
Authors: Velloso Elvira Rodrigues Pereira , Michaux Lucienne , Ferrant Augustin , Hernandez Jesus Maria , Meeus Peter , Dierlamm Judith , Criel Arnold , Louwagie Andries , Verhoef Gregor , Boogaerts Marc , Michaux Jean‐Louis , Bosly André , Mecucci Cristina , Berghe Herman Vanden
Published: October 2003

Clinical and cytogenetic data were analysed in 54 patients with acute non‐lymphocytic leukaemias (ANLL) or MDS (myelodysplastic syndromes) and deletion of the long arm of chromosome 7 (7q−), in order to determine if there is a commonly deleted region in 7q and to establish possible correlations between karyotypic features, such as karyotype pattern, karyotype complexity, associated anomalies, and/or the type of deleted segments, and outcome of patients with these disorders.

The median follow‐up of our patients was 4 months (range 1–89), as was the median survival. In 30% of the cases there was a history of preceding MDS or previous chemotherapy. Clinical and cytogenetic remission was obtained in 7/36 patients treated with chemotherapy (CT). At the time of 7q− detection, three patients previously treated with CT for ANLL were in clinical remission. 5q− was the most recurrent associated abnormality. Complex karyotypes were observed in 68% of the cases. In univariate analysis, statistical differences in survival were observed according to diagnosis (therapy‐related and secondary diseases had a worse prognosis than primary disorders), the chromosomal segments deleted (the loss of band 7q32 was of poor prognostic value), the karyotype complexity (patients with single anomalies did better than patients with complex anomalies) and the response to therapy (patients who achieved complete remission had a better survival probability). In multivariate analysis, the loss of band 7q32 was found to be significantly related to very poor prognosis. This finding suggests that band 7q32 may contain critical genes that should be explored at the molecular level.
Regulation of human breast epithelial stem cells
Authors: Clarke Robert B. , Anderson Elizabeth , Howell Anthony , Potten Christopher S.
Published: October 2003

Abstract.  Breast epithelial stem cells are thought to be the primary targets in the aetiology of breast cancer. As breast cancers are predominantly oestrogen and progesterone receptor‐positive (ERα/PR+), we investigated the biology of ERα/PR+ cells and their relationship to stem cells in normal human breast epithelium. Several complementary approaches were used to characterize the stem‐cell population and relate it to ERα/PR+ cells, including dual label colocalization on tissue sections, isolation of a Hoechst dye‐effluxing ‘side population’ using flow cytometry, and examination of DNA label retention. The intermediate or suprabasal population suggested by others to be breast stem cells comprises ERα/PR+ cells that coexpress the putative stem‐cell markers including cytokeratin 19. Human breast epithelial cells with Hoechst dye‐effluxing ‘side population’ properties characteristic of mammary stem cells in mice were demonstrated by lack of expression of myoepithelial and luminal cell‐specific antigens such as CALLA and MUC1 to be undifferentiated cells. Using DNA radiolabelling of human tissue implanted into athymic nude mice, a population of label‐retaining putative stem cells (LRC) were shown to be enriched for cells expressing the putative stem‐cell markers p21CIP1/WAF1 and Musashi‐1, which, interestingly, were expressed in separate subpopulations of ERα/PR+ cells. Finally, expression patterns of Musashi‐1 and Notch‐1 in relation to ERα/PR+ and adjacent proliferating cells suggest that the evolutionarily conserved Delta/Notch signalling pathway regulates asymmetric division of the putative stem‐cell population. The data suggest a model in which ERα/PR+ cells scattered through the epithelium are stem cells that self‐renew through asymmetric cell division and generate patches of transit amplifying and differentiated cells. ERα/PR+ breast cancers exhibit loss of the two key regulators of asymmetric cell division, Musashi‐1 and Notch‐1 and thus may arise from symmetric division of the ERα/PR+ stem cell.
Stem cells in normal breast development and breast cancer
Authors: Dontu Gabriela , Al‐Hajj Muhammad , Abdallah Wissam M. , Clarke Michael F. , Wicha Max S.
Published: October 2003

Abstract.  The main focus of this review is the role of mammary stem cells in normal breast development and carcinogenesis. We have developed a new in vitro culture system that permits, for the first time, the propagation of mammary stem and progenitor cells in an undifferentiated state, which should facilitate the elucidation of pathways that regulate normal mammary stem‐cell self‐renewal and differentiation. Furthermore, we propose a model in which transformation of stem cells, or early progenitor cells, results in carcinogenesis. A key event in this process is the deregulation of normal self‐renewal in these cells. Transformed mammary stem or progenitor cells undergo aberrant differentiation processes that result in generation of the phenotypic heterogeneity found in human and rodent breast cancers. This phenotypic diversity is driven by a small subset of mammary tumour stem cells. We will discuss the important implications of this mammary tumour stem‐cell model.
Risk factors for atopic dermatitis in infants at high risk of allergy: the PIAMA study
Authors: Kerkhof M. , Koopman L. P. , Van Strien R. T. , Wijga A. , Smit H. A. , Aalberse R. C. , Neijens H. J. , Brunekreef B. , Postma D. S. , Gerritsen J. ,   the PIAMA study group
Published: October 2003

Background
It has been suggested that the period immediately after birth is a sensitive period for the development of atopic disease.

Objective
We investigated whether birth characteristics and environmental factors are associated with the development of atopic dermatitis in the first year of life.

Methods
Seventy‐six children with and 228 without atopic dermatitis, all children of mothers with respiratory allergy or asthma (PIAMA birth cohort study) were included in the study. Atopic dermatitis was defined as a positive history of an itchy skin condition with at least two of the following characteristics: visible dermatitis, history of outer arms/leg involvement, or general dry skin. Multiple logistic regression analysis was performed to study the independent effects of various risk factors.

Results
A birth weight 4000 g compared to 3000–4000 g was a significant risk factor for atopic dermatitis (odds ratio (OR)=2.4; 95% CI: 1.1–5.1) as was day care attendance (OR=2.9; 95% CI: 1.5–5.9). Exclusive breastfeeding in the first 3 months was negatively associated with atopic dermatitis (OR=0.6; 95% CI: 0.3–1.2), especially with visible dermatitis (OR=0.4; 95% CI: 0.2–1.0). Gender, gestational age, the presence of siblings or pets, and parental smoking were not significantly associated with atopic dermatitis.

Conclusion
This study shows that a high birth weight and day care attendance increase the risk of atopic dermatitis in the first year of life, while exclusive breastfeeding is a protective factor when dermatitis is found on inspection.
Allergen sensitization and bronchial hyper‐responsiveness to adenosine monophosphate in asthmatic patients
Authors: Currie G. P. , Jackson C. M. , Lee D. K. C. , Lipworth B. J.
Published: October 2003

Background
Indirect bronchoprovocation using adenosine monophosphate (AMP) is related to atopic phenotype expression.

Objective
To evaluate the putative relationship between skin prick allergen sensitization and bronchial hyper‐responsiveness to AMP in a retrospective cross‐sectional database analysis.

Methods
We retrospectively evaluated two groups of non‐smoking asthmatics (forced expiratory volume in 1 s (FEV)160% predicted) who were reactive (responders) or unreactive (controls) to inhaled AMP. The main outcome measure was the difference in sensitization to individual allergens and the total atopic load according to the presence or absence of bronchial hyper‐responsiveness.

Results
We initially identified 180 (44%) non‐smoking asthmatics with PC20200 mg/mL, while 233 (56%) had PC201600 mg/mL. For those who had a skin prick test, the responders (n=151) and controls (n=151) were found to be matched for age, sex, inhaled corticosteroid dose and number of patients using inhaled corticosteroids. There were significant differences in the number of responders vs. controls in terms of sensitization to house dust mite (77% vs. 62%, P=0.004), aspergillus (19% vs. 9%, P=0.014), cat (61% vs. 48%, P=0.028), total atopic load (493 vs. 380 positive tests, P<0.001) and forced mid‐expiratory flow (60% vs. 68% predicted, P<0.001).

Conclusion
Sensitization to common aeroallergens increased the likelihood of bronchial inflammation as reflected by bronchial hyper‐responsiveness to inhaled AMP, independently of both FEV1 or inhaled corticosteroid use. This in turn suggests an association between allergen exposure and AMP responsiveness in asthmatics. Further prospective long‐term evaluation is indicated to assess whether allergen avoidance strategies can modify the airway response.
Health visitors’ understandings of domestic violence
Authors: Peckover Sue
Published: October 2003

Background. Feminist work has made visible the extent and nature of domestic violence and the problems women face in having their experiences recognized by health and welfare professionals. Research has demonstrated that many health care professionals, including nurses, midwives and health visitors have little working knowledge about this issue. This impacts on their ability to recognize and respond to domestic violence within their practice.

Aim. This paper is based upon a study of British health visitors, which explored their practice in relation to domestic violence. Drawing upon empirical data from interviews with health visitors, it explores their understandings of the extent and nature of domestic violence in the context of their work.

Methods. Semi‐structured interviews were undertaken with 24 health visitors selected by convenience and purposive sampling. Data collection took place during 1997–1998. The research draws on the theoretical perspectives of feminist poststructuralism.

Findings. The findings demonstrate considerable differences between health visitors in their understandings of the extent of domestic violence in their caseloads and their recognition of different types of abuse experienced by women. There were also differences between participants in their willingness to name situations other than physical violence as abusive, as well as the extent to which they recognized domestic violence within different social groups.

Conclusions. A feminist perspective provides critical insight into the professional knowledge base in relation to domestic violence, demonstrating the need for health visitors to develop their understandings further in order to respond appropriately to women and children experiencing domestic violence. This is discussed in the context of ongoing struggles for professional identity within an ever‐changing arena of health and welfare provision.