Boehringer Ingelheim (Italy)

OBJECTIVE: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906. METHODS: BI 456906 was characterized using cell-based in vitro assays to determine functional agonism. In vivo pharmacological studies were performed using acute and subchronic dosing regimens to demonstrate target engagement for the GCGR and GLP-1R, and weight lowering efficacy. RESULTS: BI 456906 is a potent, acylated peptide containing a C18 fatty acid as a half-life extending principle to support once-weekly dosing in humans. Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide. BI 456906's superior efficacy is the consequence of increased energy expenditure and reduced food intake. Engagement of both receptors in vivo was demonstrated via glucose tolerance, food intake, and gastric emptying tests for the GLP-1R, and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (amino acids, fibroblast growth factor-21) for the GCGR. The dual activity of BI 456906 at the GLP-1R and GCGR was supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay. CONCLUSIONS: BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake.

Multinuclear platinum compounds were rationally designed to bind to DNA in a different manner from that of cisplatin and its mononuclear analogues. A triplatinum compound of the series (BBR 3464) was selected for preclinical development, since, in spite of its charged nature, it was very potent as cytotoxic agent and effective against cisplatin-resistant tumour cells. Anti-tumour efficacy studies were performed in a panel of human tumour xenografts refractory or poorly responsive to cisplatin. The novel platinum compound exhibited efficacy in all tested tumours and an impressive efficacy (including complete tumour regressions) was displayed in two lung carcinoma models, CaLu-3 and POCS. Surprisingly, BBR 3464 showed a superior activity against p53-mutant tumours as compared to those carrying the wild-type gene. The involvement of p53 in tumour response was investigated in an osteosarcoma cell line, SAOS, which is null for p53 and is highly sensitive to BBR 3464, and in the same cells following introduction of the wild-type p53 gene. Thus the pattern of cellular response was investigated in a panel of human tumour cells with a different p53 gene status. The results showed that the transfer of functional p53 resulted in a marked (tenfold) reduction of cellular chemosensitivity to the multinuclear platinum complex but in a moderate sensitization to cisplatin. In addition, in contrast to cisplatin, the triplatinum complex was very effective as an inducer of apoptosis in a lung carcinoma cell line carrying mutant p53. The peculiar pattern of anti-tumour activity of the triplatinum complex and its ability to induce p53-independent cell death may have relevant pharmacological implications, since p53, a critical protein involved in DNA repair and induction of apoptosis by conventional DNA-damaging agents, is defective in several human tumours. We suggest that the peculiar DNA binding properties of the triplatinum complex may contribute to the striking profile of anti-tumour efficacy. Taken together, the available information supports that anti-tumour activity of the novel compound is mediated by a mechanism different from that of conventional platinum complexes, and compounds of this series could represent a new class of promising anti-tumour agents.

The serotonin (5-HT) releaser d-fenfluramine and its active metabolite d-norfenfluramine, or the 5-HT-uptake inhibitor citalopram, by increasing synaptic 5-HT availability, facilitated in vivo release of acetylcholine (ACh) from dorsal hippocampi of freely moving rats as determined by the microdialysis technique. The effects of d-norfenfluramine (7.5 mg/kg i.p.) and citalopram (10 microM, applied by reverse dialysis) were prevented by a 14-day chemical lesion of the raphe nuclei, suggesting mediation by the 5-HT system in the cholinergic action of the drugs. The increase in extracellular ACh content induced by d-norfenfluramine (5 mg/kg i.p.) was antagonized by the 5-HT3 receptor antagonists tropisetron (0.5 mg/kg i.p.) and DAU 6215 (60 micrograms/kg i.p.), but not by the mixed 5-HT1 and 5-HT2 receptor antagonist metergoline (2 mg/kg s.c.). In accordance with an involvement of the 5-HT3 receptor in the ACh facilitation induced by d-norfenfluramine is the finding that the selective 5-HT3 receptor agonist 2-methylserotonin (250 micrograms i.c.v., or 10 microM applied by reverse dialysis) raised ACh release. The effect of the intracerebroventricular drug was prevented by the 5-HT3 antagonists DAU 6215 (60 micrograms/kg i.p.) and ondansetron (60 micrograms/kg s.c.). These antagonists by themselves did not modify the basal ACh release, indicating that 5-HT does not tonically activate the 5-HT3 receptors involved. In conclusion, the overall regulatory control exerted by 5-HT in vivo is to facilitate hippocampal ACh release. This is mediated by 5-HT3 receptors probably located in the dorsal hippocampi.

We present results from the first phase III trial of once-daily tiotropium add-on to inhaled corticosteroids (ICS) plus one or more controller therapies in adolescents with severe symptomatic asthma. In this double-blind, parallel-group trial ( NCT01277523 ), 392 patients aged 12–17 years were randomised to receive once-daily tiotropium 5 µg or 2.5 µg, or placebo, as an add-on to ICS plus other controller therapies over 12 weeks. The primary and key secondary end-points were change from baseline (response) in peak forced expiratory volume in 1 s (FEV 1 ) within 3 h post-dosing (FEV 1(0–3h) ) and trough FEV 1 , respectively, after 12 weeks of treatment. Tiotropium 5 µg provided numerical improvements in peak FEV 1(0–3h) response, compared with placebo (90 mL; p=0.104), and significant improvements were observed with tiotropium 2.5 µg (111 mL; p=0.046). Numerical improvements in trough FEV 1 response and asthma control were observed with both tiotropium doses, compared with placebo. The safety and tolerability of tiotropium were comparable with those of placebo. Once-daily tiotropium Respimat add-on to ICS plus one or more controller therapies in adolescents with severe symptomatic asthma was well tolerated. The primary end-point of efficacy was not met, although positive trends for improvements in lung function and asthma control were observed.

In human isolated detrusor strips, submaximal contractile responses evoked by electrical stimulation were resistant to hexamethonium (30 microM) and abolished by tetrodotoxin (0.6 microM) and hyoscine (1 microM), indicating the activation of postganglionic cholinergic nerves. In methysergide (1 microM) and ondansetron (3 microM) pretreated tissues, 5-hydroxytryptamine (5-HT) (0.3 nM-1 microM) caused a concentration-dependent increase in the amplitude of contractions (pEC50 = 8.1), which was antagonized by the selective 5-HT4 receptor antagonist GR 113808 (3, 10 and 30 nM) in a competitive manner. Schild analysis yielded a pA2 estimate of 8.9, a value comparable to that reported for GR 113808 in other animal and human peripheral tissues (8.8-9.7). Our findings indicate that neuromuscular cholinergic transmission in human isolated detrusor muscle is facilitated by neural 5-HT receptors belonging to the 5-HT4 subtype. The human urinary bladder can thus be regarded as an additional site in which 5-HT4 receptors are distributed.

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.

Parenteral glutathione has therapeutic potential for targeted delivery of cysteine equivalents. Thus, high doses of reduced glutathione (GSH) protect from the nephrotoxic and urotoxic effects of cisplatinum and oxazaphosphorines. In order to elucidate the underlying mechanisms the kinetics and the effect of glutathione on plasma and urine sulphydryls were studied in 10 healthy volunteers. Following the intravenous infusion of 2 g m-2 of glutathione the concentration of total glutathione in plasma increased from 17.5 +/- 13.4 mumol l-1 (mean +/- SD) to 823 +/- 326 mumol l-1. The volume of distribution of exogenous glutathione was 176 +/- 107 ml kg-1 and the elimination rate constant was 0.063 +/- 0.027 min-1 corresponding to a half-life of 14.1 +/- 9.2 min. Cysteine in plasma increased from 8.9 +/- 3.5 mumol l-1 to 114 +/- 45 mumol l-1 after the infusion. In spite of the increase in cysteine, the plasma concentration of total cyst(e)ine (i.e. cysteine, cystine, and mixed disulphides) decreased, suggesting an increased uptake of cysteine from plasma into cells. Urinary excretion of glutathione and of cyst(e)ine was increased 300-fold and 10-fold, respectively, in the 90 min following the infusion. The present data suggest that the concentration of sulphydryls in the urinary tract and, more importantly, the intracellular availability of cysteine increase markedly following parenteral glutathione. The high intracellular concentration of cysteine may protect against cisplatinum and oxazaphosphorine toxicity either directly or indirectly by supporting the synthesis of glutathione.

Acute intravenous toxicity of some solvents, i.e. dimethyl sulfoxide (DMSO), polyethylene glycol 400 (PEG 400), dimethylformamide (DMF), absolute ethanol (EtOH) and benzyl alcohol (BeOH), was determined in three inbred (CD2F1, B6D2F1 and C57BL/6N) mouse strains used in many preclinical tests, mainly in oncology and toxicology. Haemolytic and precipitation potential tests in vitro were performed to assess the blood compatibility of the investigated solvents and its relationship with the observed symptoms. The single tested solvents did not show any major differences in acute toxicity in the three tested strains with the exclusion of DMSO (less toxic in CD2F1) and BeOH and EtOH (less toxic in B6D2F1). The tested dose ranges in the three strains (in ml/kg) were 1.0-5.66 for DMSO, 2.0-8.0 for PEG 400, 1.0-4.0 for DMF, 0.75-4.24 for EtOH, 0.025-0.4 for BeOH. The lowest tested dose was a safe dose and the highest one was the dose causing mortality in no more than half the animals in each group. The in vitro results suggest avoiding the use of BeOH (which also is more toxic than the other solvents in the in vivo test) and DMSO and using PEG400, EtOH and DMF even though the latter induced a body weight decrease in the B6D2F1 mouse strain. As a general conclusion, dilution of these solvents in water is suggested to ameliorate their blood compatibility and the use of doses not higher than the lowest dose tested in this study is recommended.

Meloxicam is a new non-steroidal anti-inflammatory drug (NSAID) which preferentially inhibits cyclooxygenase-2 (COX-2) over cyclooxygenase-1 (COX-1). Gastrointestinal (GI) tolerability of meloxicam 7.5 and 15 mg vs piroxicam 20 mg was evaluated in a 4-week, double-blind, parallel group, placebo-controlled study in 51 healthy male volunteers, using a combination of oesphago-gastro-duodenal endoscopy, faecal blood loss measurement and symptom evaluation. Analysis of covariance found no significant difference in faecal blood loss between the groups. However, significantly higher bleeding was found with piroxicam 20 mg compared with placebo using a Student's t-test on the weighted means. Endoscopy score were significantly higher with piroxicam than with meloxicam 7.5 mg or placebo (P < 0.01). A significant difference from baseline was observed in the meloxicam 15 mg and piroxicam groups (P < 0.05), but not in the meloxicam 7.5 mg and placebo groups. Six piroxicam-treated volunteers were withdrawn following a poor endoscopic score, but no such withdrawals occurred in the meloxicam and placebo groups (P < 0.01). Meloxicam 7.5 mg caused less GI damage compared with piroxicam 20 when administered to healthy young volunteers for 28 days; a possible dose dependency effect in GI tolerability was also suggested for meloxicam 7.5 and 15 mg, in relation to endoscopic findings.

Because of the nitrogen functionality, the azido group plays an important role in the synthesis of amines, and numerous reduction methods of azides to primary amines are reported. Recent reports have highlighted the capability of NaI as a useful reagent for this transformation when it is used in combination with a Lewis acid promoter. However, these methods often suffer from harsh reaction conditions; for this reason, the development of a simple and efficient protocol using NaI in presence of inexpensive and readily available cerium salts Lewis acids would extend the scope of this organic transformation. In continuation of our interest on the use of the CeCl3.7H2O/NaI system, in this paper we report how azides undergo reduction by NaI in the presence of CeCl3.7H2O in refluxing acetonitrile under neutral conditions to produce the corresponding primary amines. The rate and yield of the reaction are considerably improved by employing this microwave-assisted procedure, and this may be of value for the preparation of densely functionalized molecules having biological and pharmaceutical activities.

Abstract: Naturally occurring quinones which structurally consist of an anthracene-9,10-dione chromophore are important antitumor agents. The anthracycline antibiotics, in particular, doxorubicin, are major chemothera­ peutic agents. The pluramycins and the ene-diynes antibiotics also show pro­ i mise as antitumor drugs. The synthetic anthracene-9,10-diones such as mitoxantrone are potent antitumor agents. Analogues related to mitoxantrone have been synthesized and biologically evaluated. Aza and diaza bioisosteres related to the anthracene-9,10-diones have been prepared and evaluated and several of these chemotypes show promise for development as anticancer agents. This review will discuss the discovery of cytotoxic anthracene-9,10-diones and the synthesis and antitumor properties of the related aza and diaza bioisosteres.

The effectiveness of bromhexine in the treatment of patients with bronchiectasis, in a stage of clinical exacerbation, was assessed in a double-blind, placebo-controlled trial involving 88 in-patients. Bronchiectasis was diagnosed by bronchography and/or CT scan. Bromhexine or matched placebo was administered as 30-mg capsules three times daily per os. Ceftazidine, 1 g i.m., was given to all patients once a day for the first week only. Bromhexine seemed to improve the clinical picture, with significantly positive trends for expectoration, quantity of sputum and auscultatory findings. It also increased the FEV1 and was well-tolerated. Both patients and investigators judged it efficacious.

In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies.

1. In isolated detrusor strips from the guinea-pig urinary bladder, contractile responses to electrical field stimulation were mostly mediated by neurally released acetylcholine (ACh) and adenosine 5'-triphosphate (ATP). 2. 5-Hydroxytryptamine (5-HT) produced a concentration-dependent increase in the amplitude of stimulated detrusor strip contractions. The 5-HT concentration-response curve showed a biphasic profile: the high potency phase was obtained at sub-micromolar concentrations (10-300 nM), while the low potency phase in the range 1-30 microM. The maximum response of the first phase was 30% of the total 5-HT response. 3. Like 5-HT, the 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT: 0.3-100 microM), the 5-HT2 receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI: 30 nM-3 microM) and the 5-HT4 receptor agonist, 5-methoxytryptamine (5-MeOT: 0.1-30 microM) potentiated, though with lower potency, detrusor contractions. The resulting concentration-response curves were monophasic in nature. 2-Methyl-5-HT had a maximum effect comparable to that of 5-HT. By contrast, the maximal effects of DOI and 5-MeOT were only 20% and 30% of that elicited by 30 microM 5-HT, respectively. 4. The 5-HT3 receptor antagonist, granisetron (0.3 microM) had no effect on the high potency phase, but caused a rightward parallel shift of the low potency phase of the 5-HT curve (pKB = 7.3). Granisetron(0.3 microM) antagonized with comparable affinity (pKB = 7.1) 5-HT-induced responses after pharmacological isolation of 5-HT3 receptors with the 5-HT1/5-HT2 receptor antagonist, methiothepin (0.3 microM) and the 5-HT4 receptor antagonist, GR 125487 (30 nM). Granisetron (0.1, 0.3 and 1 microM) competitively antagonized the potentiating effect of 2-methyl-5-HT with an estimated pA2 of 7.3.5. Methiothepin (0.3 microM) and the 5-HT2A receptor antagonist, ketanserin (0.3 microM) produced a slight inhibition of the first phase of the 5-HT curve. In the presence of ketanserin, an equimolar concentration of methiothepin was ineffective in further reducing the effect of 5-HT. Similarly, the 5-HT4 receptor antagonist, GR 125487 (30 nM) slightly inhibited the first phase of the 5-HT curve. Conversely, this phase was suppressed when detrusor strips were coincubated with ketanserin (or methiothepin) and GR125487.6. In a separate set of experiments, the interactions of 5-HT with either the purinergic or cholinergic components of excitatory neuromuscular transmission were investigated. In the presence of hyoscine(1 microM), 5-HT was mostly effective at sub-micromolar concentrations, while in the presence of the P2-purinoceptor antagonist, suramin (300 microM), 5-HT-induced potentiation was mainly obtained with micromolar concentrations.7. Thus, in electrically stimulated detrusor strips from guinea-pig, 5-HT potentiated excitatory neuromuscular transmission by activating at least three separate neural 5-HT receptors. These include the 5-HT2A and 5-HT4 receptors, which mediate the 5-HT high potency phase mainly by activation of purinergic transmission. On the other hand, the potentiating effect caused by micromolar concentrations of 5-HT mostly involves cholinergic transmission and is mediated by the 5-HT3 receptors.

The anti-immobility effect of fluoxetine (40 mg kg-1) in the forced swimming test in mice was antagonized by the 5-HT1c/2 antagonist mesulergine (7.5 mg kg-1) and the dopamine D2 antagonist (+/-)-sulpiride (12.5 mg kg-1) but not by the 5-HT2/1C antagonist ritanserine (2 mg kg-1), the 5-HT1A/1B antagonist (-)-propranolol (20 mg kg-1) or the 5-HT3 antagonist DAU 6215 (0.1 mg kg-1). All compounds were administered intraperitoneally (i.p.) 6 min before fluoxetine, given i.p. 30 min before testing. The anti-immobility effect of fluoxetine was also prevented by pretreatment with p-chlorophenylalanine (300 mg kg-1 twice daily for 3 days) which produced an 80% reduction of 5-HT in brain. The results suggest that fluoxetine reduces immobility time in mice forced to swim, by acting indirectly through a mesulergine-sensitive site, probably the 5-HT1C receptor.

Nimesulide, a novel non-steroidal anti-inflammatory drug, was used in cases of abacterial prostato-vesiculitis. Thirty patients with a mean age of 33.7 years (range 18-58) were studied. Nimesulide was administered orally 100 mg b.i.d. for three cycles of 10 d each. Dysuric symptoms, semen analysis, and transrectal ultrasound were examined during the study. The concentration-time curves of nimesulide (NIM) and its metabolite, hydroxynimesulide (OH-NIM) in seminal fluid were also evaluated after single oral administration (100 mg) using an HPLC technique. Following administration of the drug, the Cmax was reached in seminal fluid at the second hour for NIM (with a mean value +/- SD of 0.58 +/- 0.13 micrograms ml-1) and at the fourth hour for OH-NIM (2.98 +/- 0.38 micrograms ml-1). Maximal seminal fluid concentrations compared to blood plasma levels were observed at the fourth hour for both substances (31.73 +/- 2.34% for NIM; 31.87 +/- 8.66% for OH-NIM. Dysuric symptoms were relieved in 20 (66%) patients. A clear amelioration of inflammatory signs were observed at transrectal ultrasound evaluation in 16 (54%) patients. No statistically significant changes of sperm count and motility in the whole sample were observed, while a significant reduction in the number of abnormal forms occurred. From these results, nimesulide appears to be an effective anti-inflammatory drug with a good diffusion into the genital apparatus and low side-effects.

The occurrence of unsaturated systems in natural products combined with the mildness and the wide range of applicability of CeCl(3) promoted methodologies suggest several potential future synthetic applications within the field of total synthesis of biologically active molecules. On this concept, the use of CeCl(3).7H(2)O-NaI system as an efficient heterogeneous promoter has been highlighted in the iodofunctionalization of carbon-carbon triple bonds. The study has shown that this method would be particularly interesting for the stereoselective formation of trisubstituted (Z)- or (E)-iodoalkenes by simply changing the nature of the solvent. The methodology has been successfully applied to the synthesis of (R)-1-[4,4-bis-(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid , named (R)-Tiagabine, which is a potent and selective gamma-aminobutyric acid (GABA) uptake inhibitor with proven anticonvulsant efficacy in humans.

OBJECTIVES: Randomized controlled trials have demonstrated that afatinib is a suitable treatment option for patients with epidermal growth factor receptor mutation-positive (EGFRm +) non-small cell lung cancer (NSCLC). However, such studies often exclude patients treated in routine clinical practice. We report interim results from a Phase 3b, open-label, multicenter, single-arm, exploratory trial, in which afatinib was investigated in a real-world setting. MATERIALS AND METHODS: Patients with EGFRm + tyrosine kinase inhibitor (TKI)-naïve NSCLC received afatinib 40 mg orally, once-daily, until disease progression, or voluntary withdrawal. Primary objective was safety. RESULTS: Overall, 479 patients received afatinib: median age 65 years, 8 % of patients had an ECOG performance status ≥ 2, 17 % had brain metastases, and 13 % had tumors containing uncommon mutations only. All but one patient (99.8 %) had an adverse event (AE). Treatment-related AEs (TRAEs; any/grade ≥ 3) occurred in 97 %/44 % of patients; most common were diarrhea (87 %/16 %) and rash (51 %/11 %). AEs leading to afatinib dose-reduction were reported in 258 patients (54 %), and 37 patients (8 %) discontinued treatment due to a TRAE. Objective response rate was 45.5 %, median duration of response was 14.1 months (95 % CI: 12.2-16.4). Overall median time to symptomatic progression and progression-free survival were 14.9 months (95 % CI: 13.8-17.6) and 13.4 months (95 % CI: 11.8-14.5), respectively, in the overall population and 19.3 months (95 % CI: 15.6-21.8) and 15.9 months (95 % CI: 13.9-19.1) in patients with EGFR exon 19 deletions. CONCLUSIONS: Afatinib administration in routine clinical practice was well tolerated with no new safety signals and demonstrated promising efficacy in patients with EGFRm + NSCLC. TRAEs were generally manageable with tolerability-guided dose reductions. Overall, these data independently support findings from randomized controlled trials of afatinib in EGFRm + NSCLC.

Lilly is developing duloxetine, a 5-HT and norepinephrine uptake inhibitor as a potential treatment for depression and urinary incontinence. In Japan, it is being jointly developed with Shionogi [187401]. Phase III trials for depression and phase II trials for urinary incontinence are underway in Japan [296442,328887]. Lilly expects to file for depression in 2002 and phase III trials for urinary incontinence are planned to start enrollment by the end of 2000 [358429,370526,373870]. Duloxetine has a half-life of 10 to 15 h in humans, and parameters reach a steady-state after 3 days of daily administration. In a 6-week, open-label study duloxetine was safe and well tolerated in 79 clinically depressed patients. Clinical response occurred in 78% of patients, and remission occurred in 60%. Insomnia and nausea occurred with an incidence of 20% [300881]. Duloxetine may offer advantages over existing antidepressants, such as Lilly's fluoxetine, because of faster recovery and fewer side effects [190226]. In June 2000, Morgan Stanley Dean Witter predicted duloxetine would reach the market in 2002 with annual sales in this year of US $50 million, rising to $200 million in 2005 [373870]. In February 1999, Deutsche Bank predicted Lilly's sales at US $200 million in 2002 rising to $400 million in 2003 [316821]. In May 2000, Deutsche Bank had made further predictions, stating that filing for duloxetine is expected in the fourth quarter of 2001, and peak sales are expected to exceed US $500 million. Also in February 1999, Lehman Brothers predicted the first major launch date (US and ex-US) to be 2002, with the year of peak sales to be 2008 [319225]. In August 1999, this prediction changed, and the expected launch date became 2001, with an 80% probability of reaching the market and sales peaking at US $150 million in 2012 [349228].

Cimetropium bromide is a new antimuscarinic compound with strong antispasmodic activity. The aim of this study was to evaluate the effects of oral cimetropium bromide on total gut transit time in patients with irritable bowel syndrome. Forty patients, divided according to their initial total gastrointestinal transit times and presenting symptoms, were treated with cimetropium bromide 50 mg t.d.s. or placebo for 1 month according to a double-blind, parallel group design. Before and after treatment all subjects ingested 24 radio-opaque markers. The total intestinal transit time was determined by evaluating the rate of disappearance of markers from plain X-ray films of the abdomen taken every 24 h for 4 days. Pain and bowel habits were also monitored. Seven patients did not complete the study. Cimetropium bromide significantly (P less than 0.01) shortened the whole gut transit time in patients with prolonged transit time (80.8 +/- 4.0 h before vs 60.8 +/- 6.7 h after treatment) and improved the global clinical condition significantly compared with placebo (P = 0.029). In patients with a short total intestinal transit time, cimetropium bromide had no effect on whole gut transit time and did not significantly improve symptoms. The results of this study indicate that oral cimetropium bromide is effective both objectively and subjectively in a subgroup of irritable bowel syndrome patients with constipation.