Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors.

Background: Autotaxin-lysophosphatidic acid (ATX-LPA) signaling has a predominant role in immunological and fibrotic processes, including cancer. Several ATX inhibitors and LPA receptor antagonists have been clinically evaluated, but none in patients with solid tumors. Many cancers are burdened with a high degree of fibrosis and an immune desert phenotype (so-called 'cold' tumors). In these cold tumors, the fibrotic stroma provides an intrinsic cancer-supporting mechanism. Furthermore, the stroma prevents penetration and limits the effectiveness of existing therapies. IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Materials and methods: In vitro and in vivo pharmacology studies have been carried out to elucidate the pharmaceutical properties and mechanism of action of IOA-289. A phase I clinical study in healthy volunteers was carried out to determine the pharmacokinetics and pharmacodynamics of IOA-289 following a single oral dose. Results: In vitro and in vivo studies showed that IOA-289 is a potent inhibitor of ATX and, as a monotherapy, is able to slow progression of lung fibrosis and tumor growth in mouse models. In a clinical study, IOA-289 showed a dose-dependent increase in plasma exposure levels and a corresponding decrease in circulating LPA. Conclusions: Our data show that IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Our data support the further development of IOA-289 as a novel therapeutic approach for the treatment of cancer, particularly those with a high fibrotic and immunologically cold phenotype.

Dexketoprofen/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain.

BACKGROUND: Combination analgesics are effective in acute pain, and a theoretical framework predicts efficacy for combinations. The combination of dexketoprofen and tramadol is untested, but predicted to be highly effective. METHODS: This was a randomised, double-blind, double-dummy, parallel-group, placebo-controlled, single-dose trial in patients with moderate or severe pain following third molar extraction. There were ten treatment arms, including dexketoprofen trometamol (12.5 mg and 25 mg) and tramadol hydrochloride (37.5 mg and 75 mg), given as four different fixed combinations and single components, with ibuprofen 400 mg as active control as well as a placebo control. The study objective was to evaluate the superior analgesic efficacy and safety of each combination and each single agent versus placebo. The primary outcome was the proportion of patients with at least 50 % max TOTPAR over six hours. RESULTS: 606 patients were randomised and provided at least one post-dose assessment. All combinations were significantly better than placebo. The highest percentage of responders (72%) was achieved in the dexketoprofen trometamol 25 mg plus tramadol hydrochloride 75 mg group (NNT 1.6, 95% confidence interval 1.3 to 2.1). Addition of tramadol to dexketoprofen resulted in greater peak pain relief and greater pain relief over the longer term, particularly at times longer than six hours (median duration of 8.1 h). Adverse events were unremarkable. CONCLUSIONS: Dexketoprofen trometamol 25 mg combined with tramadol hydrochloride 75 mg provided good analgesia with rapid onset and long duration in a model of moderate to severe pain. The results of the dose finding study are consistent with pre-trial calculations based on empirical formulae. TRIAL REGISTRATION: EudraCT (2010-022798-32); Clinicaltrials.gov (NCT01307020).

Salmeterol and fluticasone propionate given as a combination. Lack of systemic pharmacodynamic and pharmacokinetic interactions.

OBJECTIVE: To investigate the potential for systemic pharmacodynamic and pharmacokinetic interactions between inhaled salmeterol and fluticasone propionate when repeat doses of the two drugs are given in combination to healthy subjects. METHODS: Twenty-eight healthy subjects received salmeterol 100 microg, salmeterol 100 microg/fluticasone propionate 500 microg and fluticasone propionate 500 microg via a Diskus dry powder inhaler twice daily for 11 days according to a randomised, double-blind, placebo-controlled, crossover design. Subjects in the placebo group also received a single dose of salmeterol 100 microg on the morning of day 10. On day 10, the systemic effects of salmeterol [on pulse rate, blood pressure, corrected QT (QTc) interval and serum potassium and glucose levels] and fluticasone propionate (on 24-h urinary cortisol and morning plasma cortisol levels) were assessed. Maximal number and affinity of lymphocyte beta2-adrenoceptors and beta2-adrenoceptor polymorphism at loci 16 and 27 were also determined. Plasma pharmacokinetics of salmeterol and fluticasone propionate were determined after the morning dose on day 10. Dosing continued on the evening of day 10 and on day 11, and on day 12 the effect of repeat-dose treatment with salmeterol and salmeterol/fluticasone propionate on the systemic effects of cumulative doses of inhaled salbutamol (up to a total dosage of 3,200 microg) was evaluated. RESULTS: All treatments were safe and well tolerated. With the exception of a higher pulse rate after repeat administration of salmeterol [66.2 beats per minute (bpm) versus 63.6 bpm], there were no significant differences between the single-dose and repeat-dose salmeterol groups. The systemic pharmacodynamic effects of inhaled salmeterol were not affected by the co-administration of fluticasone propionate. Eleven days of treatment with salmeterol induced tachyphylaxis to the systemic effects of cumulative doses of salbutamol; however, co-administration of fluticasone propionate did not affect the response to salbutamol. Fluticasone propionate reduced 24-h urinary cortisol excretion (22.4 microg compared with 48.6 microg with placebo), but this was unaffected by the co-administration of salmeterol. Morning plasma cortisol levels were not reduced compared with placebo. There was no significant treatment effect on lymphocyte beta2-adrenoceptors and no correlation of beta2-adrenoceptor polymorphism at loci 16 and 27 with the development of tachyphylaxis. Salmeterol plasma concentrations were measurable only during the first half-hour after dosing. Co-administration of fluticasone propionate did not affect the peak plasma concentration (Cmax) of salmeterol. For fluticasone propionate, there were no statistically significant differences between salmeterol/fluticasone propionate and fluticasone propionate with respect to Cmax, plasma concentration at the end of the dosing interval (Ct), terminal elimination half-life (t1/2) or time to Cmax (tmax). The area under the concentration-time curve within a dosing interval (AUCt) for fluticasone propionate after inhalation of salmeterol/fluticasone propionate was statistically significantly higher (about 8%) than after inhalation of fluticasone propionate alone (P=0.0135). However, the 90% confidence intervals (CIs) for the AUCt and Cmax ratios for the two treatments were within the accepted limits for bioequivalence (1.03, 1.13 and 0.97, 1.12, respectively). CONCLUSION: These results in healthy subjects indicate that there is no systemic pharmacodynamic or pharmacokinetic interaction between inhaled salmeterol and fluticasone propionate when given in combination.

The effects of lacidipine on the steady/state plasma concentrations of simvastatin in healthy subjects.

AIMS: Lacidipine, a long acting 2, 4-dihydropyridine calcium channel antagonist is frequently administered with cholesterol lowering agents, particularly in elderly populations. The effects of lacidipine on the pharmacokinetics of simvastatin were investigated, since they share the CYP3A4 pathway for metabolism. METHODS: The study was an open, randomised, two-way crossover design, with at least 7 days washout. Eighteen healthy subjects received simvastatin, 40 mg once daily, alone and together with lacidipine, 4 mg once daily, for 8 days. The pharmacokinetics of simvastatin were studied on the eighth day. Analysis was made of total simvastatin acid concentrations (naive simvastatin acid plus that derived from alkaline hydrolysis of the lactone). RESULTS: Lacidipine increased the maximum concentration of simvastatin (Cmax) by approximately 70% (P=0.016) and the area under the plasma concentration-time curve AUC(0,24 h) by approximately 35% (P=0.001). The mean Cmax and AUC(0,24 h) of simvastatin (95% confidence interval) when given alone were 8.76 (6.72-11.41) ng ml(-1) and 60.36 (47.15-77.28) ng ml(-1) h. During treatment with lacidipine they were, respectively, 14.89 (10.77-20.58) ng ml(-1) and 80.96 (64.62-101.44) ng ml(-1) h. No significant differences were observed in either time to peak concentration (tmax was 1.0 h for simvastatin alone and 1.5 h for the combination) or in the half-life (t1/2,z was 8.5 h in both cases). The combination was safe and well tolerated. CONCLUSIONS: The observed increased exposure to simvastatin 40 mg following coadministration of lacidipine is unlikely to be of clinical relevance.

Evaluation of the readability of information sheets for healthy volunteers in phase-I trials.

OBJECTIVE: The aim of the present study was to assess whether information sheets/consent forms submitted to the healthy volunteers of the Clinical Pharmacology Unit (C.P.U.) panel at Glaxo-Wellcome (Verona, Italy) could be considered understandable and to verify the readability and comprehensibility of these documents. Since a volunteer bases his/her decision to take part in a study on the information sheet provided, it is of paramount ethical importance to know whether the sheet conveys all relevant information. In addition, a thorough awareness by the volunteer of the reasons and procedures of the study would increase compliance. METHODS: Four indices were used: Flesh-Vacca, Kincaid, Gunning's Fog and Gulpease. All indices rate the degree of difficulty of a text, in the light of the level of schooling of the target population. The documents evaluated were information sheets presented to volunteers. The level of schooling of the population that participated in at least one study was determined: 61.7% of volunteers finished high school and 22.6% had a University degree or diploma; the remaining 15.7% did not finish high school or the datum was not available. RESULTS: The results showed that, when the present study began, all information sheets were "readable" by all volunteers who had at least finished high school. After these preliminary results, some additional linguistic and graphic refinements were adopted in drawing up information sheets. Readability improved to such a degree that all information sheets could be understood by virtually all volunteers. CONCLUSION: A number of suggestions were identified, which are set out in this paper to assist in the preparation of improved information sheets and a recommendation to value the readability of consent sheets before giving them to the volunteers. The suggestions were split into three categories: communications to the volunteer, text format and text organisation.

Direct measurement of the anti-influenza agent zanamivir in the respiratory tract following inhalation.

In a single-center, randomized study, zanamivir (Relenza) concentrations in induced sputum samples and nasal washings of healthy adults following oral inhalation were measured. Concentrations in sputum exceeded the median viral neuraminidase 50% inhibitory concentration at 6, 12, and 24 h, and those in nasal washings did so at 6 and 12 h. There were no zanamivir-related adverse events or laboratory abnormalities.

Enantiomeric disposition of inhaled, intravenous and oral racemic-salbutamol in man--no evidence of enantioselective lung metabolism.

Aims To establish whether enantioselective metabolism of racemic (rac )-salbutamol occurs in the lungs by determining its enantiomeric disposition following inhalation, in the absence and presence of oral charcoal, compared with that following the oral and intravenous routes. Methods Fifteen healthy subjects (eight male) were randomized into an open design, crossover study. Plasma and urine salbutamol enantiomer concentrations were measured for 24 h following oral (2 mg) with or without oral charcoal (to block oral absorption), inhaled (MDI; 1200 microg) with or without oral charcoal and intravenous (500 microg) rac-salbutamol. Systemic exposure (plasma AUC(0,infinity) and urinary excretion (Au24h ) of both enantiomers were calculated, and relative exposure to (R)-salbutamol both in plasma (AUC(R)-/AUC(S)- ) and urine (Au(R)-/Au(S)- ) was derived for each route. Relative exposure after the inhaled with charcoal and oral routes were compared with the intravenous route. Results AUC(R)-/AUC(S)- [geometric mean (95% CI)] was similar following the intravenous [0.32 (0.28, 0.36)] and inhaled with charcoal rates [0.29 (0.24, 0.36); P=0.046], but was far lower following oral dosing [0.05 (0.03, 0.07); P<0.001]. Similar results were found when relative exposure was analysed using Au24h. Conclusions These results show no evidence of significant enantioselective presystemic metabolism in the lungs, whilst confirming it in the gut and systemic circulation, indicating that the (R)- and (S)-enantiomers are present in similar quantities in the airways following inhaled rac-salbutamol.

Evaluation of personality as a component of the healthy condition of volunteers participating in phase I studies.

OBJECTIVE: The present study was conceived in order to recommend use of the Minnesota Multiphasic Personality Inventory for the evaluation of the personality of volunteers participating in Phase I clinical trials. The study was intended to describe personality profiles as objectively as possible, attempting to identify any common traits or tendencies, and to evaluate whether age or cultural background can be associated with significant differences in volunteer personality profiles. SUBJECTS: 358 subjects were evaluated (290 males and 68 females; mean age 30 y, range 18-78 y). Mean values of scales and indices were compared and analysed, both for the sample as a whole and on the basis of its breakdown according to sex, age and education. RESULTS: No psychopathological values were found in terms of sex and education. The mean profile showed common traits of a substantially balanced, self-assured, reliable person, motivated by extremely realistic objectives. CONCLUSION: The Minnesota Multiphasic Personality Inventory seems to be a useful tool for screening healthy volunteers.