Tramadol hydrochloride 75 mg/dexketoprofen 25 mg oral fixed-dose combination in moderate-to-severe acute pain: sustained analgesic effect over a 56-h period in the postoperative setting.

Multimodal analgesia constitutes a common strategy in pain management. A tramadol hydrochloride 75 mg/dexketoprofen 25 mg oral fixed combination (TRAM/DKP 75 mg/25 mg) has been recently registered and released in Europe for the treatment of moderate-to-severe acute pain. This paper provides additional analyses on the results of two phase III clinical trials (DEX-TRA-04 and DEX-TRA-05) on postoperative pain to document its sustained effect. The analysis was applied to a modified intention-to-treat population (mITT, n = 933) of patients undergoing active treatment from the first dose, to assess the sustained effect of TRAM/DKP 75 mg/25 mg on pain intensity (PI-VAS 0-100) over 56 h from first drug intake. The superior analgesic effect of TRAM/DKP 75 mg/25 mg over 56 h in terms of difference in PI-VAS (mean [SE]) was shown for DEX-TRA-04 (-11.0 [0.55] over dexketoprofen 25 mg and -9.1 [0.55] over tramadol 100 mg, P ≤ 0.0001) and for DEX-TRA-05 (-10.4 [0.51] over dexketoprofen 25 mg and -8.3 [0.51] over tramadol 100 mg, P ≤ 0.0001). The statistical analysis performed on data coming from both studies confirms the superior sustained analgesia of TRAM/DKP 75 mg/25 mg over tramadol 100 mg and dexketoprofen 25 mg. These results are consistent with the previously published data obtained on the ITT population and strongly support the role of this oral fixed-dose combination in the treatment of moderate-to-severe acute pain.

The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS.

BACKGROUND: Tachykinins have been implicated in the pathophysiology of IBS with diarrhoea (IBS-D). Our aim was to study the efficacy and safety of ibodutant, a selective neurokinin-2 (NK2) receptor antagonist, in patients with IBS-D. METHODS: This multinational double-blind, placebo-controlled study recruited 559 patients with IBS-D according to Rome III criteria. After a 2-week treatment-free run-in, patients were randomised to ibodutant 1 mg, 3 mg, 10 mg or placebo once daily for eight consecutive weeks. Responders were those with a combined response of satisfactory relief (weekly binary question yes/no) of overall IBS symptoms and abdominal pain/discomfort on ≥75% weeks (primary end point). Secondary end points included abdominal pain and stool pattern. Data were also analysed according to US Food and Drug Administration (FDA)-approved interim end points (improvement of pain and stool consistency). Safety was assessed by monitoring adverse events and laboratory tests. Prespecified statistical analysis involved the whole group as well as gender subgroups. RESULTS: Demographics and baseline characteristics were comparable for all treatment arms. In the overall population, responsiveness tended to increase with escalating ibodutant doses. In the prespecified analysis by gender, ibodutant 10 mg demonstrated significant superiority over placebo in females (p=0.003), while no significant effect occurred in males. This was confirmed for secondary end points and for the responder analysis according to FDA-approved end points. The tolerability and safety of ibodutant was excellent at all doses. CONCLUSIONS: Ibodutant showed dose-dependent efficacy response in IBS-D, reaching statistical significance at the 10 mg dose in female patients. The safety and tolerability profile of ibodutant was similar to placebo. TRIAL REGISTRATION NUMBER: NCT01303224.

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).

FLORENCE: a randomized, double-blind, phase III pivotal study of febuxostat versus allopurinol for the prevention of tumor lysis syndrome (TLS) in patients with hematologic malignancies at intermediate to high TLS risk.

BACKGROUND: Serum uric acid (sUA) control is of key relevance in tumor lysis syndrome (TLS) prevention as it correlates with both TLS and renal event risk. We sought to determine whether febuxostat fixed dose achieves a better sUA control than allopurinol while preserving renal function in TLS prevention. PATIENTS AND METHODS: Patients with hematologic malignancies at intermediate to high TLS risk grade were randomized to receive febuxostat or allopurinol, starting 2 days before induction chemotherapy, for 7-9 days. Study treatment was blinded, whereas daily dose (low/standard/high containing allopurinol 200/300/600 mg, respectively, or fixed febuxostat 120 mg) depended on the investigator's choice. The co-primary end points, sUA area under curve (AUC sUA1-8) and serum creatinine change, were assessed from baseline to day 8 and analyzed through analysis of covariance with two-sided overall significance level of 5%. Secondary end points included treatment responder rate, laboratory and clinical TLS incidence and safety. RESULTS: A total of 346 patients (82.1% intermediate TLS risk; 82.7% assigned to standard dose) were randomized. Mean AUC sUA1-8 was 514.0 ± 225.71 versus 708.0 ± 234.42 mgxh/dl (P < 0.0001) in favor of febuxostat. Mean serum creatinine change was -0.83 ± 26.98% and -4.92 ± 16.70% for febuxostat and allopurinol, respectively (P = 0.0903). No differences among secondary efficacy end points were detected. Drug-related adverse events occurred in 6.4% of patients in both arms. CONCLUSION: In the largest adult trial carried out in TLS prevention, febuxostat achieved a significant superior sUA control with one fixed dose in comparison to allopurinol with comparable renal function preservation and safety profile. CLINICAL TRIAL REGISTRATION: NCT01724528.

Tachykinin receptors and gastrointestinal motility: focus on humans.

Peptides of the tachykinin (TK) family were first discovered in the gastrointestinal tissue about 75 years ago and supposed to be involved in gastrointestinal (GI) motility. This hypothesis has been repeatedly proven, although the role of TKs on motility is modulatory rather than pivotal. Furthermore, beyond the well known excitatory role, it has been acknowledged that TKs can also inhibit GI motility. TKs act at 3 receptors termed as TK NK1 (NK1r), NK2 (NK2r), and NK3 (NK3r) receptors. The view gained through intense preclinical research suggested that motor effects induced by the stimulation of NK2r were prominently mediated by a direct action on smooth muscle, those produced by the stimulation of NK1r were due to both muscular and neuronal effects, whereas the motor effects induced by NK3r were exclusively mediated by neuronal effects. Recent functional and anatomical findings in humans are challenging this concept since NK2r have been found in several kinds of myenteric neurons and selective NK2r antagonists can, in particular conditions, produce GI motor effects likely related to a neuronal site of action. Furthermore, the evidence for a myotropic role of NK1r is scarce, and very few studies, if any, have documented a functional role for NK3r. The findings that an acute or a long lasting blockade of NK2r does not alter normal GI functions and that these receptors can modulate visceral sensitivity are good starting points for testing this class of drugs in GI diseases characterised by altered GI motility.

Clinical pharmacokinetics of parenteral dexketoprofen trometamol in healthy subjects.

Dexketoprofen trometamol, a highly water-soluble salt of the active enantiomer of rac-ketoprofen, is a nonsteroidal antiinflammatory drug used for pain relief. Two studies were conducted to determine the pharmacokinetics of the drug in healthy subjects following single intravenous (i.v.) and intramuscular (i.m.) doses of dexketoprofen. In the first study, 6 male and 6 female volunteers received 50 mg dexketoprofen (74 mg dexketoprofen trometamol) by i.v. bolus. In the second one, another 6 male and 6 female subjects received 25 mg and 50 mg of dexketoprofen by the i.m. route. Dexketoprofen plasma concentrations were determined by reverse-phase high-performance liquid chromatography (HPLC). No serious adverse events were observed and all volunteers completed the study. The main pharmacokinetic parameters were determined by a noncompartmental approach. Following the i.v. bolus, mean (+/- SEM) area under the curve AUC0-x and clearance (CL) were 9005 +/- 422 ng.h/ml and 0.089 +/- 0.004 l/h/kg. Volumes of distribution Vi and Vss averaged 0.060 +/- 0.006 l/kg and 0.104 +/- 0.003 l/kg. Mean elimination half-life (t1/2e) and MRT were 1.05 +/- 0.04 h and 1.18 +/- 0.05 h. Following single i.m. 25 mg and 50 mg dexketoprofen, a rapid absorption was observed, with tmax values ranging from 0.17 h to 0.75 h. The corresponding Cmax averaged 1851 +/- 182 ng/ml and 3813 +/- 169 ng/ml, and mean AUC0-x were 3033 +/- 193 ng.h/ml and 5878 +/- 228 ng.h/ml, respectively. No significant differences by gender were obtained following both parenteral routes. A dose proportionality in Cmax and AUC0-x was observed. Dexketoprofen pharmacokinetics following i.v. and i.m. routes, together with the availability of a single 2 ml formulation, allows for a potential advantageous rapid switch to the oral formulation when clinically possible.

Single and repeated dose pharmacokinetics of dexketoprofen trometamol in young and elderly subjects.

Dexketoprofen trometamol, a high water-soluble salt of the active enantiomer of rac-ketoprofen, is a nonsteroidal antiinflammatory drug (NSAID) widely used for pain relief. This study was conducted to determine the pharmacokinetics of this analgesic agent in elderly subjects and to compare them with young volunteers following single and repeated oral doses. Twelve healthy young and 12 elderly subjects received 25 mg oral dexketo- profen (equivalent to 37 mg of its tromethamine salt) as a single dose (day 1) and 3-day repeated doses (1 dose every 8 h for a total of 10 doses). Serial concentrations of dexketoprofen were determined in plasma and urine by a reverse-phase HPLC/ultraviolet procedure over 24 h on day 1 and after the last 10th repeated t.i.d. dose. Compared to young subjects, elderly subjects showed significant increases in AUC and t1/2,z and decreases in CL/F following single and repeated doses. After single dosing, the corresponding mean +/- SD values were 5106.6 +/- 1873.0 vs. 3605.4 +/- 897.9 ng.h/ml (p = 0.015); 1.59 +/- 0.40 vs. 1.12 +/- 0.20 h (p < 0.001); and 1.11 +/- 0.29 vs. 1.63 +/- 0.36 ml/min/kg (p < 0.001). After the repeated dose, AUC, t1/2,z and CL/F averaged 5067.8 +/- 1373.4 vs. 3194.4 +/- 694.3 ng.h/ml (p < 0.001); 1.65 +/- 0.44 vs. 1.11 +/- 0.29 h (p < 0.005); and 1.12 +/- 0.23 vs. 1.87 +/- 0.42 ml/min/kg (p < 0.001). Median tmax was 0.5 h. Cumulative excretions in urine up to 24 h of unbound, conjugated and total dexketoprofen were similar among the groups. These results suggest that dexketoprofen elimination is reduced in the elderly. Although no drug accumulation in plasma was observed after single and repeated dosing, the renal function decline in elderly patients calls for a cautious dose-adjustment in this population.

Pharmacokinetics of dexketoprofen trometamol in subjects with mild and moderate chronic renal insufficiency.

The influence of mild to moderate chronic renal insufficiency on the pharmacokinetics of dexketoprofen trometamol was evaluated. Dexketoprofen was administered to volunteers with mild (n = 8) or moderate (n = 8) renal impairment and to healthy subjects (n = 8), as a single 12.5 mg oral dose (equivalent to 18.5 mg of the tromethamine salt). All subjects completed the study and no serious adverse events were recorded. Mild and moderate renal insufficiency increased Cmax by approximately 22% and 37%, respectively, as related to normal subjects (p < 0.05 for moderate renal dysfunction). No statistically significant differences between groups were obtained for tmax, AUC, CL/F, renal CL and V/F. The cumulative urinary excretion of unchanged dexketoprofen, assessed up to 24 hours postdose, was similar in all groups (median values of 7.0%, 8.1% and 9.7% of the administered dose). On the contrary, cumulative urinary excretions of conjugated dexketoprofen decreased in subjects with mild or moderate renal insufficiency when compared to healthy controls (median and 95% CI for differences: -3.3% (-14.8% to 2.6%) and -7.3% (-22.2% to -0.2%), respectively). Conservatively, a dose adjustment of dexketoprofen in patients with impaired renal function is recommended.

Single and repeated dose pharmacokinetics of dexketoprofen trometamol in patients with impaired liver function.

Dexketoprofen trometamol, a high water-soluble salt of the active enantiomer of rac-ketoprofen, is a nonsteroidal antiinflammatory drug (NSAID) used for pain relief. This study compared the pharmacokinetics of dexketoprofen in patients with impaired liver function and normal subjects following single and repeated oral dosing. Subjects with normal liver function (n = 6) and with Child-Pugh A (n = 7) or Child-Pugh B (n = 5) hepatic impairment scores completed this open-label and parallel study. They received 25 mg dexketoprofen (equivalent to 37 mg of its tromethamine salt) as a single (day 1) and a 3-day repeated dose (1 dose every 8 hours for a total of 10 doses). Dexketoprofen concentrations were determined in plasma and urine by reverse-phase high performance liquid chromatography (HPLC). Model-independent pharmacokinetic parameters were obtained. All subjects completed the study. No serious adverse events were recorded. Following the single dose, mean (+/- SEM) Cmax were 3027.7 +/- 429.3 ng/ml (healthy subjects), 2856.3 +/- 340.3 ng/ml (Child-Pugh A) and 1937.2 +/- 328.0 ng/ml (Child-Pugh B). Median tmax were 0.49 h (0.33-0.68) h, 0.50 h (0.33-0.67) h and 0.67 h (0.33-1.50) h. AUC0-x averaged 3778.0 +/- 439.0 ng.h/ml, 4890.4 +/- 539.1 ng.h/ml and 3985.0 +/- 712.0 ng.h/ml. Mean CL/F were 101.1 +/- 11.3 ml/h/kg, 73.3 +/- 9.9 ml/h/kg and 88.8 +/- 15.5 ml/h/kg and V/F averaged 0.192 +/- 0.018 l/kg, 0.162 +/- 0.006 l/kg and 0.214 +/- 0.044 l/kg. Following the repeated administration, similar results were obtained showing no drug accumulation. As related to the administered dose, median excretions of unchanged and conjugated dexketoprofen in urine were 2.1% and 67.1% in healthy subjects, 2.8% and 60.9% in Child-Pugh A subjects and 4.4% and 47.7% in Child-Pugh B volunteers. A trend towards a reduced urinary excretion of conjugated dexketoprofen in hepatic patients, more evident in the Child-Pugh B than in the Child-Pugh A groups, was observed when compared with healthy volunteers (median and 95% CI for differences: -5.4% [-19.9% to 2.0%] and -19.4% [-45.6% to 0.4%]). Conservatively, a dose adjustment of dexketoprofen trometamol in patients with impaired hepatic function is recommended.

Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours.

The doxorubicin analogue MEN-10755 has been identified as a compound with promising antitumour activity based on structure-activity studies of a new series of anthracycline disaccharides. The high antitumour activity of MEN-10755 in human tumour xenografts, including doxorubicin-resistant xenografts, and its unique pharmacological and biological properties made this novel disaccharide analogue an interesting candidate for clinical evaluation. Two pharmacokinetic phase I studies with different dosing schedules were performed in adults with solid refractory malignancies. The pharmacokinetics of MEN-10755 were studied after a 15-min i.v. infusion given once every 3 weeks or once every week for 3 weeks followed by 1 week rest. Plasma and urine levels of MEN-10755 were measured by HPLC with fluorescent detection. It was possible to combine the pharmacokinetic results of the two studies because there was no accumulation of MEN-10755 before the next infusion of MEN-10755 in the weekly study with 1 week rest. The administered dose levels on day 1 in this study were all in the lower range from the 3-weekly study. The postinfusion plasma kinetics of MEN-10755 were best described by a triexponential model. The plasma peak levels (Cmax) of MEN-10755 showed a linear relationship with the administered dose. Peak plasma MEN-10755 levels ranged between 474 and 21,587 microg/l. The mean elimination half-life (T(1/2gamma)) was 20.7+/-9.0 h. The AUC(0-infinity) was proportional to the administered dose. The mean plasma clearance of MEN-10755 was 6.0+/-2.2 l/h per m2 with a mean volume of distribution (Vss) of 95.6+/-43.4 l/m2. The mean renal excretion of unchanged drug within 24 h was 4.3+/-1.8%. Compared to epirubicin and doxorubicin, the pharmacokinetics of MEN-10755 were characterized by an approximately twofold shorter terminal half-life, a much lower total plasma clearance and a much smaller volume of distribution.

Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers.

The oxidative modification of low density lipoprotein is of importance in atherogenesis. Antioxidant supplementation has been shown, in published work, to increase low density lipoprotein resistance to oxidation in both healthy subjects and diabetic subjects; in animal studies a contemporary reduction in atherogenesis has been demonstrated. Troglitazone is a novel oral antidiabetic drug which has similarities in structure with vitamin E. The present study assessed the effect of troglitazone 400 mg twice daily for 2 weeks on the resistance of low density lipoprotein to oxidation in healthy male subjects. Ten subjects received troglitazone and ten received placebo in a randomised, placebo-controlled, parallel-group design. The lag phase (a measure of the resistance of low density lipoprotein to oxidation) was determined by measurement of fluorescence development during copper-catalysed oxidative modification of low density lipoprotein. The lag phase was increased by 27 % (p < 0.001) at week 1 and by 24% (p < 0.001) at week 2 in the troglitazone treated group compared with the placebo group. A number of variables known to influence the resistance of low density lipoprotein to oxidation were measured. They included macronutrient consumption, plasma and lipoprotein lipid profile, alpha-tocopherol, beta-carotene levels in low density lipoprotein, low density lipoprotein particle size, mono and polyunsaturated fatty acid content of low density lipoprotein and pre-formed low density lipoprotein hydroperoxide levels in low density lipoprotein. Troglitazone was associated with a significant reduction in the amount of pre-formed low density lipoprotein lipid hydroperoxides. At weeks 1 and 2, the low density lipoprotein hydroperoxide content was 17% (p < 0.05) and 18% (p < 0.05) lower in the troglitazone group compared to placebo, respectively. In summary the increase in lag phase duration in the troglitazone group appeared to be due to the compound's activity as an antioxidant and to its ability to reduce the amount of preformed low density lipoprotein lipid hydroperoxides. This antioxidant activity could provide considerable benefit to diabetic patients where atherosclerosis accounts for the majority of total mortality.