Trabectedin and Eribulin: Where Do They Fit in the Management of Soft Tissue Sarcoma?

OPINION STATEMENT: Trabectedin and eribulin are two agents that have been recently approved for the treatment of specific soft tissue sarcoma subtypes. They have proved to be a much-needed line of additional treatment for patients with these rare tumors, but their activity remains admittedly modest in most cases. Further exploitation of these novel agents is likely to require a more granular understanding of the salient mechanisms of action. For example, if as some studies suggest, eribulin derives its benefit from restructuring of tumor vasculature to improve efficacy of subsequent lines of therapy, then patients may benefit from its use earlier in the treatment pathway. The sequencing of trabectedin with other agents is also worth examining. In a disease like myxoid liposarcoma, consideration should be given to using trabectedin before other salvage regimens like gemcitabine and docetaxel, given its tolerability and excellent efficacy against this sarcoma subtype. Also, to be further investigated is the use of trabectedin in sarcoma subtypes which were excluded from the phase III study, but in which activity has been documented in earlier trials and subsequent reports. Combinations of trabectedin with other agents, particularly doxorubicin, have been explored, but the data to date do not support the routine use of these regimens.

Applications of Higenamine in pharmacology and medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum has been used as local and traditional medicines in many asian regions for the treatment of various diseases such as collapse, syncope, painful joints, oedema, bronchial asthma et al. Higenamine, a plant-based alkaloid, was initially isolated from Aconitum and identified as the active cardiotonic component of Aconitum. It has been tested as a candidate of pharmacologic stress agent in the detection of coronary artery diseases (CADs) and now researchers have just accomplished the phase III clinical studies successfully in China. Besides, a large number of studies have revealed the various pharmacological properties and potentially multi-spectral medical applications of higenamine. However, to date, no comprehensive review on higenamine has been published. AIM OF THE REVIEW: This present paper aims to compile a comprehensive update regarding the biochemistry, pharmacokinetic features, pharmacological activities, clinical and potential clinical uses and toxicities on higenamine with the ultimate objective of providing a guide for future research on this drug. MATERIALS AND METHODS: The selection of relevant data was made through a search using the keyword "higenamine" in "Web of science", "Pubmed", and "China Knowledge Resource Integrated (CNKI)". Information was also acquired from local classic herbal literature, government reports and conference papers. RESULTS: In addition to Aconitum, higenamine also exists in many other plants including Tinospora crispa, Nandina domestica THUNBERG, Gnetum Parvifolium C.Y. Cheng, sarum Heterotropoides,Nelumbo nucifera,N.nucifera. The pharmacokinetic studies conducted in animals and humans showed that higenamine conformed to a two-compartment pharmacokinetic model. Studies over the last four decades on higenamine have revealed its various pharmacological properties such as positive inotropic and chronotropic effect, activating slow channel effect, vascular and tracheal relaxation effect, anti-thrombotic, anti-apoptotic and anti-oxidative effect, anti-inflammatory and immunomodulatory effect. This phytochemical constituent has shown its potential therapeutic effects for diseases like heart failure, disseminated intravascular coagulation (DIC), shock, arthritis, asthma, ischemia/reperfusion (I/R) injuries and erectile dysfunction. CONCLUSIONS: Extensive basic and clinical studies on higenamine showed valuable therapeutic effects on different disorders. However, the underlying mechanisms of higenamine have not been established. Therefore, the safety, tolerability and efficacy of higenamine are as yet, not fully understood. Additionally, some of the studies were small sample-sized and unreliable. To sum up, there is a need for deeper investigation in the mechanisms of higenamine action, as well as well-designed preclinical and clinical trials studies to test the safety and clinical value of the drug.

Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity.

Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF), induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d), three bromo-substituted products of crebanine (2a, 2b, 2c), N-methylcrebanine (2d), and dehydrostephanine (4a) displayed antiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p < 0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p < 0.01), and the number of rats that maintained sinus rhythm for more than 20 min (p < 0.01). Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50 = 59.62 mg/kg, mice), simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.

Potential harmful effects of dietary supplements in sports medicine.

PURPOSE OF REVIEW: The purpose of this article is to collect the most recent data regarding the safety of well-known or emerging dietary supplements used by athletes. RECENT FINDINGS: From January 2014 to April 2016, about 30 articles have been published in the field. New data show that 90% of sports supplements contain trace of estrogenic endocrine disruptors, with 25% of them having a higher estrogenic activity than acceptable. About 50% of the supplements are contaminated by melamine, a source of nonprotein nitrogen. Additional data accumulate toward the safety of nitrate ingestion. In the last 2 years, the safety of emerging supplements such as higenamine, potentially interesting to lose weight, creatine nitrate and guanidinoacetic acid has been evaluated but still needs further investigation. SUMMARY: The consumption of over-the-counter supplements is very popular in athletes. Although most supplements may be considered as safe when taking at the recommended doses, athletes should be aware of the potential risks linked to the consumption of supplements. In addition to the risks linked to overdosage and cross-effects when combining different supplements at the same time, inadvertent or deliberate contamination with stimulants, estrogenic compounds, diuretics or anabolic agents may occur.

A Case of Paraspinal Muscle Rhabdomyolysis in a 22-Year-Old Male After Ingesting a Supplement Containing Higenamine.

Rhabdomyolysis is a painful and potentially life-threatening injury in which muscle breaks down in response to an insult. In this case report, we describe the clinical course of a 22-year-old man who developed paraspinal muscle rhabdomyolysis and possible compartment syndrome in association with strenuous activity and the ingestion of an exercise supplement containing the stimulant higenamine. Although he did not experience any renal damage, he did experience a high level of pain acutely and for the next 4 months. A history of exercise supplement intake should increase the index of suspicion for rhabdomyolysis when a patient presents with moderate to severe muscle pain, even if the muscle group is not in a classic location for rhabdomyolysis.

Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced recurrent or refractory ovarian cancer: a systematic review and economic evaluation.

BACKGROUND: Ovarian cancer is the fifth most common cancer in the UK, and the fourth most common cause of cancer death. Of those people successfully treated with first-line chemotherapy, 55-75% will relapse within 2 years. At this time, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrent, advanced ovarian cancer. OBJECTIVES: To determine the comparative clinical effectiveness and cost-effectiveness of topotecan (Hycamtin(®), GlaxoSmithKline), pegylated liposomal doxorubicin hydrochloride (PLDH; Caelyx(®), Schering-Plough), paclitaxel (Taxol(®), Bristol-Myers Squibb), trabectedin (Yondelis(®), PharmaMar) and gemcitabine (Gemzar(®), Eli Lilly and Company) for the treatment of advanced, recurrent ovarian cancer. DATA SOURCES: Electronic databases (MEDLINE(®), EMBASE, Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluations Database) and trial registries were searched, and company submissions were reviewed. Databases were searched from inception to May 2013. METHODS: A systematic review of the clinical and economic literature was carried out following standard methodological principles. Double-blind, randomised, placebo-controlled trials, evaluating topotecan, PLDH, paclitaxel, trabectedin and gemcitabine, and economic evaluations were included. A network meta-analysis (NMA) was carried out. A de novo economic model was developed. RESULTS: For most outcomes measuring clinical response, two networks were constructed: one evaluating platinum-based regimens and one evaluating non-platinum-based regimens. In people with platinum-sensitive disease, NMA found statistically significant benefits for PLDH plus platinum, and paclitaxel plus platinum for overall survival (OS) compared with platinum monotherapy. PLDH plus platinum significantly prolonged progression-free survival (PFS) compared with paclitaxel plus platinum. Of the non-platinum-based treatments, PLDH monotherapy and trabectedin plus PLDH were found to significantly increase OS, but not PFS, compared with topotecan monotherapy. In people with platinum-resistant/-refractory (PRR) disease, NMA found no statistically significant differences for any treatment compared with alternative regimens in OS and PFS. Economic modelling indicated that, for people with platinum-sensitive disease and receiving platinum-based therapy, the estimated probabilistic incremental cost-effectiveness ratio [ICER; incremental cost per additional quality-adjusted life-year (QALY)] for paclitaxel plus platinum compared with platinum was £24,539. Gemcitabine plus carboplatin was extendedly dominated, and PLDH plus platinum was strictly dominated. For people with platinum-sensitive disease and receiving non-platinum-based therapy, the probabilistic ICERs associated with PLDH compared with paclitaxel, and trabectedin plus PLDH compared with PLDH, were estimated to be £25,931 and £81,353, respectively. Topotecan was strictly dominated. For people with PRR disease, the probabilistic ICER associated with topotecan compared with PLDH was estimated to be £324,188. Paclitaxel was strictly dominated. LIMITATIONS: As platinum- and non-platinum-based treatments were evaluated separately, the comparative clinical effectiveness and cost-effectiveness of these regimens is uncertain in patients with platinum-sensitive disease. CONCLUSIONS: For platinum-sensitive disease, it was not possible to compare the clinical effectiveness and cost-effectiveness of platinum-based therapies with non-platinum-based therapies. For people with platinum-sensitive disease and treated with platinum-based therapies, paclitaxel plus platinum could be considered cost-effective compared with platinum at a threshold of £30,000 per additional QALY. For people with platinum-sensitive disease and treated with non-platinum-based therapies, it is unclear whether PLDH would be considered cost-effective compared with paclitaxel at a threshold of £30,000 per additional QALY; trabectedin plus PLDH is unlikely to be considered cost-effective compared with PLDH. For patients with PRR disease, it is unlikely that topotecan would be considered cost-effective compared with PLDH. Randomised controlled trials comparing platinum with non-platinum-based treatments might help to verify the comparative effectiveness of these regimens. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003555. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Acupuncture versus solifenacin for treatment of overactive bladder and its correlation with urine nerve growth factor levels: a randomized, placebo-controlled clinical trial.

OBJECTIVE: To determine whether acupuncture is effective as an overactive bladder (OAB) treatment compared with solifenacin and placebo, and to investigate its relation with urine nerve growth factor (NGF) levels. PATIENTS AND METHODS: The study was conducted with methodological rigor based on the Consolidated Standards of Reporting Trials criteria. 90 female patients with OAB were included and randomly assigned to a solifenacin, acupuncture or placebo group. The medicated group received solifenacin 5 mg/day; the acupuncture and placebo groups were treated twice a week for 4 weeks. Symptom scores, quality of life scores, frequency of micturition and urine NGF levels were used to assess treatment efficiency. RESULTS: The study was completed with 82 patients (n = 30 in the solifenacin group, n = 28 in the acupuncture group and n = 24 in the placebo group). After treatment, comparison of the medical and acupuncture therapy groups with the placebo group showed significant differences between recovery concerning quality of life (p < 0.001 and p < 0.01, respectively) and symptom scores (p < 0.001 and p < 0.001, respectively). The decrease of NGF levels after treatment compared to before treatment was determined in each group (solifenacin, acupuncture, placebo group; p < 0.001, p < 0.001, p = 0.359, respectively). Sufficient symptomatic improvement was not achieved in 8 patients in the acupuncture group. Therefore, comparisons were assessed twice with and without including these patients, and NGF levels in the acupuncture group were higher than at first comparison in which all patients in the acupuncture group were included. CONCLUSIONS: In patients with OAB in whom anticholinergic treatment is contraindicated, acupuncture may be considered another treatment option.

Cost-effectiveness analysis of solifenacin versus oxybutynin immediate-release in the treatment of patients with overactive bladder in the United Kingdom.

OBJECTIVE: To carry out a cost-utility analysis comparing initial treatment with solifenacin 5 mg/day vs oxybutynin immediate-release (IR) 15 mg/day for the treatment of patients with overactive bladder (OAB) from the perspective of the U.K. National Health Service (NHS). METHODS: A Markov model with six health states was developed to follow a cohort of OAB patients treated with either solifenacin or oxybutynin during a 1-year period. Costs and utilities were accumulated as patients transited through the health states in the model and a drop-out state. Some of the solifenacin patients were titrated from 5 mg to 10 mg/day at 8 weeks. A proportion of drop-out patients were assumed to continue treatment with tolterodine ER. Utility values were obtained from a Swedish study and pad use was based on a multinational clinical trial. Adherence rates for individual treatments were derived from a U.K. database study. For pad use and utility values, the drop-out state was split between those patients who were no longer receiving treatment and those on second-line therapy. Patients on second-line therapy who drop-out were referred for a specialist visit. Results were expressed in terms of incremental cost-utility ratios. RESULTS: Total annual costs for solifenacin and oxybutynin were £504.30 and £364.19, respectively. First-line drug use represents 49% and 4% of costs and pad use represent 23% and 40% of costs for solifenacin and oxybutynin, respectively. Differences between cumulative utilities were small but were greater for solifenacin (0.7020 vs. 0.6907). The baseline incremental cost-effectiveness ratio was £12,309/QALY. CONCLUSION: Under the baseline assumptions, solifenacin would appear to be cost-effective with an incremental cost-utility of less than £20,000/QALY. However, small differences in utility between the alternatives and the large number of drop-outs means that the results are sensitive to small adjustments in the values of utilities assigned to the drop-out state.

Solifenacin succinate versus percutaneous tibial nerve stimulation in women with overactive bladder syndrome: results of a randomized controlled crossover study.

AIMS: This study compared the effectiveness of solifenacin succinate (SS) versus percutaneous tibial nerve stimulation (PTNS) in women with overactive bladder syndrome (OABS). METHODS: A randomized controlled crossover study of 40 women with OABS was performed. Patients were randomized into two groups. In group A, patients received SS and then PTNS. In group B, patients underwent PTNS and then SS. Voiding diaries, quality of life surveys and patient perception of intensity of urgency questionnaire were performed before and after each treatment. The global impression of improvement questionnaire was performed at the end of the study. RESULTS: A reduction in the number of daily micturitions, episodes of nocturia and urge incontinence were found with both SS and PTNS in all groups, but PTNS showed a greater effectiveness than SS. There was an increase in voided volume in all groups with both SS and PTNS, but patients treated with PTNS had a greater increase. PTNS showed greater effectiveness in patient perception of urgency and quality of life. CONCLUSION: This study demonstrates the effectiveness of SS and PTNS In women with overactive bladder symptoms. However, greater improvements were found with PTNS.

A novel series of (S)-2,7-substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: peroxisome proliferator-activated receptor α/γ dual agonists with protein-tyrosine phosphatase 1B inhibitory activity.

Novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-7-(2-{2-[(E)-2-cyclopentylvinyl]-5-methyloxazol-4-yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14c) was identified as a peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist. The transactivation activity of 14c was comparable to that of rosiglitazone in human PPARγ (EC50=0.14 µM) and was much higher than in human PPARα (EC50=0.20 µM). In addition, 14c, but not rosiglitazone, showed human protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activity (IC50=1.85 µM). 14c showed about 10-fold stronger hypoglycemic and hypotriglyceridemic effects than rosiglitazone by repeated application for 14 d in male KK-Ay mice. Furthermore, 14c, but not rosiglitazone, increased hepatic peroxisome acyl CoA oxidase activity at 30 mg/kg/d for 7 d in male Syrian hamsters, probably due to its PPARα agonist activity. 14c did not affect plasma volume at 100 mg/kg/d for 14 d in male ICR mice, while rosiglitazone significantly increased it. In conclusion, 14c is a promising candidate for an efficacious and safe anti-diabetic drug with triple actions as a PPARα/γ dual agonist with PTP-1B inhibitory activity.

Wide-spectrum characterization of trabectedin: biology, clinical activity and future perspectives.

Ecteinascidin-743 (trabectedin, Yondelis((R)); PharmaMar, Madrid, Spain), a 25-year-old antineoplastic alkylating agent, has recently shown unexpected and interesting mechanisms of action. Trabectedin causes perturbation in the transcription of inducible genes (e.g., the multidrug resistance gene MDR1) and interaction with DNA repair mechanisms (e.g., the nucleotide excision repair pathway) owing to drug-related DNA double strand breaks and adduct formation. Trabectedin was the first antineoplastic agent from a marine source (namely, the Caribbean tunicate Ecteinascidia turbinata) to receive marketing authorization. This article summarizes the mechanisms of action, the complex metabolism, the main toxicities, the preclinical and clinical evidences of its antineoplastic effects in different types of cancer and, finally, the future perspectives of this promising drug.

Quinaprilat: a review of its pharmacokinetics, pharmacodynamics, toxicological data and clinical application.

BACKGROUND: Quinaprilat is an ACE inhibitor for intravenous use especially in patients with arterial hypertension or chronic heart failure. In contrast to the oral prodrug quinapril, it has not been approved for clinical application. OBJECTIVE: In this review, the pharmacokinetic and pharmacodynamic profile of quinaprilat as well as toxicological data and results of preclinical and clinical studies are summarized. METHODS: In a PubMed search for the terms "quinaprilat" and "quinapril", literature relevant for this review was selected. RESULTS: Quinaprilat is a potent nonsulfhydryl selective ACE inhibitor with a short elimination half-life of 2 - 3 h, but due to slow dissociation from tissue ACE, once daily dosing is sufficient for effective ACE inhibition. Quinaprilat is excreted mainly in urine. In long-term animal studies, quinaprilat was not teratogenic, mutagenic or carcinogenic. However, due to the risk of fetal and neonatal morbidity and death, it should not be administrated in pregnancy. Quinaprilat is characterized by an excellent safety profile; adverse events occur infrequently and are rarely serious. CONCLUSION: Quinaprilat is an attractive ACE inhibitor, which potently inhibits tissue ACE.

Comparison of the efficacy and tolerability of solifenacin succinate with or without previous use of trospium chloride.

Overactive bladder syndrome (OBS) is described as urinary urgency with or without incontinence, usually with increased daytime frequency and nocturia in the absence of another identifiable pathological process. Nowadays and despite other alternative therapies, the mainstay of OBS is still the pharmacological approach, mainly with anti-muscarinic drugs. To compare the efficacy of a 30-day solifenacin succinate (5 mg OD) treatment with or without previous medication with trospium chloride, a prostective open, two-arm, parallel group study was conducted for 5 weeks in 40 patients with OBS. The primary endpoint was patient self-assessment of improvement after 30 days of medication. Secondary endpoints included the reduction of the daily number of voids and urgency or involuntary leakage episodes. Adverse reactions and therapeutic stoppage were also evaluated. To be included in the trospium chloride treatment group, patients were required to have been treated with such drug for 1 to 6 months before the present study. Evaluation and efficacy assessment were accomplished using a 3-day bladder diary and an urgency severity scale (USS). Safety assessment was done by recording all the patients' complaints after starting medication. A total of 40 patients were enrolled for this study, 19 without previous medication and 21 who had already tried trospium chloride. Two patients from the non-previous medication group were excluded. Globally, there was a statistically significant reduction for the USS (2.73-->1.73), the daily number of voids (9.5-->7.0), of urgency episodes (9.1-->4.0) and of involuntary leakage episodes (3.6-->1.0) over the 24 h. Six patients had no improvement, four from the previous trospium chloride group and two from the non-previous medication group. Three patients reported side effects, two cases of dry mouth and one case of constipation. One patient dropped out of the treatment due to an unspecified intolerance. Solifenacin succinate 5 mg seems to be effective concerning patients' self-assessment of improvement and decrease in the mean number of daily voids, urgency episodes and incontinence episodes. This was reported both in patients who have already been medicated with trospium chloride and those who have never taken any kind of medication. Regarding side effects, solifenacin is quite well-tolerated in both groups.

Solifenacin: treatment of overactive bladder.

An investigational muscarinic antagonist, solifenacin is indicated in the treatment of overactive bladder. Solifenacin works to decrease bladder activity by inhibiting contraction of the smooth muscle wall surrounding the bladder. Micturition normally occurs following stimulation of acetylcholine muscarinic M3 receptors within the detrusor muscle wall. As a potent and selective muscarinic receptor antagonist, solifenacin acts specifically at the M3 receptor site. Initial data have shown solifenacin to be more bladder-selective than its predecessors. It is this selective mode of action that gives solifenacin the potential to limit commonly experienced anticholinergic side effects. These developments could translate into higher patient compliance with the potential for better long-term results. Solifenacin has been shown to have a favorable risk/benefit ratio. At a once-daily oral dose of 5 mg/day, clinical data have shown solifenacin to be effective in reducing the symptoms of overactive bladder, with an incidence of dry mouth comparable to that associated with placebo. Results from phase I, II and III clinical trials have shown solifenacin to have a promising efficacy and safety profile for the treatment of overactive bladder. Comparative clinical trials are now needed to determine whether these initial results can prove solifenacin to be more beneficial than other commonly administered antimuscarinics.