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2.
J Laryngol Otol ; 132(6): 519-522, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29909794

ABSTRACT

OBJECTIVE: The present study aimed to compare the anti-biofilm activities of four commonly available antiseptic eardrops against biofilms from methicillin-resistant Staphylococcus aureus and quinolone-resistant Pseudomonas aeruginosa in vitro. METHODS: The anti-biofilm activities of 50 per cent Burow's solution, vinegar with water (1:1), 2 per cent acetic acid solution, and 4 per cent boric acid solution were evaluated using biofilm assays. Additionally, the anti-biofilm activities of the four antiseptic solutions against tympanostomy tube biofilms were compared using a scanning electron microscope. RESULTS: The inhibition of biofilm formation from methicillin-resistant S aureus and quinolone-resistant P aeruginosa occurred after treatment with 4 per cent boric acid solution, 2 per cent acetic acid solution, and vinegar with water (1:1). However, 50 per cent Burow's solution did not exhibit effective anti-biofilm activity. CONCLUSION: The results indicate that 4 per cent boric acid solution and vinegar with water (1:1) are potent inhibitors of biofilms from methicillin-resistant S aureus and quinolone-resistant P aeruginosa, and provide safe pH levels for avoiding ototoxicity.


Subject(s)
Acetates/pharmacology , Acetic Acid/pharmacology , Anti-Infective Agents, Local/pharmacology , Biofilms/drug effects , Boric Acids/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Prostheses and Implants/microbiology , Pseudomonas aeruginosa/drug effects , Administration, Topical , Drug Resistance, Bacterial , Humans , Hydrogen-Ion Concentration , In Vitro Techniques , Microscopy, Electron, Scanning , Middle Ear Ventilation/instrumentation , Pharmaceutical Solutions/pharmacology , Prosthesis-Related Infections , Quinolones
3.
N Engl J Med ; 378(15): 1408-1418, 2018 Apr 12.
Article in English | MEDLINE | ID: mdl-29420164

ABSTRACT

BACKGROUND: Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS: A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS: Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .).


Subject(s)
Adenocarcinoma/drug therapy , Androgen Antagonists/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Thiohydantoins/therapeutic use , Adenocarcinoma/secondary , Aged , Aged, 80 and over , Androgen Antagonists/adverse effects , Disease Progression , Disease-Free Survival , Double-Blind Method , Exanthema/chemically induced , Humans , Male , Middle Aged , Neoplasm Metastasis/prevention & control , Proportional Hazards Models , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/pathology , Thiohydantoins/adverse effects
4.
Invest New Drugs ; 36(3): 476-486, 2018 06.
Article in English | MEDLINE | ID: mdl-29177975

ABSTRACT

Purpose Trabectedin is metabolized by the liver and has been associated with transient, noncumulative transaminase elevation. Two recent studies further characterize hepatic tolerability with trabectedin therapy: a phase 1 pharmacokinetic study (Study #1004; NCT01273493) in patients with advanced malignancies and hepatic impairment (HI), and a phase 3 study (Study #3007; NCT01343277) of trabectedin vs. dacarbazine in patients with advanced sarcomas and normal hepatic function. Methods In Study #1004, patients received a single 3-h intravenous (IV) infusion of trabectedin: control group, trabectedin 1.3 mg/m2; HI group (baseline total bilirubin >1.5 and ≤3× upper limit of normal [ULN]; AST and ALT ≤2.5× ULN), trabectedin 0.58 or 0.9 mg/m2. In Study #3007, the trabectedin group received 1.5 mg/m2 by 24-h IV infusion every 3 weeks until disease progression or unacceptable toxicity. Results In Study #1004, dose-normalized trabectedin exposure was higher in HI patients (n = 6) versus controls (n = 9) (geometric mean ratios [90% CI] AUClast: 1.97 [1.20; 3.22]). In Study #3007, following trabectedin administration, 90% of patients had elevated ALT (32% grade 3-4) and 84% had elevated AST (17% grade 3-4). Transaminase elevations were transient and noncumulative. Progression-free survival was similar in patients with grade 3-4 hepatotoxicity (n = 109) versus grade 0-2 hepatotoxicity (n = 231) (median [95% CI]: 4.63 [4.01, 5.85] months versus 3.55 [2.73, 4.63] months; P = 0.545, HR = 0.91 [0.68-1.23]). Conclusion Trabectedin treatment of patients with HI results in higher plasma exposures. Hepatotoxicity in patients with normal liver function can be effectively addressed through dose reductions and delays.


Subject(s)
Liver/pathology , Trabectedin/adverse effects , Trabectedin/pharmacokinetics , Adult , Aged , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Trabectedin/blood
5.
N Engl J Med ; 377(4): 352-360, 2017 07 27.
Article in English | MEDLINE | ID: mdl-28578607

ABSTRACT

BACKGROUND: Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. RESULTS: After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. CONCLUSIONS: The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285 .).


Subject(s)
Abiraterone Acetate/administration & dosage , Androgen Antagonists/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prednisolone/administration & dosage , Prostatic Neoplasms/drug therapy , Abiraterone Acetate/adverse effects , Adult , Aged , Aged, 80 and over , Androgen Antagonists/adverse effects , Androgen Antagonists/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Humans , Male , Middle Aged , Neoplasm Metastasis/drug therapy , Prednisolone/adverse effects , Prostatic Neoplasms/mortality , Prostatic Neoplasms/radiotherapy , Prostatic Neoplasms/surgery , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Survival Analysis
6.
Clin Pharmacokinet ; 56(1): 55-63, 2017 01.
Article in English | MEDLINE | ID: mdl-27324190

ABSTRACT

BACKGROUND AND OBJECTIVES: Recent analysis revealed strong associations between prostate-specific antigen (PSA) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) and supported PSA dynamics as bridging surrogacy endpoints for clinical benefit from treatment with abiraterone acetate plus prednisone. This analysis aimed to investigate the abiraterone exposure-PSA dynamics relationship in mCRPC. METHODS: Abiraterone pharmacokinetics-PSA models were constructed using data from the COU-AA-301 (chemotherapy-pretreated) and COU-AA-302 (chemotherapy-naïve) trials comparing abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily with prednisone alone in mCRPC. The drug effect-PSA dynamics relationship was modeled as a function of selected pharmacokinetic measures. The influences of baseline demographic variables, laboratory values, and disease status on PSA dynamics were assessed. RESULTS: A tumor growth inhibition model best described PSA dynamics post-treatment with abiraterone acetate. Abiraterone acetate treatment in chemotherapy-pretreated and chemotherapy-naïve patients increased the PSA decay rate (k dec) to the same extent (1.28-fold, 95 % confidence interval [CI] 0.58-1.98; and 0.93-fold, 95 % CI 0.6-1.27, respectively). Lower baseline lactate dehydrogenase and higher baseline testosterone significantly increased k dec. Findings from our analysis suggest a maximum-effect relationship between abiraterone trough concentration and PSA dynamics in both patient populations. The majority of patients had a steady-state trough concentration greater than the estimated half maximal effective concentration. CONCLUSION: The model appropriately described the exposure-response relationship between abiraterone and PSA dynamics in chemotherapy-pretreated and chemotherapy-naïve patients following oral administration of abiraterone acetate.


Subject(s)
Abiraterone Acetate/pharmacokinetics , Models, Biological , Prednisone/pharmacokinetics , Prostate-Specific Antigen/drug effects , Prostatic Neoplasms, Castration-Resistant/drug therapy , Abiraterone Acetate/administration & dosage , Area Under Curve , Drug Therapy, Combination , Humans , L-Lactate Dehydrogenase/blood , Male , Prednisone/administration & dosage , Prednisone/pharmacology , Severity of Illness Index , Socioeconomic Factors , Testosterone/blood
7.
Clin Cancer Res ; 21(14): 3170-7, 2015 Jul 15.
Article in English | MEDLINE | ID: mdl-25829400

ABSTRACT

PURPOSE: We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA). EXPERIMENTAL DESIGN: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy pretreated, n = 1,184) and COU-AA-302 (chemotherapy naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model. RESULTS: The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naïve and -pretreated patients. PSA kinetics [e.g., PSA nadir, PSA response rate (≥30%, 50%, and 90%), time to PSA progression, PSA doubling time (PSADT)] were highly associated with OS in both populations. The model-based posttreatment PSADT had the strongest association with OS (HR ∼0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic endpoints, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic endpoints. A strong correlation was also observed between PSA and radiographic progression-free survival. CONCLUSIONS: The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naïve patients, thereby providing a rationale to consider PSA kinetics as surrogacy endpoints to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment.


Subject(s)
Abiraterone Acetate/therapeutic use , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/blood , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/drug therapy , Antineoplastic Agents, Hormonal/therapeutic use , Double-Blind Method , Drug Resistance, Neoplasm , Humans , Kaplan-Meier Estimate , Kinetics , Male , Proportional Hazards Models , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/mortality
8.
Lancet Oncol ; 16(2): 152-60, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25601341

ABSTRACT

BACKGROUND: Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies. METHODS: In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198. FINDINGS: At a median follow-up of 49.2 months (IQR 47.0-51.8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34.7 months [95% CI 32.7-36.8] vs 30.3 months [28.7-33.3]; hazard ratio 0.81 [95% CI 0.70-0.93]; p=0.0033). The most common grade 3-4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the abiraterone acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [<1%]), and hypertension (25 [5%] vs 17 [3%]). INTERPRETATION: In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. FUNDING: Janssen Research & Development.


Subject(s)
Androstenes/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Bone Neoplasms/mortality , Prednisone/therapeutic use , Prostatic Neoplasms, Castration-Resistant/mortality , Aged , Antineoplastic Combined Chemotherapy Protocols , Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Disease Progression , Double-Blind Method , Follow-Up Studies , Humans , Male , Neoplasm Staging , Prognosis , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Survival Rate
9.
Eur Urol ; 66(5): 815-25, 2014 Nov.
Article in English | MEDLINE | ID: mdl-24647231

ABSTRACT

BACKGROUND: Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy. OBJECTIVE: Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302. DESIGN, SETTING, AND PARTICIPANTS: Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1). INTERVENTION: Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets α-spending function was used for OS. Adverse events were summarised descriptively. RESULTS AND LIMITATIONS: With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; p<0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66-0.95]; p=0.0151) but did not reach the prespecified statistical efficacy boundary (α-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61-0.89]; p=0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports. CONCLUSIONS: The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ≥24 mo. TRIAL REGISTRATION: Study COU-AA-302, ClinicalTrials.gov number, NCT00887198. PATIENT SUMMARY: The updated results of this ongoing study showed that disease progression was delayed in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone, and there was a continued trend in prolongation of life compared with patients treated with prednisone alone. Treatment with abiraterone acetate and prednisone was well tolerated by patients who were treated for >2 yr.


Subject(s)
Androstenes/administration & dosage , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Neoplasms, Hormone-Dependent/drug therapy , Prostatic Neoplasms, Castration-Resistant/drug therapy , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Abiraterone Acetate , Aged , Androstenes/adverse effects , Antineoplastic Agents, Hormonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cytochrome P-450 Enzyme Inhibitors/adverse effects , Disease Progression , Disease-Free Survival , Double-Blind Method , Drug Administration Schedule , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Metastasis , Neoplasms, Hormone-Dependent/enzymology , Neoplasms, Hormone-Dependent/mortality , Neoplasms, Hormone-Dependent/pathology , Prednisone/administration & dosage , Proportional Hazards Models , Prostatic Neoplasms, Castration-Resistant/enzymology , Prostatic Neoplasms, Castration-Resistant/mortality , Prostatic Neoplasms, Castration-Resistant/pathology , Risk Factors , Steroid 17-alpha-Hydroxylase/metabolism , Time Factors , Treatment Outcome
10.
J Eur Acad Dermatol Venereol ; 27(1): e1-7, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23030660

ABSTRACT

BACKGROUND: Optimum dose ratios of rimabotulinumtoxinB (BTX-B) and onabotulinumtoxinA (BTX-A) have not been determined for forehead wrinkles. OBJECTIVE: To compare the efficacy and safety of BTX-B and BTX-A for the treatment of forehead lines. METHODS: Twenty-two women (mean age, 40 years) with symmetrical moderate to severe forehead lines were randomized to receive single intramuscular injections of BTX-A and BTX-B on either side of the forehead, at a potency ratio of 1 : 70 or 1 : 100. Subjects were followed-up for 16 weeks. Four physicians evaluated patients' photographs according to the 4-point Facial Wrinkling Grade (FWG). Clinical Improvement Scale (CIS) was calculated by subtracting FWG score at each visit from that at baseline. Patient satisfaction scores and adverse events were also recorded. RESULTS: Both BTX-A and BTX-B were effective for the treatment of forehead lines. At both potency ratios, BTX-A had a longer duration of action than BTX-B, while BTX-B led to faster improvement than BTX-A. There was no significant difference in CIS between 700 U and 1000 U BTX-B treatments. Adverse effects were mild and transient. CONCLUSION: Both BTX-A and BTX-B were effective and well tolerated for the treatment of forehead wrinkles at potency ratios of 1 : 70 and 1 : 100.


Subject(s)
Botulinum Toxins, Type A/therapeutic use , Botulinum Toxins/therapeutic use , Skin Aging/drug effects , Adult , Botulinum Toxins/adverse effects , Botulinum Toxins, Type A/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Esthetics , Facial Muscles/drug effects , Female , Forehead , Humans , Injections, Intramuscular , Korea , Middle Aged , Patient Satisfaction , Pilot Projects , Prospective Studies , Risk Assessment , Single-Blind Method , Treatment Outcome , Young Adult
11.
Eur J Cancer ; 48(15): 2361-8, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22541893

ABSTRACT

AIM: Trabectedin in combination with pegylated liposomal doxorubicin (PLD) improves progression-free survival (PFS) compared to PLD alone in recurrent ovarian cancer (J Clin Oncol 2010;28:3107-14). METHODS: Women, stratified by performance status (0-1 versus 2) and platinum sensitivity (platinum-free interval [PFI]<6 versus ≥ 6 months), were randomly assigned to receive PLD 30 mg/m(2) IV followed by a 3-h infusion of trabectedin 1.1mg/m(2) every 3 weeks or PLD 50mg/m(2) every 4 weeks. The study was powered to show a 33% increase in overall survival (OS) after 520 deaths had occurred. RESULTS: After a median follow-up of 47.4 months, there were 522 deaths among 672 subjects. The median OS for trabectedin+PLD and PLD arms was 22.2 and 18.9 months, respectively (hazard ratio [HR]=0.86; 95% confidence interval [CI]: 0.72-1.02; p=0.0835). An unexpected but significant imbalance in the PFI favouring the PLD arm (mean PFI: PLD=13.3 months, trabectedin+PLD=10.6 months) was identified. On the basis of this finding, an unplanned hypothesis generating analysis adjusting for the PFI imbalance and other prognostic factors suggested an improvement in OS associated with the trabectedin+PLD arm (HR=0.82; 95%CI: 0.69-0.98; p=0.0285). In another unplanned exploratory analysis, the subset of patients with a PFI of 6-12 months had the largest difference in OS (HR=0.64; 95%CI: 0.47-0.86; p=0.0027). CONCLUSIONS: The final OS analysis did not meet the protocol-defined criterion for statistical significance. Despite stratification on platinum sensitivity, there was an imbalance in mean platinum free interval that had an effect on OS.


Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Doxorubicin/analogs & derivatives , Neoplasms, Glandular and Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Polyethylene Glycols/therapeutic use , Aged , Antibiotics, Antineoplastic/administration & dosage , Carcinoma, Ovarian Epithelial , Dioxoles/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Doxorubicin/therapeutic use , Female , Humans , Middle Aged , Neoplasm Recurrence, Local , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/pathology , Polyethylene Glycols/administration & dosage , Survival Analysis , Tetrahydroisoquinolines/administration & dosage , Trabectedin
12.
Acta Anaesthesiol Scand ; 56(1): 116-23, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22091986

ABSTRACT

BACKGROUND: Therapeutic hypothermia in adult victims who suffer cardiac arrest following drowning has been applied in only a small number of cases. In the last 4 years, we have employed therapeutic hypothermia to decrease hypoxia-induced brain injury in these patients. The purpose of the present study was to report the results of the treatment of these patients. METHODS: This study investigated the utilisation of therapeutic hypothermia on consecutive patients with cardiac arrest because of drowning between 2005 and 2008. The study was conducted retrospectively, collecting data by reviewing medical records. Hypothermia, with a target temperature of 32-34°C, was induced for 24 h. Neurological outcomes were classified using the cerebral performance categories (CPCs). The primary outcome was neurological function at discharge. RESULTS: Twenty patients were treated with therapeutic hypothermia. Four patients (20%) exhibited a favourable neurological outcome (CPC 1-2). Two patients (10%) remained in a vegetative state at discharge (CPC 4), and 14 patients (70%) died (CPC 5). The most common complications during therapeutic hypothermia were pancreatitis and rhabdomyolysis. A longer duration of advanced cardiac life support (P = 0.035), an absence of motor response to pain after 3 days (P = 0.003), an abnormal brain imaging (P = 0.005) and a lack of cortical response to somatosensory evoked potential (P = 0.008) were related to an unfavourable outcome (CPC 3-5). CONCLUSION: The present study did not demonstrate an advantage of therapeutic hypothermia in adult cardiac arrest after drowning compared with previous studies treated with conventional therapy. Further prospective studies are needed to evaluate the effects of therapeutic hypothermia.


Subject(s)
Heart Arrest/therapy , Hypothermia, Induced , Near Drowning/therapy , Adolescent , Adult , Advanced Cardiac Life Support , Aged , Body Temperature , Cardiopulmonary Resuscitation , Emergency Medical Services , Evoked Potentials, Somatosensory/physiology , Female , Heart Arrest/etiology , Humans , Length of Stay , Male , Middle Aged , Nervous System Diseases/etiology , Neurologic Examination , Prognosis , Seizures/etiology , Survival , Treatment Outcome , Young Adult
13.
IET Syst Biol ; 5(5): 317-23, 2011 Sep.
Article in English | MEDLINE | ID: mdl-22010758

ABSTRACT

Based on the similarity between a reentrant wave in cardiac tissue and a vortex in fluid dynamics, the authors hypothesised that a new non-dimensional index, like the Reynolds number in fluid dynamics, may play a critical role in categorising reentrant wave dynamics. Therefore the goal of the present study is to devise a new index to characterise electric wave conduction in cardiac tissue and examined whether this index can be used as a biomarker for categorising the reentrant wave pattern in cardiac tissue. Similar to the procedure used to derive the Reynolds number in fluid dynamics, the authors used a non-dimensionalisation technique to obtain the new index. Its usefulness was verified using a two-dimensional simulation model of electrical wave propagation in cardiac tissue. The simulation results showed that electrical waves in cardiac tissue move into an unstable region when the index exceeds a threshold value.


Subject(s)
Heart Conduction System/physiology , Heart/physiology , Models, Cardiovascular , Action Potentials , Arrhythmias, Cardiac/physiopathology , Biomarkers/metabolism , Cardiology/methods , Computational Biology , Computer Simulation , Electrophysiology/methods , Humans , Models, Theoretical , Reference Standards , Rheology/methods , Systems Biology/methods
14.
Cancer Chemother Pharmacol ; 68(5): 1223-31, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21416137

ABSTRACT

PURPOSE: This analysis provides a cross-study evaluation of the cardiac safety of trabectedin. METHODS: Drug-related cardiac adverse events (CAEs) were retrieved from phase I-III clinical trials, pharmacovigilance databases, and spontaneously reported cases. Left ventricular ejection fraction (LVEF) was monitored in combination phase I studies with doxorubicin or pegylated liposomal doxorubicin (PLD) and in a phase III trial (with PLD). RESULTS: CAEs [grade 4 cardiac arrest with severe pancytopenia and sepsis (n = 1 patient), grade 4 atrial fibrillation (n = 2), and grade 1 tachycardia (n = 1)] occurred in 4/283 patients (1.4%) in 6 single-agent phase I trials. CAEs (grade 1 sinus tachycardia in a hypertensive patient and grade 1 ventricular dysfunction) occurred in 2/155 patients (1.3%) in 4 phase I combination trials. Results from 19 single-agent phase II trials showed CAEs in 20/1,132 patients (1.8%): arrhythmias (tachycardia/palpitations; n = 13; 1.1%) were the most common. A rather similar rate of symptomatic CAEs was observed in both arms of a phase III trial in recurrent ovarian cancer: 6/330 patients (1.8%; PLD) and 11/333 patients (3.3%; trabectedin/PLD). No clinically relevant LVEF changes occurred in phase I combination trials. In the phase III trial, LVEF decreases from baseline were similar: 9% of patients (PLD) and 7% (trabectedin/PLD), with no relevant symptoms. During postmarketing experience in soft tissue sarcoma (2,046 patients treated), 4 CAEs (2 cardiac arrest, 2 cardiac failure; ~0.2%) occurred in patients with preexisting conditions. CONCLUSIONS: Trabectedin has a low incidence of CAEs, consisting mainly of arrhythmias. This extensive data review indicates a low cardiac risk profile for trabectedin.


Subject(s)
Antineoplastic Agents, Alkylating/adverse effects , Dioxoles/adverse effects , Heart/drug effects , Tetrahydroisoquinolines/adverse effects , Antineoplastic Agents, Alkylating/therapeutic use , Dioxoles/therapeutic use , Humans , Risk Assessment , Tetrahydroisoquinolines/therapeutic use , Trabectedin
15.
J Clin Oncol ; 27(25): 4188-96, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19652065

ABSTRACT

PURPOSE: To evaluate the safety and efficacy of trabectedin in a phase II, open-label, multicenter, randomized study in adult patients with unresectable/metastatic liposarcoma or leiomyosarcoma after failure of prior conventional chemotherapy including anthracyclines and ifosfamide. PATIENTS AND METHODS: Patients were randomly assigned to one of two trabectedin regimens (via central venous access): 1.5 mg/m(2) 24-hour intravenous infusion once every 3 weeks (q3 weeks 24-hour) versus 0.58 mg/m(2) 3-hour IV infusion every week for 3 weeks of a 4-week cycle (qwk 3-hour). Time to progression (TTP) was the primary efficacy end point, based on confirmed independent review of images. RESULTS: Two hundred seventy patients were randomly assigned; 136 (q3 weeks 24-hour) versus 134 (qwk 3-hour). Median TTP was 3.7 months versus 2.3 months (hazard ratio [HR], 0.734; 95% CI, 0.554 to 0.974; P = .0302), favoring the q3 weeks 24-hour arm. Median progression-free survival was 3.3 months versus 2.3 months (HR, 0.755; 95% CI, 0.574 to 0.992; P = .0418). Median overall survival (n = 235 events) was 13.9 months versus 11.8 months (HR, 0.843; 95% CI, 0.653 to 1.090; P = .1920). Although somewhat more neutropenia, elevations in AST/ALT, emesis, and fatigue occurred in the q3 weeks 24-hour, this regimen was reasonably well tolerated. Febrile neutropenia was rare (0.8%). No cumulative toxicities were noted. CONCLUSION: Prior studies showed clinical benefit with trabectedin in patients with sarcomas after failure of standard chemotherapy. This trial documents superior disease control with the q3 weeks 24-hour trabectedin regimen in liposarcomas and leiomyosarcomas, although the qwk 3-hour regimen also demonstrated activity relative to historical comparisons. Trabectedin may now be considered an important new option to control advanced sarcomas in patients after failure of available standard-of-care therapies.


Subject(s)
Anthracyclines/therapeutic use , Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/therapeutic use , Dioxoles/administration & dosage , Drug Resistance, Neoplasm , Ifosfamide/therapeutic use , Leiomyosarcoma/drug therapy , Liposarcoma/drug therapy , Tetrahydroisoquinolines/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Alkylating/adverse effects , Australia , Dioxoles/adverse effects , Disease-Free Survival , Drug Administration Schedule , Europe , Female , Humans , Infusions, Intravenous , Kaplan-Meier Estimate , Leiomyosarcoma/secondary , Liposarcoma/secondary , Male , Middle Aged , Neoplasm Staging , North America , Proportional Hazards Models , Risk Assessment , Tetrahydroisoquinolines/adverse effects , Time Factors , Trabectedin , Treatment Failure , Young Adult
16.
Epilepsy Behav ; 16(1): 80-1, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19608461

ABSTRACT

In a prior study of epilepsy and atmospheric pressure, we were able to show a small association between changes in atmospheric pressure and increased seizure frequency in consecutive patients with epilepsy undergoing video telemetry. In this study, we used a larger data set of similar patients undergoing telemetry at another Seattle institution, and examined the possible impact of atmospheric pressure (AP) changes on seizure onset in subtypes of seizures (focal, generalized, and nonepileptic). Comparisons were made between AP score at time of seizure onset and AP score at selected time ranges prior to the event (hour of seizure and 3, 6, and 24 hours prior) and a random sample of AP scores collected over similar time frames using nonparametric testing with correction for multiple comparisons. We could find no evidence to suggest atmospheric pressure changes made seizure occurrence more likely in any of the seizure groups across any of the time periods.


Subject(s)
Atmospheric Pressure , Epilepsy/epidemiology , Seizures/epidemiology , Electroencephalography , Epilepsy/physiopathology , Humans , Retrospective Studies , Seizures/classification , Telemetry , Washington/epidemiology , Weather
17.
Blood ; 114(6): 1166-73, 2009 Aug 06.
Article in English | MEDLINE | ID: mdl-19470696

ABSTRACT

This phase 3, multicenter, open-label study evaluated the efficacy and safety of tipifarnib compared with best supportive care (BSC), including hydroxyurea, as first-line therapy in elderly patients (>or=70 years) with newly diagnosed, de novo, or secondary acute myeloid leukemia. A total of 457 patients were enrolled with 24% 80 years of age or older. Tipifarnib 600 mg orally twice a day was administered for the first 21 consecutive days, in 28-day cycles. The primary endpoint was overall survival. The median survival was 107 days for the tipifarnib arm and 109 days for the BSC arm. The hazard ratio (tipifarnib vs BSC) for overall survival was 1.02 (P value by stratified log-rank test, .843). The complete response rate for tipifarnib in this study (8%) was lower than that observed previously, but with a similar median duration of 8 months. The most frequent grade 3 or 4 adverse events were cytopenias in both arms, slightly more infections (39% vs 33%), and febrile neutropenia (16% vs 10%) seen in the tipifarnib arm. The results of this randomized study showed that tipifarnib treatment did not result in an increased survival compared with BSC, including hydroxyurea. This trial was registered at www.clinicaltrials.gov as #NCT00093990.


Subject(s)
Antineoplastic Agents/administration & dosage , Hydroxyurea/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Quinolones/administration & dosage , Administration, Oral , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Disease-Free Survival , Female , Humans , Hydroxyurea/adverse effects , Leukemia, Myeloid, Acute/diagnosis , Male , Neutropenia/chemically induced , Neutropenia/drug therapy , Neutropenia/mortality , Quinolones/adverse effects , Survival Rate , Time Factors
18.
Breast Cancer Res Treat ; 110(2): 327-35, 2008 Jul.
Article in English | MEDLINE | ID: mdl-17851757

ABSTRACT

BACKGROUND: This study assessed the clinical efficacy of the farnesyltransferase inhibitor, tipifarnib, combined with letrozole in patients with advanced breast cancer and disease progression following antiestrogen therapy. PATIENTS AND METHODS: Postmenopausal women with estrogen-receptor-positive advanced breast cancer that had progressed after tamoxifen were given 2.5 mg letrozole once daily and were randomly assigned (2:1) to tipifarnib 300 mg (TL) or placebo (L) twice daily for 21 consecutive days in 28-day cycles. The primary endpoint was objective response rate. RESULTS: Of 120 patients treated with TL (n = 80) or L (n = 40), 113 were evaluable for response. Objective response rate was 30% (95% CI; 20-41%) for TL and 38% (95% CI; 23-55%) for L. There was no significant difference in response duration, time to disease progression or survival. Clinical benefit rates were 49% (TL) and 62% (L). Tipifarnib was generally well tolerated; a higher incidence of drug-related asymptomatic grade 3/4 neutropenia was observed for TL (18%) than for L (0%). Tipifarnib population pharmacokinetics were similar to previous studies, with no significant difference in trough letrozole concentrations between the TL and L groups. CONCLUSIONS: Adding tipifarnib to letrozole did not improve objective response rate in this population of patients with advanced breast cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Estrogen Receptor Modulators/therapeutic use , Farnesyltranstransferase/antagonists & inhibitors , Nitriles/administration & dosage , Quinolones/administration & dosage , Triazoles/administration & dosage , Adult , Aged , Aged, 80 and over , Double-Blind Method , Female , Humans , Letrozole , Middle Aged , Time Factors , Treatment Outcome
19.
J Invest Dermatol ; 117(5): 1218-24, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11710936

ABSTRACT

To the best of our knowledge, no study has been conducted to date to directly compare the collagen metabolism of photoaged and naturally aged human skin. In this study, we compared collagen synthesis, matrix metalloproteinase-1 levels, and gelatinase activity of sun-exposed and sun-protected skin of both young and old subjects. Using northern blot analysis, immunohistochemical stain, and Western blot analysis, we demonstrated that the levels of procollagen type I mRNA and protein in photoaged and naturally aged human skin in vivo are significantly lower than those of young skin. Furthermore, we demonstrated, by northern blot analysis, that the procollagen alpha1(I) mRNA expression of photoaged skin is much greater than that of sun-protected skin in the same individual. In situ hybridization and immunohistochemical stain were used to show that the expression of type I procollagen mRNA and protein in the fibroblasts of photoaged skin is greater than for naturally aged skin. In addition, it was found, by Western blot analysis using protein extracted from the dermal tissues, that the level of procollagen type I protein in photoaged skin is lower than that of naturally aged skin. The level of matrix metalloproteinase-1 protein and the activity of matrix metalloproteinase-2 were higher in the dermis of photoaged skin than in naturally aged skin. Our results suggest that the natural aging process decreases collagen synthesis and increases the expression of matrix metalloproteinases, whereas photoaging results in an increase of collagen synthesis and greater matrix metalloproteinase expression in human skin in vivo. Thus, the balance between collagen synthesis and degradation leading to collagen deficiency is different in photoaged and naturally aged skin.


Subject(s)
Aging/metabolism , Collagen/metabolism , Skin Aging/physiology , Skin/metabolism , Adult , Aged , Aged, 80 and over , Buttocks , Collagen Type I/genetics , Collagen Type I/metabolism , Dermis/metabolism , Female , Fibroblasts/metabolism , Forearm , Humans , Male , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 2/metabolism , Middle Aged , RNA, Messenger/metabolism , Skin/cytology , Tissue Distribution
20.
Arch Dermatol ; 137(8): 1043-51, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11493097

ABSTRACT

BACKGROUND: Severe wrinkles and pigmentary changes of the exposed skin indicate substantial damage due to UV radiation. Many investigators believe that the principal manifestation of photodamage in Asians is pigmentary change rather than wrinkles. However, to our knowledge, no well-designed study has investigated the characteristics of cutaneous photodamage in Asian skin. OBJECTIVE: To access the severity of wrinkles and dyspigmentation in Koreans exposed to sun and who smoked. METHODS: We developed new photographic scales for grading wrinkles and dyspigmentation in 407 Koreans to assess the severity of the wrinkles and dyspigmentation. We interviewed subjects to determine cumulative sun exposure and smoking history, and measured the skin color of individual subjects. RESULTS: Our photographic scales provided a reliable evaluation of photodamage severity in Koreans. The pattern of wrinkling in both sexes is similar, but women tended to have more severe wrinkles (prevalence odds ratio, 3.7). However, the pattern of dyspigmentation differed between the sexes. Seborrheic keratosis is the major pigmentary lesion in men, whereas hyperpigmented macules are the prominent features in women. Cigarette smoking is an independent risk factor for wrinkles, but not for dyspigmentation, in Koreans, and causes additive detrimental effects to wrinkles induced by aging and sun exposure. The constitutive skin color did not show any correlation with wrinkles or dyspigmentation. However, facultative pigmentation (sun exposure index) may reflect lifetime sun exposure, and it shows a good correlation with wrinkles in Koreans. CONCLUSION: Wrinkling is a major feature of photoaging in Koreans, as are pigmentary changes; smoking, sun exposure, and female sex are independent risk factors for wrinkles.


Subject(s)
Asian People , Skin Aging , Skin Pigmentation , Smoking , Sunlight/adverse effects , Adult , Aged , Aged, 80 and over , Female , Humans , Korea , Male , Middle Aged , Sex Factors
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