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Dermatology Reports Dec 2015Acne is a common skin disease involving colonization with Propionibacterium acnes (P. acnes), hyperproliferation of the follicular epithelium and inflammatory events....
Acne is a common skin disease involving colonization with Propionibacterium acnes (P. acnes), hyperproliferation of the follicular epithelium and inflammatory events. Valrubicin is a second-generation anthracycline, non-toxic upon contact, and available in a topical formulation. Valrubicin's predecessor doxorubicin possesses antibacterial effects and previously we demonstrated that valrubicin inhibits keratinocyte proliferation and skin inflammation suggesting beneficial topical treatment of acne with valrubicin. This study aims to investigate valrubicin's possible use in acne treatment by testing valrubicin's antibacterial effects against P. acnes and P. acnes-induced skin inflammation in vitro and in vivo. Valrubicin was demonstrated not to possess antibacterial effects against P. acnes. Additionally, valrubicin was demonstrated not to reduce mRNA and protein expression levels of the inflammatory markers interleukin (IL)-1β, IL-8, and tumor necrosis factor (TNF)-α in vitro in human keratinocytes co-cultured with P. acnes. Moreover, in vivo, valrubicin, applied both topically and intra-dermally, was not able to reduce signs of inflammation in mouse ears intra-dermally injected with P. acnes. Taken together, this study does not support beneficial antibacterial and anti inflammatory effects of topical valrubicin treatment of acne.
PubMed: 26734122
DOI: 10.4081/dr.2015.6246 -
Indian Journal of Urology : IJU :... 2015Non-muscle-invasive bladder cancer (NMIBC) is characterized by a tendency for recurrence and capacity for progression. Intravesical instillation therapy has been... (Review)
Review
Non-muscle-invasive bladder cancer (NMIBC) is characterized by a tendency for recurrence and capacity for progression. Intravesical instillation therapy has been employed in various clinical settings, which are summarized within this review. Several chemotherapeutic agents have shown clinical efficacy in reducing recurrence rates in the post-transurethral resection of bladder tumor (TURBT) setting, including mitomycin C (MMC), doxorubicin, and epirubicin. Mounting evidence also supports the use of intravesical MMC following nephroureterectomy to reduce later urothelial bladder recurrence. In the adjuvant setting, bacillus Calmette-Guérin (BCG) immunotherapy is an established first-line agent in the management of carcinoma in situ (CIS) and high-grade non muscle invasive urothelial carcinoma (UC). Among high and intermediate-risk patients (based on tumor grade, size, and focality) improvements in disease-free intervals have been seen with adjunctive administration of MMC prior to scheduled BCG dosing. Following failure of first-line intravesical therapy, gemcitabine and valrubicin have demonstrated modest activity, though valrubicin remains the only agent currently Food and Drug Administration (FDA)-approved for the treatment of BCG-refractory CIS. Techniques to optimize intravesical chemotherapy delivery have also been explored including pharmacokinetic methods such as urinary alkalization and voluntary dehydration. Chemohyperthermia and electromotive instillation have been associated with improved freedom from recurrence intervals but may be associated with increased urinary toxicity. Improvements in therapeutic selection may be heralded by novel opportunities for genomic profiling and refinements in clinical risk stratification.
PubMed: 26604440
DOI: 10.4103/0970-1591.166446 -
Expert Review of Anticancer Therapy 2015The most effective intravesical regimen for the treatment of non-muscle invasive bladder cancer (NMIBC) refractory to Bacillus Calmette-Guérin (BCG) has still not been... (Review)
Review
The most effective intravesical regimen for the treatment of non-muscle invasive bladder cancer (NMIBC) refractory to Bacillus Calmette-Guérin (BCG) has still not been identified or optimized to minimize recurrence-free survival and prevent progression reliably and consistently. Valrubicin, however, is a cytotoxic chemotherapeutic agent that is used as an intravesical agent for BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. Here we analyze the literature regarding the treatment of non-muscle invasive urothelial malignancies with intravesical valrubicin for refractory bladder cancer, present our opinion on its current clinical impact and speculate on how its utilization will evolve in the near future.
Topics: Administration, Intravesical; Antineoplastic Agents; BCG Vaccine; Disease Progression; Disease-Free Survival; Doxorubicin; Humans; Urinary Bladder Neoplasms
PubMed: 26569509
DOI: 10.1586/14737140.2015.1115350 -
Current Opinion in Oncology May 2015To summarize clinical management of nonmuscle-invasive bladder cancer (NMIBC) and discuss recent advances in the field. (Review)
Review
PURPOSE OF REVIEW
To summarize clinical management of nonmuscle-invasive bladder cancer (NMIBC) and discuss recent advances in the field.
RECENT FINDINGS
NMIBC remains a common and expensive clinical entity. Prevention, early detection, and risk-adapted treatment are the mainstays of clinical management, all of which may improve as a result of recent research. Photodynamic diagnosis has demonstrated improved detection of nascent disease, and specific clinical scenarios have been identified in which photodynamic diagnosis may improve clinical outcomes. New intravesical chemotherapeutic and immunotherapeutic agents challenge our current paradigm for intermediate/high-risk NMIBC and may delay need for cystectomy after bacillus Calmette-Guerin failure. Progress in risk stratification increasingly permits individualized management regimens for NMIBC.
SUMMARY
NMIBC includes many heterogeneous disease states with a variety of clinical behaviors that may evolve over time. Improved detection and risk stratification promise assignment of the optimal treatment option for an individual patient at a given time.
Topics: Administration, Intravesical; Antineoplastic Agents; Cystectomy; Doxorubicin; Early Detection of Cancer; Humans; Neoplasm Recurrence, Local; Risk Assessment; Risk Reduction Behavior; United States; Urinary Bladder Neoplasms
PubMed: 25695463
DOI: 10.1097/CCO.0000000000000173 -
Materials Science & Engineering. C,... Apr 2015In this study, an electrochemical sensor was fabricated based on gold nanoparticles/ ethylenediamine/ multi-wall carbon-nanotubes modified gold electrode...
Fabrication of an electrochemical sensor based on carbon nanotubes modified with gold nanoparticles for determination of valrubicin as a chemotherapy drug: valrubicin-DNA interaction.
In this study, an electrochemical sensor was fabricated based on gold nanoparticles/ ethylenediamine/ multi-wall carbon-nanotubes modified gold electrode (AuNPs/en/MWCNTs/AuE) for determination of valrubicin in biological samples. Valrubicin was effectively accumulated on the surface of AuNPs/en/MWCNTs/AuE and produced a pair of redox peaks at around 0.662 and 0.578V (vs. Ag/AgCl) in citrate buffer (pH4.0). The electrochemical parameters including pH, buffer, ionic strength, scan rate and size of AuNPs have been optimized. There was a good linear correlation between cathodic peak current and concentration of valrubicin in the range of 0.5 to 80.0μmolL(-1) with the detection limit of 0.018μmolL(-1) in citrate buffer (pH4.0) and 0.1molL(-1) KCl. Finally, the constructed sensor was successfully applied for determination of valrubicin in human urine and blood serum. In further studies, the different sequences of single stranded DNA probes have been immobilized on the surface of AuNPs decorated on MWCNTs to study the interaction of oligonucleotides with valrubicin.
Topics: Biosensing Techniques; DNA; Doxorubicin; Electrochemical Techniques; Electrodes; Ethylenediamines; Gold; Humans; Hydrogen-Ion Concentration; Limit of Detection; Metal Nanoparticles; Nanotubes, Carbon; Osmolar Concentration; Oxidation-Reduction; Particle Size; Serum; Urine
PubMed: 25687007
DOI: 10.1016/j.msec.2015.01.072 -
Bladder Cancer (Amsterdam, Netherlands) 2015There are few approved drugs available for the treatment of patients with non-muscle invasive bladder cancer (NMIBC) and none have been approved in the twenty-first...
There are few approved drugs available for the treatment of patients with non-muscle invasive bladder cancer (NMIBC) and none have been approved in the twenty-first century. Four drugs; thiotepa in 1959, BCG Tice in 1989, BCG Connaught in 1990, and valrubicin in 1998, have been approved for the treatment of NMIBC. In addition to these four agents, mitomycin is commonly used off-label as an intravesical treatment for NMIBC. New drugs are needed for the management of NMIBC. This article outlines important aspects of the design and conduct of clinical trials to develop new therapies for these patients and to obtain marketing approval. It includes a discussion of the patient population, BCG-unresponsive disease, and the appropriate endpoints for drug approval. It is hoped that this article will spur drug development in NMIBC within the Center for Drug Evaluation and Research at the Food and Drug Administration.
PubMed: 27088122
DOI: 10.3233/BLC-150016 -
European Urology May 2015Urothelial carcinoma in situ (CIS) has a high propensity for progression. It is usually reported within the heterogeneous context of non-muscle-invasive bladder cancer... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Urothelial carcinoma in situ (CIS) has a high propensity for progression. It is usually reported within the heterogeneous context of non-muscle-invasive bladder cancer (NMIBC) but warrants special consideration.
OBJECTIVE
To review the contemporary literature on the diagnosis and management of CIS.
EVIDENCE ACQUISITION
A systematic search using broad terms to capture the diagnosis and treatment of CIS was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria. Full-text original articles, reviews, and editorials from 1966 to 2014 in English were included. References from selected articles, relevant guidelines, and conference abstracts were searched. Abstracts were excluded.
EVIDENCE SYNTHESIS
A total of 1887 articles were identified, of which 120 were used in this review. Most reports were retrospective and heterogeneous in caseload. There is a lack of standardised classification of CIS. Many studies consider CIS in the context of NMIBC without a clear separation of the subset with CIS. Recent prospective phase 2 and 3 studies have improved the evidence base.
CONCLUSIONS
We are beginning to understand that CIS has a spectrum of biologic potential. Bacillus Calmette-Guérin immunotherapy appears superior to other intravesical agents and may alter the natural history of CIS. New imaging modalities, agents, and treatment strategies have emerged in recent years with the aim of better identification of CIS, more bladder-preserving treatments, and prevention of surgical overtreatment.
PATIENT SUMMARY
Improvements in imaging techniques combined with new bladder-preserving treatments will continue to have an impact on the outcomes of bladder carcinoma in situ.
Topics: Adjuvants, Immunologic; Administration, Intravesical; Carcinoma in Situ; Carcinoma, Transitional Cell; Humans; Multimodal Imaging; Treatment Outcome; Urinary Tract; Urologic Neoplasms
PubMed: 25466937
DOI: 10.1016/j.eururo.2014.10.040 -
Therapeutic Advances in Urology Oct 2014The objective was to conduct a US multicenter, retrospective medical record study examining the effectiveness, safety, and patterns of use of valrubicin for treatment of...
OBJECTIVES
The objective was to conduct a US multicenter, retrospective medical record study examining the effectiveness, safety, and patterns of use of valrubicin for treatment of nonmuscle-invasive bladder cancer (NMIBC) by clinicians since the 2009 reintroduction of valrubicin.
METHODS
Patients ≥ 18 years with NMIBC who received had one or more instillations of valrubicin (October 2009- September 2011) were eligible. The primary endpoint was event-free survival (EFS). Safety and tolerability were also assessed.
RESULTS
The medical records of 113 patients met the inclusion criteria; 100 patients (88.5%) completed valrubicin treatment. The median age was 75 years (range 42-95 years). The median NMIBC duration was 31 months since diagnosis: 51.3% (58/113) had carcinoma in situ (CIS) alone, and 31.9% (36/113) had unspecified NMIBC. Most patients, 94.7% (107/113), had more than three valrubicin instillations and 70.8% (80/113) completed a full course. The EFS rate (95% confidence interval) was 51.6% (40.9-61.3%), 30.4% (20.4-41.1%), and 16.4% (7.9-27.5%) at 3, 6, and 12 months, respectively. Median time to an event was 3.5 (2.5-4.0) months after the first valrubicin instillation. Local adverse reactions (LARs) were experienced by 49.6% (56/113) of patients; most LARs were mild (93.6%). The most frequent LARs were hematuria, pollakiuria, micturition urgency, bladder spasm, and dysuria. In total, 4.4% (5/113) of patients discontinued valrubicin because of adverse events or LARs.
CONCLUSIONS
Data from the present retrospective study are consistent with previous prospective clinical trials that demonstrated valrubicin effectiveness and tolerability for select patients with CIS, before considering cystectomy. Additional prospective studies are warranted to evaluate valrubicin safety and efficacy in the broader patient population with NMIBC.
PubMed: 25276228
DOI: 10.1177/1756287214541798 -
Journal of Drugs in Dermatology : JDD Oct 2013Valrubicin is a semisynthetic anthracycline developed as an anti-cancer drug able to ameliorate psoriasis and non-melanoma skin cancer (NMSC) by topical application in...
BACKGROUND
Valrubicin is a semisynthetic anthracycline developed as an anti-cancer drug able to ameliorate psoriasis and non-melanoma skin cancer (NMSC) by topical application in animal models. Valrubicin decreases cell proliferation, and induces apoptosis; however its mode of action is still unknown. Valrubicin localizes in the cytoplasm and its valerate moiety resembles diacylglycerol, an activator of protein kinase C (PKC) α, which belongs to the PKC family of cytoplasmic serine/threonine protein kinases. PKCα is observed in the suprabasal layers of normal skin and is associated to keratinocyte growth arrest and differentiation processes. In hyper-proliferative skin diseases the presence of PKCα is altered.
OBJECTIVE
The aim of the present study was to investigate valrubicin's mode of action in keratinocytes by studying its possible effect on PKCα activation.
METHODS
PKCα's characteristic to translocate from the cytoplasm to the cellular membrane when activated was assessed by measuring the amount of PKCα in the soluble and membrane-bound protein fractions isolated from valrubicin stimulated keratinocytes and by visualizing PKCα in stimulated cells over time. Downstream signaling was investigated by measuring the amount of phosphorylated Myristoylated Alanine-rich C-kinase substrate (MARCKS) and extracellular signal-regulated kinases (ERK) 1/2 of valrubicin-stimulated keratinocytes. To investigate whether there was a direct interaction between valrubicin and PKCα, an activity assay employing purified PKCα protein was used.
RESULTS
Valrubicin activates PKCα in vitro as shown by PKCα's translocation and phosphorylation of downstream signaling molecules.
CONCLUSION
Valrubicin stimulates PKCα activity and downstream signaling which may contribute to its beneficial effect in psoriasis and NMSC.
Topics: Antineoplastic Agents; Cell Differentiation; Cell Line; Cell Proliferation; Doxorubicin; Humans; Intracellular Signaling Peptides and Proteins; Keratinocytes; Lipid Metabolism; MAP Kinase Signaling System; Membrane Proteins; Myristoylated Alanine-Rich C Kinase Substrate; Phosphorylation; Protein Kinase C-alpha; Protein Transport; Skin Diseases
PubMed: 24085052
DOI: No ID Found -
Current Urology Reports Apr 2013The definitive treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) who fail to respond to intravesical bacillus Calmette-Guérin (BCG) is... (Review)
Review
The definitive treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) who fail to respond to intravesical bacillus Calmette-Guérin (BCG) is cystectomy. However, many patients who experience recurrence after BCG are either poor operative candidates or refuse surgery due to the long-term impact on their quality of life. In the last decade, there has been an increased interest in alternative intravesical therapies, and several novel chemotherapeutics have emerged as promising agents for high-risk NMIBC patients unable or unwilling to undergo cystectomy. Additionally, extended treatment regimens with combined induction and maintenance therapy have been investigated, and may increase the durability of response to these new agents, as has been shown for conventional intravesical therapy.
Topics: Administration, Intravesical; Antineoplastic Agents; BCG Vaccine; Carcinoma, Transitional Cell; Deoxycytidine; Docetaxel; Doxorubicin; Humans; Mitomycin; Paclitaxel; Taxoids; Thiotepa; Treatment Failure; Urinary Bladder Neoplasms; Gemcitabine
PubMed: 23378162
DOI: 10.1007/s11934-013-0312-2