Thermo reversible hydrogel based delivery of mitomycin C for treatment of upper tract urothelial carcinoma (UTUC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16089-e16089 ◽  
Author(s):  
Jeffery Shyh-Jye Lin ◽  
Nir Kleinmann ◽  
Gregory J Wirth ◽  
Surena F. Matin ◽  
Gil Mayer ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Adverse Events ◽  
Mitomycin C ◽  
Unmet Need ◽  
Water Soluble ◽  
Phase Iii ◽  
Temperature Sensitive ◽  
Low Grade ◽  
Compassionate Use ◽  
Ureteral Catheter

e16089 Background: There is a large unmet need for novel drug delivery systems and effective therapy for UTUC, especially for patients with CKD and anatomic solitary kidneys. A temperature sensitive water-soluble gel formulation of Mitomycin C (MMC) demonstrated increased drug delivery time (4 to 6 hrs) and safety in the pelvicalyceal system of swine and human bladders. We report the efficacy and safety of gel+MMC as primary treatment (tx) of UTUC on a compassionate use basis. Methods: Compassionate use approval was obtained on an individual patient basis from the respective regulatory authorities and IRBs. 22 patients were approved for tx to date from 14 institutions in 4 countries. Tx included 6 weekly instillations instilled via ureteral catheter or percutaneous nephrostomy. Gel volume ranged from 5-20cc and MMC concentration was 2-6 mg/cc. Adverse events were recorded throughout treatment. Ureteroscopy was performed 2-6 weeks following tx completion for response determination. Results: Median age of the cohort was 75 yrs, with 15 males. 18 patients (pts) had low-grade (LG) tumor, 2 high-grade (HG), and 2 indeterminate grade. 16 (73%) completed treatment - 9 pts had a complete response, CR (41%; 59% of those who completed tx), 5 pts had a partial response, PR (23%; 31%), and 2 pts had no response, NR (9.1%, 12.5%). 4 patients could not complete tx due to adverse events (pyelonephritis, acute renal failure, pancytopenia, and unstable cardiac condition), 1 patient was diagnosed with a non-urothelial cancer during treatment, and 1 patient died prior to the third instillation due to suspected pulmonary embolus, determined to be unrelated to treatment with MitoGel. A total of 77 adverse events were recorded with 6 events related to MitoGel and serious (requiring intervention), and 21 events related to treatment and not serious. CR (9) and PR (5) were observed in 14 of 15 evaluable patients completing treatment for LG tumors. Conclusions: This compassionate use program of a thermosensitive gel+MMC for chemoablation of UTUC demonstrates proof of concept for treatment of low-grade tumors. A single arm Phase III multi-center registration trial to treat patients with low-grade renal pelvis tumors has been activated.

scholarly journals UGN-101 (mitomycin gel): a novel treatment for low-grade upper tract urothelial carcinoma

2020 ◽  
Vol 12 ◽  
pp. 175883592093795
Author(s):  
Andrea Kokorovic ◽  
Surena F. Matin
Keyword(s):  
Urothelial Carcinoma ◽  
Mitomycin C ◽  
Unmet Need ◽  
Invasive Disease ◽  
Upper Tract Urothelial Carcinoma ◽  
Phase Iii ◽  
Low Grade ◽  
Upper Tract ◽  
Carcinoma Of The Bladder ◽  
Rare Malignancy

Upper tract urothelial carcinoma (UTUC) is a rare malignancy. The standard treatment for localized high-risk disease is radical nephroureterectomy, which confers significant morbidity and is not appropriate for all patients. Patients harboring low-risk, non-invasive disease may be candidates for organ-sparing treatment, which includes endoscopic resection with or without intracavitary drug therapy. Successful administration of intracavitary chemotherapy to the upper tracts is impeded by rapid washout of the agent and short dwell times. This has limited the clinical utility of mitomycin C for treatment of upper tract tumors, despite the successful outcomes observed in low-grade urothelial carcinoma of the bladder. Currently, there is an unmet need for development of a technically feasible and oncologically sound intracavitary therapy for management of low-grade UTUC. UGN-101 (Jelmyto™) is a novel formulation of mitomycin C that uses a unique hydrogel designed to increase urinary dwell time, and thereby efficacy of treatment. Preclinical data demonstrated promising results regarding the safety and feasibility of this agent. Preliminary results of a phase III trial (OLYMPUS study) [ClinicalTrials.gov identifier: NCT02793128] demonstrated the efficacy of UGN-101 as a successful chemo-ablative agent for low-grade upper tract tumors. UGN-101 may represent a pivotal paradigm shift in the treatment of low-grade UTUC. Indeed, the drug has recently been granted approval by the US Food and Drug Administration as the first treatment for low-grade UTUC, which may lead to significant improvements in patient care and a long-awaited decrease in the burden of disease.

Mitomycin-C induction and maintenance topical therapy for upper tract urothelial carcinoma

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 411-411 ◽  
Author(s):  
Gavin Neal Wagenheim ◽  
John Papadopolous ◽  
Neema Navai ◽  
John W. Davis ◽  
Jose A. Karam ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Mitomycin C ◽  
Topical Therapy ◽  
Percutaneous Nephrostomy ◽  
Low Grade ◽  
High Grade ◽  
Ureteral Catheter ◽  
Upper Tract ◽  
Endoscopic Control

411 Background: Reported recurrence rates following endoscopic treatment of upper tract urothelial carcinoma (UTUC) are high, from 30% to 70%. Adjuvant BCG topical therapy results are inferior to what is seen in adjuvant treatment of bladder cancer. This is likely due to difficulty in definitive delivery to the upper tract and the absence of a reservoir for dwell times. There is limited reported use of adjuvant mitomycin-c (MMC) for UTUC, and to our knowledge no reported experience of topical delivery using the SWOG maintenance regimen. We hypothesized that a chemotherapeutic agent may be effective topical therapy of the upper tract, particularly when given using SWOG recommendations. We report efficacy, safety, and tolerability of this approach. Methods: We reviewed charts of patients undergoing primary endoscopic biopsy/resection and ablation of an UTUC, recording clinical, pathologic, laboratory, and follow up information. Patients were offered induction and maintenance topical therapy after endoscopic control. MMC was given as initial adjuvant topical agent for 6 weeks induction and 3 weeks maintenance for up to 2 years per SWOG protocol. Delivery was either via percutaneous nephrostomy or ureteral catheter, per patient preference. Results: 28 patients were identified, 21 (75%) low grade and 7 (25%) high grade. Delivery of MMC was via percutaneous nephrostomy in 29% and ureteral catheter in 71%. 46% were treated on an imperative basis, 46% elective, and 7% palliative. No patients discontinued therapy due to intolerance, and 61% received maintenance. Only 11% of patients undergoing induction and 6% maintenance incurred complications. With a mean follow up of 22 months (range 1−79), recurrence-free, progression-free, and nephroureterectomy-free survival in all patients, low-grade patients, and high-grade patients was 68%, 67%, and 71%; 89%, 90%, and 86%; and 89%, 90%, and 86%, respectively. Conclusions: In patients with complete endoscopic control, upper tract topical instillation of MMC induction and maintenance via percutaneous nephrostomy or ureteral catheter is a well−tolerated, feasible, and perhaps beneficial treatment of low-grade and possibly high-grade tumors.

scholarly journals Randomized, Multicenter, Placebo-Controlled Clinical Trial of Duloxetine Versus Placebo for Aromatase Inhibitor–Associated Arthralgias in Early-Stage Breast Cancer: SWOG S1202

2018 ◽  
Vol 36 (4) ◽  
pp. 326-332 ◽  
Author(s):  
N. Lynn Henry ◽  
Joseph M. Unger ◽  
Anne F. Schott ◽  
Louis Fehrenbacher ◽  
Patrick J. Flynn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Aromatase Inhibitor ◽  
Pain Score ◽  
Joint Pain ◽  
Early Stage ◽  
Early Stage Breast Cancer ◽  
Phase Iii ◽  
Musculoskeletal Symptoms ◽  
Low Grade

Purpose Adherence to aromatase inhibitor (AI) therapy for early-stage breast cancer is limited by AI-associated musculoskeletal symptoms (AIMSS). Duloxetine is US Food and Drug Administration approved for treatment of multiple chronic pain disorders. We hypothesized that treatment of AIMSS with duloxetine would improve average joint pain compared with placebo. Methods This randomized, double-blind, phase III trial included AI-treated postmenopausal women with early-stage breast cancer and who had average joint pain score of ≥ 4 out of 10 that developed or worsened since AI therapy initiation. Patients were randomly assigned 1:1 to duloxetine or placebo for 13 weeks. The primary end point was average joint pain through 12 weeks, examined using multivariable linear mixed models, adjusted for stratification factors (baseline pain score of 4 to 6 v 7 to 10 and prior taxane use). Clinically significant change in average pain was defined as a ≥ 2-point decrease from baseline. Results Of 299 enrolled patients, 127 patients treated with duloxetine and 128 who received placebo were evaluable for the primary analysis. By 12 weeks, the average joint pain score was 0.82 points lower for patients who received duloxetine compared with those who received placebo (95% CI, −1.24 to −0.40; P = .0002). Similar patterns were observed for worst joint pain, joint stiffness, pain interference, and functioning. Rates of adverse events of any grade were higher in the duloxetine-treated group (78% v 50%); rates of grade 3 adverse events were similar. Conclusion Results of treatment with duloxetine for AIMSS were superior to those of placebo among women with early-stage breast cancer, although it resulted in more frequent low-grade toxicities.

Effectiveness and Tolerance of Azacitidine for Treating Patients with Chronic Myelomonocytic Leukemia in Community-Based Management.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4855-4855
Author(s):  
Regina Garcia ◽  
Maria E Amutio ◽  
Manuel Almagro ◽  
Alicia Bailen ◽  
Jose F Falantes ◽  
...  
Keyword(s):  
Adverse Events ◽  
Injection Site Reaction ◽  
Chronic Myelomonocytic Leukemia ◽  
Phase Iii ◽  
World Health ◽  
Compassionate Use ◽  
Community Based ◽  
Dosing Schedule ◽  
Grade 3 ◽  
Myelomonocytic Leukemia

Abstract Abstract 4855 Introduction Azacitidine (AZA) was recently approved in Europe by the EMEA for the treatment of Chronic Myelomonocytic Leukemia (CMMoL). Traditionally, CMMoL has been considered as part of the myelodysplastic syndrome (MDS) according to the FAB (French-American-British) classification. Nowadays, according to the criteria proposed by the World Health Organization (WHO), it is included as a subgroup of diseases of mixed characteristics named as myelodysplastic/myeloproliferative diseases (MDS/MPD) separate from MDS. Recent discoveries in the molecular biology of CMMoL have provided new therapeutic agents to test. Treatment with AZA was approved by the EMEA on the basis of the AZA-001 phase III clinical trial. AZA is also approved for the treatment of the MDS. AZA was available in Spain under compassionate use before its regulatory approval (May 2009). We present the effectiveness and tolerance data for AZA clinical activity in patients with CMMoL included in the Spanish compassionate use registry. Material and Methods We present the preliminary clinical results taken from data from a longitudinal, multicenter Spanish patient registry, which retrospectively collected data from community-based hematology clinics on the disease course and management of patients with CMMoL treated in a compassionate use setting with AZA, in whom the dosing schedule administered was documented. AZA dosing was applied to the patients in two different dosing schedules in 28-day cycles: either days 1, 2, 3, 4 and 5 or days 1, 2, 3, 4, 5, 8 and 9. Choice of schedule was based on patient status. As of August 1, 2009, data from 10 patients with MDS diagnosed according to the WHO criteria had been collected. Response to treatment was assessed using the International Working Group (IWG 2006) criteria. Treatment toxicity was assessed using the NCI-CTCAE version 3.0 criteria. Results Data collection comprised results from 8 male and 2 female, with a median age of 64 years (range 62-80). An intermediate-2/high IPSS risk was documented in 20% of the patients and a 0-1 ECOG status before treatment initiation was documented 80% of the patients. Patients received a median of 5 cycles of AZA (range 2-12). The most frequently used dose was 75 mg/m2 (90%). A 5-day dosing schedule was administered to 70% of the patients and a 5+2 day dosing schedule with 2 free days was administered to the remaining 30%. The most frequent administration route was subcutaneous injection (70%). According to the IWG 2006 response criteria, 20% of patients obtained a complete response, 20% achieved a complete bone marrow response, and, in a further 10%, hematological response was documented. The grade 3-4 adverse events, regardless of their relationship with the active treatment, were of hematological nature (neutropenia n=5, thrombocytopenia n=4, anemia n=1). Other grade 3-4 adverse events documented were rash (n=2), injection site reaction (n=1), hypotension (n=1) and constitutional symptoms (n=1). These rates do not differ from those obtained in the AZA-001 study. Conclusions These results demonstrate that AZA is effective for the treatment of patients with CMMoL in community-based management. Different dosing schedules are prescribed to patients with CMMoL treated with AZA in the community-based setting. Further analyses from this registry are awaited. Disclosures No relevant conflicts of interest to declare.

Time course of regorafenib-associated adverse events in the phase III CORRECT study

2013 ◽  
Vol 51 (08) ◽  
Author(s):  
C Denzlinger ◽  
A Grothey ◽  
AF Sobrero ◽  
E van Cutsem ◽  
S Siena ◽  
...  
Keyword(s):  
Adverse Events ◽  
Time Course ◽  
Phase Iii

Formulation Optimization of Sustained Release Resinate Microcapsules of Tramadol Hydrochloride by Using 3/2 Factorial Design

2017 ◽  
Vol 6 (2) ◽  
pp. 57
Author(s):  
Kamble Ravindra K. ◽  
Chauhan Chetan S. ◽  
Kamble Priyadarshani R. ◽  
Naruka Pushpendra S.
Keyword(s):  
Drug Delivery ◽  
Ion Exchange ◽  
Sustained Release ◽  
Factorial Design ◽  
Linear Regression Analysis ◽  
Extended Period ◽  
Multiple Linear Regression Analysis ◽  
Water Soluble ◽  
Tramadol Hydrochloride ◽  
Release Drug

The main aim of the present work was to develop the microcapsules of tramadol hydrochloride for the oral sustained release drug delivery. Tramadol hydrochloride a BCS class I drug a centrally acting synthetic analgesic was complexed with Indion 254 ion exchange resin. The microcapsules were prepared by encapsulating the prepared resinates by o/o solvent evaporation technique. In the investigation 32 full factorial design was used to investigate the joint influence of two formulation variable amount of eudragit RS 100 and plasticized PEG 400. The results of multiple linear regression analysis indicated that for obtaining a sustained release drug delivery the optimum concentrations of both the plasticizer and coating solution to be used. The factorial models were used to prepare optimized microcapsules and optimized formulations showed sustained release profiles for the extended period of more than 12 hrs. From the present investigations concluded that resinate microcapsules of highly water soluble drug can provide controlled release of drug for extended period.Key Words: Tramadol hydrochloride, ion exchange resinate, microcapsules, sustained release

Development of Solid-Self Micron Emulsifying Drug Delivery Systems

2013 ◽  
Vol 6 (2) ◽  
pp. 2014-2021
Author(s):  
Preethi Sudheer ◽  
Koushik Y ◽  
Satish P ◽  
Uma Shankar M S ◽  
R S Thakur
Keyword(s):  
Drug Delivery ◽  
Systemic Circulation ◽  
Water Soluble ◽  
Future Research ◽  
Steady Increase ◽  
Liquid Form ◽  
Lipophilic Compounds ◽  
Modern Drug ◽  
Pharmaceutical Scientist ◽  
Pharmacologically Active

As a consequence of modern drug discovery techniques, there has been a steady increase in the number of new pharmacologically active lipophilic compounds that are poorly water soluble and solubility is one of the most important parameter to achieve desired concentration of drug in systemic circulation for therapeutic response. It is a great challenge for pharmaceutical scientist to convert those molecules into orally administered formulation with sufficient bioavailability.  Among the several approaches to improve oral bioavailability of these molecules, Self-micron emulsifying drug delivery system (SMEDDS) is one of the approaches usually used to improve the bioavailability of hydrophobic drugs. However, conventional SMEDDS are mostly prepared in a liquid form, which can have several disadvantages. Accordingly, solid SMEDDS (S-SMEDDS) prepared by solidification of liquid/semisolid self-micron emulsifying (SME) ingredients into powders have gained popularity. This article provides an overview of the recent advancements in S-SMEDDS such as methodology, techniques and future research directions.

Recent Advances in Novasome Formulation Technology

2014 ◽  
Vol 7 (2) ◽  
pp. 2407-2411
Author(s):  
J M Shah ◽  
N.H Shah ◽  
Hadiya P D
Keyword(s):  
Drug Delivery ◽  
Effective Means ◽  
Entrapment Efficiency ◽  
Bilayer Membrane ◽  
Water Soluble ◽  
Delivery Methods ◽  
Liposomal Drug ◽  
Pharmaceutical Technology ◽  
Insoluble Drugs ◽  
Novel Drug

Pharmaceutical technology has developed various newer modes of novel drug delivery aspects. Modifications in the previously existing drug delivery methods have led to various newly innovated technologies serving as a safe and effective means of improvement over the existing ones. Novasome technology is one of the new innovations of liposomes which have solved many of the problems related to liposomal drug delivery system. It offers a seven bilayer membrane which has the ability to incorporate both water soluble and insoluble drugs. It has an excellent entrapment efficiency which provides better medication. Formulation of novasomes is achieved in a high shear device. Due to its numerous advantages, novasomes have been used extensively in various fields like cosmetics, chemical, personal care, foods, pharmaceuticals and agrochemicals.

Self Microemulsifying Nutraceutical and Drug Delivery Systems

2014 ◽  
Vol 7 (3) ◽  
pp. 2520-2528 ◽  
Author(s):  
Vikrant P Wankhade ◽  
Nivedita S Kale ◽  
K.K Tapar
Keyword(s):  
Drug Delivery ◽  
Drug Delivery System ◽  
Delivery System ◽  
Ternary Phase Diagram ◽  
Aqueous Solubility ◽  
Oral Formulation ◽  
Water Soluble ◽  
Drug Dissolution ◽  
The Novel ◽  
Peristaltic Movement

Many chemical entities and nutraceuticals are poor water soluble and show high lipophilicity. It’s difficult to formulate them into oral formulation because of its low aqueous solubility which ultimately affects bioavailability. To enhance the bioavailability of such drugs compounds, self microemulsifying drug delivery system is the reliable drug delivery system. In this system the drug is incorporated in the isotropic system and formulated as unit dosage form. Self microemulsifying drug delivery system is the novel emulsified system composed of anhydrous isotropic mixture of oils, surfactant, and co solvent and sometimes co surfactant. Drug is directly dispersed into the entire gastro intestinal tract with continuous peristaltic movement and drug is available in the solution form of microemulsion, absorbed through lymphatic system and bypasses the dissolution step. Hence they increase the patient compliance. The excipients are selected on basis of construction of ternary phase diagram. Self micro-emulsifying drug delivery system is very useful for drug in which drug dissolution is rate limiting step. This review describes the novel approaches and evaluation parameters of the self microemulsifying drug delivery system towards different classic drugs, proteins-peptides, and nutraceuticals in various oral microemulsion compositions and microstructures.

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