Experience with non-cremophor-based paclitaxel-gemcitabine regimen in advanced pancreatic cancer: Results from a single tertiary cancer centre

Background & objectives: Gemcitabine combined with non-cremophor-based paclitaxel is one of the standards of care in advanced inoperable pancreatic cancer. This study was undertaken to retrospectively evaluate real world non-trial outcomes with this combination. Methods: Patients with histologically proven advanced inoperable pancreatic adenocarcinoma (PDAC), treated with non-cremophor-based paclitaxel-gemcitabine combination (PG) (gemcitabine-nanoxel or gemcitabine-abraxane) between January 2012 and June 2015, were retrospectively analyzed. Response assessment was done every 8-12 wk with computed tomography scan and responses were measured as per the Response Evaluation Criteria in Solid Tumours 1.1 criteria where feasible. Toxicity was recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) v4 criteria. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results: A total of 78 patients with PDAC were treated with the combination. Of these, 83.3 per cent of patients had metastatic disease. The median number of chemotherapy cycles administered was three. The objective response rate for the whole group was 30.8 per cent. Grade III/IV toxicities were seen in 35.9 per cent of patients. Median PFS was 5.6 months and median OS was 11.6 months. Interpretation & conclusions: Non-cremophor-based paclitaxel in combination with gemcitabine appeared efficacious for advanced pancreatic cancers in routine clinical practice. Within the confines of a single-centre retrospective analysis, gemcitabine-nanoxel and gemcitabine-abraxane appeared to have similar efficacy and toxicity in advanced pancreatic cancers.

Non-convulsive seizure related to Cremophor EL™-free, polymeric micelle formulation of paclitaxel: a case report

Paclitaxel is a chemotherapeutic agent that is effective against ovarian, breast, lung, and other cancers. Although peripheral neurotoxicity is among the most common side effects of paclitaxel treatment, central neurotoxicity is rarely reported. When centrally mediated side effects are observed, they are attributed to Cremophor EL™ (CrEL), a surfactant-containing vehicle used for paclitaxel administration. In the present report, we discuss the case of a 72-year-old woman with ovarian carcinoma who experienced a non-convulsive seizure following administration of a CrEL-free, polymeric micelle formulation of paclitaxel. One week after her fourth round of chemotherapy, she experienced a transient episode of aphasia for 45 minutes. Electroencephalography demonstrated epileptiform discharges. To our knowledge, this is the first reported case of seizure associated with a CrEL-free formulation of paclitaxel. Although rare, patients and clinicians should remain aware of the risk of non-convulsive seizure following infusion of this paclitaxel formulation.

An Open-Label, Randomized, Parallel, Phase III Trial Evaluating the Efficacy and Safety of Polymeric Micelle-Formulated Paclitaxel Compared to Conventional Cremophor EL-Based Paclitaxel for Recurrent or Metastatic HER2-Negative Breast Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Genexol-PM is a Cremophor EL–free formulation of low-molecular-weight, non-toxic, and biodegradable polymeric micelle-bound paclitaxel. We conducted a phase III study comparing the clinical efficacy and toxicity of Genexol-PM with conventional paclitaxel (Genexol). MATERIALS AND METHODS: Patients were randomly assigned (1:1) to receive Genexol-PM 260 mg/m² or Genexol 175 mg/m² intravenously every 3 weeks. The primary outcome was the objective response rate (ORR). RESULTS: The study enrolled 212 patients, of whom 105 were allocated to receive Genexol-PM. The mean received dose intensity of Genexol-PM was 246.8±21.3 mg/m² (95.0%), and that of Genexol was 168.3±10.6 mg/m² (96.2%). After a median follow-up of 24.5 months (range, 0.0 to 48.7 months), the ORR of Genexol-PM was 39.1% (95% confidence interval [CI], 31.2 to 46.9) and the ORR of Genexol was 24.3% (95% CI, 17.5 to 31.1) (p(non-inferiority)=0.021, p(superiority)=0.016). The two groups did not differ significantly in overall survival (28.8 months for Genexol-PM vs. 23.8 months for Genexol; p=0.52) or progression-free survival (8.0 months for Genexol-PM vs. 6.7 months for Genexol; p=0.26). In both groups, the most common toxicities were neutropenia, with 68.6% occurrence in the Genexol-PM group versus 40.2% in the Genexol group (p < 0.01). The incidences of peripheral neuropathy of greater than grade 2 did not differ significantly between study treatments. CONCLUSION: Compared with standard paclitaxel, Genexol-PM demonstrated non-inferior and even superior clinical efficacy with a manageable safety profile in patients with metastatic breast cancer.

The Hidden Culprit: A Case of Repeated Anaphylaxis to Cremophor

Drug-induced anaphylaxis is a big pitfall in patients receiving antineoplastic chemotherapy. We report a case of lung cancer patient who experienced two near-fatal anaphylactic reactions that resulted from paclitaxel and multivitamin, seperately. Recurrent severe reactions to different agents led to further investigation to which material the patient was hypersensitive. The skin prick test revealed sensitization to cremophor, which is a commonly used emulsifying agent. This case emphasizes the importance of correctly identifying the culprit drug of anaphylaxis to avoid potentially fatal reaction.

Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?

Tacrolimus and cyclosporine have been used in various formulations, but their hypersensitivity reactions are rare in practice. Castor oil derivatives are nonionic surfactants used in aqueous preparations of hydrophobic active pharmaceutical ingredients. Castor oil derivatives that can be used as additives to tacrolimus and cyclosporine may play a role in the development of hypersensitivity reactions, especially anaphylaxis. Various immunologic and nonimmunologic mechanisms have been implicated in hypersensitivity reactions induced by castor oil derivatives. Physicians should be aware that not only the drug itself, but also its additives or metabolites could induce hypersensitivity reactions. We report a case of anaphylaxis caused by vitamin K (phytonadine), serotonin antagonist (granisetron), intravenous tacrolimus, and cyclosporine. Interestingly, the patient tolerated oral cyclosporine, which did not contain Cremophor EL or polysorbate 80.

Dissolution Enhancement of Loratadine by Formulating Oleic Acid and Cremophor EL Based Self Emulsifying Drug Delivery System (SEDDS).

For this experiment, Oleic Acid and Cremophor EL based Loratadine SEDDS were prepared. Different amount of solvent and surfactant were used to prepare SEDDS. After preparation of different formulations their dissolution studies were performed at 50-rpm, paddle method in which dissolution medium was maintained at 37°C (0.5°C) temperature by using Dissolution Tester USP II. Three capsules from each formulation were used in each dissolution study and the release profile of Loratadine was monitored up to one hour. For the formulation development with fixed dose Loratadine (10 mg) and varying amounts of oleic Acid and Cremophor EL were used. In the experiment major determinant is found to be surfactant concentration. In all cases it is found that higher surfactant concentration increased the drug release. Other two determinant factors are amount of Oleic acid and percent drug loading. It was observed that without Cremophor EL, drug release from the formulation was slow. The rate and extent of drug release increased from the matrices with increasing the amount of Cremophor EL in the formulation.

Dissolution enhancement of Capmul PG8 and Cremophor EL based Ibuprofen Self Emulsifying Drug Delivery System (SEDDS) using Response surface methodology.

In this study, a solubility enhancing technique, Self-emulsifying drug delivery system (SEDDS), was considered to be developed for Ibuprofen, a poorly soluble drug. Capmul PG 8 was used as a co-solvent. As surfactant, hydrophilic surfactant Cremophor EL was considered. A fixed amount of Ibuprofen was added with fixed amount of excipients. Capmul PG8 showed a good solubilizing capacity which dissolved 300 mg/ml of Ibuprofen. Cremophor EL also showed a good solubilizing capacity which dissolved 300 mg/ml of Ibuprofen. Ibuprofen is a poorly soluble drug which was used as experimental drug and pH 7.2 phosphate buffer was used as dissolution medium. The amount of drug was measured form the absorbance of UV spectrophotometer at 221 nm. A 3-level factorial design was carried out to optimize the formulation using design expert software trial version 8.0.3.1. Capmul PG8 and Cremophor EL were used as independent variables where percent drug release at 5, 15 and 45 minutes. The optimized formula contains 24.10 mg Capmul PG8 and 71.02 mg Cremophor EL which releases 27.78%, 44.6% and 74.24% ibuprofen at the mentioned time interval. The present study shows that the Capmul PG8 and Cremophor EL have effect the release profile of capsule Ibuprofen. It is found that it is possible to increase the release of Ibuprofen by using Capmul PG8 and Cremophor EL.

Dissolution enhancement of Capmul PG8 and Cremophor EL based Ibuprofen Self Emulsifying Drug Delivery System (SEDDS) using Response surface methodology.

In this study, a solubility enhancing technique, Self-emulsifying drug delivery system (SEDDS), was considered to be developed for Ibuprofen, a poorly soluble drug. Capmul PG 8 was used as a co-solvent. As surfactant, hydrophilic surfactant Cremophor EL was considered. A fixed amount of Ibuprofen was added with fixed amount of excipients. Capmul PG8 showed a good solubilizing capacity which dissolved 300 mg/ml of Ibuprofen. Cremophor EL also showed a good solubilizing capacity which dissolved 300 mg/ml of Ibuprofen. Ibuprofen is a poorly soluble drug which was used as experimental drug and pH 7.2 phosphate buffer was used as dissolution medium. The amount of drug was measured form the absorbance of UV spectrophotometer at 221 nm. A 3-level factorial design was carried out to optimize the formulation using design expert software trial version 8.0.3.1. Capmul PG8 and Cremophor EL were used as independent variables where percent drug release at 5, 15 and 45 minutes. The optimized formula contains 24.10 mg Capmul PG8 and 71.02 mg Cremophor EL which releases 27.78%, 44.6% and 74.24% ibuprofen at the mentioned time interval. The present study shows that the Capmul PG8 and Cremophor EL have effect the release profile of capsule Ibuprofen. It is found that it is possible to increase the release of Ibuprofen by using Capmul PG8 and Cremophor EL

Effect of (-)- Δ9 -tetrahydrocannabinoid on the hepatic redox state of mice

(-)-∆9-Tetrahydrocannabinol (∆9-THC), a psychoactive component of marijuana, has been reported to induce oxidative damage in vivo and in vitro. In this study, we administered (∆9-THC to healthy C57BL/6J mice aged 15 weeks in order to determine its effect on hepatic redox state. Mice were divided into 3 groups: (∆9-THC (N = 10), treated with 10 mg/kg body weight (∆9-THC daily; VCtrl (N = 10), treated with vehicle [1:1:18, cremophor EL® (polyoxyl 35 castor oil)/ethanol/saline]; Ctrl (N = 10), treated with saline. Animals were injected ip twice a day with 5 mg/kg body weight for 10 days. Lipid peroxidation, protein carbonylation and DNA oxidation were used as biomarkers of oxidative stress. The endogenous antioxidant defenses analyzed were glutathione (GSH) levels as well as enzyme activities of superoxide dismutase, catalase, glutathione S-transferase, glutathione reductase, and glutathione peroxidase (GPx) in liver homogenates. The levels of mRNA of the cannabinoid receptors CB1 and CB2 were also monitored. Treatment with ∆9-THC did not produce significant changes in oxidative stress markers or in mRNA levels of CB1 and CB2 receptors in the liver of mice, but attenuated the increase in the selenium-dependent GPx activity (∆9-THC: 8 percent; VCtrl: 23 percent increase) and the GSH/oxidized GSH ratio (∆9-THC: 61 percent; VCtrl: 96 percent increase), caused by treatment with the vehicle. ∆9-THC administration did not show any harmful effects on lipid peroxidation, protein carboxylation or DNA oxidation in the healthy liver of mice but attenuated unexpected effects produced by the vehicle containing ethanol/cremophor EL®.

Inhibitive Effect of Cremophor RH40 or Tween 80-based Self-microemulsiflying Drug Delivery System on Cytochrome P450 3A Enzymes in Murine Hepatocytes / 华中科技大学学报（医学）（英德文版）

This study examined the effect of self-microemulsiflying drug delivery system (SMEDDS) containing Cremophor RH40 or Tween 80 at various dilutions on cytochrome P450 3A (CYP3A) enzymes in rat hepatocytes, with midazolam serving as a CYP3A substrate. The particle size and zeta potential of microemulsions were evaluated upon dilution with aqueous medium. In vitro release was detected by a dialysis method in reverse. The effects of SMEDDS at different dilutions and surfactants at different concentrations on the metabolism of MDZ were investigated in murine hepatocytes. The cytotoxicity of SMEDDS at different dilutions was measured by LDH release and MTT technique. The effects of SMEDDS on the CYP3A enzymes activity were determined by Western blotting. Our results showed that dilution had less effect on the particle size and zeta potential in the range from 1:25 to 1:500. The MDZ was completely released in 10 h. A significant decrease in the formation of 1'-OH-MDZ in rat hepatocytes was observed after treatment with both SMEDDS at dilutions ranging from 1:50 to 1:250 and Cremophor RH 40 or Tween 80 at concentrations ranging from 0.1% to 1% (w/v), with no cytotoxicity observed. A significant decrease in CYP3A protein expression was observed in cells by Western blotting in the presence of either Cremophor RH40 or Tween 80-based SMEDDS at the dilutions ranging from 1:50 to 1:250. This study suggested that the excipient inhibitor-based formulation is a potential protective platform for decreasing metabolism of sensitive drugs that are CYP3A substrates.

The Effect of Cycolsporine A on the Expression of Von Willebrand Factor in Human Glomerular Endothelial Cells / 대한신장학회잡지

Cyclosporine(CsA) is a modulator of the immune system used therapeutically to prevent organ transplant rejection. However, it is nephrotoxic and causes thrombotic phenomena after renal and bone marrow transplantation. CsA nephrotoxicity in vivo is associated with elevated levels of von Willebrand factor(vWf), which is a multimeric plasm glycoprotein secreted by endothelial cells and platelets. CsA is not soluble in water and the intravenous form given to patients is dissolved in a vehicle called cremophor EL. The vehicle has been implicated in anaphylatic reactions and associated with the release of histamine in vivo. We hypothesized that CsA or cremophor might affect the release of vWf from human glomerular endothelial cells. vWf was measured in culture supernant using ELISA kit after speed vaccum for 3 hour. The expression of vWf in cultured human glomerular endothelial cells was relatively low compared to human plasm in vivo. CsA alone did not increase vWf release(100%, 99.9+/-0.7%, 99.1+/-2.9%, 106+/-21.5%, CsA 0, 0.1, 1, 10microM mean S.E., n=2), but cremophor EL increased vWf release (100%, 104.0+/-8.6%, 117.6+/-9.5%, 121.3+/-12.2%, mean+/-S.E., n=3). These results were same as the results of experiments under thrombin(1IU/ml) and histamine(10(-4)M). The increased expression of vWf in human glomerular endothelial cells in response to CsA seems to be related to cremophor, the solvent, rather than CsA itself in vitro culture experiments.