Polyethoxylated Castor Oil Research Articles

High-abundance peaks and peak clusters associate with pharmaceutical polymers and excipients in urinary untargeted clinical metabolomics data: exploration of their origin and possible impact on label-free quantification.

Pharmaceutical polymers and excipients represent interesting but often overlooked chemical classes in clinical exposure and bioanalytical research. These chemicals may cause hypersensitivity reactions, they can be useful to confirm exposure to pharmaceuticals, and they may pose bioanalytical challenges, including ion suppression in liquid chromatography-mass spectrometry (LC-MS-)based workflows. In this work, we assessed these chemicals in light of a rather surprising finding presented in two previously published studies, namely that usage of cyclosporine A, an immunosuppressive drug which is known to be cleared through excretion in the bile, explained the largest amount of variance in principal component analysis of urinary LC-SWATH/MS small-molecule profiling data. Specifically, we examined the freely-accessible 24-hour urine metabolomics data of 570 kidney transplant recipients included in the TransplantLines Biobank and Cohort Study (NCT03272841). These data unveiled thousands of high-abundance polymer peaks in some samples, which were associated with the use of the macrogol (i.e., polyethylene glycol) 3350 oral laxative agent. In addition, we found multiple clusters of high-abundance peaks which were linked to the exposure to two pharmaceutical excipients, namely short-chain polyethylene glycol (molecular weight <1000 Da) and polyethoxylated castor oil (also known as Kolliphor® EL or Cremophor® EL). Respectively, these excipients are used in temazepam capsules and cyclosporine A capsules, and the latter provides a plausible explanation for the rather surprising finding that instigated our work. Moreover, such explanation and our findings in general put emphasis on taking into consideration these and other pharmaceutical polymers and excipients when exploring, processing, and interpreting clinical small-molecule profiling data.

Micellar Suzuki Cross-Coupling between Thiophene and Aniline in Water and under Air

The Suzuki–Miyaura cross-coupling reaction plays a fundamental role in modern synthetic organic chemistry, both in academia and industry. For this reason, scientists continue to search for new, more effective, cheaper and environmentally friendly procedures. Recently, micellar synthetic chemistry has been demonstrated to be an excellent strategy for achieving chemical transformations in a more efficient way, thanks to the creation of nanoreactors in aqueous environments using selected surfactants. In particular, the cheap and commercially available surfactant Kolliphor EL (a polyethoxylated castor oil derivative) has been used with success to achieve metal-catalyzed transformations in water with high yields and short reaction times, with the advantage of using air-sensitive catalysts without the need for inert atmosphere. In this work, the Kolliphor EL methodology was applied to the Suzuki cross-coupling reaction between thiophene and aniline, using the highly effective catalyst Pd(dtbpf)Cl2. The cross-coupling products were achieved at up to 98% yield, with reaction times of up to only 15 min, working at room temperature and without the need for inert atmosphere.

Design, Optimization and Characterization of Nanostructured Lipid Carriers of Raloxifene Hydrochloride for Transdermal Delivery

Introduction: Raloxifene Hydrochloride (RXL), a BCS class II drug, is used for the treatment of invasive breast cancer and osteoporosis in post menopausal women. Even though the drug is highly efficient, it shows poor bioavailability of 2% when administered orally. The aim of the study was to develop, statistically optimize, and characterize Raloxifene Hydrochloride loaded Nanostructured Lipid Carriers (NLC) for transdermal delivery to overcome the bioavailability issue. Methods: The RXL-NLC’s were developed using glyceryl behenate (Compritol® 888 ATO), glyceryl monostearate (GMS), and capric triglyceride (Miglyol® 810) as solid and liquid lipids, and Polysorbate 80 (Tween 80) and cremophor EL were used as surfactants and co-surfactant. A response surface methodology was applied for the optimization of NLC, using Box-Behnken experimental design. Amount of the drug, tween 80 and polyethoxylated castor oil (cremophor EL), each at three levels, were selected as independent variables, while particle size and polydispersity index were identified as dependent variables. The optimized batch was characterized for Particle size (79.8 nm±3), Polydispersity index (0.229±0.05), Zeta potential (-12.3±5) and Entrapment efficiency (79.14%±5). Surface morphology of the NLC’s were studied using Transmission Electron microscopy (TEM) and the shift in the endotherm of Differential scanning calorimetry confirmed the entrapment of the drug within NLC. In vitro drug release studies were performed using dialysis bag (12000-14000 Da) method. The optimized NLC dispersion was then incorporated into gel and characterized for gel uniformity, spreadability, pH, viscosity and drug content. Results: In vivo skin penetration study was carried out by tape stripping method, which showed increase in penetration when incorporated into nanogel as compared to plain drug gel. Conclusion: Based on the above result it can be concluded that transdermal delivery of NLC’s can be a superior alternative for orally low bioavailable drugs such as RXL which undergoes rapid first pass metabolism.

Slow Pyrolysis of Biomass in Acidic or Metallic Catalysis

Achieving the process of pyrolysis of biomass in mild conditions is a viable option for optimizing yield in liquid products and reducing coke yield. The partially dried digestate was stabilized by suspending in a reverse emulsion containing the lipid fraction resulting from the processing of the crude digestate, a hydrophobic surfactant of the polyethoxylated castor oil type and a hydrophilic sorbitol-polyethoxylated fatty acid ester type. The pyrolysis of the digestate was carried out in a continuous system, in a quartz tubular reactor, positioned in the central area of a vertical furnace provided with an automatic temperature control system. The experimental program was performed in the presence of two catalysts, Cu and respectively polyphosphoric acid at atmospheric pressure, temperature in the isothermal reaction zone 460 oC and liquid hourly space velocity of 0.33 h-1. The composition of the liquid fractions obtained on the two catalysts differs by the presence of a higher concentration of branched isomers in the case of the polyphosphoric acid catalyst.

Allergic reactions to polyethoxylated castor oil derivatives: A guide to decipher confusing names on pharmaceutical labels

Allergic reactions to polyethoxylated castor oil derivatives: A guide to decipher confusing names on pharmaceutical labels

One‐Pot Transformation of Ketoximes into Optically Active Alcohols and Amines by Sequential Action of Laccases and Ketoreductases or ω‐Transaminases

AbstractAn enzymatic one‐pot process for asymmetric transformation of prochiral ketoximes into alcohols or amines was developed by sequential coupling of a laccase‐catalyzed deoximation either with a ketone reduction (ketoreductase, KRED) or bioamination (ω‐transaminase, ω‐TA) in aqueous medium. An accurate selection of biocatalysts provided the corresponding products in excellent enantiomeric excesses and overall conversions ranging from 83 to &gt;99 % for alcohols and 70 to &gt;99 % for amines. Likewise, the employment of exclusively 1 % (w/w) of Cremophor®, a polyethoxylated castor oil, as co‐solvent enabled to reach concentrations up to 100 mM in the chiral alcohols cascade.

Synthesis, Biological Evaluation and Low-Toxic Formulation Development of Glycosylated Paclitaxel Prodrugs.

Paclitaxel (PTX) is a famous anti-cancer drug with poor aqueous solubility. In clinical practices, Cremophor EL (polyethoxylated castor oil), a toxic surfactant, is used for dissolution of PTX, which accounts for serious side effects. In the present study, a single glucose-conjugated PTX prodrug (SG-PTX) and a double glucose-conjugated PTX prodrug (DG-PTX) were synthesized with a glycosylated strategy via succinate linkers. Both of the two prodrugs presented significant solubility improvement and drug-like lipophilicities. Compared to DG-PTX, SG-PTX manifested more promising release of the parent drug in serum. A high percentage of PTX released from SG-PTX could be detected after enzymatic hydrolysis of β-glucuronidase. Besides, both of the two prodrugs exhibited effective cytotoxicity against breast cancer cells and ovarian cancer cells, but presented reduced cytotoxicity against normal breast cells. Moreover, SG-PTX manifested impressive solubility in a low toxic formulation (without ethanol) with a different percentage of Cremophor EL. These results indicated that glycosylation is a promising strategy for PTX modification and SG-PTX may be a feasible and potential type of PTX prodrug. In addition, ethanol-free formulation with a low percentage of Cremophor EL might have the potential to develop a safer formulation for further studies of glycosylated PTX prodrugs.

Preformulation studies to guide the development of raloxifene lipid-based delivery systems

This study sought to evaluate raloxifene hydrochloride (RLX) solubility and compatibility with lipid excipients (oils, water-soluble and water-insoluble surfactants) with a view of assisting in the proper choice of excipients in the development of lipid-based drug delivery systems. Drug–lipid excipient compatibility was studied using thermal analysis (differential scanning calorimetry and thermogravimetry), and isothermal stress testing (IST) with a validated HPLC method. Drug solubility was determined using equilibrium solubility and pharmacopoeial methods. Among the eleven studied excipients, sunflower oil and soy lecithin presented clear signs of thermal interaction and reduction in the stability of RLX, while mixtures containing emulium® 22 showed a significant reduction in drug content. These three materials were considered incompatible with RLX. The solubility study revealed that RLX has higher solubility in castor oil and in its derivative, polyethoxylated castor oil. Plurol Isostearique® showed the best result among the water-insoluble surfactants. Thermal analysis associated with accelerated IST studies and together with solubility determinations have been shown to be a valuable strategy for the development of lipid-based drug delivery systems containing RLX.

Practical Liposomal Formulation for Taxanes with Polyethoxylated Castor Oil and Ethanol with Complete Encapsulation Efficiency and High Loading Efficiency.

Taxanes including paclitaxel and docetaxel are effective anticancer agents preferably sufficient for liposomal drug delivery. However, the encapsulation of these drugs with effective amounts into conventional liposomes is difficult due to their high hydrophobicity. Therefore, an effective encapsulation strategy for liposomal taxanes has been eagerly anticipated. In this study, the mixture of polyethoxylated castor oil (Cremophor EL) and ethanol containing phosphate buffered saline termed as CEP was employed as a solvent of the inner hydrophilic core of liposomes where taxanes should be incorporated. Docetaxel-, paclitaxel-, or 7-oxacetylglycosylated paclitaxel-encapsulating liposomes were successfully prepared with almost 100% of encapsulation efficiency and 29.9, 15.4, or 29.1 mol% of loading efficiency, respectively. We then applied the docetaxel-encapsulating liposomes for targeted drug delivery. Docetaxel-encapsulating liposomes were successfully developed HER2-targeted drug delivery by coupling HER2-specific binding peptide on liposome surface. The HER2-targeting liposomes exhibited HER2-specific internalization and enhanced anticancer activity in vitro. Therefore, we propose the sophisticated preparation of liposomal taxanes using CEP as a promising formulation for effective cancer therapies.

Selection of excipients for the development of carvedilol loaded lipid-based drug delivery systems

Carvedilol (CARV) is a widely used drug, which has shown low oral bioavailability. Lipid-based drug delivery systems (LBDDS) appear as promising alternatives to overcome CARV pharmacokinetic issues. Despite the pharmaceutical potential of LBDDS, the lipids used in these systems present stability issues and their use demands caution. This study set out to evaluate different lipid vehicles for CARV in terms of their ability to dissolve the drug and preserve its stability in LBDDS. The CARV solubility was determined in nine commonly used lipid excipients. Thermal and spectroscopic analysis (DSC, TG, FTIR), and accelerated stability studies were used to characterize drug-excipient interaction. CARV has highest solubility in polyethoxylated castor oil (PcasO), castor oil (CasO) and caprylic/capric triglycerides (CCT), ranging from 70 to 4 mg mL−1. DSC and FTIR analyses showed evidence of drug-oil interaction. TG results gained in inert and oxidative atmosphere showed that these interactions lead to a drug stability loss at temperatures above 300 °C, especially in binary mixtures of CARV with CCT, sesame oil (SesO) and CasO. On the other hand, in accelerated stability studies performed at 50 °C, CARV solutions in CCT and SesO were the most stable systems. The results of this study showed that CARV had high solubility and stability in PcasO. This means that PcasO is suitable for systems demanding high drug concentration and which are produced at high temperatures. On the other hand, SesO and CCT can give rise to less concentrated systems which can be stable when produced at low temperatures.

Abstract 3657: Preclinical evaluation of water-soluble pyrrolo[3,2-d]pyrimidines as single agents with tubulin and multiple receptor tyrosine kinase inhibition and as antitumor agents

Abstract Multiple classes of microtubule targeting agents have been identified and these include the Vinca alkaloids and colchicine (microtubule-destabilizers) and taxanes (microtubule-stabilizers). Although tubulin targeting agents are some of the most successful drugs used in the treatment of a wide range of malignancies, multidrug resistance due to overexpression of P-glycoprotein (Pgp) and/or βIII-tubulin can severely limit their clinical efficacy. Antitubulin agents like paclitaxel and other taxanes, due to poor water solubility, are formulated with polyethoxylated castor oil which can cause hypersensitivity reactions and require prolonged administration time. Recently, we reported water-soluble pyrrolo[3,2-d]pyrimidine analogs acting as antitubulin agents that circumvent these drawbacks. These analogs also exhibit potency comparable to erlotinib in cancer cell lines overexpressing epidermal growth factor receptor (EGFR) and to that of sunitinib in cancer cell lines overexpressing vascular endothelial growth factor receptor-2 (VEGFR2) and platelet derived growth factor receptor-β (PDGFRβ), in addition to inhibiting tubulin. Promising evidence for the clinical success of combination chemotherapy using multiple RTK inhibitors with antitubulin agents suggests that these dual acting compounds would serve as a single entity with both these activities. To explore the activity of these dual RTK/tubulin inhibitors, compound AG165 was evaluated in in vitro and in vivo xenograft models. In vitro AG165 inhibited the growth of MDA-MB-435 cells with an IC50 of 8.8 nM, comparable to paclitaxel. The compound is also active in paclitaxel resistant cancer cells overexpressing βIII-tubulin or Pgp, thus overcoming two important mechanisms associated with clinical resistance to paclitaxel. Compound AG165 (subcutaneous doses of 75 mg/kg x 7, cumulative dose 525 mg) showed significant (p&amp;lt;0.001) inhibition of tumor growth 15 days after treatment initiation. AG165 caused recoverable weight loss without any evidence of adverse effects. In this study, we have identified a water-soluble, dual acting RTK/ tubulin inhibitory agent that address some critical limitations of existing therapies and demonstrates in vivo antitumor effects with an acceptable toxicity profile. Citation Format: Khushbu Shah, Aleem Gangjee, Roheeth Pavana, Dybdal-Hargreaves F. Nicholas, Susuan Mooberry. Preclinical evaluation of water-soluble pyrrolo[3,2-d]pyrimidines as single agents with tubulin and multiple receptor tyrosine kinase inhibition and as antitumor agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3657. doi:10.1158/1538-7445.AM2015-3657

Different preparations, doses, and treatment regimens of cyclosporine A cause adverse effects but no robust changes in seizure thresholds in rats

Neuronal transplantation is a promising experimental treatment approach for intractable epilepsies, but rejection of porcine or human cells in rodent epilepsy models requires adequate immunosuppression to enable long-term survival of xenografts. The commonly used immunosuppressive drug cyclosporine A (CsA) itself was suggested to affect seizure thresholds. However, putative pro- or anticonvulsant effects of CsA have not yet been sufficiently explored in a direct comparison study involving different preparations, dosages, and application routes. We therefore comprehensively investigated the effects of acute versus chronic treatment using different dosages (5mg/kg, 10mg/kg), application routes (i.p., s.c.), and preparations of CsA (pure substance solved in polyethoxylated castor oil and a ready-to-use drug additionally containing ethanol) on acute seizure thresholds in rats in the pentylenetetrazole seizure threshold test and verified the most harmless protocol in the chronic amygdala-kindling model for temporal lobe epilepsy. None of the CsA treatment regimens induced acute changes of seizure thresholds. Chronic CsA treatment also did not robustly change seizure thresholds. As evaluated by whole blood analyses, bioavailability of CsA was significantly higher after i.p. application of the ready-to-use preparation compared to the pure substance and compared to s.c. Observed adverse effects differed between CsA treatment regimens and included reversible diarrhea, lowered body temperature, and tremor, the latter two of which were also induced by vehicle injections containing ethanol and/or polyethoxylated castor oil. Our data suggest that chronic treatment (2 weeks) with 10mg/kg CsA injected i.p. in the ready-to-use preparation is an appropriate protocol for use in neural transplantation in epilepsy research applying the presently used rat models. Transplantation studies in experimental epilepsy research require a careful assessment of putative CsA effects on seizure thresholds in the specific experimental settings to be used.

Study of the Corrosion Inhibitor of Steel in the Medium Acid in Different Concentrations of Imidazole

Imidazole is a heterocyclic compound a five-membered of diunsaturated cyclic the structure composed of atoms three carbon and two atoms nitrogen in non-adjacent positions. The simplest member of the family is imidazole itself, colorless to pale yellow crystalline solid yellow with a faint odor amine like, soluble in water and alcohol, melts at 89°C to 256°C. After Imidazole’s are poorly soluble in water in general, but are dissolved in organic solvents such as chloroform, propylene glycol and polyethoxylated castor oil. Imidazole’s have antibacterial, antifungal, antiprotozoal, and anthelmintic. Several distinct phenylimidazoles are therapeutically useful as antifungal agents against superficial infections or systemic be. Thiabendazoles that deworming and anti-fungal properties are compounds of the imidazole class. Benzimidazole is a bicyclic compound having an imidazole ring fused to the benzene. The Benzimidazole structure is a part of the portion of the nucleotide vitamin B12 and the core in some drugs, such as inhibitors of the proton pump and anthelmintic agents. Imidazole has two nitrogen atoms. One is slightly acidic, while the other is at the bottom. The imidazole and its derivatives are widely used as intermediates in the synthesis of biological target or pharmaceutical compounds, agrochemicals, dyes, photographic chemicals, corrosion inhibitors, curing agents for epoxy resin adhesives and plastic modifiers.

Effect of Lipophilicity of Drugs on Dissolution Profiles of Self-Nanoemulsifying Drug Delivery System

The low solubility of poorly water-soluble drug is a major problem of oral drug adsorption. The self-emulsifying system can be applied to eliminate the drug dissolution step and improve the drug absorption. In this research, liquid self-nanoemulsifying drug delivery system (SNEDDS) composing of polyethoxylated castor oil, caprylic/capric glyceride and diethylene glycol monoethyl ether was developed. The drugs with similar structure but different lipophilicity (log P), nifedipine (NDP), felodipine (FDP) and manidipine (MDP), were investigated. Size and size distribution of emulsion after dilution in acid medium and in vitro drug dissolution were determined. The results showed that the size of emulsions obtained from dilution of SNEDDS in acidic medium ranged from 100-150 nm. Drug dissolution from SNEDDS was different depending on lipophilicity of drug, i.e., 98.6, 74.3 and 52.5% for NDP (log P 2.50), FDP (log P 4.46) and MDP (log P 5.46), respectively. The results suggested that the difference in lipophilicity may influence the drug dissolution from SNEDDS.

P2-34-3 - Three Cases of Hemodialysis Patients with Advanced Gastric Cancer Treated with Paclitaxel and Nab Paclitaxel

Background: S-1 an oral fluoropyrimidine plus cisplatin is a standard regimen for unresectable advanced or recurrent gastric cancer URGC in East Asia. There is no standard treatment for hemodialysis patients with URGC. Moreover the benefits of chemotherapy in hemodialysis patients remain uncertain.Case: Case1) a 71-year-old man and case 2) a 64-year- old man, were each given a diagnosis of URGC. They had been under dialysis for chronic renal failure. We decided to give chemotherapy. Paclitaxel were administered on days 1,8, and 15 every 28 days. Adverse reactions observed included Grade 2 anorexia nausea and hair loss and Grade 3 neutropenia and anemia. Grade4 severe adverse ivent was not observed during the 8 and 6 courses of chemotherapy. The liver metastases show partial response for more than half a year after initiation of therapy. Case3) A 62-year-old man was given a diagnosis of URGC. The day after starting PTX Grade3 drug eruption appeared that increased with strong itching.The PTX may introduce hypersensitivity reactions associated with the polyethoxylated castor oil ethanol solvent. He has been changed to the drug albumin bound paclitaxel(nab-paclitaxel)(60mg/m2) intravenously on day 1 of a 21-day cycle and there was no recurrence of drug eruption.Conclusions: We conclude that paclitaxel and nab paclitaxel is safe and effective for URGC patients undergoing hemodialysis.

Trends in Biomedical Nanotechnology

The nanotechnology, as defined by the US National Nanotechnology Initiative (NNI), is fabrication of materials with at least one dimension in 1-100 nm range [1]. The field of nanotechnology has generated tremendous excitement because these materials exhibit fundamental properties that are significantly different from that of bulk material, and are attributable to their small size (≤100 nm). For instance, quantum dots are nanoparticles (2-10 nm) of semi-conducting materials, usually selenides or sulfides of metals like zinc and cadmium. The quantum dots, owing to their nano size, exhibit superior signal brightness, size dependent emission of light, which, is resistant to photo bleaching, contrary to organic fluorescent dyes. Thus by controlling the size of quantum dots, it is possible to control the wavelength of emission for these nanomaterials. The size-based tunable light emission and resistance to photo bleaching observed in quantum dots is attributed to their nano size, and is not present in bulk materials. The main aim of nanotechnology is to take advantage of these unique properties in fabricating novel materials and devices, or developing unique applications. The major thrust of biomedical nanotechnology is to apply the benefits of nanotechnology to healthcare (e.g., imaging and diagnostics; nanodrugs; drug delivery; prostheses; and implants; etc.) [2,3]. Nanotechnology has been earlier used to improve drug properties. For example, pacliaxel (taxol), an anticancer drug, which is used to treat primary epithelial ovarian carcinoma, breast, colon, and lung cancers, exhibits low water solubility and, therefore, poor bioavailability. Therefore, it was formulated in Chremophor EL (polyethoxylated castor oil), which has been implicated in several drug associated toxicities. To overcome these shortcomings associated with the use of Cremophor, paclitaxel bound to albumin nanoparticles (Abraxane) were developed for clinical use. There is a huge interest in employing nanotechnology for cancer drug delivery. The interest in cancer drug delivery stems from the fact that the nanoparticles passively target tumors by a process called enhanced permeability and retention (EPR) effect, as elucidated by Maeda and coworkers [4-6]. It occurs because the tight junctions between endothelial cells of microvessels measure around 2 nm (6 nm in kidney, liver, and spleen), whereas the pore size of tumor microvessels varies from 100 to 1200 nm. Therefore, nanoparticles of appropriate size are able to extravasate into tumors, and not normal tissues, where they are retained because of slow venous return and poor

Bioequivalence of Liposome-Entrapped Paclitaxel Easy-To-Use (LEP-ETU) Formulation and Paclitaxel in Polyethoxylated Castor Oil: A Randomized, Two-Period Crossover Study in Patients With Advanced Cancer

BackgroundPreclinical studies comparing paclitaxel formulated with polyethoxylated castor oil with the sonicated formulation of liposome-entrapped paclitaxel (LEP) have demonstrated that LEP was associated with reduced toxicity while maintaining similar efficacy. Preliminary studies on the pharmacokinetics in patients support earlier preclinical data, which suggested that the LEP Easy-to-Use (LEP-ETU) formulation and paclitaxel formulated with castor oil may have comparable pharmacokinetic properties. ObjectivesOur objectives were: (1) to determine bioequivalence of paclitaxel pharmaceutically formulated as LEP-ETU (test) and paclitaxel formulated with castor oil (reference); and (2) to assess the tolerability of LEP-ETU following intravenous administration. MethodsPatients with advanced cancer were studied in a randomized, 2-period crossover bioequivalence study. Patients received paclitaxel 175 mg/m2 administered as an intravenous infusion over 180 minutes, either as a single-treatment cycle of the test formulation followed by a single-treatment cycle of the reference formulation, or vice versa. ResultsThirty-two of 58 patients were evaluable and were included in the analysis for bioequivalence. Mean total paclitaxel Cmax values for the test and reference formulations were 4955.0 and 5108.8 ng/mL, respectively. Corresponding AUC0-∞ values were 15,853.8 and 18,550.8 ng·h/mL, respectively. Treatment ratios of the geometric means were 97% (90% CI, 91%–103%) for Cmax and 84% (90% CI, 80%–90%) for AUC0-∞. These results met the required 80% to 125% bioequivalence criteria. The most frequently reported adverse events after LEP-ETU administration were fatigue, alopecia, and myalgia. ConclusionAt the studied dose regimen, LEP-ETU showed bioequivalence with paclitaxel formulated with polyethoxylated castor oil.

Drug-Induced Subacute Cutaneous Lupus Erythematosus Associated with Nab-Paclitaxel Therapy

Drug-induced lupus erythematosus (dile) syndromes are documented complications of chemotherapeutic agents, including paclitaxel. Subacute cutaneous lupus erythematosus (scle) is a distinct dile syndrome presenting with characteristic annular or papulosquamous skin lesions in a photosensitive distribution with associated high anti-ssa titres. Previously, dile syndromes complicating paclitaxel therapy have been attributed to polyethoxylated castor oil (Kolliphor EL: BASF, Ludwigshafen, Germany), the biologic solvent included in the drug's original formulation (Taxol: Bristol-Myers Squibb, Montreal, QC), rather than the parent chemotherapy molecule. Here, we report a characteristic case of drug-induced scle complicating treatment with nanoparticle albumin bound (nab)-paclitaxel (Abraxane: Celgene, Summit, NJ, U.S.A.), a solvent-free taxane formulation. The pertinent English-language literature is also discussed. This case report is the first to link solvent-free paclitaxel with scle, and it suggests that the parent molecule is responsible for the reaction.

Abstract 2477: Design, synthesis and biological evaluation of substituted monocyclic pyrimidines as potent microtubule targeting antitumor agents that circumvent Pgp and βIII-tubulin-mediated resistance.

Abstract Tubulin binding agents are the most effective drugs in p53 resistant cancer cell lines. Although microtubule disrupting agents like paclitaxel are highly successful, they have major limitations against multidrug resistance (MDR) tumors. Overexpression of P-glycoprotein (Pgp) and/or βIII-tubulin can severely limit their clinical utility as cancer chemotherapeutic agents. Antitubulin agents like paclitaxel and other taxoids also have poor water solubility, and this hampers their administration to patients since these compounds must be formulated with polyethoxylated castor oil. This medium can cause hypersensitivity reactions and requires prolonged administration times. Recently, we reported analogs with the pyrrolo[3,2-d]pyrimidine scaffold that circumvent these drawbacks. To explore the structure-activity relationships of these compounds, including simplification of the pyrrolo[3,2-d]pyrimidine scaffold, we designed conformationally flexible substituted monocyclic N-methyl-4-methoxyanilino pyrimidines 1-6 from the corresponding 4-chloro analogs by treatment with N-methyl-4-methoxyaniline followed by N6-alkylation for 2-6 . Compounds 1-6 inhibited tubulin assembly (4, IC50 = 1.5 ± 0.2 μM) and binding of colchicine to tubulin (4, 75% inhibition at 1 μM, 95% at 5 μM with 5 μM [3H]colchicine). Four of these compounds inhibited the growth of human cancer cells in culture with nanomolar IC50’s from 15 to 62 nM. These compounds are also active in paclitaxel resistant tumor cells overexpressing either βIII-tubulin or Pgp, thus apparently overcoming two important mechanisms associated with clinical resistance to paclitaxel. Thus, we have identified simplified substituted monocyclic pyrimidines containing a novel structural scaffold for inhibition of tubulin assembly and colchicine binding and which have potent cytotoxic activity against human cancer cells in culture. Citation Format: Aleem Gangjee, Rishabh Mohan, Ernest Hamel, Ruoli Bai. Design, synthesis and biological evaluation of substituted monocyclic pyrimidines as potent microtubule targeting antitumor agents that circumvent Pgp and βIII-tubulin-mediated resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2477. doi:10.1158/1538-7445.AM2013-2477

A multicenter phase II randomized study of Cremophor‐free polymeric nanoparticle formulation of paclitaxel in women with locally advanced and/or metastatic breast cancer after failure of anthracycline

Paclitaxel is extensively used in the treatment of advanced carcinomas of the breast, ovary and non-small cell lung cancer. In clinical use it is formulated in the non-ionic surfactant polyethoxylated castor oil (Cremophor) and dehydrated alcohol to enhance drug solubility. Cremophor adds to toxic effects of paclitaxel by producing or contributing to the well-described hypersensitivity reactions that commonly occur during its infusion, affecting a large number of patients. This randomized trial was conducted to evaluate efficacy and safety of novel nanoparticle-based paclitaxel in the treatment of patients with advanced breast cancer. Patients were randomized to receive either nanoparticle paclitaxel (NP) 300 mg/m(2) , (NP300) or NP220 mg/m(2) or Cremophor paclitaxel 175 mg/m(2) (CP 175). NP was administered as a 1-h infusion without premedication and CP as a 3-h infusion with premedication every 3 weeks. In total, 194 patients who had been administered at least one dose were included for safety analysis and 170 patients who completed at least two cycles of therapy were analyzed for efficacy. NP showed an overall response rate (complete response + partial response) of 40% in the NP220 and NP300 arms as compared to 31% in the CP arm. The incidence of neutropenia (all grades) was lowest in the NP220 arm (39.4%) compared to the NP300 (55%) and CP arm (50%). NP is well tolerated and can be safely administered without any premedication in comparison to conventional paclitaxel, which requires the use of premedication before administration. NP demonstrates promising efficacy with a favorable safety profile.