Retinoic Acid Metabolism Blocking Agents Research Articles

Exploring Talarozole as a Novel Therapeutic Approach for Osteoarthritis: Insights From Experimental Studies.

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by the slow degeneration of joint components that primarily affects the elderly. There is currently no cure for OA; thus, treatment focuses on symptom reduction. This article investigates the potential of talarozole, a retinoic acid metabolism-blocking agent (RAMBA), as a new treatment for hand OA. Talarozole showed promising results by inhibiting retinoic acid degradation and increasing its levels in the body. Six hours after destabilization of the medial meniscus, talarozole significantly reduced inflammation in mice's cartilage. The findings underscore the importance of the protein encoded by the ALDH1A2 gene in retinoic acid metabolism, shedding light on its potential implications for the management of OA. Maintaining adequate retinoic acid levels may help to reduce mechano-inflammatory gene regulation. Furthermore, RAMBAs like talarozole may emerge as disease-modifying OA therapies, promising improved symptom control and slower disease progression. In conclusion, this research provides critical genetic insights into severe hand OA and promotes talarozole as a prospective therapy option. These findings pave the door for additional research that could revolutionize OA treatment by targeting retinoic acid metabolism to reduce symptoms and slow disease progression.

Virtual screening and biological evaluation to identify pharmaceuticals potentially causing hypertension and hypokalemia by inhibiting steroid 11β-hydroxylase

Several drugs were found after their market approval to unexpectedly inhibit adrenal 11β-hydroxylase (CYP11B1)-dependent cortisol synthesis. Known side-effects of CYP11B1 inhibition include hypertension and hypokalemia, due to a feedback activation of adrenal steroidogenesis, leading to supraphysiological concentrations of 11-deoxycortisol and 11-deoxycorticosterone that can activate the mineralocorticoid receptor. This results in potassium excretion and sodium and water retention, ultimately causing hypertension. With the risk known but usually not addressed in preclinical evaluation, this study aimed to identify drugs and drug candidates inhibiting CYP11B1. Two conceptually different virtual screening methods were combined, a pharmacophore based and an induced fit docking approach. Cell-free and cell-based CYP11B1 activity measurements revealed several inhibitors with IC50 values in the nanomolar range. Inhibitors include retinoic acid metabolism blocking agents (RAMBAs), azole antifungals, α2-adrenoceptor ligands, and a farnesyltransferase inhibitor. The active compounds share a nitrogen atom embedded in an aromatic ring system. Structure activity analysis identified the free electron pair of the nitrogen atom as a prerequisite for the drug-enzyme interaction, with its pKa value as an indicator of inhibitory potency. Another important parameter is drug lipophilicity, exemplified by etomidate. Changing its ethyl ester moiety to a more hydrophilic carboxylic acid group dramatically decreased the inhibitory potential, most likely due to less efficient cellular uptake. The presented work successfully combined different in silico and in vitro methods to identify several previously unknown CYP11B1 inhibitors. This workflow facilitates the identification of compounds that inhibit CYP11B1 and therefore pose a risk for inducing hypertension and hypokalemia.

Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis.

More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in ALDH1A2, which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.

MAINTAINING ALL-TRANS RETINOIC ACID LEVELS WITH TALAROZOLE SUPPRESSES MECHANFLAMMATION FOLLOWING CARTILAGE INJURY THROUGH A PERIXOSOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA-DEPENDENT MECHANISM

Purpose: Severe hand osteoarthritis (OA) is associated with polymorphic variants in the ALDH1A2 gene. ALDH1A2 encodes the enzyme that catalyses the rate limiting step in the synthesis of all-trans retinoic acid (atRA). Injury of porcine articular cartilage, by explantation, causes upregulation of inflammatory genes by a process we have termed “mechanoflammation”. Injury also causes a rapid drop in atRA-responsive genes suggesting that atRA levels within the cell drop upon injury. If levels of atRA are maintained using talarozole, a retinoic acid metabolism blocking agent (RAMBA), this inhibits the mechano-inflammatory response.

Preclinical assessment of dual CYP26[A1/B1] inhibitor, DX308, as an improved treatment for keratinization disorders.

BackgroundRetinoid‐based therapies are commonly used in the treatment of disorders of keratinization and other skin disorders but can result in non‐specific effects and adverse reactions. Use of retinoic acid metabolism blocking agents (RAMBAs) such as DX308 may address these shortcomings.ObjectivesCharacterize the therapeutic potential of recently discovered, CYP26‐selective RAMBA, DX308.Materials and MethodsPreliminary in vitro assessment of potential off‐target activity, metabolic and toxicologic profiling. Studies to assess safety and efficacy of topical treatment in correcting abnormal skin morphology in rhino mice. Extensive gene expression profiling by RNA sequencing and qPCR in 3D epidermis grown with keratinocytes (KCs) from keratinization disorders and healthy controls, to investigate modulation of retinoid biopathways.ResultsIn vitro, DX308 does not interact with off‐target nuclear receptors or CYP450s, is not genotoxic, and is stable in skin, despite vigorous hepatic metabolism. In vivo, topical DX308 induces comedolysis and epidermal thickening without apparent adverse effects. Gene expression profiling shows potent modulation of retinoid‐responsive genes by DX308 in both healthy and keratinization disorder KCs. Pathway analysis suggests DX308 may inhibit inflammatory and immune responses in KCs.ConclusionsThese preliminary studies suggest that DX308 is an efficacious topical therapeutic with a favourable metabolic and safety profiles. DX308 may present an improved therapeutic alternative for the treatment of keratinization disorders and other retinoid‐responsive skin ailments.

Liposomal delivery of hydrophobic RAMBAs provides good bioavailability and significant enhancement of retinoic acid signalling in neuroblastoma tumour cells

Retinoid treatment is employed during residual disease treatment in neuroblastoma, where the aim is to induce neural differentiation or death in tumour cells. However, although therapeutically effective, retinoids have only modest benefits and suffer from poor pharmacokinetic properties. In vivo, retinoids induce CYP26 enzyme production in the liver, enhancing their own rapid metabolic clearance, while retinoid resistance in tumour cells themselves is considered to be due in part to increased CYP26 production. Retinoic acid metabolism blocking agents (RAMBAs), which inhibit CYP26 enzymes, can improve retinoic acid (RA) pharmacokinetics in pre-clinical neuroblastoma models. Here, we demonstrate that in cultured neuroblastoma tumour cells, RAMBAs enhance RA action as seen by morphological differentiation, AKT signalling and suppression of MYCN protein. Although active as retinoid enhancers, these RAMBAs are highly hydrophobic and their effective delivery in humans will be very challenging. Here, we demonstrate that such RAMBAs can be loaded efficiently into cationic liposomal particles, where the RAMBAs achieve good bioavailability and activity in cultured tumour cells. This demonstrates the efficacy of RAMBAs in enhancing retinoid signalling in neuroblastoma cells and shows for the first time that liposomal delivery of hydrophobic RAMBAs is a viable approach, providing novel opportunities for their delivery and application in humans.

Update on etiopathogenesis and treatment of Acne.

Acne, the most common skin disease, is a disorder of pilosebaceous units that affects adolescents mainly and adults occasionally. The pathogenesis is multifactorial. Besides genetic predisposition, other major factors include the action of androgens, pro-inflammatory lipids acting as ligands of peroxisome proliferator-activated receptors in the sebocytes, toll-like receptor-2 acting on keratinocytes, recognition of pathogen-associated molecular patterns, cytokines, chemokines, inflammasomes, neuroendocrine regulatory mechanisms, diet and other pro-inflammatory targets implicated in the activation of immune detection and response. Most of these factors converge on mammalian target of rapamycin complex1 (mTORC1) activation which is further enhanced by the nutrient signaling of Western diet. This multitude of pathogenic factors has led to a new armamentarium of drugs for the treatment of acne. Topical anti-androgens, insulin-like growth factor-1 inhibitors, peroxisome proliferator-activated receptor-modulators, acetylcholine inhibitors, topical retinoic acid metabolism-blocking agents, vitamin D analogues, antimicrobial peptides, interleukin-1α and interleukin-1β blockers and immunotherapy are some of the novel treatment options.

Design, synthesis, and biological evaluation of amide imidazole derivatives as novel metabolic enzyme CYP26A1 inhibitors

All-trans-retinoic acid (ATRA) as a physiological metabolite of vitamin A is widely applied in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. CYP26A1 enzyme, induced by ATRA in liver and target tissues, metabolizes ATRA into 4-hydroxyl-RA. Inhibition of CYP26A1 metabolic enzyme represents a promising strategy for discovery of new specific anticancer agents.Herein, we describe the design, synthesis and biological evaluation of a series of new amide imidazole derivatives as retinoic acid metabolism blocking agents (RAMBAs) toward CYP26A1 enzyme. First, based on the recent theoretical models (Sun et al., J. Mol. Graph. Model., 2015, 56, 10–19) a series of RAMBAs with novel scaffolds were designed using fragment-based drug discovery approach. Subsequently, the new RAMBAs were synthesized and evaluated for their biological activities. All the compounds demonstrated appropriate enzyme activities and cell activities. The promising inhibitors 20 and 23 with IC50 value of 0.22μM and 0.46μM toward CYP26A1, respectively, were further evaluated for CYP selectivity and the metabolic profile of ATRA. Both compounds 20 and 23 showed higher selectivity for CYP26A1 over other CYPs (CYP2D6, CYP3A4) when compared to liarozole. They also showed better inhibitory activities for the metabolism of ATRA when also compared to liarozole. These studies further validated the pharmacophore and structure–activity relationship models obtained about CYP26A1 inhibitors and highlighted the promising activities of the new series of CYP26A1 inhibitors designed from such models. They also paved the way for future development of those candidates as potential drugs.

Liarozole, an Inhibitor of Retinoic Acid Metabolism, Retarded Atherogenesis in LDLR-/-Mice

Liarozole is a Retinoic Acid Metabolism Blocking Agent (RAMBA). As retinoic acid (RA) and its precursor, beta-carotene (BC), have been shown to inhibit atherosclerosis development in mouse models, in the present study we investigated whether liarozole can mimic the anti-atherogenic effect of RA. We demonstrate, by using the LDL receptor-knockout mouse model fed a high-fat diet, that liarozole significantly reduces by 50% the aortic sinus atherosclerotic lesion area.

Molecular recognition of CYP26A1 binding pockets and structure–activity relationship studies for design of potent and selective retinoic acid metabolism blocking agents

All-trans-retinoic acid (ATRA), the biologically most active metabolite of vitamin A, plays a major role in the regulation of cellular differentiation and proliferation, and it is also an important pharmacological agent particularly used in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. However, ATRA is very easy to be metabolized into 4-hydroxyl-RA in vivo by CYP26A1, an inducible cytochrome P450 enzyme, eventually into more polar metabolites. Therefore, it is vital to develop specific retinoic acid metabolism blocking agents (RAMBAs) to inhibit the metabolic enzyme CYP26A1 in the treatment of relevant diseases aforementioned.In this study, CYP26A1 and its interactions with retinoic acid-competitive metabolism blocking agents were investigated by a combined ligand- and structure-based approach. First, since the crystal structure of CYP26A1 protein has not been determined, we constructed the 3D structure of CYP26A1 using homology modeling. In order to achieve a deeper insight into the mode of action of RAMBAs in the active site, the molecular superimposition model and the common feature pharmacophore model were constructed, and molecular docking was performed. The molecular superimposition model is composed of three features: the main chain groups, side chain groups, and azole groups. The common feature pharmacophore model consists of five chemical features: four hydrophobic groups and one hydrogen acceptor (HHHHA). The results of molecular docking show that the characteristic groups of RAMBAs were mapped into three different active pockets, respectively.A structure–activity relationship (SAR) was obtained by a combination of the molecular superimposition and docking results with the pharmacophore model. This study gives more insight into the interaction model inside the CYP26A1 active site and provides guidance for the design of more potent and possibly more selective RAMBAs.

Abstract 2704: Simultaneous targeting of androgen receptor (AR) and Eukaryotic Initiation Factor 4E (eIF4E) dependent translation initiation by RAMBA Retinamides promotes apoptosis and impedes cell growth, cell proliferation and matrix invasion in androgen sensitive and castration-resistant prostate cancers

Abstract Introduction: Prostate cancer (PCa) remains the second most leading cause of cancer-related death in Western male population. Although initially counteracted by androgen deprivation therapy (ADT), PCa cells eventually progress to a hormone-independent state thereby limiting treatment options and rendering the discovery of new therapeutic approaches a clinical priority. Direct targeting of translational machinery has gained enormous attention in recent years for treating castration resistant prostate cancers (CRPC). The present study aims to investigate the effect of our novel retinoic acid metabolism blocking agents (RAMBA) retinamides (RRs) on eukaryotic translation initiation factor 4E (eIF4E) translational machinery and androgen receptor (AR) signaling in prostate cancers. Methods: Androgen-sensitive (LNCaP), androgen-resistant (PC-3, C4-2B and CWR22Rv1), enzalutamide resistant (MR49F) prostate cancer cells and normal prostatic epithelial cells (PWR-1E) were used analyzing the effect of RRs on prostate cancers. Results: 24 h treatment of PCa cells to RRs resulted in substantial down-regulation of androgen receptor (AR), degradation of MAPK-interacting kinases (MNK), and attenuation of eukaryotic translation initiation factor 4E (eIF4E) cap dependent translation initiation. Down-regulation of AR and MNK mediated eIF4E translation initiation by RRs in PCa cells were in turn associated with inhibition of cell growth and proliferation, induction of cell cycle arrest, increased apoptosis, and inhibition of matrix invasion and metastasis. Most importantly, the effects of our RRs on AR degradation, eIF4E translation initiation and subsequent oncogenic program were far more potent than the clinically relevant retinoids, established MNK inhibitors (CGP 57380 and/or cercosporamide) and the FDA approved PCa drugs (Casodex, Enzalutamide and Abiraterone acetate). Conclusion: RAMBA retinamides which can exclusively target the degradation of both AR and MNK- the two divergent axes in PCa, at pharmacologically feasible concentrations are novel therapeutic compounds for treatment of both androgen-sensitive and androgen-resistant prostate cancers. Citation Format: Vidya priyadarsini Ramamurthy, Senthilmurugan Ramalingam, Lalji Gediya, Vincent C.O Njar. Simultaneous targeting of androgen receptor (AR) and Eukaryotic Initiation Factor 4E (eIF4E) dependent translation initiation by RAMBA Retinamides promotes apoptosis and impedes cell growth, cell proliferation and matrix invasion in androgen sensitive and castration-resistant prostate cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2704. doi:10.1158/1538-7445.AM2014-2704

First Mnks degrading agents block phosphorylation of eIF4E, induce apoptosis, inhibit cell growth, migration and invasion in triple negative and Her2-overexpressing breast cancer cell lines

Some retinoic acid metabolism blocking agents (RAMBAs) are known to exhibit a wide range of anticancer activities by mechanisms that are still not completely resolved. This study investigated the anticancer efficacy and mechanism(s) of novel RAMBA retinamides (RRs) in triple negative and Her-2 overexpressing breast cancer cells. Specifically, we examined the possibility that RRs affect the translational machinery in these breast cancer (BC) cells. Recent findings suggest that overexpression of eukaryotic translation initiation factor 4E (eIF4E) in breast cancers critically augments CAP-dependent mRNA translation and synthesis of proteins involved in cell growth, cell proliferation, invasion and apoptosis evasion. The oncogenic potential of eIF4E is strictly dependent on serine209 phosphorylation by upstream MAPK-interacting kinases (Mnks). Targeting Mnk/eIF4E pathway for blocking Mnk function and eIF4E phosphorylation is therefore a novel approach for treating BCs, particularly for Her2-positive and triple negative breast cancers that have no indications for endocrine therapy or effective treatment regimes. We report for the first time that the degradation of Mnk1 by RRs in BC cells blocks eIF4E phosphorylation and subsequently inhibits cell growth, colonization, invasion, and migration and induce apoptosis. Most importantly, the anticancer efficacy of RRs was mediated via degrading Mnk rather than inhibiting its kinase activity like Mnk inhibitors (cercosporamide and CGP57380). Furthermore, RRs potencies on peIF4E down-regulation and growth inhibition were superior to those of two clinically relevant retinoids and the Mnk inhibitors. Together our findings provide the first preclinical proof-of-concept of novel Mnk degrading agents for Mnk/eIF4E based therapeutic treatment of breast cancers.

Oral liarozole in the treatment of patients with moderate/severe lamellar ichthyosis: results of a randomized, double‐blind, multinational, placebo‐controlled phase II / III trial

SummaryBackgroundOral liarozole, a retinoic acid metabolism-blocking agent, may be an alternative to systemic retinoid therapy in patients with lamellar ichthyosis.ObjectiveTo demonstrate the efficacy and safety of once-daily oral liarozole in the treatment of moderate/severe lamellar ichthyosis.MethodsThis was a double-blind, multinational, parallel phase II/III trial (NCT00282724). Patients aged ≥ 14 years with moderate/severe lamellar ichthyosis [Investigator's Global Assessment (IGA) score ≥ 3] were randomized 3 : 3 : 1 to receive oral liarozole (75 or 150 mg) or placebo once daily for 12 weeks. Assessments included: IGA; a five-point scale for erythema, scaling and pruritus severity; Short Form-36 health survey; Dermatology Life Quality Index (DLQI); and safety parameters. The primary efficacy variable was response rate at week 12 (responder: ≥ 2-point decrease in IGA from baseline).ResultsSixty-four patients were enrolled. At week 12, 11/27 (41%; liarozole 75 mg), 14/28 (50%; liarozole 150 mg) and one out of nine (11%; placebo) patients were responders; the difference between groups (liarozole 150 mg vs. placebo) was not significant (P = 0·056). Mean IGA and scaling scores decreased from baseline in both liarozole groups at weeks 8 and 12 vs. placebo; erythema and pruritus scores were similar between treatment groups. Improvement in DLQI score was observed in both liarozole groups. Treatment with liarozole for 12 weeks was well tolerated.ConclusionsThe primary efficacy variable did not reach statistical significance, possibly owing to the small sample size following premature termination. However, once-daily oral liarozole, 75 and 150 mg, improved scaling and DLQI and was well tolerated in patients with moderate/severe lamellar ichthyosis.

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

Retinoic acid (RA), the active metabolite of vitamin A, is an important endogenous signaling molecule regulating cell cycle and maintenance of epithelia. RA isomers are also used as drugs to treat various cancers and dermatological diseases. However, the therapeutic uses of RA isomers are limited due to side effects such as teratogenicity and resistance to treatment emerging mainly from autoinduction of RA metabolism. To improve the therapeutic usefulness of retinoids, RA metabolism blocking agents (RAMBAs) have been developed. These inhibitors generally target the cytochrome P450 (CYP) enzymes because RA clearance is predominantly mediated by P450s. Since the initial identification of inhibitors of RA metabolism, CYP26 enzymes have been characterized as the main enzymes responsible for RA clearance. This makes CYP26 enzymes an attractive target for the development of novel therapeutics for cancer and dermatological conditions. The basic principle of development of CYP26 inhibitors is that endogenous RA concentrations will be increased in the presence of a CYP26 inhibitor, thus, potentiating the activity of endogenous RA in a cell-type specific manner. This will reduce side effects compared to administration of RA and allow for more targeted therapy. In clinical trials, inhibitors of RA metabolism have been effective in treatment of psoriasis and other dermatological conditions as well as in some cancers. However, no CYP26 inhibitor has yet been approved for clinical use. This review summarizes the history of development of RAMBAs, the clinical and preclinical studies with the various structural series and the available knowledge of structure activity relationships of CYP26 inhibitors.

Murine toxicology and pharmacokinetics evaluation of retinoic acid metabolism blocking agent (RAMBA), VN/12-1

Novel retinoic acid metabolism blocking agent (RAMBA), VN/12-1, is a highly potent anti-cancer agent that induces autophagy. Its combination with autophagy inhibitor chloroquine (CHL) has been shown to synergistically enhance apoptosis in breast cancer cells. The purpose of this study was to determine the toxicity and pharmacokinetic profile of VN/12-1 and its combination with CHL. Preliminary toxicology of VN/12-1 was determined using female SCID mice (n=4 for each group). ATRA was used for comparison. We selected four different doses of VN/12-1 and ATRA. Two of the doses were low and less frequent (2.5 and 5mg/kg twice a week), and the remaining doses were high and more frequent (10 and 20mg/kg every day). The dose of CHL was 50mg/kg twice a week. For pharmacokinetic (PK) study, 20mg/kg of VN/12-1 was injected subcutaneously (s.c.) into the mice, and their plasma was collected at various intervals (n=2) and analyzed by HPLC. The lower and less frequent doses of VN/12-1 and ATRA were found to be least toxic. However, high and more frequent doses of these compounds were toxic to the mice. PK results showed that VN/12-1 has a half-life of 6h. The area under the curve (AUC) for VN/12-1 was 83.78hμg/ml. VN/12-1 and ATRA are non-toxic when used as 5mg/kg twice a week as single agents or in combination with CHL. The favorable PK properties of VN/12-1 can potentially be used for its further advanced pre-clinical and clinical development.

Anti-tumor effects of a novel retinoic acid metabolism blocking agent VN/14-1 in the N-methyl-N-nitrosourea-induced rat mammary carcinoma model and its effects on the uterus

VN/14-1 [4-(±)-(1H-Imidazol-1-yl)-(E)-retinoic acid], a novel retinoic acid metabolism blocking agent (RAMBA), works by inhibiting the breakdown of all-trans-retinoic acid. The purpose of this study was to evaluate the anti-tumor effects of VN/14-1 on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, and peripheral organ effects on the uteri of immature ovariectomized (OVX) rats. In tumor burden experiments, after 56 days of administration of VN/14-1 5, 10, and 20 mg/kg/day, significant tumor reductions in mean tumor weight of 19.1, 34.4, and 44.3%, compared to tumors in control animals occurred. Cumulative tumor growth was also significantly slower in a dose-dependent manner in groups receiving 5, 10, and 20 mg/kg/day of VN/14-1 compared to growth rates in the control group. Tumor apoptosis was significant increases in animals treated with 5, 10, and 20 mg/kg/day of VN/14-1. In uterotrophic experiments, immature OVX rats given VN/14-1 significantly reduced uterine weight and blocked endometrial stimulation induced by unopposed β-estradiol (E2). In both rat models, adverse toxicities included weakness, anorexia, and reduction in body weight in the groups given the highest dose of 20 mg/kg/day. In summary, VN/14-1 inhibited tumor growth in the MNU-induced estrogen receptor (ER)-positive rat mammary tumor model, and antagonized the stimulatory effect of estrogens on the uterus. The studies suggest that VN/14-1 may be a useful novel therapy for ER-positive breast cancer.

Ion mobility spectrometry of talarozole, a new azole drug, in cleaning quality control

Ion mobility spectrometry (IMS) gains increased pharmaceutical interest as an analytical technique for the verification of equipment cleaning. Using a fractional factorial design, we developed an IMS method for talarozole, which represents a new generation of retinoic acid metabolism blocking agents (RAMBA) that can be used for the treatment of different dermatological diseases, such as psoriasis and acne. Using a Smiths Detection Ionscan-LS and the optimal IMS settings obtained, talarozole showed a drift time of 16.648 ms, corresponding to a reduced ion mobility K0 of 1.072 cm²V−1s−1. Total analysis times below 1 min were achieved. Talarozole was well separated in the plasmagram from other azole compounds and the limit of detection was found to be 43 ng/ml. Swab samples collected from steel and glass plates were successfully analyzed, thereby showing that IMS is indeed a suitable technique for the quantitative analysis of talarozole in cleaning quality control.

Nutrition and psoriasis

Nutritional supplementation may provide a viable treatment alternative in patients with psoriasis. Randomized, controlled trials have shown the effectiveness of topical vitamin A and D derivatives, intravenous ω-3 fatty acids, oral inositol, and various combined therapies. Dual therapies of ultraviolet B phototherapy and fish oil, retinoids and thiazolidinediones, and cyclosporine and a low-calorie diet were effective in the treatment of psoriasis in randomized, controlled trials. This contribution also reviews the potential negative effect of alcohol and the potential positive effects of vitamin B 12, selenium, retinoic acid metabolism-blocking agents, and a gluten-free diet in the treatment of psoriasis.

Ichthyosis

Ichthyoses constitute a large group of cornification disorders that affect the entire integument. The skin is characterized by visible scaling and in many cases by inflammation, for example, in bullous/keratinopathic ichthyosis or Netherton syndrome. From the viewpoint of classification it is useful to distinguish non-syndromic from syndromic types of ichthyosis. Ichthyosis vulgaris and recessive X-linked ichthyosis are common disorders - often of delayed onset, in contrast to congenital ichthyoses, which belong to the group of rare diseases and present at birth with either the features of collodion membrane or congenital ichthyosiform erythroderma. The diagnostic steps are based on clinical data, analyses such as the steroid sulfatase activity test, skin biopsies, and genetic results. However, the dramatic increase in knowledge about the pathophysiology of these conditions has not led to a curative therapy so far. The therapeutic management is multidisciplinary and involves ichthyosis patient organizations in many countries. The mainstay of treatment remains with moisturizing creams containing, for example, urea, lactic acid and other humectants and keratolytics, regular bathing, and mechanical scale removal. Patients with lamellar ichthyosis or ichthyosiform erythroderma in particular profit from oral therapy with retinoids or retinoic acid metabolism-blocking agents.

Effects of novel retinoic acid metabolism blocking agent (VN/14-1) on N-methyl-N-nitrosourea (MNU)-induced mammary carcinoma and uterus in the rat model.

Abstract Abstract #2133 Background: All-trans-retinoic acid (ATRA) and other retinoids play key roles in prevention and therapy of many proliferative diseases including cancers. VN/14-1 [4-(±)-(1H-Imidazol-1-yl)-(E)-retinoic acid], which is a new generation novel retinoic acid metabolism blocking agent (RAMBA), works by inhibiting the breakdown of ATRA. The inhibitory effects of VN/14-1 on the growth of human breast cancer cells and human breast tumors in the nude mouse model have been previously demonstrated. The purpose of this study was to evaluate the effects of VN/14-1 on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, as well as on the uterus in immature ovariectomized (OVX) rats.
 Methods: (1) VN/14-1 (5, 10, and 20 mg/kg/d) was given by oral gavage to grouped female Sprague Dawley (SD) rats bearing MNU-induced mammary carcinoma for 8 weeks, after which tumor weight and volume, as well as histology were measured. (2) VN/14-1 (10 and 20 mg/kg/d) and b-estradiol (10 mg/kg/d) were given alone or in combination, by oral gavage (VN/14-1) and subcutaneous injection (b-estradiol), to immature OVX SD rats for 3 days, after which uterine weight and histology were measured.
 Results: (1) At the end of the treatment period, the administration of 5, 10 and 20 mg/kg/d VN/14-1 caused significant reductions of 19.1, 34.4 and 44.3%, respectively, in mean tumor weight compared with the control animals (all p < 0.05). The cumulative tumor growth was also significantly slower in groups receiving 5, 10 and 20 mg/kg/d compared to the control group in a dose-dependent manner. (2) Immature OVX rats given VN/14-1 at doses of 10 and 20 mg/kg, had reduction in uterine wet weight of up to 56% compared to OVX controls (P < 0.001). OVX rats given VN/14-1 of 10 and 20 mg/kg in combination with β-estradiol had reduction in uterine wet weight of up to 58% compared to the OVX rats given β-estradiol alone (P < 0.001). The adverse toxic effects such as fatigue and anorexia were occurred in the groups at high dose of 20 mg/kg.
 Conclusions: RAMBA VN/14-1 was able to inhibit the growth of tumors in the MNU-induced ER positive rat mammary tumor model and antagonized the stimulatory effect of β-estradiol on the uterus. The studies suggest VN/14-1 might be an effective novel therapy for ER positive breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2133.