Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia.

Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase that regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD) that plays a vital role in energy metabolism. Here, we show that KPT-9274 strongly inhibits B-ALL cell growth regardless of cytogenetic abnormalities. We also demonstrate the potent in vivo efficacy and tolerability of KPT-9274 in a patient-derived xenograft murine model of B-ALL. Interestingly, although KPT-9274 is a dual PAK4/NAMPT inhibitor, B-ALL cell growth inhibition by KPT-9274 was largely abolished with nicotinic acid supplementation, indicating that the inhibitory effects on B-ALL cells are mainly exerted by NAD+ depletion through NAMPT inhibition. Moreover, we have found that the extreme susceptibility of B-ALL cells to NAMPT inhibition is related to the reduced cellular NAD+ reserve. NAD+ depletion may be a promising alternative approach to treating patients with B-ALL.

KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells.

Acute myeloid leukemia (AML) is a clonal hematologic malignant disease of developing myeloid cells that have acquired aberrant survival, uncontrolled proliferation and a block in normal hematopoietic cell differentiation. Standard chemotherapy often induces remissions in AML patients, but the disease frequently relapses due to incomplete targeting of leukemia-initiating cells (LICs), emphasizing the need for novel effective treatments. Exportin 1 (XPO1)-mediated nuclear export, which is inhibited by the drug selinexor, is an attractive new therapeutic target in AML. Selinexor has shown impressive activity in Phase I/II clinical trials for AML. Here we report the anti-leukemic efficacy and tolerability of KPT-8602, a second-generation XPO1 inhibitor. KPT-8602 demonstrates substantially reduced brain penetration compared to selinexor, with resultant attenuation of the central nervous system mediated side effects of anorexia and weight loss. Due to its improved tolerability profile, KPT-8602 can be given daily compared to the two or three times weekly regimen of selinexor, and exhibits greater anti-leukemic efficacy against both leukemic blasts and LICs in AML patient-derived xenograft models. Importantly, normal hematopoietic stem and progenitor cell (HSPC) frequency is not significantly reduced by KPT-8602, providing a therapeutic window for elimination of relapse-driving LICs while sparing normal HSPCs. These findings strongly endorse clinical testing of KPT-8602 in patients with relapsed and refractory AML.

Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies.

The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.

The efficacy of three desensitizing agents in treatment of dentine hypersensitivity.

PURPOSE: The purpose of this study was to evaluate the efficacy of three desensitizing agents vs. placebo. MATERIALS AND METHODS: One hundred and six hypersensitive teeth of 26 patients were included in this study, and the baseline hypersensitivity level of all teeth was established as 'moderate' by using Visual Analogue Scale (VAS). The teeth were divided into four groups: to the first group 5% potassium nitrate bio-adhesive gel, to the second 2% sodium fluoride bio-adhesive gel and to the third one step adhesive system Prompt L-Pop were applied as desensitizing agents. Group 4 was the control group in which a desensitizer-free bio-adhesive gel was used as placebo. Post treatment and eighth week control measurements were recorded on VAS. RESULTS: It was observed that the efficacy of three desensitizing agents did not differ from each other (P >0.05) and except for placebo all reduced moderate dentin hypersensitivity effectively (P <0.05). CLINICAL RELEVANCE: Five per cent potassium nitrate, 2% sodium fluoride bio-adhesive gels and one-step bonding agent Prompt L-Pop were effective in reducing moderate dentine hypersensitivity.

An alternative evaluation method for swelling studies of bioadhesive tablet formulations.

A new and alternative evaluation method is preferred for swelling studies of bioadhesive tablet formulations. CIELAB color coordinates, related to visual color response, are used for the first time to follow the swelling state and to calculate the swelling volume. The results are evaluated statistically. A simple equation is given to explain the relation between the swelling volume change % and color difference for three different bioadhesive formulations. It was found that the estimated equation is in good agreement with observed swelling volume results.

An in vitro investigation for vaginal bioadhesive formulations: bioadhesive properties and swelling states of polymer mixtures.

Bioadhesive tablet formulations have been developed for mucosal application. Sixteen different bioadhesive tablet formulations were prepared and evaluated. Their bioadhesion to vaginal mucosa were studied by tensile testing method. The swelling behaviour of the tablets in three different solutions was also investigated. In addition, the effect of the formulations on pH of the medium was followed. The most favorable formulation resulted a mixture of Carbopol 934 and Pectin (2:1). The highest bioadhesive strength, the highest swelling volume and the lowest pH reduction were obtained with this formulation.

A randomized controlled trial of a new ovule formulation of ornidazole for the treatment of bacterial vaginosis.

OBJECTIVE: To compare the efficacy of 500 mg ornidazole vaginal ovules (VO) and vaginal tablets (VT) in the treatment of bacterial vaginosis. METHOD: Patients were allocated at random to one group of 50 subjects to be treated with a VO (500 mg) prepared in our laboratory and to a second group of 50 subjects to be treated with a VT of ornidazole (500 mg). Therapeutic efficacy was assessed by Nugent's scoring system and clinical criteria (Amsel's criteria) before and 1 week after treatment. RESULTS: At the first follow-up visit, complete disappearance of the signs and symptoms or highly significant reduction in intensity of symptoms was observed in both treatment groups. No significant difference was evident between the two ornidazole formulations.

Synthesis and microtubule binding of fluorescent paclitaxel derivatives.

The preparation of two new fluorescent derivatives of paclitaxel in which the fluorophore is bonded to paclitaxel at the C-10 position is reported. Both analogues, 10-deacetyl-10-(m-aminobenzoyl)paclitaxel (1, BTax) and 10-deacetyl-10-[7-(diethylamino) coumarin-3-carbonyl]paclitaxel (2, CTax) retain good activity as promoters of in vitro tubulin assembly. Microtubule binding enhances the emission intensity of both probes.

The effect of the type and the concentration of the lipophilic surfactant on the stability and release kinetics of the W/O/W multiple emulsions.

Stable multiple emulsions that contain different lipophilic surfactants in the internal aqueous phase have been formulated. The multiple systems were assessed by evaluating several parameters such as macroscopic aspect, droplet size, percent release and accelerated stability under centrifugation or elevated temperature. The effect of polymeric and monomeric surfactants on the release mechanism and stability was examined. An excess of monomeric surfactant in the oil phase enhances the release rate and decreases stability. The release rate can be decreased by an increase of the lipophilic surfactant concentration. It appears that the more the oil globule swells, the less hydrosoluble drug is released. As a result a high swelling capacity is associated with better stability.

The taxane diterpenoids

The structures of over 350 taxane diterpenoids are classified and presented with information on their plant source, yield, melting point, and optical activity. The biotransformations and biosynthesis of the taxoids are also reviewed.

A new semisynthesis of paclitaxel from baccatin III.

A new method for the semisynthesis of paclitaxel (Taxol) from baccatin III via a dioxo-oxathiazolidine intermediate is reported.

Sustained-release microcapsules of nitrofurantoin and amoxicillin; preparation, in-vitro release rate, kinetic and micromeritic studies.

In this work, nitrofurantoin and amoxicillin trihydrate microcapsules were prepared by complex coacervation at pH 3.5 using carboxymethylcellulose-gelatin at a weight ratio of 3:7. Release rates were studied as a function of core:wall ratios of microcapsules. Dissolution tests of microcapsules and their tabletted microcapsules were studied in artificial gastric and intestinal media without enzyme using the USP XXII basket method. Release rates were examined kinetically and the ideal kinetic models were estimated for drug release. In addition, the micromeritics of these microcapsules were investigated. In order to standardize the drug powder and the microcapsule product for industrial application, the micromeritic properties of microcapsules were studied by determining their bulk volume and weight, tapping volume and weight, fluidity, angle of repose, weight deviation, particle size distribution, density and porosity. Hausner ratio and consolidation index were also calculated to understand flowability rates of microcapsules when tableting or filling into gelatin capsules. The results indicated that the nitrofurantoin microcapsules need appropriate glidant but the amoxicillin trihydrate microcapsules did not. Moreover, it was observed that the microencapsulation changed the micromeritic properties of the drugs significantly.