One step assembly of ginsenoside Rb1-based nanovehicles with fast cellular transport in photothermal-chemical combined cancer therapy.

Nowadays, the research of photothermal-chemical co-therapy provides new ideas for the treatment of cancer. However, the harsh photothermal temperature hinders the clinical development of photothermal therapy. To ensure low-temperature photothermal-chemical combined therapy, a safe and feasible drug delivery system is highly desirable. Herein, through one step co-precipitation method, ginsenoside Rb1-based nanovehicles composed of the hydrophobic drug doxorubicin, the photochemical reagent Cypate and the heat shock protein inhibitor gambogic acid was prepared, resulting from the amphiphilicity and membrane permeability of Rb1. Encouragingly, this platform exhibited excellent biocompatibility and rapid cellular uptake, both of which led to significant and irreversible death of breast cancer cells under the trigger of short-term near-infrared light.

Identification of selective ligands targeting two GPCRs by receptor-affinity chromatography coupled with high-throughput sequencing techniques.

The rapid growth of demands for drug discovery has necessitated the ongoing pursuit of new methods for specific ligands screening and identification. This work combined receptor-affinity chromatography (RAC) with high-throughput sequencing techniques to rapidly screen and identify the specific ligands. By this method, immobilized angiotensin II type I receptor (AT1R) and endothelin receptor A (ETAR) based on RAC were utilized for lead screening from a DNA-encoded library. The specific ligands of AT1R (ligand A1, A2) and ETAR (ligand B1, B2) were synthesized after decoding by high-throughput sequencing techniques. The dissociation rate constants (kd) of ligand A1, A2 to AT1R and B1, B2 to ETAR were 9.65 × 10-4, 31.1 × 10-4 and 0.66, 1.22 s-1 by peak profiling assay. The association constant (KA) to the receptors of four ligands was 5.4 × 106, 3.3 × 106 and 1.6 × 106, 2.2 × 105 by injection amount dependent method. The kinetic and thermodynamic parameters of the four specific ligands are similar to those of the positive drugs. This indicates that they are promising to drug candidates. The druggability of the four ligands through pharmacokinetic investigation by HPLC-MS/MS presented desired pharmacokinetic behavior including the fast absorption, the relatively slow elimination. These results, taking together, indicated that the RAC combined with high-throughput sequencing techniques can screen and identify the specific ligands according to various proteins, thus creating a general strategy for rapid discovery of promising drug candidates.

A Data-Mining Approach for the Quantitative Assessment of Physicochemical Properties of Molecular Compounds in the Skin Flux.

This paper aimed to provide an insight into the mechanism of transdermal penetration of drug molecules with respect to their physicochemical properties, such as solubility (S), the presence of enantiomer (ET) and logarithm of octanol-water partition coefficient (log P), molecular weight (MW), and melting point (MP). Propionic acid derivatives were evaluated for their flux through full-thickness skin excised from hairless mice upon being delivered from silicone-based pressure-sensitive adhesive (PSA) matrices in the presence or absence of various enhancers. The skin fluxes of model compounds were calculated based on the data obtained using the method engaged with the diffusion cell system. The statistical design of experiments (DoE) based on the factorial approach was used to find variables that have a significant impact on the outcomes. For the prediction of skin flux, a quantitative equation was derived using the data-mining approach on the relationship between skin permeation of model compounds (~125 mg/ml) and involved physicochemical variables. The most influential variables for the skin flux of propionic acid derivatives were the melting point (0.97) followed by the presence of enantiomer (0.95), molecular mass (0.93), log P values (0.86), and aqueous solubility (0.80). It was concluded that the skin flux of molecular compounds can be predicted based on the relationship between their physicochemical properties and the interaction with cofactors including additives and enhancers in the vehicles.

PET Imaging of Hepatocellular Carcinomas: 18F-Fluoropropionic Acid as a Complementary Radiotracer for 18F-Fluorodeoxyglucose.

OBJECTIVE: To evaluate the preclinical value of 18F-fluoropropionic acid (18F-FPA) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) for imaging HCCs. METHODS: The 18F-FPA and 18F-FDG uptake patterns in 3 HCC cell lines (Hep3B, HepG2, and SK-Hep1) were assessed in vitro and in vivo. The 18F-FPA uptake mechanism was investigated using inhibition experiments with orlistat and 5-tetradecyloxy-2-furoic acid. The 18F-FPA PET imaging was performed in different tumor animal models and compared with 18F-FDG. We also evaluated the expressions of glucose transporter-1 (GLUT1), fatty acid synthase (FASN), and matrix metalloproteinase-2 (MMP2) in these cell lines. RESULTS: In vitro experiments showed that the radiotracer uptake patterns were complementary in the HCC cell lines. Orlistat and 5-tetradecyloxy-2-furoic acid decreased the uptake of 18F-FPA. The tumor-to-liver ratio of 18F-FPA was superior to that of 18F-FDG in the SK-Hep1 and HepG2 tumors ( P < .05). However, in the Hep3B tumors, the tumor-to-liver normalized uptake of 18F-FDG was higher than 18F-FPA ( P < .01). FASN was highly expressed in cell lines with high 18F-FPA uptake, whereas GLUT1 was highly expressed in cell lines with high 18F-FDG uptake. The 18F-FPA uptake correlated with FASN ( r = 0.89, P = .014) and MMP2 ( r = 0.77, P = .002) expressions. CONCLUSIONS: PET imaging with 18F-FPA combined with 18F-FDG can be an alternative for detecting HCC.

Thromboxane-prostaglandin receptor antagonist, terutroban, prevents neurovascular events after subarachnoid haemorrhage: a nanoSPECT study in rats.

BACKGROUND: Several lipid metabolites in cerebrospinal fluid are correlated with poor outcomes in aneurysmal subarachnoid haemorrhage. Most of these metabolites bind to ubiquitous thromboxane-prostaglandin (TP) receptors, causing vasoconstriction and inflammation. Here, we evaluated terutroban (TBN), a specific TP receptor antagonist, for the prevention of post-haemorrhage blood-brain barrier disruption, neuronal apoptosis and delayed cerebral hypoperfusion. METHODS: The rat double subarachnoid haemorrhage model was produced by twice injecting (days 1 and 2) autologous blood into the cisterna magna. Seventy-eight male Sprague-Dawley rats were assigned to experimental groups. Rats exposed to subarachnoid haemorrhage were allocated to no treatment (SAH group) or TBN treatment by gastric gavage during the first 5 days after haemorrhage (SAH+TBN group). Control rats received artificial cerebrospinal fluid injections (CSF group). Sham-operated rats with or without TBN administration were also studied. Body weight and Garcia neurological scores were assessed on day 2 and day 5. We used nanoscale single-photon emission computed tomography (nanoSPECT) to measure brain uptake of three radiolabelled agents: 99mTechnetium-diethylenetriaminepentacetate (99mTc-DTPA), which indicated blood-brain barrier permeability on day 3, 99mTechnetium-annexin V-128 (99mTc-Anx-V128), which indicated apoptosis on day 4, and 99mTechnetium-hexamethylpropyleneamineoxime (99mTc-HMPAO), which indicated cerebral perfusion on day 5. Basilar artery narrowing was verified histologically, and cerebral TP receptor agonists were quantified. RESULTS: 99mTc-DTPA uptake unveiled blood-brain barrier disruption in the SAH group. TBN mitigated this disruption in the brainstem area. 99mTc-Anx-V128 uptake was increased in the SAH group and TBN diminished this effect in the cerebellum. 99mTc-HMPAO uptake revealed a global decreased perfusion on day 5 in the SAH group that was significantly counteracted by TBN. TBN also mitigated basilar artery vasoconstriction, neurological deficits (on day 2), body weight loss (on day 5) and cerebral production of vasoconstrictors such as Thromboxane B2 and Prostaglandin F2α. CONCLUSIONS: Based on in vivo nanoscale imaging, we demonstrated that TBN protected against blood-brain barrier disruption, exerted an anti-apoptotic effect and improved cerebral perfusion. Thus, TP receptor antagonists showed promising results in treating post-haemorrhage neurovascular events.

The modulating effect of lipid bilayer/p-coumaric acid interactions on electrical properties of model lipid membranes and human glioblastoma cells.

Biological membranes are one of the most important elements of living cells determining their permeability to the active compounds. Still, little is known about the drug-membrane interactions in terms of pharmacological properties of potential drugs. Chemoprevention based on natural compounds is becoming a strong trend in modern oncopharmacology, and p-coumaric acid (p-CoA) is one such compound with tentative anticancer activity. The microelectrophoretic mobility measurements and electrochemical impedance spectroscopy were applied to study the effects of p-CoA on electrical properties of liposomes, spherical bilayers, and human glioblastoma cell membranes. Our results demonstrated that after treatment with p-CoA, the surface charge of LBC3, LN-229 and LN-18 cell lines was significantly changed in alkaline pH solutions, but not in acidic pH solutions. In contrast, no changes in surface charge density values were registered for phosphatidylethanolamine liposomal membranes and A172 cell membranes after p-CoA treatment. The impedance data showed an increase in values of both the electrical capacitance and the electrical resistance, indicating that p-CoA can be partially inserted into the phosphatidylcholine bilayers. The MTT assay showed cell line-dependent cytotoxic effect of p-CoA. Further molecular analyses revealed the ATP depletion and gene transcription modulation, which might indicate organelle membrane-crossing potential of p-CoA. These results suggest, that changes in surface charge of membranes of living cells not only might be potential predictor of membrane permeability, but also indicate differential composition of cell membranes in various cell lines. Thus further multidirectional analyses are required to implement electrochemical methods as standard testing procedures during drug development process.

Pharmacokinetic Profile, Safety, and Tolerability of Clascoterone (Cortexolone 17-alpha propionate, CB-03-01) Topical Cream, 1% in Subjects With Acne Vulgaris: An Open-Label Phase 2a Study

Clascoterone (cortexolone 17α-propionate, CB-03-01) 1% cream, a topical, androgen receptor (AR) inhibitor under investigation for the treatment of acne vulgaris, is rapidly metabolized to cortexolone in human plasma. The primary objectives of this study were to determine the pharmacokinetic (PK) properties and adrenal suppression potential of clascoterone topical cream, 1% in subjects with acne vulgaris. Study Design: This study was an open-label, multicenter study in 42 subjects ≥12 years of age with moderate-to-severe acne (Grade 3-4 on the Investigator's Global Assessment [IGA]), on the face, chest and/or back. Cohort 1(>18 years of age) and Cohort 2 (12-18 years of age) applied clascoterone topical cream, 1% twice daily (BID) for 14 days. Primary safety endpoints included hypothalamic-pituitary-adrenal (HPA) axis response to cosyntropin via a Cosyntropin Stimulation Test (CST) upon screening (day 1) and at day 14 (HPA axis suppression was defined as a post-stimulation serum cortisol level <18 µg/dL at day 14); and PK evaluation including concentration-time profiles of clascoterone and cortexolone in plasma­PK parameters were determined using "non-compartmental" analysis. Secondary safety endpoints included clinical laboratory testing, local and systemic adverse events (AEs), physical examination/vital signs, and electrocardiogram (ECG). Results: 42 subjects (Cohort 1=20, Cohort 2= 22) enrolled. Cohort 1 was comprised of 15 females (15/20, 75%) and 5 males (5/20, 25%), non-Hispanic/Latino (20/20, 100%), mean age is 24.4 years. Cohort 2 was comprised of 12 females (12/22, 54.5%) and 10 males (10/22, 45.5%), non-Hispanic/Latino (21/22, 95.5%), and mean age is 15.6 years. Three subjects (3/42,7%), 1 adult and 2 adolescents, demonstrated an abnormal HPA axis response with post-stimulation serum cortisol levels ranging from 14.9 to 17.7 µg/dL at day 14. All returned to normal HPA axis function, four weeks after day 14. None showed clinical evidence of adrenal suppression. Clascoterone plasma concentrations achieved PK steady-state by day 5. Clascoterone systemic exposure was similar between both cohorts. At steady-state, plasma concentrations increased ~1.8 to 2.1 fold versus first dose with mean (coefficient of variation [CV] %) maximum plasma concentrations of 4.4 ng/mL (67%) and 4.6 ng/mL (103%) in Cohort 1 and Cohort 2, respectively. Cortexolone plasma concentrations trended below the lower limit of quantitation (0.5 ng/mL) in both cohorts. Local skin reactions (LSRs) were mostly mild, with only one moderate case of pruritus. There were nine AEs categorized as follows: definitely related (N=2), probably related (N=4), unlikely/not related (N=3), to clascoterone. Conclusion: This study demonstrates the safety and tolerability of clascoterone topical cream, 1% in adolescents and adults with acne vulgaris treated BID for 14 consecutive days. J Drugs Dermatol. 2019;18(6):563-568.

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour. RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.

Design and optimization of 2,3-dihydrobenzo[b][1,4]dioxine propanoic acids as novel GPR40 agonists with improved pharmacokinetic and safety profiles.

GPR40 has become a new potential therapeutic target for the treatment of diabetes due to its role in mediating the enhancement of glucose-stimulated insulin secretion in pancreatic ß cells with a low risk of hypoglycemia. As an effort to extend the chemical space and identify structurally distinct GPR40 agonists with improved liver safety, a novel series of fused-ring phenyl propanoic acid analogues were designed. Comprehensive structure-activity relationship studies around novel scaffolds were conducted and led to several analogues exhibited potent GPR40 agonistic activities and high selectivity against other fatty acid receptors. Further evaluation of pharmacokinetic (PK) profiles and in vivo efficacy identified compound 40a with excellent PK properties and significant glucose-lowering efficacy during an oral glucose tolerance test. In addition, compound 40a displayed lower hepatobiliary transporter inhibition and favorable druggability. All results indicate that compound 40a is a promising candidate for further development.

Measurement of Cyanine Dye Photobleaching in Photosensitizer Cyanine Dye Conjugates Could Help in Optimizing Light Dosimetry for Improved Photodynamic Therapy of Cancer.

Photodynamic therapy (PDT) of cancer is dependent on three primary components: photosensitizer (PS), light and oxygen. Because these components are interdependent and vary during the dynamic process of PDT, assessing PDT efficacy may not be trivial. Therefore, it has become necessary to develop pre-treatment planning, on-line monitoring and dosimetry strategies during PDT, which become more critical for two or more chromophore systems, for example, PS-CD (Photosensitizer-Cyanine dye) conjugates developed in our laboratory for fluorescence-imaging and PDT of cancer. In this study, we observed a significant impact of variable light dosimetry; (i) high light fluence and fluence rate (light dose: 135 J/cm², fluence rate: 75 mW/cm²) and (ii) low light fluence and fluence rate (128 J/cm² and 14 mW/cm² and 128 J/cm² and 7 mW/cm²) in photobleaching of the individual chromophores of PS-CD conjugates and their long-term tumor response. The fluorescence at the near-infrared (NIR) region of the PS-NIR fluorophore conjugate was assessed intermittently via fluorescence imaging. The loss of fluorescence, photobleaching, caused by singlet oxygen from the PS was mapped continuously during PDT. The tumor responses (BALB/c mice bearing Colon26 tumors) were assessed after PDT by measuring tumor sizes daily. Our results showed distinctive photobleaching kinetics rates between the PS and CD. Interestingly, compared to higher light fluence, the tumors exposed at low light fluence showed reduced photobleaching and enhanced long-term PDT efficacy. The presence of NIR fluorophore in PS-CD conjugates provides an opportunity of fluorescence imaging and monitoring the photobleaching rate of the CD moiety for large and deeply seated tumors and assessing PDT tumor response in real-time.

Pharmacokinetic, Antiproliferative and Apoptotic Effects of Phenolic Acids in Human Colon Adenocarcinoma Cells Using In Vitro and In Silico Approaches.

Colon cancer is the second most common cause of cancer deaths in the USA and Europe. Despite aggressive therapies, many tumors are resistant to current treatment protocols and epidemiological data suggest that diet is a major factor in the etiology of colon cancer. This study aimed to evaluate the antioxidant activity and the influence of 3,4-dihydroxyphenylacetic (3,4-DHPAA), p-coumaric (p-CoA), vanillic (VA) and ferulic (FA) acids on cell viability, cell cycle progression, and rate of apoptosis in human colon adenocarcinoma cells (HT-29). The results showed that all compounds tested reduce cell viability in human colon cancer cells. 3,4-DHPAA promoted the highest effect antiproliferative with an increase in the percentage of cells in G0/G1 phase, accompanied by a reduction of cells in G2/M phase. Cell cycle analysis of VA and FA showed a decrease in the proportion of cells in G0/G1 phase (10.0 µM and 100.0 µM). p-CoA and FA acids increased the percentage of apoptotic cells and non-apoptotic cells. 3,4-DHPAA seems to be the substance with the greatest potential for in vivo studies, opening thus a series of perspectives on the use of these compounds in the prevention and treatment of colon cancer.

Bioequivalence and food effect study of two zaltoprofen preparations in healthy Chinese volunteers
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OBJECTIVE: Zaltoprofen, a propionic acid derivative of nonsteroidal anti-inflammatory drug (NSAID), has powerful anti-inflammatory and analgesic effects on inflammatory pain. This study was undertaken to investigate the effect of food on the pharmacokinetic parameters of zaltoprofen capsule (trial preparation, T) and tablet (reference preparation, R), and to assess the relative bioequivalence of two zaltoprofen preparations. MATERIALS AND METHODS: In this open-label, randomized, crossover, two-state, four-period study, 24 healthy Chinese volunteers were randomized to receive a single oral dose of zaltoprofen capsule/tablet (80 mg) under fasting and fed state. Plasma samples were obtained for 24 hours and measured by a developed LC-MS/MS method. Pharmacokinetic parameters were calculated using noncompartmental analysis. Safety and tolerability were assessed throughout the study. RESULTS: 24 healthy participants received two zaltoprofen preparations. For zaltoprofen capsule and tablet, coadministration of high-fat food significantly decreased Cmax by 23 and 22%, respectively; tmax was prolonged by 0.7 hours and 0.8 hours, while the AUClast (for T, geometric mean ratio (GMR): 101.81%, 90% confidence interval (CI): 94.71 - 108.14%; for R, GMR: 101.02%, 90% CI: 93.78 - 107.12%) was not significantly affect by the food. Under fasting or fed condition, the 90% CI of T/R ratios of the geometric means for the primary pharmacokinetic parameters AUC and Cmax were within the acceptance range of 80 - 125%. CONCLUSION: These data suggest that the absorption of zaltoprofen is delayed by high-fat-food administration while total exposure is not affected. The two zaltoprofen preparations (capsule and tablet) are bioequivalent under fasting and fed state.
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Oral administration of propionic acid during lactation enhances the colonic barrier function.

BACKGROUND: Propionic acid is a three-carbon short chain fatty acid (SCFA) that has various effects on colonic functions. Although several studies have shown the effects of propionic acid on intestinal mucosal barrier function, studies of the promotion effect during pre-weaning are rare in the literature as far as we know. METHODS: Pre-weaning male Sprague-Dawley rats 7 days after birth were given an oral 0.2 mL/10 g of 200 mM propionic acid solution in the propionic acid group or normal saline solution in the control group by gavage twice a day for ten days. The proximal colonic contents were used for extraction and determination of propionic acid by gas chromatographic analysis; the transepithelial electrical resistance (TER) of colonic tissue was detected by an Ussing chamber; the alterations of ZO-1, Claudin-1, Claudin-8 and Occludin proteins were analyzed by Western blot and immunohistochemistry; and The activity of ERK and p38 MAPK was determined by the phosphorylation status of ERK1/2 and p38 with Western blot. RESULTS: Our results suggested a higher concentration (23.5 ± 1.9 mmol/kg) of propionic acid compared to the physiological concentration (18.1 ± 0.9 mmol/kg) in colonic contents after oral administration increased the value of TER and the expression of ZO-1, Claudin-1, Claudin-8 and Occludin compared to the control group. Furthermore, the expression levels of phosphorylated ERK1/2 and p38 MAPK were increased in propionic acid group. CONCLUSIONS: We concluded that continuous oral administration of propionic acid during lactation may increase its concentration in the proximal colon and promote epithelial barrier function of proximal colon by enhancing the expression of ZO-1, Claudin-8, Claudin-1 and Occludin via increases in the expression of ERK1/2 and p38 MAPK.

Pharmacokinetics, pharmacodynamics and safety profiling of IS01957, a preclinical candidate possessing dual activity against inflammation and nociception.

In spite of unprecedented advances in modern systems of medicine, there is necessity for exploration of traditional plant based secondary metabolites or their semisynthetic derivatives which may results in better therapeutic activity, low toxicity and favourable pharmacokinetics. In this context, computational model based predictions aid medicinal chemists in rational development of new chemical entity having unfavourable pharmacokinetic properties which is a major hurdle for its further development as a drug molecule. Para-coumaric acid (p-CA) and its derivatives found to be have promising antiinflammatory and analgesic activity. IS01957, a p-CA derivative has been identified as dual acting molecule against inflammation and nociception. Therefore, objective of the present study was to investigate pharmacokinetics, efficacy and safety profile based on in-silico, in-vitro and in-vivo model to assess drug likeliness. In the present study, it has excellent pharmacological action in different animal models for inflammation and nociception. Virtual pharmacokinetics related properties of IS01957 have resemblance between envision and experimentation with a few deviations. It has also acceptable safety pharmacological profile in various animal models for central nervous system (CNS), gastro intestinal tract (GIT)/digestive system and cardiovascular system (CVS). Finally, further development of IS01957 is required based on its attractive preclinical profiles.

Oxaprozin-Loaded Lipid Nanoparticles towards Overcoming NSAIDs Side-Effects.

PURPOSE: Nanostructured Lipid Carriers (NLCs) loading oxaprozin were developed to address an effective drug packaging and targeted delivery, improving the drug pharmacokinetics and pharmacodynamics properties and avoiding the local gastric side-effects. Macrophages actively phagocyte particles with sizes larger than 200 nm and, when activated, over-express folate beta receptors - features that in the case of this work constitute the basis for passive and active targeting strategies. METHODS: Two formulations containing oxaprozin were developed: NLCs with and without folate functionalization. In order to target the macrophages folate receptors, a DSPE-PEG2000-FA conjugate was synthesized and added to the NLCs. RESULTS: These formulations presented a relatively low polydispersity index (approximately 0.2) with mean diameters greater than 200 nm and zeta potential inferior to -40 mV. The encapsulation efficiency of the particles was superior to 95% and the loading capacity was of 9%, approximately. The formulations retained the oxaprozin release in simulated gastric fluid (only around 10%) promoting its release on simulated intestinal fluid. MTT and LDH assays revealed that the formulations only presented cytotoxicity in Caco-2 cells for oxaprozin concentrations superior to 100 µM. Permeability studies in Caco-2 cells shown that oxaprozin encapsulation did not interfered with oxaprozin permeability (around 0.8 × 10(-5) cm/s in simulated intestinal fluid and about 1.45 × 10(-5) cm/s in PBS). Moreover, in RAW 264.7 cells NLCs functionalization promoted an increased uptake over time mainly mediated by a caveolae uptake mechanism. CONCLUSIONS: The developed nanoparticles enclose a great potential for oxaprozin oral administration with significant less gastric side-effects.

Preparation, optimization, and evaluation of Zaltoprofen-loaded microemulsion and microemulsion-based gel for transdermal delivery.

CONTEXT: Zaltoprofen, a non-steroidal anti-inflammatory drug, has potent inhibitory action against nociceptive responses. However, gastrointestinal ulcer accompanied with anemia due to the bleeding are most cited side effects associated with it. Due to this, administration of Zaltoprofen is not suitable for individuals with gastric ulcer. Thus, there is unmet need to develop an alternative delivery system that will be easy to administer and can avoid ulcerogenic side effects associated with it. OBJECTIVE: Present study was aimed to prepare and evaluate microemulsion (ME) and microemulsion-based gel formulation of Zaltoprofen for transdermal delivery. MATERIALS AND METHODS: Pseudo-ternary phase diagrams were utilized to prepare ME formulations. Effect of surfactant and co-surfactant mass ratio on the ME formation and permeation of ME were evaluated and formulation was optimized. Permeation studies were performed using excised pigskin was studied. Efficacy of optimized formulations was evaluated in rat model of inflammation and pain. RESULTS: Composition of optimized formulation was 1% (w/w) Zaltoprofen, 20% (w/w) Capryol 90, 50% (w/w) Smix (2:1, Cremophor RH 40 and Transcutol P). Optimized formulation showed globule size of 22.11 nm, polydispersity index of 0.251 and zeta potential of -11.4 mV. ME gel was found safe in skin irritation study. Significant analgesic activity and anti-inflammatory activity of ME gel was observed in hot plate test and rat paw edema test, respectively. CONCLUSION: In conclusion, results of present study suggest that ME could be a promising formulation for transdermal administration of Zaltoprofen.

Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Prodrugs as Drug Candidates for the Treatment of Ischemic Disorders: Insights into NO-Releasing Prodrug Biotransformation and Hemoglobin-NO Biochemistry.

We have developed novel nitric oxide (NO)-releasing prodrugs of efaproxiral (RSR13) for their potential therapeutic applications in a variety of diseases with underlying ischemia. RSR13 is an allosteric effector of hemoglobin (Hb) that decreases the protein's affinity for oxygen, thereby increasing tissue oxygenation. NO, because of its vasodilatory property, in the form of ester prodrugs has been found to be useful in managing several cardiovascular diseases by increasing blood flow and oxygenation in ischemic tissues. We synthesized three NO-donor ester derivatives of RSR13 (DD-1, DD-2, and DD-3) by attaching the NO-releasing moieties nitrooxyethyl, nitrooxypropyl, and 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate, respectively, to the carboxylate of RSR13. In vitro studies demonstrated that the compounds released NO in a time-dependent manner upon being incubated with l-cysteine (1.8-9.3%) or human serum (2.3-52.5%) and also reduced the affinity of Hb for oxygen in whole blood (ΔP50 of 4.9-21.7 mmHg vs ΔP50 of 25.4-32.1 mmHg for RSR13). Crystallographic studies showed RSR13, the hydrolysis product of the reaction between DD-1 and deoxygenated Hb, bound to the central water cavity of Hb. Also, the hydrolysis product, NO, was observed exclusively bound to the two α hemes, the first such HbNO structure to be reported, capturing the previously proposed physiological bis-ligated nitrosylHb species. Finally, nitrate was observed bound to ßHis97. Ultraperformance liquid chromatography-mass spectrometry analysis of the compounds incubated with matrices used for the various studies demonstrated the presence of the predicted reaction products. Our findings, beyond the potential therapeutic application, provide valuable insights into the biotransformation of NO-releasing prodrugs and their mechanism of action and into hemoglobin-NO biochemistry at the molecular level.

A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours.

BACKGROUND: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. METHODS: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. RESULTS: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. CONCLUSIONS: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

Phase I study on the safety, pharmacokinetic profile, and efficacy of the combination of TSU-68, an oral antiangiogenic agent, and S-1 in patients with advanced hepatocellular carcinoma.

PURPOSE: We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-ß, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment. PATIENTS AND METHODS: Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed. RESULTS: Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively. CONCLUSION: The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest.

Natural occurrence of organofluorine and other constituents from Streptomyces sp. TC1.

Antioxidant-directed fractionation of an ethyl acetate extract of Streptomyces sp. TC1 resulted in the isolation of a novel secondary metabolite with an aromatic organofluorine scaffold (1), an atypical tripod-type triallyl phenol (2), and a leucine residue comprised polyamine (3). Their structures were established by comprehensive spectroscopic analysis of 1D and 2D NMR data, and compound 1 was confirmed by (19)F NMR and single-crystal X-ray diffraction studies. The absolute configuration of compound 3 was assigned by comparison of its ECD spectra and quantum chemical ECD calculations. Of these, compound 1 displayed antioxidant and DNA and protein binding properties.