Enhancer Potency Research Articles

Proline, hydroxyproline, and pyrrolidone carboxylic acid derivatives as highly efficient but reversible transdermal permeation enhancers

Overcoming the skin barrier properties efficiently, temporarily, and safely for successful transdermal drug delivery remains a challenge. We synthesized three series of potential skin permeation enhancers derived from natural amino acid derivatives proline, 4-hydroxyproline, and pyrrolidone carboxylic acid, which is a component of natural moisturizing factor. Permeation studies using in vitro human skin identified dodecyl prolinates with N-acetyl, propionyl, and butyryl chains (Pro2, Pro3, and Pro4, respectively) as potent enhancers for model drugs theophylline and diclofenac. The proline derivatives were generally more active than 4-hydroxyprolines and pyrrolidone carboxylic acid derivatives. Pro2–4 had acceptable in vitro toxicities on 3T3 fibroblast and HaCaT cell lines with IC50 values in tens of µM. Infrared spectroscopy using the human stratum corneum revealed that these enhancers preferentially interacted with the skin barrier lipids and decreased the overall chain order without causing lipid extraction, while their effects on the stratum corneum protein structures were negligible. The impacts of Pro3 and Pro4 on an in vitro transepidermal water loss and skin electrical impedance were fully reversible. Thus, proline derivatives Pro3 and Pro4 have an advantageous combination of high enhancing potency, low cellular toxicity, and reversible action, which is important for their potential in vivo use as the skin barrier would quickly recover after the drug/enhancer administration is terminated.

Abstract 1525: Enhancing potency of antigen presenting cells via signal 2/3 mRNA engineering through Cell Squeeze® technology

Abstract Antigen-specific CD8+ T cells are critical effectors of the immune system that help limit persistence of tumors and virally infected cells. During priming, T cells integrate three signals which determine the magnitude and quality of response generated. Signal one is T cell receptor(TCR) and peptide-MHC (pMHC) engagement, which determines the specificity of the response.Signal two is cell surface costimulation by antigen presenting cells (APCs). Signal three is provided through the local cytokine milieu at the time of priming. Here, we use microfluidic CellSqueeze® technology to deliver mRNAs encoding antigen (signal 1), costimulatory molecules(signal 2), and chimeric membrane-tethered cytokines (signal 3) to the cytosol of human peripheral blood mononuclear cells (PBMCs), generating antigen presenting cells (APCs) with multiple enhanced functions. We demonstrate that microfluidic squeezing enables delivery and expression of single or multiple mRNAs encoding signal 1 (various antigens), signal 2 (CD70 orCD86) and/or signal 3 (membrane-tethered form of IL-2) by the major subsets of PBMCs (T cells, B cells, NK cells, and monocytes). While unsqueezed PBMCs showed no to minimal expression of signal 2 and no expression of signal 3 molecules, expression of delivered signal 2and 3 mRNAs in squeezed PBMCs could be observed on the cell surface for several days post squeeze delivery - a timeframe that could potentially support improved T cell priming. When these signal 2/3 molecules were delivered alone or in combination, antigen-specific CD8+ T cell responses could be increased as much as ten-fold compared to delivery of antigen alone.Therefore, microfluidic cell squeezing enables us to efficiently deliver mRNA antigens that have potential to generate multiple immune epitopes in an HLA agnostic manner. Moreover,multiplexing these antigens with signal 2/3 mRNAs enhances the antigen presenting potency ofSQZ APCs inducing stronger antigen-specific CD8+ T cell responses. The potential to deliver numerous materials simultaneously and engineer compound signals via mRNA could allow for applications for HLA-agnostic patient population in oncology and infectious disease areas. Citation Format: Emrah Ilker Ozay, Paul Dunbar, Kelly Volk, Michael F. Maloney, Christian Yee, Mubeen Mosaheb, Christine Trumpfheller, Pablo Umana, Katherine J. Seidl, Howard Bernstein, Scott M. Loughhead. Enhancing potency of antigen presenting cells via signal 2/3 mRNA engineering through Cell Squeeze® technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1525.

The potency of mungbeans enhancement in Sambas Regency West Kalimantan

Agricultural Development is very important as a motor of national economy. Local Resources need to be empowered to improve the welfare of the farming community. This empowerment impacts the problems and opportunities in the development of mungbeans in West Kalimantan. The Indonesian Ministry of Agriculture makes West Kalimantan Province as one of the priorities for the development of legumes and tuber Agro-industries. The development of legumes such as mungbeans is part of an effort to diversify food. This research was conducted in June to October 2017 in Sambas Regency, West Kalimantan. The methodology used is the PRA (Participatory Rural Appraisal) with 30 respondents farmers owners and traders. The results showed that Sambas Regency has the potency for enhancing mungbeans in West Kalimantan. This is supported by natural resources, land resources and farmer resources. From the results of financial analysis in 4 sub districts in Sambas Regency, it can be seen that the highest net income received by farmers in the Teluk Keramat District is IDR. 17,136,750, - with an R / C value of 3.49 and B / C ratio of 2.49.

The Origin of Corrosion Resistance Change Induced by Sn and Nb Alloying in Zr Alloys

As nuclear fuel cladding, Zr alloys have need for a good corrosion resistance. For decades, through adjusting content of Sn and Nb, several generations of Zr alloys with excellent corrosion resistance are developed. However, the mechanism of Sn and Nb influencing the corrosion resistance is still not clear. Here, our computational simulations indicate, the segregations of Sn or Nb at grain boundary (GB) can occur, and results in variation of GB cohesion, which influences the difficulty of the formation of micro-cracks in oxide film and then changes protectiveness of oxide film which determines the corrosion resistance. Using the first-principles method, we find that Sn segregation can reduce GB cohesion, and results in a potency of reduction of oxide film protectiveness; however, Nb segregation can enhance GB cohesion, and results in a potency of enhancement of oxide film protectiveness; the results are well consistent with the previous experimental observations that reducing Sn and adding Nb can promote corrosion resistance of Zr alloys. These findings provide a basis for understanding the roles of alloying elements in Zr alloys, which is very useful to future design of new Zr alloys with more excellent corrosion resistance.

Enhancing Potency and Selectivity of a DC-SIGN Glycomimetic Ligand by Fragment-Based Design: Structural Basis.

Chemical modification of pseudo‐dimannoside ligands guided by fragment‐based design allowed for the exploitation of an ammonium‐binding region in the vicinity of the mannose‐binding site of DC‐SIGN, leading to the synthesis of a glycomimetic antagonist (compound 16) of unprecedented affinity and selectivity against the related lectin langerin. Here, the computational design of pseudo‐dimannoside derivatives as DC‐SIGN ligands, their synthesis, their evaluation as DC‐SIGN selective antagonists, the biophysical characterization of the DC‐SIGN/16 complex, and the structural basis for the ligand activity are presented. On the way to the characterization of this ligand, an unusual bridging interaction within the crystals shed light on the plasticity and potential secondary binding sites within the DC‐SIGN carbohydrate recognition domain.

Fertility Enhancing Potency of Omega-3 Fatty Acids in Male Rats

Abstract Cases of some grave side effects of some allopathic medicines used in treatment of infertility has caused a global need for alternatives with minimal or no side effect, hence the demand to evaluate the fertility enhancing potential of omega-3 fatty acids (O3FA) in male rats. This study evaluated the fertility enhancing potential of omega-3 fatty acids (O3FA) in male rats. Seventy-two sexually mature male albino rats 11-13 weeks of age, weighing between 171 - 180 g were assigned into six groups (I - VI) fed graded doses of O3FA. Administration of O3FA lasted twenty-eight days at 48 hour intervals. At the end of the treatment, organosomatic index of testes, testicular and epididymis sperm cells counts and testicular histology were assessed following standard methods. The actual and relative testicular weights, testicular and epididymis sperm counts of all O3FA treated rats were significantly increased (p < 0.05) when compared with the control group rats. The photomicrographs of testes in O3FA treated rats showed normal spermatogonial cell layers and active spermatogenesis with appearance of spermatids in the lumen of some tubules. The findings of this study depicts that O3FA possesses the potency of enhancing various fertility indices in male rats with regards to absolute and relative testicular weights as well as sperm counts.

Skin Permeation Enhancement in Aqueous Solution: Correlation With Equilibrium Enhancer Concentration and Octanol/Water Partition Coefficient

The effectiveness of skin penetration enhancers and the enhancer concentration required for effective skin permeation enhancement are difficult to predict. A comprehensive quantitative structure-enhancement relationship of chemical penetration enhancers for skin permeation is not currently available. The present study (a) investigated the relationship between skin permeation enhancement and chemical enhancer concentration and (b) examined a simple quantitative structure-enhancement relationship for predicting skin permeation enhancement to guide enhancer formulation development. In the present analysis, data from previous skin permeation studies that used the symmetric/equilibrium configuration and skin parallel pathway model were summarized to determine the relationship between enhancement factor and enhancer concentration. Under the equilibrium conditions, semilogarithmic linear relationships between enhancement factor (E) and enhancer aqueous concentration (C) were observed and an enhancer potency parameter (α) was defined. A correlation between the potency parameter α and enhancer octanol/water partition coefficient (Koct) was obtained. The enhancement factor relationship was derived: Log E = 0.32 ∙ C ∙ Koct. The results suggest that a “threshold” of (C ∙ Koct) > 0.5 M is required to induce effective skin permeation enhancement under these conditions. Consistent with the analyses in previous studies, the data suggest that octanol represents the skin barrier microenvironment for the penetration enhancers.

Docking and 3D-QSAR Studies on Some HCV NS5b Inhibitors

A theoretical study has been carried out to interpret and support experimental findings regarding inhibition mechanism of HCV NS5b. Twenty-five HCV NS5b inhibitors were docked by QM-Polarized Ligand Docking (QPLD) technique. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used to derive 3D-QSAR models for the selected inhibitors. The CoMFA and CoMSIA models show good cross-validated (Q2) and non-cross-validated (R2) coefficients for the suggested inhibitors of 0.43, 0.98 and 0.65, 0.99, respectively. The inhibition mechanism was explored and validated. Details of the interactions between the inhibitors and HCV NS5b are given in terms of steric, electrostatic, hydrophobic, hydrogen bonding fields. Enhancing potency via substitutions at positions, which were explored based on these parameters. A good correlation was found between 3D-QSAR and docking results.

Analysis of β-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives.

Valerenic acid (VA)—a β2/3-selective GABA type A (GABAA) receptor modulator—displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we analyzed β-subunit-dependent enhancement of GABA-induced chloride currents (IGABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced IGABA enhancement was determined in oocytes expressing α1β1γ2S, α1β2γ2S, or α1β3γ2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. β2/3-selective VA derivatives such as VA-amide (VA-A) modulating α1β3γ2S (VA-A: Emax = 972 ± 69%, n = 6, P < 0.05) and α1β2γ2S receptors (Emax = 1119 ± 72%, n = 6, P < 0.05) more efficaciously than VA (α1β3γ2S: VA: Emax = 632 ± 88%, n = 9 versus α1β2γ2S: VA: Emax = 721 ± 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 ± 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 ± 1.9 mg/kg PTZ, P < 0.05). Similarly, VA’s methylamide (VA-MA) enhancing IGABA through β3-containing receptors more efficaciously than VA (Emax = 1043 ± 57%, P < 0.01, n = 6) displayed stronger anticonvulsive effects. Increased potency of IGABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole (α1β3γ2S: VA-TET: EC50 = 6.0 ± 1.0 μM, P < 0.05; VA-TET: 0.3 mg/kg: 47.3 ± 0.5 mg/kg PTZ versus VA: 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ, P < 0.05). At higher doses (≥10 mg/kg), VA-A, VA-MA, and VA-TET reduced locomotion. In contrast, unselective VA derivatives induced anticonvulsive effects only at high doses (30 mg/kg) or did not display any behavioral effects. Our data indicate that the β2/3-selective compounds VA-A, VA-MA, and VA-TET induce anticonvulsive effects at low doses (≤10 mg/kg), whereas impairment of locomotion was observed at doses ≥10 mg/kg.

Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence

Canonical siRNA design algorithms have become remarkably effective at predicting favorable binding regions within a target mRNA, but in some cases (e.g., a fusion junction site) region choice is restricted. In these instances, alternative approaches are necessary to obtain a highly potent silencing molecule. Here we focus on strategies for rational optimization of two siRNAs that target the junction sites of fusion oncogenes BCR-ABL and TMPRSS2-ERG. We demonstrate that modifying the termini of these siRNAs with a terminal G-U wobble pair or a carefully selected pair of terminal asymmetry-enhancing mismatches can result in an increase in potency at low doses. Importantly, we observed that improvements in silencing at the mRNA level do not necessarily translate to reductions in protein level and/or cell death. Decline in protein level is also heavily influenced by targeted protein half-life, and delivery vehicle toxicity can confound measures of cell death due to silencing. Therefore, for BCR-ABL, which has a long protein half-life that is difficult to overcome using siRNA, we also developed a nontoxic transfection vector: poly(lactic-coglycolic acid) nanoparticles that release siRNA over many days. We show that this system can achieve effective killing of leukemic cells. These findings provide insights into the implications of siRNA sequence for potency and suggest strategies for the design of more effective therapeutic siRNA molecules. Furthermore, this work points to the importance of integrating studies of siRNA design and delivery, while heeding and addressing potential limitations such as restricted targetable mRNA regions, long protein half-lives, and nonspecific toxicities.

Quantitative structure-chemiluminescence intensity relationships of 4-substituted phenols acting as luminol signal enhancers

Luminol-peroxidase-H2O2 is among the most popular systems in chemiluminescence-based analytical applications. The addition of a forth compound into this system has been thoroughly explored over the years, namely an enhancer promoting potency in the signal attained. Improvements in this regard serve to increase sensitivity and applicability of various biochemical methods. Studies exploring the ability of compounds to act as enhancers have proposed several chemical groups as possible candidates, amongst which 4-substituted phenols have been widely employed. Although some studies have explored the effect of the substituent on enhancer potency, no quantitative structure – property relationships (QSPR) employing molecular descriptors for this group of compounds have been presented. Current study provides two such cross- and externally validated models, constructed by the projection to latent structures by means of partial least squares (PLS) multivariate linear regression method: i) a PLS-DA model contributing to the classification of such compounds into classes (relative to the signal), and ii) a PLS model for predicting the signal acquired. Validation was based on statistical metrics Q2ext(F3) for the test set and Roy's metrics r2m(Av) &r2m(δ), assessing both predictive stability and internal validity. Applied in tandem, those models can assist in the recognition of available compounds as potential enhancers or inspire the synthesis of novel analogues. The significance of some characteristics governing the compounds' behaviour are also discussed based on the molecular descriptors chosen.

A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication.

Types 1 and 2 diabetes affect some 380 million people worldwide. Both result ultimately from a deficiency of functional pancreatic insulin-producing beta cells. Beta cells proliferate in humans during a brief temporal window beginning around the time of birth, with peak beta cell labeling indices achieving approximately 2% in first year of life1-4. In embryonic life and after early childhood, beta cell replication rates are very low. While beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such efforts1-8. Hence, there remains an urgent need for diabetes therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo. Here, we report the results of a high-throughput small molecule screen (HTS) revealing a novel class of human beta cell mitogenic compounds, analogues of the small molecule, harmine. We also define dual specificity tyrosine-regulated kinase-1a (DYRK1A) as the likely target of harmine, and the Nuclear Factors of activated T-cells (NFAT) family of transcription factors as likely mediators of human beta cell proliferation as well as beta cell differentiation. These observations suggest that harmine analogues (“harmalogs”) may have unique therapeutic promise for human diabetes therapy. Enhancing potency and beta cell specificity are important future challenges.

A cycloartane glycoside derived from Actaea racemosa L. modulates GABAA receptors and induces pronounced sedation in mice.

23-O-Acetylshengmanol 3-O-β-D-xylopyranoside (Ac-SM) isolated from Actaea racemosa L.-an herbal remedy for the treatment of mild menopausal disorders-has been recently identified as a novel efficacious modulator of GABAA receptors composed of α1-, β2-, and γ2S-subunits. In the present study, we analyzed a potential subunit-selective modulation of GABA-induced chloride currents (IGABA) at GABA concentrations eliciting 3-8% of the maximal GABA response (EC3-8) through nine GABAA receptor isoforms expressed in Xenopus laevis oocytes by Ac-SM with two-microelectrode voltage clamp and behavioral effects 30 minutes after intraperitoneal application in a mouse model. Efficacy of IGABA enhancement by Ac-SM displayed a mild α-subunit dependence with α2β2γ2S (maximal IGABA potentiation [Emax] = 1454 ± 97%) and α5β2γ2S (Emax = 1408 ± 87%) receptors being most efficaciously modulated, followed by slightly weaker IGABA enhancement through α1β2γ2S (Emax = 1187 ± 166%), α3β2γ2S (Emax = 1174 ± 218%), and α6β2γ2S (Emax = 1171 ± 274%) receptors and less pronounced effects on receptors composed of α4β2γ2S (Emax = 752 ± 53%) subunits, whereas potency was not affected by the subunit composition (EC50 values ranging from α1β2γ2S = 35.4 ± 12.3 µM to α5β2γ2S = 50.9 ± 11.8 µM). Replacing β2- with β1- or β3-subunits as well as omitting the γ2S-subunit affected neither efficacy nor potency of IGABA enhancement by Ac-SM. Ac-SM shifted the GABA concentration-response curve toward higher GABA sensitivity (about 3-fold) and significantly increased the maximal GABA response by 44 ± 13%, indicating a pharmacological profile distinct from a pure allosteric GABAA receptor modulator. In mice, Ac-SM significantly reduced anxiety-related behavior in the elevated plus maze test at a dose of 0.6 mg/kg, total ambulation in the open field test at doses ≥6 mg/kg, stress-induced hyperthermia at doses ≥0.6 mg/kg, and significantly elevated seizure threshold at doses ≥20 mg/kg body weight. High efficacy and long biologic half-life of Ac-SM suggest that potential cumulative sedative side effects upon repetitive intake of A. racemosa L. preparations might not be negligible.

Structure Enhancement Relationship of Chemical Penetration Enhancers in Drug Transport across the Stratum Corneum.

The stratum corneum is a major barrier of drug penetration across the skin in transdermal delivery. For effective transdermal drug delivery, skin penetration enhancers are used to overcome this barrier. In the past decades, a number of research studies were conducted to understand the mechanisms of skin penetration enhancers and to develop a structure enhancement relationship. Such understanding allows effective prediction of the effects of skin penetration enhancers, assists topical and transdermal formulation development, and avoids extensive enhancer screening in the transdermal delivery industry. In the past two decades, several hypotheses on chemical enhancer-induced penetration enhancement for transport across the skin lipoidal pathway have been examined based on a systematic approach. Particularly, a hypothesis that skin penetration enhancement is directly related to the concentration of the enhancers in the stratum corneum lipid domain was examined. A direct relationship between skin penetration enhancer potency (based on enhancer aqueous concentration in the diffusion cell chamber) and enhancer n-octanol-water partition coefficient was also established. The nature of the microenvironment of the enhancer site of action in the stratum corneum lipid domain was found to be mimicked by n-octanol. The present paper reviews the work related to these hypotheses and the relationships between skin penetration enhancement and enhancer concentration in the drug delivery media and stratum corneum lipids.

Mastering the Canonical Loop of Serine Protease Inhibitors: Enhancing Potency by Optimising the Internal Hydrogen Bond Network

BackgroundCanonical serine protease inhibitors commonly bind to their targets through a rigid loop stabilised by an internal hydrogen bond network and disulfide bond(s). The smallest of these is sunflower trypsin inhibitor (SFTI-1), a potent and broad-range protease inhibitor. Recently, we re-engineered the contact β-sheet of SFTI-1 to produce a selective inhibitor of kallikrein-related peptidase 4 (KLK4), a protease associated with prostate cancer progression. However, modifications in the binding loop to achieve specificity may compromise structural rigidity and prevent re-engineered inhibitors from reaching optimal binding affinity.Methodology/Principal FindingsIn this study, the effect of amino acid substitutions on the internal hydrogen bonding network of SFTI were investigated using an in silico screen of inhibitor variants in complex with KLK4 or trypsin. Substitutions favouring internal hydrogen bond formation directly correlated with increased potency of inhibition in vitro. This produced a second generation inhibitor (SFTI-FCQR Asn14) which displayed both a 125-fold increased capacity to inhibit KLK4 (K i = 0.0386±0.0060 nM) and enhanced selectivity over off-target serine proteases. Further, SFTI-FCQR Asn14 was stable in cell culture and bioavailable in mice when administered by intraperitoneal perfusion.Conclusion/SignificanceThese findings highlight the importance of conserving structural rigidity of the binding loop in addition to optimising protease/inhibitor contacts when re-engineering canonical serine protease inhibitors.

Comparison of potency between histone deacetylase inhibitors trichostatin A and valproic acid on enhancing in vitro development of porcine somatic cell nuclear transfer embryos

Epigenetic modification influences reprogramming and subsequent development of somatic cell nuclear transfer (SCNT) embryos. Such modification includes an increase in histone acetylation. Histone deacetylase inhibitors (HDACi), such as trichostatin A (TSA) and valproic acid (VPA), have been known to maintain a high cellular level of histone acetylation. Hence, treatment of nuclear transfer embryos with HDACi may increase the efficiency of cloning. The present study attempted direct comparison of TSA and VPA with regard to the potency of enhancement of in vitro development in porcine SCNT embryos. Reconstructed oocytes using fetal fibroblasts were cultured in PZM-3 containing no HDACi (control), 5 mM VPA, or 50 nM TSA for 24 h, and another 5 d thereafter without HDACi. The frequency of blastocyst formation was significantly higher (P<0.05) in embryos treated with VPA than the frequencies with TSA and without HDACi (125/306, 40.8% vs. 94/313, 30.2% vs. 80/329, 23.4%). In addition, VPA treatment significantly increased (P<0.05) the number of inner cell mass (ICM) cells compared with the control (15.6 ± 1.7 vs. 10.8 ± 2.6), whereas no differences were observed between the TSA treatment and control groups (12.9 ± 3.0 vs. 10.8 ± 2.6). The present study demonstrates that VPA enhances in vitro development of porcine SCNT embryos, particularly by an increase in blastocyst formation and in the number of ICM cells, suggesting that VPA may be more potent than TSA in supporting developmental competence of cloned embryos.

Effects of Oxygen-Containing Terpenes as Skin Permeation Enhancers on the Lipoidal Pathways of Human Epidermal Membrane

The present study investigated the effects of oxygen-containing terpenes as skin permeation enhancers on the lipoidal pathways of human epidermal membrane (HEM). The enhancement (EHEM) effects of menthol, thymol, carvacrol, menthone, and cineole on the transport of a probe permeant, corticosterone, across HEM were determined. It was found that the enhancer potencies of menthol, thymol, carvacrol, and menthone were essentially the same and higher than that of cineole based on their aqueous concentration in the diffusion cell chamber at EHEM=4. Thymol and carvacrol also had the same EHEM=10 concentration further supporting that they had the same enhancer potency based on the aqueous concentration. The uptake amounts of terpene into the HEM stratum corneum (SC) intercellular lipid under the same conditions indicate that the intrinsic potencies of the studied terpenes are the same based on their concentration in the SC and similar to those of n-alkanol and n-alkylphenyl alcohol. Moreover, they are all better enhancers compared to branched-chain alkanol. The approximately same uptake enhancement of β-estradiol induced by the studied terpenes and alcohols at EHEM conditions into the SC intercellular lipids suggests that the mechanism of enhancement action for the terpenes and those of alcohols are essentially the same. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3617–3632, 2009

Enhancing Potency Among Male Adolescents at Risk to Drug Abuse: An Action Research

Potency defined as one’s self-control, self-confidence, and the belief that society is just and significant, is considered to be an important personality resource for coping with life stressors. The aim of the current study was to examine the impact of a two- stage intervention model on the level of potency. The intervention model consisted of physically and mentally challenging boot camp (five days) and group therapy (24 sessions). The sample consisted of 34 adolescents at risk of drug abuse divided into two groups, a study and comparison group. Participants were administered self-report questionnaires before and after the intervention. The following scales were measured: potency, self-esteem, optimism, social support from friends and family, and past traumatic experiences. Results indicated that the levels of potency, self-esteem, and optimism were significantly higher in the study group compare to the comparison group. In addition, there was a decline of all the variables in the comparison group at the second time of data collection, indicating that intervention during adolescence is critical.

Enhancing potency of anti-HIV chimeric immune receptor (CIR) (128.5)

Abstract Immunotherapies that have the potential to eradicate reservoirs of HIV infected cells may be useful to suppress or cure HIV/AIDS. in combination with current antiviral drug therapies. T cells expressing chimeric immune receptors (CIR) through gene modification ("designer T cells") can be redirected to kill HIV-infected cells. Previously, an anti-HIV CIR, CD4-ζ (1st generation), was created to bind to HIV-1 gp120 antigen through its CD4 extracellular domain and induction of signaling through cytoplasmic CD3ζ chain. However, the adoptive transfer of autologous CD4-ζ T cells to HIV/AIDS patients failed to control the viral infection in clinical trials. To improve potency, our laboratory has created 2nd generation anti-HIV designer T cells that incorporate CD28 costimulation (CD4-CD28-ζ). 2nd generation designer T cells kill HIV-Env expressing Jurkat cells and HIV-1 infected CEM-SS cells as well or better than 1st generation designer T cells. Stimulation with anti-CD4 mAb induces more IL2 production in 2nd generation than 1st generation designer T cells. In addition, 2nd generation designer T cells showed significantly better proliferative response upon culture with HIV-Env expressing HeLa cells or HIV-1 infected CEM-SS cells. These data suggest that gene modified CD8+ T cells could be an effective therapy to eradicate HIV+ cells during and after anti-retroviral therapy. We hypothesize that CD28 domain in the CIR will confer a benefit of longer T cell survival after infusion into HIV patients. Research supported by NIH, R21.

Effects of Chemical Enhancers on Human Epidermal Membrane: Structure-Enhancement Relationship Based on Maximum Enhancement (Emax)

Chemical penetration enhancers are widely used in transdermal pharmaceuticals as well as cosmetic products. Selection of suitable enhancers in topical formulations requires an understanding of the mechanism of action of these enhancers. The objective of the present study was to evaluate the enhancement effects of a number of commonly known enhancers and cosmetic ingredients on permeation across human epidermal membrane (HEM). The potencies of these chemical enhancers—maximum enhancement, Emax—were compared at their highest thermodynamic activity in equilibrium with HEM (i.e., solubility equilibrium). This was achieved by the treatment of HEM with the enhancer or phosphate buffered saline (PBS) saturated with the enhancer. Passive transport experiments were then conducted with a model permeant corticosterone to determine the effects of these enhancers on the lipoidal pathway of HEM. The results suggest that Emax of an enhancer is related to its octanol/water partition coefficient and its solubility in the HEM lipid domain. A relationship between enhancer Emax and its solubility in silicone elastomer was also observed, suggesting the use of silicone solubility to predict enhancer potency. Based on the Emax results, some common topical ingredients were found to be more potent enhancers than a number of well-known chemical enhancers.