Potency Of Agents Research Articles

A Quick Guide for Topical Treatment for Psoriasis

Psoriasis, a chronic inflammatory skin disorder, presents a therapeutic challenge due to its diverse manifestations and impact on patients' lives. This review delves into the intricacies of topical agents used in managing psoriasis, encompassing corticosteroids, vitamin D analogs, retinoids, calcineurin inhibitors, and unconventional treatments like coal tar and salicylic acid. Each agent's potency, application, and considerations for different age groups are discussed, providing clinicians with a comprehensive guide for treatment selection. The multifaceted nature of psoriasis requires tailored approaches, and understanding the nuances of these topical therapies is crucial for optimizing outcomes. Ongoing research promises further advancements in psoriasis management, holding potential for more personalized and effective interventions.

Abstract 4640: Development of antibody-drug conjugate technology based on novel DNA-interacting agents and unique linker technology

Abstract Antibody-Drug Conjugation (ADC) is gaining momentum as a next generation antibody therapeutics approach in oncology. Tumor specific delivery of the cell-killing agent maximizes the agent's potency while avoiding damage to healthy tissue resulting in a high therapeutic window. Synthon's Potent Payload Technology comprises the combination of highly potent DNA-alkylating duocarmycin derivatives and unique releasable linker technology. Duocarmycin analogs and the CC-1065 derivatives represent a class of highly potent, cell-killing, DNA-alkylating, minor groove binding agents. This class is suitable to target solid tumors and has shown activity in a variety of Multi-Drug Resistant (MDR) models.Synthon SpaceLink technology is the only releasable linker technology for ADC that can couple the toxin via its hydroxyl group to the antibody, validated in vivo. Synthon has combined its linkers with duocarmycin derivatives that have a hydroxyl group crucial for biological activity. The data package to be presented supports that SpaceLink and duocarmycins form an excellent chemical match for ADC therapy, possessing an intrinsic complementarity. Strong in vivo Proof of Concept with Potent Payload ADCs has been obtained against multiple targets. In human tumor xenograft models, substantial efficacies have been obtained based on low, single dose treatments, with minimal or absent side effects. We discuss applicability and several other aspects of multiple, validated Potent Payload-based Antibody-Drug Conjugates (ADCs). Latest results of preclinical development progress (in vivo efficacy, safety, etc.) will be presented, including in vitro drug and ADC potencies, plasma stabilities, cathepsin cleavage kinetics, linker cyclization kinetics and in vivo therapeutic window aspects for ADCs directed against HER2 and potentially other (collaborator) targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4640. doi:1538-7445.AM2012-4640

PK-PD modeling of β-lactam antibiotics: In vitro or in vivo models?

A modified E(max)-pharmacokinetic-pharmacodynamic (PK-PD) model was previously proposed in literature for describing the antimicrobial activity of β-lactam antibiotics based on in vitro experiments. However, bacteria behave differently in vitro and in vivo. Thus, the aims of this study were to model the killing effect of piperacillin (PIP) against Escherichia coli on immunocompromised infected rats using this model and to compare the parameters obtained in vitro and in vivo for the same bacteria/drug combination. The PK-PD parameters determined in vitro and in vivo were as follows: generation rate constant of 1.30 ± 0.10 and 0.76 ± 0.20 h(-1), maximum killing effect of 3.11 ± 0.27 and 1.38 ± 0.20 h(-1) and concentration to produce 50% of the maximum effect of 5.44 ± 0.03 and 1.31 ± 0.27 μg ml(-1), respectively. The comparison between the in vitro and in vivo parameters was not straightforward and had to take into consideration the intrinsic differences of the models involved. So far, the main application of the PK-PD model evaluated is for the comparison of different antimicrobial agent's potency and efficacy, under equivalent conditions.

Abstract 4397: Development of antibody-drug conjugate technology based on novel linkers & DNA alkylating duocarmycin derivatives

Abstract Antibody-Drug Conjugation (ADC) is gaining momentum as a next generation antibody therapeutics approach in oncology. Tumor specific delivery of the cell-killing agent maximizes the agent's potency while avoiding damage to healthy tissue resulting in a high therapeutic window. Syntarga's Potent Payload Technology comprises the combination of highly potent DNA-alkylating duocarmycin derivatives and suitable linker technologies. Duocarmycin analogs and the CC-1065 derivatives represent a class of highly potent, cell-killing, DNA-alkylating, minor groove binding agents. This class is suitable to target solid tumors and has not been associated with Multi-Drug Resistance (MDR). Strong in vivo Proof of Concept with Potent Payload ADCs has been obtained against multiple targets. In human tumor xenograft models, substantial efficacies have been obtained based on single dose treatments, with minimal or absent side effects. We discuss applicability and several other aspects of multiple, validated Potent Payload-based Antibody-Drug Conjugates (ADCs). Latest results of preclinical development progress (in vivo efficacy, safety, etc.) will be presented, including drug potencies, linker stability and therapeutic window aspects for ADCs directed against HER2. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4397.

Development of high-specific-activity 68Ga-labeled DOTA-rhenium-cyclized α-MSH peptide analog to target MC1 receptors overexpressed by melanoma tumors

A previous report on (68)Ga-1,4,7,10-tetraazacyclodedecane-N,N',N'',N'''-tetraacetic acid (DOTA)-Re(Arg(11))CCMSH was shown to indicate the imaging agent's potency for early detection of metastatic melanoma. However, the main limiting factor to developing high-specific-activity (68)Ga-DOTA-Re(Arg(11))CCMSH is the short half-life of (68)Ga, which precludes further purification of the agent. To circumvent this problem, we incorporated the microwave technique to rapidly radiolabel the peptide with (68)Ga, thereby allowing enough time to include high-performance liquid chromatography (HPLC) purification in the overall procedure. DOTA-Re(Arg(11))CCMSH was radiolabeled with (68)Ga in <1 min using a circular-cavity microwave apparatus. Reverse-phase HPLC purification was accomplished in less than 20 min. (68)Ga-DOTA-Re(Arg(11))CCMSH was then administered on B16/F1 murine melanoma-bearing C57 mice to study its biodistribution and positron emission tomography (PET) imaging capability. The production of high-specific-activity (68)Ga-DOTA-Re(Arg(11))CCMSH resulted in an improved tumor uptake [6.93+/-1.11%ID/g at 30 min postinjection (p.i.) and 6.27+/-1.60%ID/g at 1 h p.i.] and tumor retention (5.85+/-1.32%ID/g at 4 h p.i.). Receptor-mediated tumor uptake was verified by blocking studies. Furthermore, high-resolution PET images of the tumor were obtained, owing to high tumor-to-nontarget organ ratios at an early time point (i.e., at 1 h biodistribution: tumor/blood, 14.3; tumor/muscle, 89.6; tumor/skin, 12.3) and fast clearance of the labeled peptide from kidney and other healthy tissues. High-specific-activity (68)Ga-DOTA-Re(Arg(11))CCMSH may have a potential role in the early diagnosis of metastasized melanoma.

Pediatricians who Prescribe Clotrimazole-Betamethasone Diproprionate (Lotrisone) often Utilize it in Inappropriate Settings Regardless of their Knowledge of the Drug's Potency

Clotrimazole-betamethasone diproprionate (C-BMV) is a fluorinated, high potency topical steroid that has been formulated with clotrimazole in the brand-named product, Lotrisone. The product is frequently used inappropriately in intertriginous areas, particularly in children. The following evaluates the use of this combination based upon a survey of 106 US-based pediatricians with at least two years post-residency, who attended the 1999 American Academy of Pediatrics. Of pediatricians who prescribe C-BMV, 23% prescribe it for diaper dermatitis. 11% of C-BMV prescriptions exceed the recommended duration of therapy. Only 18% of prescribing pediatricians correctly identify "Lotrisone" as a high potency steroid. There is no significant association between knowledge of C-BMV potency and frequency of use (p>.1). These self-reported data confirm and complement the findings of previous studies that used representative national data to assess the use of C-BMV. Pediatricians continue to utilize C-BMV in inappropriate settings, such as diaper dermatitis, regardless of their knowledge of the agent's potency. Our advice is to refrain from using high-potency steroids, such as C-BMV, in pediatric cases as there are more appropriate, safer alternatives with many fewer side effects.

Direct measurement of muscarinic agents in the central nervous system of mice using ex vivo binding

Muscarinic agents produce a range of side effects including hypothermia and tremor. Although these responses can be used to estimate the in vivo activity of these muscarinic agents in the central nervous system (CNS), the approach is limited by compensatory feedback mechanisms and the difficulty of equating degree of receptor occupancy to effect. We have developed an ex vivo assay to measure the potency and penetration of muscarinic agents into the CNS. The muscarinic antagonists scopolamine and N-methylscopolamine dose dependently inhibited the ex vivo binding of [ 3H]oxotremorine-M to homogenates to mouse whole brain membranes. Following intraperitoneal administration these compounds had ED 50 values of 2.6. and 26 mg/kg respectively, which were comparable to the doses which inhibited RS86 induced hypothermia in mice. Three muscarinic agonists RS86, pilocarpine and arecoline also demonstrated CNS activity in this assay with ED 50 values of 11, 23 and 220 mg/kg. RS86 and pilocarpine additionally showed good penetration into the CNS with estimated values of 1.5 and 0.31% of the administered dose. These values were comparable with the ability of these compounds to induce a centrally mediated hypothermic response. These studies demonstrate a simple, quick and reliable biochemical means of assessing a muscarinic agent's potency and penetration within the CNS.