scholarly journals Dispersive effects and focused biodistribution of recombinant human hyaluronidase PH20: A locally acting and transiently active permeation enhancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254765
Author(s):  
David W. Kang ◽  
Beate Bittner ◽  
Barry J. Sugarman ◽  
Monica L. Zepeda ◽  
Marie A. Printz
Keyword(s):  
Enzymatic Activity ◽  
Systemic Exposure ◽  
Therapeutic Agents ◽  
Intradermal Injection ◽  
Blue Dye ◽  
Permeation Enhancer ◽  
Local Dispersion ◽  
Digital Caliper ◽  
Recombinant Human Hyaluronidase

Background Recombinant human hyaluronidase PH20 (rHuPH20) facilitates the dispersion and absorption of subcutaneously administered therapeutic agents. This study aimed to characterize the transient, local action of rHuPH20 in the subcutaneous (SC) space using focused biodistribution and dye dispersion studies conducted in mice. Materials and methods To evaluate the biodistribution of rHuPH20, mice were intradermally administered rHuPH20 (80 U). The enzymatic activity of rHuPH20 was analyzed in the skin, lymph nodes, and plasma. Animal model sensitivity was determined by intravenous administration of rHuPH20 (80 U) to the tail vein. To evaluate local dispersion, mice received an intradermal injection of rHuPH20 followed by an intradermal injection of Trypan Blue dye at a contralateral site 45 minutes later. Dye dispersion was measured using a digital caliper. Results After intradermal rHuPH20 injection, enzymatic activity was detected within the skin near the injection site with levels decreasing rapidly after 15 minutes. There was no clear evidence of systemic exposure after administration of rHuPH20, and no discernible rHuPH20 activity was observed in lymph or plasma as a function of time after dosing. In the dye dispersion study, delivery of rHuPH20 at one site did not impact dye dispersion at a distal skin site. Conclusion These observations support the classification of rHuPH20 as a transiently active and locally acting permeation enhancer.

scholarly journals How I treat hypereosinophilic syndromes

Blood ◽  
2009 ◽  
Vol 114 (18) ◽  
pp. 3736-3741 ◽  
Author(s):  
Amy D. Klion
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Agents ◽  
Peripheral Eosinophilia ◽  
Therapeutic Decisions ◽  
Organ Manifestations ◽  
Diagnosis And Classification ◽  
Humanized Monoclonal Antibodies ◽  
Peripheral Blood Eosinophilia

Abstract Hypereosinophilic syndromes (HESs) are a heterogeneous group of uncommon disorders characterized by marked peripheral eosinophilia and end organ manifestations attributable to the eosinophilia or unexplained in the clinical setting. Whereas corticosteroids remain the mainstay of treatment for most patients, recent diagnostic advances and the development of novel targeted therapies, including tyrosine kinase inhibitors and humanized monoclonal antibodies, have increased the complexity of therapeutic decisions in HESs. This review presents a treatment-based approach to the diagnosis and classification of patients with peripheral blood eosinophilia of 1.5 × 109/L (1500/mm3) or higher and discusses the role of currently available therapeutic agents in the treatment of these patients.

scholarly journals A Review on Recent Advances in Stabilizing Peptides/Proteins upon Fabrication in Hydrogels from Biodegradable Polymers

2017 ◽  
Author(s):  
Faisal Raza ◽  
Hajra Zafar ◽  
Ying Zhu ◽  
Yuan Ren ◽  
Aftab -Ullah ◽  
...  
Keyword(s):  
Biodegradable Polymers ◽  
Clinical Medicine ◽  
Dynamic Properties ◽  
Therapeutic Agents ◽  
Primary Objective ◽  
Review Literature ◽  
Fine Tuning ◽  
Life Threatening ◽  
Physical And Chemical

Hydrogels evolved as an outstanding carrier material for local and controlled drug delivery that tend to the shortcomings of old conventional dosage forms for small drugs (NSAIDS) and large peptides and proteins. Aqueous swellable and crosslinked polymeric network structure of hydrogels is composed of various natural, synthetic and semisynthetic biodegradable polymers. Hydrogels have remarkable properties of functionality, reversibility, sterilizability, and biocompatibility. All these dynamic properties of hydrogels have increased the interest in their use as a carrier for peptides and proteins to be released slowly in a sustained manner. The therapeutical peptide and proteins are remarkable therapeutic agents in today’s world that allows the treatment of severe, chronic and life‐threatening diseases, such as diabetes, rheumatoid arthritis, hepatitis in an easy manner. Despite few limitations, hydrogels provide fine tuning of proteins and peptides delivery with enormous impact in clinical medicine. The primary objective of this article is to review current issues concerned with the therapeutics peptides and proteins and impact of remarkable properties of hydrogels on these therapeutic agents. Different routes for pharmaceutical peptides and proteins and superiority over other drugs candidates are presented. The article will also review literature concerning classification of hydrogels on different basis, polymers used, release mechanisms their physical and chemical characteristics and diverse applications.

An Approach of Anomaly Detection and Neural Network Classifiers to Measure Cellulolytic Activity

2019 ◽  
Vol 21 (9) ◽  
pp. 681-692
Author(s):  
Luis Francisco Barbosa-Santillán ◽  
María de los Angeles Calixto-Romo ◽  
Juan Jaime Sánchez-Escobar ◽  
Liliana Ibeth Barbosa-Santillán
Keyword(s):  
Neural Network ◽  
Enzymatic Activity ◽  
Real Time ◽  
High Throughput Screening ◽  
Cellulolytic Activity ◽  
Color Patterns ◽  
Cellulolytic Microorganisms ◽  
The Neural Network ◽  
Neural Network Classifiers

Aim and Objective: A common method used for massive detection of cellulolytic microorganisms is based on the formation of halos on solid medium. However, this is a subjective method and real-time monitoring is not possible. The objective of this work was to develop a method of computational analysis of the visual patterns created by cellulolytic activity through artificial neural networks description. Materials and Methods: Our method learns by an adaptive prediction model and automatically determines when enzymatic activity on a chromogenic indicator such as the hydrolysis halo occurs. To achieve this goal, we generated a data library with absorbance readings and RGB values of enzymatic hydrolysis, obtained by spectrophotometry and a prototype camera-based equipment (Enzyme Vision), respectively. We used the first part of the library to generate a linear regression model, which was able to predict theoretical absorbances using the RGB color patterns, which agreed with values obtained by spectrophotometry. The second part was used to train, validate, and test the neural network model in order to predict cellulolytic activity based on color patterns. Results: As a result of our model, we were able to establish six new descriptors useful for the prediction of the temporal changes in the enzymatic activity. Finally, our model was evaluated on one halo from cellulolytic microorganisms, achieving the regional classification of the generated halo in three of the six classes learned by our model. Conclusion: We assume that our approach can be a viable alternative for high throughput screening of enzymatic activity in real time.

A phase I study assessing the feasibility and safety of intraductal pegylated liposomal doxorubicin (PLD) in women with breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e11506-e11506
Author(s):  
L. K. Jacobs ◽  
N. Khouri ◽  
S. Jeter ◽  
P. Powers ◽  
M. Rudek ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Safety Data ◽  
Systemic Exposure ◽  
Pegylated Liposomal Doxorubicin ◽  
Maximum Tolerated Dose ◽  
Outpatient Setting ◽  
Blue Dye ◽  
Breast Cancers ◽  
Serious Adverse Events ◽  
Biomarker Analysis

e11506 Background: Most breast cancers originate in epithelial cells lining the breast ducts. Preclinical data suggest that intraductal administration of chemotherapy including PLD decrease tumor volume, prevent the development of new lesions, and eradicate pre-malignant disease. We initiated a clinical trial to determine the feasibility, safety, and maximum tolerated dose of PLD administered into one duct of women awaiting mastectomy. Methods: Women 18 or older awaiting mastectomy for breast cancer were eligible. Preoperative chemotherapy was allowed. T4 tumors, prior breast irradiation, or surgeries that may have altered the ductal system were excluded. Nipple aspiration and ductal cannulation were completed and the first 3 women received 5 mL of intraductal dextrose. PLD was administered to subsequent participants on a dose escalation schema based on preclinical pharmacokinetic and safety data. Serial doxorubicin (Dox) and doxorubicinol (Doxol) concentrations were determined in plasma by LC/MS/MS. At mastectomy (completed at least 2 weeks after intraductal administration of PLD), blue dye was injected into the treated duct and tissue was obtained for pharmacokinetic and biomarker analysis. Results: From 2/06 to 6/08, 14 women enrolled, and 12 underwent all study procedures. All dose levels up to 10 mg PLD per one duct were completed without serious adverse events. Median pain score was 0.9 (0–2.3). Intraductal PLD resulted in a dose-dependent increase in both systemic and local exposure to dox and doxol. Neither dox nor the metabolite was detected in the contralateral breast. Systemic exposure was lower than with conventionally administered PLD. Inflammatory changes were not observed on histopathological review of mastectomy specimens. Conclusions: We have established the logistics of intraductal administration of agents in an outpatient setting and it is feasible in women with and without prior chemotherapy. Biomarker data will be completed prior to the meeting. Future studies will evaluate other agents administered to one or more ducts. [Table: see text]

scholarly journals Quasi-Stationary Spiral Structure in Galaxies

1983 ◽  
Vol 100 ◽  
pp. 117-118 ◽  
Author(s):  
C. C. Lin
Keyword(s):  
Spiral Structure ◽  
Normal Modes ◽  
Short Wave ◽  
Distribution Functions ◽  
Morphological Classification ◽  
Present Contribution ◽  
Local Dispersion ◽  
Grand Design ◽  
Spiral Structures

The hypothesis of quasi-stationary spiral structure in galaxies was explicitly formulated in the early 1960's in papers of Bertil Lindblad and of Lin and Shu. It asserts that the grand design observed in spiral galaxies may be described by the superposition (and interaction) of a small number of spiral modes. (See Lin and Bertin, 1981 for a fairly extensive review of the theory.) We wish to re-affirm the correctness of this hypothesis in the present contribution. Early numerical experiments by P.O. Lindblad and by Miller, Prendergast and Quirk demonstrated that spiral structures occur naturally in certain models of stellar systems, although it was difficult to control the morphological types of galaxies simulated. We are now able to simulate galaxies of various morphological types in a controllable manner. Numerical fluid-dynamical codes developed by Pannatoni (1979) and improved by Haass (1982) have been used to calculate normal modes of various spiral types (Haass, Bertin, and Lin 1982) in the morphological classification of Hubble, Sandage, and de Vaucoulers. Furthermore, the processes that govern the maintenance and the excitation of these modes simulating both normal spirals and barred spirals, can be understood by using analytical theories which are closely related to the local dispersion relationship, as Bertin will describe in his paper at this conference. Understanding these mechanisms enables us to choose the parameters and the distribution functions in our models more properly in order to exhibit the desired characteristics in the computed modes. Such an approach also has important implications on observational studies. Much of the previous work on comparison between theory and observations in normal spirals used only the short trailing waves. A mode must consist of at least two waves propagating in opposite directions. It has been found that, at least in normal spiral modes, the long wave branch provides essentially only a modulation of the amplitude along the short wave branch, which accurately describes the phase. Previous calculations are thereby justified. [These points were not adequately covered in the previous paper reviewing theory of spiral modes.]

scholarly journals Emerging Treatments for Non-infectious Uveitis

2018 ◽  
Vol 11 (2) ◽  
pp. 81
Author(s):  
Alay S Banker ◽  
Carlos Pavesio ◽  
Pauline Merrill ◽  
◽  
◽  
...  
Keyword(s):  
Systemic Corticosteroid ◽  
Systemic Exposure ◽  
Therapeutic Agents ◽  
Targeted Interventions ◽  
Systemic Corticosteroids ◽  
Emerging Treatments ◽  
Infectious Uveitis ◽  
Intraocular Drug Delivery ◽  
Pro Inflammatory Cytokines

The primary goals of treatment in patients with non-infectious uveitis (NIU) are to control ocular inflammation and prevent sight-threatening complications such as macular edema and glaucoma. Systemic corticosteroids are the mainstay of treatment in NIU of the posterior segment (NIU-PS); however, long-term use is associated with treatment-limiting adverse effects. The need for agents with improved safety and tolerability coupled with recent insights into the pathogenesis of NIU-PS have led to the development of novel targeted interventions that potentially reduce or eliminate systemic corticosteroid exposure. Targeted interventions include intraocular drug delivery systems that provide high local concentrations at the site of inflammation with low systemic exposure and therapeutic agents, such as monoclonal antibodies that target specific pro-inflammatory cytokines and cytokine-mediated signaling pathways. The expanding range of therapeutic options enhances the ability to tailor therapy according to individual patient circumstances and optimize outcomes in patients with NIU-PS.

scholarly journals Cutaneous Anaphylaxis Induced by 4-Quinolone Antibacterials in Guinea Pigs

1993 ◽  
Vol 12 (1) ◽  
pp. 49-53
Author(s):  
Farrel L. Fort ◽  
Ken Hahn
Keyword(s):  
Nalidixic Acid ◽  
Guinea Pigs ◽  
Positive Control ◽  
Negative Control ◽  
Intradermal Injection ◽  
Blue Dye ◽  
Chlorpheniramine Maleate ◽  
Simple Method ◽  
Vasoactive Mediators ◽  
Anaphylactoid Reactions

Several 4-quinolone antibacterials (norfloxacin HCl, enoxacin, ofloxacin, cinoxacin, ciprofloxacin, and nalidixic acid) were administered intradermally to male and female hairless guinea pigs (Crl:IAF(HA)BR). Immediately prior to the intradermal injection, the guinea pigs were given an intravenous injection of Evans blue dye. The diameter of the blue spots at the sites of intradermal injection 15 to 30 minutes after intradermal injection were used as a measure of cutaneous anaphylactoid activity. The quinolones were given in concentrations ranging from 0.009 to 4.0 mg/mL. Compound 48/80 was used as a positive control, and saline was used as the negative control. All the 4-quinolones tested, except nalidixic acid, were positive for cutaneous anaphylactoid activity. Norfloxacin, enoxacin, and ciprofloxacin were positive at concentrations of 0.13 mg/mL or higher. Ofloxacin and cinoxacin were positive at concentrations of 2.0 mg/mL or higher. Pretreatment with the H1 blocker, chlorpheniramine maleate, resulted in diminished responses. These results demonstrate the potential for adverse cutaneous anaphylactoid reactions, presumably due to release of vasoactive mediators, with 4-quinolone antibacterials, and illustrate a simple method to screen new compounds for this activity.

Biological Safety Assessment of a Colored Zirconia Ceramic: Cell Toxicity and Skin Sensitivity Tests

2011 ◽  
Vol 492 ◽  
pp. 509-512
Author(s):  
Huai Xiu Lu ◽  
Bin Deng ◽  
Long Quan Shao ◽  
Yuan Fu Yi ◽  
Jie Liu ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Skin Irritation ◽  
Skin Inflammation ◽  
Intradermal Injection ◽  
Test Material ◽  
Zirconia Ceramic ◽  
Blue Dye ◽  
Skin Sensitivity ◽  
Filtration Method ◽  
Biological Safety

Objective: To evaluate the biological safety of a colored zirconia ceramic in terms of cellular toxicity and a skin sensitivity test. Methods: the cytotoxicity of the ceramic was evaluated by a molecular filtration method and skin irritation activity of the composite was assessed via intradermal injection of a guinea pig test solution, by inducing, enhancing, and stimulating an allergic response after local tissue exposure. Results: cell-coated filter paper in contact with test material showed the appearance of intracellular blue dye at the same staining density as in control samples, leading to a 0 toxicity rating. Guinea pigs showed no obvious erythema or edema from the irritation test, such that the assessment of colored zirconia ceramic skin allergy response in guinea pig was 0%. Conclusion: this colored zirconia ceramic showed low cytotoxicity and elicited no allergic skin inflammation response, indicating good overall biological safety under these conditions.

scholarly journals Impact of Rantes and MCP-1 Chemokines on In Vivo Basophilic Cell Recruitment in Rat Skin Injection Model and Their Role in Modifying the Protein and mRNA Levels for Histidine Decarboxylase

Blood ◽  
1997 ◽  
Vol 89 (11) ◽  
pp. 4120-4127 ◽  
Author(s):  
Pio Conti ◽  
Xinzhu Pang ◽  
William Boucher ◽  
Richard Letourneau ◽  
Marcella Reale ◽  
...  
Keyword(s):  
Mast Cells ◽  
Cell Activation ◽  
Histidine Decarboxylase ◽  
Rank Order ◽  
Intradermal Injection ◽  
Blue Dye ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Basophilic Cell

Abstract RANTES and related molecules, constitute the C-C class of chemokine supergene family and a group of cytokines produced by hematopoietic cells constitute the MCP-1 or C-X-C class. The roles of most of these chemokines are not well known, although members of the C-X-C family are inflammatory agents. Here, we report that intradermal injection of RANTES 10 ng/50 μL subcutaneously in the abdominal skin produced a strong inflammatory reaction, as evidenced by Evans blue dye, greater than FMLP (10−6 mol/L) (∼57%); while MCP-1, 10 ng/50 μL was less effective than FMLP (10−6 mol/L) (∼54%). Moreover, the histologic analysis of the cells stained with Toluidine blue (0.1%) were analyzed at a magnification of ×40). RANTES 10 ng/50 μL and LPS produced higher numbers (142 ± 11 and 193 ± 21 of cells/200 mm2, respectively) of basophilic cell accumulation in the skin injection sites compared with FMLP (10−6 mol/L) (127 ± 14/200 mm2), while MCP-1 10 ng/50 μL was less effective (88 ± 10/200 mm2). Electron microscopy (×13,800) studies of skin injection sites revealed that RANTES was chemoattractant for mast cells. In a Northern blot analysis from homogeneous tissue biopsy from the intradermal injection sites, RANTES was more potent than MCP-1 in increasing histidine decarboxylase (HDC) mRNA, the sole enzyme responsible for the production of histamine from histidine. Since PGD2 is formed by mast cells on cell activation, we also studied the effect of RANTES and MCP-1 on PGD2 production in inflamed tissue in vivo. RANTES (20, 10, and 5 ng) and MCP-1 (20, 10, and 5 ng) strongly stimulated PGD2 , in a dose-dependent manner, with a potency rank order of RANTES (10 ng/mL) approximately two times greater than MCP-1 (10 ng/mL).

Sign in / Sign up

Export Citation Format

Share Document