scholarly journals Development of a Phototoxicity Testing Strategy for Accurate Photosafety Evaluation of Pharmaceuticals Based on the Assessment of Possible Melanin-Binding Effects

2018 ◽  
Vol 37 (4) ◽  
pp. 296-307
Author(s):  
Jelle Reinen ◽  
Pieter van Sas ◽  
Ton van Huygevoort ◽  
Leticia Rubio ◽  
Kevin Scase ◽  
...  
Keyword(s):  
Cellular Damage ◽  
In Vivo Studies ◽  
Brown Norway ◽  
Albino Rats ◽  
Guidance Document ◽  
High Affinity ◽  
Drug Concentrations ◽  
Melanin Binding

Drug-induced phototoxicity occurs when drugs absorb natural sunlight, leading to chemical reactions causing cellular damage. Distribution to light-exposed tissues is critical and is enhanced by binding to melanin. The International Council on Harmonization S10 guidance document on photosafety evaluation of pharmaceuticals states that although nonpigmented skin tends to be more sensitive than pigmented skin, pigmented skin models should be considered for drugs that bind significantly to melanin. In this study, an in vitro melanin-binding assay was evaluated as prescreening tool for animal model selection. Binding of various structurally diverse phototoxic drugs to synthetic melanin was investigated in vitro and the high-affinity binder sparfloxacin (SPX), moderate-affinity binder 8-methoxypsoralen (8-MOP), and low-affinity binder pirfenidone (PIF) were selected for in vivo studies. Pigmented Brown Norway (BN) rats were compared with nonpigmented Wistar Albino rats to evaluate their sensitivity for the assessment of phototoxicity and skin concentrations of the drugs were measured. For SPX, the onset of phototoxic symptoms was faster for BN rats and drug concentrations were significantly higher in skin of BN rats. For 8-MOP, both models showed comparable sensitivity and skin concentrations did not differ. For the low-affinity binder PIF, no phototoxic effects were observed and skin concentrations in both models were similar. A combined in vitro/in vivo approach was developed that can be applied for accurate photosafety evaluation of pharmaceuticals based on the assessment of possible melanin-binding effects. In view of the presented data, the pigmented model could be considered for compounds showing a high-affinity binding capacity in vitro.

scholarly journals Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors?

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Veronika Barbara Felber ◽  
Manuel Amando Valentin ◽  
Hans-Jürgen Wester
Keyword(s):  
Salivary Gland ◽  
Solid Phase ◽  
Solid Phase Peptide Synthesis ◽  
In Vivo Studies ◽  
Tumor Xenograft ◽  
Tumor Uptake ◽  
Lncap Cells ◽  
High Affinity

Abstract Aim To investigate whether modifications of prostate-specific membrane antigen (PSMA)-targeted radiolabeled urea-based inhibitors could reduce salivary gland uptake and thus improve tumor-to-salivary gland ratios, several analogs of a high affinity PSMA ligand were synthesized and evaluated in in vitro and in vivo studies. Methods Binding motifs were synthesized ‘on-resin’ or, when not practicable, in solution. Peptide chain elongations were performed according to optimized standard protocols via solid-phase peptide synthesis. In vitro experiments were performed using PSMA+ LNCaP cells. In vivo studies as well as μSPECT/CT scans were conducted with male LNCaP tumor xenograft-bearing CB17-SCID mice. Results PSMA ligands with A) modifications within the central Zn2+-binding unit, B) proinhibitor motifs and C) substituents & bioisosteres of the P1′-γ-carboxylic acid were synthesized and evaluated. Modifications within the central Zn2+-binding unit of PSMA-10 (Glu-urea-Glu) provided three compounds. Thereof, only natLu-carbamate I (natLu-3) exhibited high affinity (IC50 = 7.1 ± 0.7 nM), but low tumor uptake (5.31 ± 0.94% ID/g, 1 h p.i. and 1.20 ± 0.55% ID/g, 24 h p.i.). All proinhibitor motif-based ligands (three in total) exhibited low binding affinities (> 1 μM), no notable internalization and very low tumor uptake (< 0.50% ID/g). In addition, four compounds with P1′-ɣ-carboxylate substituents were developed and evaluated. Thereof, only tetrazole derivative natLu-11 revealed high affinity (IC50 = 16.4 ± 3.8 nM), but also this inhibitor showed low tumor uptake (3.40 ± 0.63% ID/g, 1 h p.i. and 0.68 ± 0.16% ID/g, 24 h p.i.). Salivary gland uptake in mice remained at an equally low level for all compounds (between 0.02 ± 0.00% ID/g and 0.09 ± 0.03% ID/g), wherefore apparent tumor-to-submandibular gland and tumor-to-parotid gland ratios for the modified peptides were distinctly lower (factor 8–45) than for [177Lu]Lu-PSMA-10 at 24 h p.i. Conclusions The investigated compounds could not compete with the in vivo characteristics of the EuE-based PSMA inhibitor [177Lu]Lu-PSMA-10. Although two derivatives (3 and 11) were found to exhibit high affinities towards LNCaP cells, tumor uptake at 24 h p.i. was considerably low, while uptake in salivary glands remained unaffected. Optimization of the established animal model should be envisaged to enable a clear identification of PSMA-targeting radioligands with improved tumor-to-salivary gland ratios in future studies.

NITROGEN METABOLISM IN COLD-EXPOSED RATS

1963 ◽  
Vol 41 (5) ◽  
pp. 1169-1179 ◽  
Author(s):  
John R. Beaton ◽  
T. Orme ◽  
J. Laufer ◽  
A. Turner
Keyword(s):  
Food Intake ◽  
Cold Exposure ◽  
Body Weight Gain ◽  
Urine Volume ◽  
Nitrogen Retention ◽  
In Vivo Studies ◽  
Albino Rats ◽  
Period 2

In these studies, male albino rats were exposed to cold (2–3 °C) for a 7-day period. In vivo studies included the daily measurement of body weight gain, food intake, urine volume, body and liver composition, and nitrogen retention. In vitro, the activities of the following liver enzymes were measured: aspartic acid transaminase, alanine transaminase, arginase, glutamic acid dehydrogenase, and phosphate-activated glutaminase. The results of these experiments demonstrate that exposure of rats to cold increases amino acid catabolism, in part at least to meet increased energy requirements, and reduces protein synthesis as a consequence in the period 2–5 days inclusive, despite a marked increase in food intake. Cold exposure was without effect upon protein absorption but, after 24 hours in the cold, the nitrogen which appeared in the urine increased from about 55% (at 22 °C) to about 76% of the amount that had been absorbed. No effect of cold exposure on nitrogen retention was apparent in the first 24 hours of cold exposure. The subsequent decreased nitrogen retention, on a time basis, appears to bear a relationship to changes in liver enzyme activities, particularly to the increased activities of liver transaminases and arginase.

Cellular and humoral responses to collagen–polyvinylpyrrolidone administered during short and long periods in humans

2003 ◽  
Vol 81 (11) ◽  
pp. 1029-1035 ◽  
Author(s):  
Janette Furuzawa-Carballeda ◽  
Emilio Rojas ◽  
Mahara Valverde ◽  
Irma Castillo ◽  
Lino Diaz de León ◽  
...  
Keyword(s):  
Dna Damage ◽  
Type I Collagen ◽  
Cellular Damage ◽  
In Vivo Studies ◽  
Type I ◽  
Healthy Donors ◽  
Collagen Antibodies ◽  
Humoral Responses

Collagen, particularly type I, and its related derivatives have been extensively employed in many areas of pharmacology. The present study was performed to determine the safety of collagen–polyvinylpyrrolidone (collagen–PVP) by in vitro and in vivo studies. Sera and peripheral blood cells from healthy donors without treatment and patients treated with collagen–PVP were evaluated. We observed that the biodrug does not stimulate lymphoproliferation or DNA damage in vitro, nor does it induce human anti-porcine type I collagen or anti-collagen–PVP antibodies in vivo. Furthermore, no hepatic or renal metabolic dysfunctions were observed when collagen–PVP was administered by intradermal or intramuscular routes in short- or long-term treatments. In conclusion, the present work shows that no cellular damage or immunological adverse effects (cellular and humoral) occurred during collagen–PVP treatment, even after more than 400 weeks of consecutive administrations.Key words: collagen–polyvinylpyrrolidone, DNA damage, collagen antibodies, hypertrophic scar.

scholarly journals Production and Evaluation of Nutritional Contents of Traditional Couscous from Sprouted Wheat Fortified with Glycine max (L.) merr (Soya Bean) and Cucurbita pepo (Pumpkin) Seeds

2020 ◽  
Vol 4 (2) ◽  
pp. p1
Author(s):  
Raihanatu MB ◽  
Falmata AS ◽  
Bintu BP ◽  
Maryam BK ◽  
Hadiza Ahmed Ali ◽  
...  
Keyword(s):  
Glycine Max ◽  
Cucurbita Pepo ◽  
Protein Quality ◽  
Soya Bean ◽  
In Vivo Studies ◽  
Albino Rats ◽  
Nutritional Requirement ◽  
Pumpkin Seeds

The study was carried to process, produce, and evaluate nutritional contents of traditional couscous from sprouted wheat (Triticum aestivum), fortified with Soya bean (Glycine max) and Pumpkin (Cucurbita pepo) seeds. The composite couscous blends were traditionally produced and compared with commercial couscous. The sprouted wheat couscous blends were blended in different ratios, they include; unprocessed (Raw wheat, 100), blend 1 (sprouted wheat mixed with soya bean and pumpkin seeds, 70:20:10), blend 2 (sprouted wheat mixed with soya bean, 60:40) and blend 3 (sprouted wheat mixed with pumpkin seeds, 60:40). Traditional wheat couscous blends were fed to experimental albino rats of wister strain weighing between (35 g and 45 g) for a period of 28 days. The nutritional and physiochemical analysis were determined using standard laboratory methods. The Statistical Package for Social Sciences (SPSS), version 20.0 was used to analyze the data collected which were expressed as means ± SE. One way analysis of variance (ANOVA) and Duncan’s multiple range tests were used to compare the means obtained after each experiment. Differences were considered significant at p < 0.05. Processing (Sprouting) decreases the levels of anti-nutrients, mineral elements and vitamins. Supplementation with soya bean and pumpkin seeds increased the nutritional composition of the sprouted wheat couscous blends. Results of chemical composition showed that blend 2, recorded high protein (29.95%), fat (8.95%) and low carbohydrate content (49.56%), followed by blend 1 and then blend 3, while commercial couscous crude protein, fat and carbohydrate were 12.53%, 1.42% and 75.10% respectively. There was improved level of in vitro protein digestibility at 1 hour (76.64% to 98.59%) and at 6 hours (96.80% to 99.33%). Results of in vivo studies showed that raw wheat couscous recorded protein quality when compared with spouted wheat couscous blends produced. The biological values of the composite couscous blends range from 95.04% to 95.73% and blend 2, recorded high net protein utilization (98.57%). In terms of sensory evaluation using hedonic method, blend 2 was most acceptable and differ significantly (p < 0.05) with other sprouted wheat couscous blends and commercial couscous. The cost of producing sprouted wheat couscous blends is cheaper than the commercial couscous. The study has therefore, revealed that with proper selection of locally available cereal, it is possible to produce nutritious complementary couscous blends that would be acceptable and nutritionally adequate to meet up the nutritional requirement for both children and adults. It also compares favourably with the commercial couscous in terms of nutrient contents.

scholarly journals A SYNERGISTIC INSULINOTROPIC EFFECT OF GREEN TEA EXTRACT AND POMEGRANATE EXTRACT WITH ROSIGLITAZONE: BOTH IN VIVO AND IN VITRO EXPERIMENT

2020 ◽  
pp. 96-99
Author(s):  
REKHA S ◽  
CHANDRASHEKHARA S
Keyword(s):  
Green Tea ◽  
Type Ii Diabetes ◽  
Body Weight Gain ◽  
Serum Insulin ◽  
In Vivo Studies ◽  
Albino Rats ◽  
Type Ii ◽  
Insulinotropic Effect

Objective: Scientists have growing interest in traditional medicinal plants as they contain active ingredients for the treatment of various diseases. Tea is one of the most popular beverages worldwide. The variety of tea and tea extracts in the market has different polyphenol profiles, which are the bioactive chemical entities. We performed a direct comparison between Thea sinensis, green tea extracts (GTEs), and Punica granatum peel powder (PGPP), which have been chemically well characterized in a type II diabetic mouse model. Methods: We conducted both in vivo and in vitro experiments in the present paper. In vivo studies were carried out on male Swiss albino rats having type II diabetes, induced by single intravenous injection of streptozotocin (0.7 mg/Kg i.m.) and IDDM rats received either PGPP (200 mg/kg) or GTE (100 mg/kg) as a single oral dose. After the above result, the extracts were further subjected to know the effect of insulin secretion by RIN-5F cells providing confirmation of insulinotropic effect. Results: The results revealed that both PGPP and GTE substantially lowered blood glucose levels and ameliorated glucose intolerance, both were effective in antihyperglycemic activity and in lowering body weight gain. Serum insulin levels significantly increased in GTE group as well as in PGPP group, suggesting that they were exerting hypoglycemic effects through different pathways. Conclusion: Synergistic action of PGPP and GTE is an effective alternative for the treatment of type II diabetes through the regeneration of β cells of pancreas.

scholarly journals In Vitro and In Vivo Studies of the Trypanocidal Activity of a Diarylthiophene Diamidine against Trypanosoma cruzi

2008 ◽  
Vol 52 (9) ◽  
pp. 3307-3314 ◽  
Author(s):  
Cristiane França da Silva ◽  
Marcos Meuser Batista ◽  
Denise da Gama Jaen Batista ◽  
Elen Mello de Souza ◽  
Patrícia Bernardino da Silva ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
In Vivo Studies ◽  
Groove Binding ◽  
Dna Minor Groove ◽  
Drug Concentrations ◽  
Mammalian Infection ◽  
Related Compounds

ABSTRACT Aromatic diamidines are DNA minor groove-binding ligands that display excellent antimicrobial activity against fungi, bacteria, and protozoa. Due to the currently unsatisfactory chemotherapy for Chagas’ disease and in view of our previous reports regarding the effect of diamidines and analogues against both in vitro and in vivo Trypanosoma cruzi infection, this study evaluated the effects of a diarylthiophene diamidine (DB1362) against both amastigotes and bloodstream trypomastigotes of T. cruzi, the etiological agent of Chagas’ disease. The data show the potent in vitro activity of DB1362 against both parasite forms that are relevant for mammalian infection at doses which do not exhibit cytotoxicity. Ultrastructural analysis and flow cytometry studies show striking alterations in the nuclei and mitochondria of the bloodstream parasites. In vivo studies were performed at two different drug concentrations (25 and 50 mg/kg/day) using a 2-day or a 10-day regimen. The best results were obtained when acutely infected mice were treated with two doses at the lower concentration, resulting in 100% survival, compared to the infected and untreated mice. Although it did not display higher efficacy than benznidazole, DB1362 reduced both cardiac parasitism and inflammation, and in addition, it protected against the cardiac alterations (determined by measurements) common in T. cruzi infection. These results support further investigation of diamidines and related compounds as potential agents against Chagas’ disease.

scholarly journals AACC Guidance Document on Biotin Interference in Laboratory Tests

2020 ◽  
Vol 5 (3) ◽  
pp. 575-587 ◽  
Author(s):  
Danni Li ◽  
Angela Ferguson ◽  
Mark A Cervinski ◽  
Kara L Lynch ◽  
Patrick B Kyle
Keyword(s):  
Laboratory Tests ◽  
Clinical Laboratory ◽  
Case Reports ◽  
In Vivo Studies ◽  
High Dose ◽  
Guidance Document ◽  
Health Related ◽  
Biotin Binding

Abstract Background Laboratory tests that use streptavidin–biotin binding mechanisms have the potential to be affected by high circulating biotin concentrations, which would produce positive and negative interference in biotinylated competitive and noncompetitive (sandwich) immunoassays, respectively. Consumption of high-dose biotin supplements for cosmetic or health-related reasons has drawn attention to biotin interference in clinical laboratory tests. Case reports and in vivo studies show that ingestion of supplemental biotin can cause clinically significant errors in select biotinylated immunoassays. Content This AACC Academy document is intended to provide guidance to laboratorians and clinicians for preventing, identifying, and dealing with biotin interference. In vivo and in vitro spiking studies have demonstrated that biotin concentrations required to cause interference vary by test and by manufacturer. This document includes discussion of biotin’s mechanisms for interference in immunoassays, pharmacokinetics, and results of in vitro and in vivo studies and cites examples of assays known to be affected by high biotin concentrations. This document also provides guidance recommendations intended to assist laboratories and clinicians in identifying and addressing biotin interference in laboratory testing. Summary The recent increase in the use of high-dose biotin supplements requires laboratorians and clinicians to be mindful of the potential for biotin interference in biotinylated immunoassay-based laboratory tests. Laboratories, clinicians, regulators, and patients should work together to ensure accurate laboratory results. Laboratories have several options for identifying suspected biotin interference in specimens. Alternatively, the relatively fast elimination of biotin allows the potential for rapid follow-up specimen analysis if necessary.

scholarly journals In vitro activity of six antiviral drugs against equid alphaherpesvirus type 1 indicates ganciclovir as promising drug for in vivo studies

2018 ◽  
Vol 48 (12) ◽  
Author(s):  
Amanda Lovato de Oliveira ◽  
Juliana Felipetto Cargnelutti ◽  
Ana Paula Gnocato Mortari ◽  
Eduardo Furtado Flores ◽  
Rudi Weiblen
Keyword(s):  
Specific Treatment ◽  
Vitro Activity ◽  
In Vivo Studies ◽  
In Vitro Activity ◽  
In Vivo Experiments ◽  
Drug Concentrations ◽  
Viral Plaque

ABSTRACT: Equid alphaherpesvirus type 1 (EHV-1) is distributed worldwide and is a major agent of abortion, respiratory and neurological disease in horses. No specific treatment is available for EHV-1 infection, yet the potential of antiviral therapy has been explored. In this study we investigated the in vitro activity of Acyclovir, Ganciclovir, Foscarnet, Famciclovir, Vidarabina and Cidofovir against EHV-1. For this, the MTT test was performed, in which all the tested drugs showed no toxicity up to 200μg/mL. Subsequently, different drug concentrations were submitted to viral plaque reduction assays in cell culture. The selectivity index (SI) of the compounds was determined using the cytotoxic concentration for 50% of cells (CC50), obtained by MTT, and effective drug concentration to inhibit by 50% the number of viral plaques (EC50). Ganciclovir (SI: 490; EC50: 1.9 μg/mL) was the most efficient and safest drug against EHV-1, followed by Cidofovir (SI: 150, EC50: 5.7μg/mL), Acyclovir (SI: 37.4, EC50: 22.2μg/mL), Famciclovir (SI: 25.1, EC50: 24.5μg/mL), Vidarabine (SI: 12.2, EC50: 40.9μg/mL) and Foscarnet (SI: 6.9, EC50: 49.5 μg/mL), respectively. These results indicated that Ganciclovir (followed by Cidofovir), is a promising candidate for use in in vivo experiments.

NITROGEN METABOLISM IN COLD-EXPOSED RATS

1963 ◽  
Vol 41 (1) ◽  
pp. 1169-1179 ◽  
Author(s):  
John R. Beaton ◽  
T. Orme ◽  
J. Laufer ◽  
A. Turner
Keyword(s):  
Food Intake ◽  
Cold Exposure ◽  
Body Weight Gain ◽  
Urine Volume ◽  
Nitrogen Retention ◽  
In Vivo Studies ◽  
Albino Rats ◽  
Period 2

In these studies, male albino rats were exposed to cold (2–3 °C) for a 7-day period. In vivo studies included the daily measurement of body weight gain, food intake, urine volume, body and liver composition, and nitrogen retention. In vitro, the activities of the following liver enzymes were measured: aspartic acid transaminase, alanine transaminase, arginase, glutamic acid dehydrogenase, and phosphate-activated glutaminase. The results of these experiments demonstrate that exposure of rats to cold increases amino acid catabolism, in part at least to meet increased energy requirements, and reduces protein synthesis as a consequence in the period 2–5 days inclusive, despite a marked increase in food intake. Cold exposure was without effect upon protein absorption but, after 24 hours in the cold, the nitrogen which appeared in the urine increased from about 55% (at 22 °C) to about 76% of the amount that had been absorbed. No effect of cold exposure on nitrogen retention was apparent in the first 24 hours of cold exposure. The subsequent decreased nitrogen retention, on a time basis, appears to bear a relationship to changes in liver enzyme activities, particularly to the increased activities of liver transaminases and arginase.

Inhibitory Effect of Sulfobutyl Ether β‐cyclodextrin on DY‐9760e‐Induced Cellular Damage: In vitro and in vivo Studies

2003 ◽  
Vol 92 (12) ◽  
pp. 2466-2474 ◽  
Author(s):  
Yukihiko Nagase ◽  
Hidetoshi Arima ◽  
Koki Wada ◽  
Tadaki Sugawara ◽  
Hiroshi Satoh ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Cellular Damage ◽  
In Vivo Studies ◽  
Sulfobutyl Ether
Sign in / Sign up

Export Citation Format

Share Document