Publications by authors named "Georg A Mathis"

3 Publications

  • Page 1 of 1

Effects of a sustained release formulation of 1,25-dihydroxyvitamin D3-glycosides for milk fever prevention on serum 1,25-dihydroxyvitamin D3, calcium and phosphorus in dairy cows.

J Steroid Biochem Mol Biol 2017 10 23;173:301-307. Epub 2017 Mar 23.

Institute for Animal Nutrition, Ludwig Maximilians University München, D-85764 Oberschleissheim, Germany. Electronic address:

Milk fever (MF) is a metabolic disease in dairy cows around parturition. The clinical lead sign is muscular paresis leading in severe cases to paralysis of the affected animal. Multiparturient animals of high performing dairy breeds are most likely to be affected and have a high probability of recurrence. An acute drop in blood calcium levels causes the disease when the demand for calcium at the onset of lactation exceeds the ability to replete blood calcium levels through mobilization from bone and intestinal uptake. With the understanding of the underlying mechanism, calcium supply management and vitamin D supplementation became prime candidates for MF prevention and therapy. Several strategies have been developed for MF prevention. Application of the active form of Vitamin D, 1,25(OH)D, was found to prevent MF effectively. In order to prevent a delayed hypocalcemia, which was occasionally seen after stopping the treatment with 1,25(OH)D a new approach was chosen by applying Solanum glaucophyllum extract (SGE), which contains 1,25(OH)D-glycosides, as instant-release (irSGE) in combination with slow-release (srSGE) tablets. In a first study, non-lactating cows were treated with a single bolus of either synthetic 1,25(OH)D, irSGE, or srSGE and the results were compared to a control group without treatment. Blood serum levels of 1,25(OH)D (1,25D), calcium (Ca), phosphate (P) and magnesium (Mg) were followed for 11days and the area under the curve (AUC) was calculated. Calcium and phosphate excretion in urine were determined during 15days. While serum concentration of 1,25(OH)D was back to pre-treatment level in the irSGE, srSGE and 1,25(OH)D treated group within 3days, calcium and phosphate levels remained elevated for up to 9days. AUC of serum 1,25(OH)D was 2.89 (1,25D), 3.13 (irSGE) and 4.21 (srSGE) times higher than control. Serum calcium levels were 1.07 (for 1.25D); 1.08 (for irSGE) and 1.12 (for srSGE) times higher than control. Serum phosphate levels were 1.20 (for 1,25D); 1.30 (for irSGE) and 1.41 (for srSGE) times higher than control, with p<0.05. In a second field study calving cows treated with one bolus containing ir- and sr- tablets of SGE were compared to an untreated control group and to a group treated with 4 boli of commercial calcium salts. As a result, calcium serum levels increased (+19% compared to baseline) around calving after treatment with the single bolus of SGE. The single bolus of SGE lead also to an increase of serum phosphate (+31% compared to baseline). These calcium and phosphate increases were statistically significant (p<0.001) 0-24h after calving compared to the control group and to the group treated with calcium salts. The sample size of the study was too small to draw a conclusion on the effect on MF prevention. In conclusion, application of a single bolus of a SGE extract lead to an increase of serum calcium and phosphate for up to 9days and may thus have the potential to prevent a hypocalcemia and -phosphatemia, an important cause for clinical milk fever.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jsbmb.2017.03.020DOI Listing
October 2017

The Early Preclinical Development Program for Locally Administered Investigational Medicinal Products in Ophthalmology: Preclinical Data Required for Starting a First-in-Human Clinical Trial in Europe-Basic Considerations and 2 Case Studies.

Ther Innov Regul Sci 2018 05 5;52(3):321-328. Epub 2017 Sep 5.

1 Appletree CI Group AG, Winterthur, Switzerland.

Background: Although regulatory guidance defines which preclinical data are required in general before proceeding to first-in-human clinical trials, a certain level of flexibility exists in the actual planning, timing, and design of a drug development program. Developing an ophthalmic medicinal product adds additional challenges, since the eye is a complex organ with unique features and specialized ophthalmic guidance documents are sparse.

Methods: We analyzed the preclinical guidelines with a focus on European Union legislation and guidance documents provided by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). We elaborated the particularities specific to ophthalmic drug developments and deduced the preclinical knowledge needed to safely enter a first-in-human trial program. Two hypothetical medicinal products for ophthalmic indications were chosen and specificities for ophthalmic preclinical tests were elaborated.

Results And Conclusion: We conclude that the preclinical program of ophthalmic medicines is flexible and differs, based on the intended use and the nature of the active substance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2168479017725110DOI Listing
May 2018

1,25-Dihydroxyvitamin D3-glycoside of herbal origin exhibits delayed release pharmacokinetics when compared to its synthetic counterpart.

J Steroid Biochem Mol Biol 2013 Jul 26;136:333-6. Epub 2012 Sep 26.

Herbonis AG, Gellertstrasse 33, CH-4001 Basel, Switzerland.

Vitamin D requires two metabolic steps to become biologically active. In a first step 25-hydroxyvitamin D3 is formed, which acts as storage form. After a tightly controlled step in kidney the active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is formed. Because kidney is the relevant metabolic organ for this conversion, 1,25(OH)2D3 needs to be supplemented in patients with kidney malfunction or kidney failure. Synthetic 1,25(OH)2D3 (calcitriol) has been available as a drug for decades. Due to its high potency and its kinetic profile (fast absorption and rapid elimination) its therapeutic windows has proven to be relatively narrow. A natural form of the active metabolite was identified in a few plants, such as Solanum glaucophyllum (SG) and suggested as alternative for animal and human health. An extract of a SG variety bred for high and uniform level of glycosylated 1,25(OH)2D3 was chemically characterized. Among the typical pharmaceutically inactive plant components (carbohydrates 54.3%, protein 24.9%, minerals 17.1% and water 4.1%) high levels of 1,25(OH)2D3 and a unique flavonoid content was found (1.11mg total quercetin/g extract) consisting exclusively of the quercetin glycosides hyperoside, isoquercetin, rutin and apinosylrutin. The molecular distribution of glycosyl moieties in 1,25(OH)2D3 extracted from SG as determined by gel permeation chromatography was found to be 1-10 hexose units per aglycone. 1,25(OH)2D3-1-β-glucopyranoside was identified in the SG extract, while a di- and triglycoside have been identified in SG by other groups. The pharmacokinetic properties of synthetic 1,25(OH)2D3 and glycosylated 1,25(OH)2D3 extracted from SG were compared in male rats. When compared to synthetic 1,25(OH)2D3, SG-derived 1,25(OH)2D3 exhibited delayed absorption and elimination characteristics, resulting in delayed Tmax (6-12h vs. 1h) and increased T½ (approximately 30h vs. 23h). This putative modified release pattern may be attributed to the glycosylation of herbal 1,25(OH)2D3 because de-glycosylation by ubiquitous intestinal enzymes prior to intestinal uptake of the aglycone appears to be the rate limiting step. In effect, 1,25(OH)2D3 of herbal origin behaves like a precursor of calcitriol, resulting in a wider therapeutic window and thus better pharmacological tolerance. This article is part of a Special Issue entitled 'Vitamin D Workshop.'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jsbmb.2012.09.016DOI Listing
July 2013