Vitamin A-containing dietary supplements from German and US online pharmacies: market and risk assessment.

Vitamin A supplements are used by many people, and the number of newly registered dietary supplements is continuously increasing. The preparations fall under food law and are not subject to the strict controls of pharmaceuticals. Risk indications and maximum quantity recommendations, e.g., from the Bundesinstitut für Risikobewertung (BfR) and the U.S. Food and Drug Administration (FDA) are not binding, which means that overdoses and potentially serious health problems can easily occur. The hepatotoxicity and teratogenicity of vitamin A are well documented, and other negative effects of high doses of vitamin A are also being discussed. Nevertheless, preparations with exorbitantly high doses are freely available for sale and unrestricted. In this study, 75 supplements containing vitamin A available in Germany and 26 available in the USA were critically examined on the basis of various parameters such as the recommended daily dose according to the manufacturer, daily therapy costs (DTC), the presence of warnings about overdose, use during pregnancy and breastfeeding, and information on adverse effects/interactions. The aim was to gain insights into their risk potential and to examine the need for closer monitoring and stricter guidelines for these preparations. The results show some considerable country-specific differences. Overall, there are serious deficiencies in compliance with the labeling requirements for both the German and the US preparations, and the dosages are often far too high in view of the applicable expert recommendations. Overall, these deficits can pose a risk for consumers that is difficult to assess in its entirety, especially for vulnerable consumer groups. It should be noted that the US preparations perform better overall than the German preparations. This suggests better regulation of dietary supplements in the US market. Based on the available data and literature research, it is doubtful whether the intake of vitamin A-containing preparations, without a diagnosed vitamin A deficiency, has a positive health benefit. Furthermore, it should be examined whether vitamin A should continue to be offered over-the-counter as a food supplement.

Prescriptions of homeopathic remedies at the expense of the German statutory health insurance from 1985 to 2021: scientific, legal and pharmacoeconomic analysis.

The prescription of homeopathic remedies at the expense of the statutory health insurance (SHI) system in Germany has been criticized for years due to a lack of evidence. Now, on the planned abolition of the reimbursement of homeopathic medicines in Germany, the debate on this topic has been reignited. The aim of this paper is to show the costs and their development over time incurred by homeopathic remedies in the healthcare system from 1985 to 2021. For this purpose, 15 selected homeopathic medicines were chosen from the drug prescription report (Arzneiverordnungsreport) and analyzed with regard to their development of DDD (Defined Daily Dose) using data from the Wissenschaftliches Institut der Ortskrankenkassen (WidO, Scientific Institute of the General Local Health Insurance Funds) and compared with their respective rational pharmacological alternatives. The price comparison was based on the DDD costs and the pharmacy retail price of the smallest packaging in each case. The clinical study situation for the preparations was also analyzed. For this purpose, the clinical studies provided by the manufacturer and those on PubMed were divided into evidence levels and analyzed. In addition, the presentation of homeopathic remedies on company websites, in online pharmacies, in specialist information and package leaflets was analyzed with regard to side effects, interactions, indication, and information on the alleged effect/proof of efficacy. In many media, information on homeopathic medicines remained incomplete, and non-compliance with the Therapeutic Product Advertising Act (Heilmittelwerbegesetz) was noted. Naming of the products if often very suggestive, too. Manufacturers' claims of efficacy go far beyond what can be considered proven in terms of evidence-based medicine and the quality of most clinical studies is poor. Homeopathic remedies are on average significantly more expensive than their rational pharmacological alternatives. Furthermore, DDD costs have continued to rise over the years analyzed. In aggregate, from a pharmacoeconomic, legal, and scientific perspective, abolition of reimbursement of homeopathic medicines in Germany at the expense of the SHI system is well justified.

Critical analysis of ginkgo preparations: comparison of approved drugs and dietary supplements marketed in Germany.

Demographic change is taking place in the population of western industrialized countries, and the population is aging constantly. As a result, the mortality rate of patients due to dementia is rising steadily. To counteract this, the relevance of neuroprotective agents is increasing. Preparations from the medicinal tree species Ginkgo biloba ("gingko") are becoming increasingly popular. In this study, 63 ginkgo preparations marketed in Germany were analyzed. The following data were collected from the package inserts of the preparations: Country of manufacture, approval as a drug, compliance to target values of flavone glycosides, compliance to target values of terpene lactones, compliance to target values of ginkgolic acids, dosage per unit in milligrams (mg), duration of use, interactions with other drugs, contraindications, adverse effects and daily defined dose costs. In the next step, these data were compared in the following form: Total preparations versus preparations with drug approval versus dietary supplements. Almost without exception, the results indicate a pharmaceutical reliability of the preparations with drug approval and a dubious reliability of the preparations marketed as dietary supplements. Thus, ginkgo preparations marketed as dietary supplements appear to have an economic rather than a medical focus. We discuss the evidence of efficacy, and other criteria mentioned above, to evaluate the adequacy of the costs for the statutory health insurance that pay for preparations with drug approval in Germany. From the analysis of our results it is very doubtful that ginkgo biloba extract preparations of the food industry have any health benefit. It must be evaluated whether prohibition of selling ginkgo biloba extract as a dietary supplement is an option.

Assessing the Use of the sGC Stimulator BAY-747, as a Potential Treatment for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx/mTRG2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx/mTRG2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx/mTRG2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx/mTRG2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx/mTRG2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD.

Dimeric carbamoylguanidine-type histamine H2 receptor ligands: A new class of potent and selective agonists.

The bioisosteric replacement of the acylguanidine moieties in dimeric histamine H2 receptor (H2R) agonists by carbamoylguanidine groups resulted in compounds with retained potencies and intrinsic activities, but considerably improved stability against hydrolytic cleavage. These compounds achieved up to 2500 times the potency of histamine when studied in [(35)S]GTPγS assays on recombinant human and guinea pig H2R. Unlike 3-(imidazol-4-yl)propyl substituted carbamoylguanidines, the corresponding 2-amino-4-methylthiazoles revealed selectivity over histamine receptor subtypes H1R, H3R and H4R in radioligand competition binding studies. H2R binding studies with three fluorescent compounds and one tritium-labeled ligand, synthesized from a chain-branched precursor, failed due to pronounced cellular accumulation and high non-specific binding. However, the dimeric H2R agonists proved to be useful pharmacological tools for functional studies on native cells, as demonstrated for selected compounds by cAMP accumulation and inhibition of fMLP-stimulated generation of reactive oxygen species in human monocytes.

Synthesis and cannabinoid receptor activity of ketoalkenes from Echinacea pallida and nonnatural analogues.

Despite its popularity and widespread use, the efficacy of Echinacea products remains unclear and controversial. Among the various compounds isolated from Echinacea, ketoalkenes and ketoalkenynes exclusively found in the pale purple coneflower (E. pallida) are major components of the extracts. In contrast to E. purpurea alkamides, these compounds have not been synthesized and studied for immunostimulatory effects. We present a practical and useful synthetic approach to the ketoalkenes using palladium-catalyzed cross-coupling reactions and the pharmaceutical results at the human cannabinoid receptors. The synthetic route developed provides overall good yields for the ketoalkenes and is applicable to other natural products with similar 1,4-diene motifs. No significant activity was observed at either receptor, indicating that the ketoalkenes from E. pallida are not responsible for immunomodulatory effects mediated via the cannabinergic system. However, newly synthesized non-natural analogues showed micro-molar potency at both cannabinoid receptors.

Acylguanidines as bioisosteres of guanidines: NG-acylated imidazolylpropylguanidines, a new class of histamine H2 receptor agonists.

N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidines are potent histamine H2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.

Generation of a homology model of the human histamine H(3) receptor for ligand docking and pharmacophore-based screening.

The human histamine H(3) receptor (hH(3)R) is a G-protein coupled receptor (GPCR), which modulates the release of various neurotransmitters in the central and peripheral nervous system and therefore is a potential target in the therapy of numerous diseases. Although ligands addressing this receptor are already known, the discovery of alternative lead structures represents an important goal in drug design. The goal of this work was to study the hH(3)R and its antagonists by means of molecular modelling tools. For this purpose, a strategy was pursued in which a homology model of the hH(3)R based on the crystal structure of bovine rhodopsin was generated and refined by molecular dynamics simulations in a dipalmitoylphosphatidylcholine (DPPC)/water membrane mimic before the resulting binding pocket was used for high-throughput docking using the program GOLD. Alternatively, a pharmacophore-based procedure was carried out where the alleged bioactive conformations of three different potent hH(3)R antagonists were used as templates for the generation of pharmacophore models. A pharmacophore-based screening was then carried out using the program Catalyst. Based upon a database of 418 validated hH(3)R antagonists both strategies could be validated in respect of their performance. Seven hits obtained during this screening procedure were commercially purchased, and experimentally tested in a [(3)H]N(alpha)-methylhistamine binding assay. The compounds tested showed affinities at hH(3)R with K ( i ) values ranging from 0.079 to 6.3 muM.