Pharmacodynamic Effects of an Angiotensin II Receptor-Antagonist in Phase I—Comparison between Healthy Subjects and Patients with Hypertension

Biomarkers are increasingly used to provide decision making data early in phase I by showing Proof of Mechanism or Proof of Concept (PoM/PoC). For antihypertensive agents, the administration of multiple doses (md) to hypertensive patients is assumed to be necessary for an early go/no-go decision. We compared the effects of an Angiotensin II receptor antagonist (ARA) on Plasma Renin and blood pressure (BP) following an oral single dose (sd) and once daily md for seven days to healthy volunteers and patients with essential hypertension (diastolic BP 95 mmHg to 114 mmHg; systolic BP 130 mmHg to 200 mmHg). Methods: 5–12 healthy male subjects/dose received 10 mg to 300 mg ARA sd and 50 to 300 mg md for 7 days; patients (9–10/dose) received 20 mg–400 mg ARA for 7 days. The studies were designed as randomized, single-blind, placebo-controlled, group comparison or crossover dose-escalation studies. Plasma Renin and BP were monitored up to 24 hours after dosing. Results: Plasma Renin showed a high interindividual variability in both healthy volunteers and patients. Healthy subjects showed a dose- and time-related increase in plasma Renin after sd from 40 mg to 300 mg and md of 50 mg to 300 mg (p < 0.05 for doses of 200 mg and 300 mg). In patients, increases in plasma Renin occurred at 8 hours and beyond starting at sd of 100 mg and md of 50 mg (p < 0.05 for the dose of 400 mg). While healthy volunteers showed no relevant decrease in BP, in hypertensive patients a reduction in BP in doses of 100 mg to 400 mg occurred (p < 0.05); effects were more pronounced after md compared to sd. Conclusion: Early PoM for an antihypertensive agent can be shown by use of laboratory biomarkers following sd to healthy subjects. PoC can be achieved after sd in hypertensive patients. Administration of sd to healthy volunteers is sufficient for an early go/no-decision

TaReCa – Cascade utilization of horticultural biomass for a resource efficient production of valuable bioactive substances

Viele pflanzliche Sekundärmetabolite haben antioxidative oder andere bioaktive Eigenschaften, weshalb sie einerseits wichtige Bestandteile der menschlichen Ernährung sind, andererseits aber auch als pharmazeutische Verbindungen oder als Substrat für die chemische Synthese von bioaktiven Substanzen verwendet werden. Pflanzen induzieren die Produktion solcher nutzbaren Sekundärmetabolite wie z.B. Flavonoiden als Reaktion auf abiotischen Stress. Die Produktion von Gemüse und Früchten in Gewächshäusern hinterlässt große Mengen an ungenutzter pflanzlicher Biomasse, welche eine potentielle Ressource für die Gewinnung wertvoller Metabolite darstellt. Durch eine kaskadenartige Verwendung von Gartenbaukulturen zur Produktion von Früchten und Gemüse mit einer anschließenden Gewinnung hochwertiger Substanzen aus der verbleibenden Restbiomasse würde ein erheblicher Mehrwert generiert. Das Projekt TaReCa bearbeitet die Entwicklung einer maßgeschneiderten Kaskadenverwertung von Paprikapflanzen-Restbiomasse aus dem Gartenbau. Dabei soll der pflanzliche Sekundärmetabolismus durch spezifische abiotische Stressbedingungen nach der Fruchternte gezielt induziert werden, um die Konzentrationen der Zielmetaboliten zu steigern. Durch umweltfreundliche und wirtschaftliche Extraktionsprozesse und eine anschließende Verwertung des verbleibenden Pflanzenmaterials in einer Bioraffinerie wird die Wertschöpfungskette erweitert. Eine Analyse der Anwendungsgebiete sowie Untersuchungen zur Akzeptanz der induzierten Inhaltsstoffe, Prozesse und Technologien werden helfen, das Marktpotenzial der Restbiomasse für die Nutzung in Kaskaden zu evaluieren. Die maßgeschneiderte Nutzung von Gartenbaubiomasse durch Lebensmittelproduktion, Extraktion bioaktiver Sekundärmetabolite und Bioraffinerien kann wirtschaftlich relevante, biobasierte Produkte für industrielle Anwendungen erzeugen und somit zur Entwicklung einer nachhaltigen, effizienten und integrierten Bioökonomie beitragen, ohne mit der Lebensmittelproduktion zu konkurrieren.Many plant secondary metabolites have antioxidant or pharmaceutically relevant properties, which makes them important components of the human diet, but also as pharmaceutical compounds or for the chemical synthesis of bioactive substances. Plants induce the production of secondary metabolites, e.g. flavonoids in response to environmental stress stimuli. The production of vegetables and fruits in greenhouses leaves huge amounts of so far under-utilized biomass after fruit harvest, which is a potential source for production of valuable metabolites. A cascade utilization of horticultural crops to produce fruits and vegetables with subsequent extraction of high quality compounds would generate significant added value. The project TaReCa is working on the development of a tailored cascade utilization of bell pepper plant residues from horticulture. The secondary metabolism will be induced by specific abiotic stress treatments after the last fruit harvest, in order to increase the concentrations of the target metabolites. Eco-friendly and economical extraction processes and subsequent utilization of the remaining plant material in a biorefinery will expand the value chain. An analysis of the application areas as well as studies on the acceptance of the induced ingredients, processes and technologies will help to evaluate the market potential of the residual biomass for the proposed cascaded use. The tailored utilization of horticultural biomass in food production, extraction of bioactive secondary metabolites and biorefineries can produce economically relevant bio-based products for industrial applications and thus contribute to the development of a sustainable, efficient and integrated bioeconomy without competing with food production

Cinaciguat (BAY 58 -2667) Improves Cardiopulmonary Hemodynamics in Patients With Acute Decompensated Heart Failure

Background-Cinaciguat (BAY 58 -2667) is the first of a new class of soluble guanylate cyclase activators in clinical development for acute decompensated heart failure. We aimed to assess the hemodynamic effects, safety, and tolerability of intravenous cinaciguat in patients with acute decompensated heart failure (pulmonary capillary wedge pressure Ն18 mm Hg). Methods and Results-After initial dose finding (part A; nϭ27), cinaciguat was evaluated in the nonrandomized, uncontrolled proof-of-concept part of the study (part B; nϭ33) using a starting dose of 100 g/h, which could be titrated depending on hemodynamic response. Patients were categorized as responders if their pulmonary capillary wedge pressure decreased by Ն4 mm Hg compared with baseline. Final doses of cinaciguat after 6 hours of infusion in part B were 50 g/h (nϭ2), 200 g/h (nϭ12), and 400 g/h (nϭ16). Compared with baseline, a 6-hour infusion of cinaciguat led to significant reductions in pulmonary capillary wedge pressure (Ϫ7.9 mm Hg), mean right atrial pressure (Ϫ2.9 mm Hg), mean pulmonary artery pressure (Ϫ6.5 mm Hg), pulmonary vascular resistance (Ϫ43.4 dynes · s · cm Ϫ5 ), and systemic vascular resistance (Ϫ597 dynes · s · cm Ϫ5 ), while increasing heart rate by 4.4 bpm and cardiac output by 1.68 L/min. The responder rate was 53% after 2 hours, 83% after 4 hours, and 90% after 6 hours. Cinaciguat was well tolerated, with 13 of 60 patients reporting 14 drug-related treatment-emergent adverse events of mild to moderate intensity, most commonly hypotension. Conclusions-Cinaciguat has potent preload-and afterload-reducing effects, increasing cardiac output. Further investigation of cinaciguat for acute decompensated heart failure is warranted

A Novel Substrate-Based HIV-1 Protease Inhibitor Drug Resistance Mechanism

BACKGROUND: HIV protease inhibitor (PI) therapy results in the rapid selection of drug resistant viral variants harbouring one or two substitutions in the viral protease. To combat PI resistance development, two approaches have been developed. The first is to increase the level of PI in the plasma of the patient, and the second is to develop novel PI with high potency against the known PI-resistant HIV protease variants. Both approaches share the requirement for a considerable increase in the number of protease mutations to lead to clinical resistance, thereby increasing the genetic barrier. We investigated whether HIV could yet again find a way to become less susceptible to these novel inhibitors. METHODS AND FINDINGS: We have performed in vitro selection experiments using a novel PI with an increased genetic barrier (RO033-4649) and demonstrated selection of three viruses 4- to 8-fold resistant to all PI compared to wild type. These PI-resistant viruses did not have a single substitution in the viral protease. Full genomic sequencing revealed the presence of NC/p1 cleavage site substitutions in the viral Gag polyprotein (K436E and/or I437T/V) in all three resistant viruses. These changes, when introduced in a reference strain, conferred PI resistance. The mechanism leading to PI resistance is enhancement of the processing efficiency of the altered substrate by wild-type protease. Analysis of genotypic and phenotypic resistance profiles of 28,000 clinical isolates demonstrated the presence of these NC/p1 cleavage site mutations in some clinical samples (codon 431 substitutions in 13%, codon 436 substitutions in 8%, and codon 437 substitutions in 10%). Moreover, these cleavage site substitutions were highly significantly associated with reduced susceptibility to PI in clinical isolates lacking primary protease mutations. Furthermore, we used data from a clinical trial (NARVAL, ANRS 088) to demonstrate that these NC/p1 cleavage site changes are associated with virological failure during PI therapy. CONCLUSIONS: HIV can use an alternative mechanism to become resistant to PI by changing the substrate instead of the protease. Further studies are required to determine to what extent cleavage site mutations may explain virological failure during PI therapy