Enhancing therapeutic reasoning: key insights and recommendations for education in prescribing.

Background: Despite efforts to improve undergraduate clinical pharmacology & therapeutics (CPT) education, prescribing errors are still made regularly. To improve CPT education and daily prescribing, it is crucial to understand how therapeutic reasoning works. Therefore, the aim of this study was to gain insight into the therapeutic reasoning process.

Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory.

Introduction: The development of cognitive dysfunction is not necessarily associated with diet-induced obesity. We hypothesized that cognitive dysfunction might require additional vascular damage, for example, in atherosclerotic mice.

Methods: We induced atherosclerosis in male C57BL/6N mice by injecting AAV-PCSK9 (2x10 VG) and feeding them a cholesterol-rich Western diet.

Autoimmune pre-disease.

Approximately 5% of the world-wide population is affected by autoimmune diseases. Overall, autoimmune diseases are still difficult to treat, impose a high burden on patients, and have a significant economic impact. Like other complex diseases, e.

AFM-based nanoindentation indicates an impaired cortical stiffness in the AAV-PCSK9 atherosclerosis mouse model.

Investigating atherosclerosis and endothelial dysfunction has mainly become established in genetically modified ApoE or LDL-R mice transgenic models. A new AAV-PCSK9DY mouse model with no genetic modification has now been reported as an alternative atherosclerosis model. Here, we aimed to employ this AAV-PCSK9 mouse model to quantify the mechanical stiffness of the endothelial surface, an accepted hallmark for endothelial dysfunction and forerunner for atherosclerosis.

Telmisartan induces a specific gut microbiota signature which may mediate its antiobesity effect.

Telmisartan prevents diet-induced obesity (DIO) in rodents. Given that the precise underlying mechanism is not known, we examined whether a gut-related mechanism might be involved. Sprague-Dawley rats received cafeteria diet (CD) for 3 months to develop DIO and were administered either telmisartan (8 mg/kg) or vehicle.

Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior.

Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity.

Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice.

Carbon dioxide (CO), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H receptor, and endothelial Gα proteins mediate the CO/H effect on cerebrovascular reactivity in mice.

Telmisartan prevents development of obesity and normalizes hypothalamic lipid droplets.

The AT1 receptor blocker telmisartan (TEL) prevents diet-induced obesity. Hypothalamic lipid metabolism is functionally important for energy homeostasis, as a surplus of lipids induces an inflammatory response in the hypothalamus, thus promoting the development of central leptin resistance. However, it is unclear as to whether TEL treatment affects the lipid status in the hypothalamus.

The antiobese effect of AT1 receptor blockade is augmented in mice lacking Mas.

We recently showed that the antiobese efficacy of the AT1 receptor blocker telmisartan (TEL) is at least partially related to an Ang(1-7)-dependent mechanism. Ang(1-7) acts via Mas, thus raising the question of whether Mas-deficient (Mas-ko) mice are likewise predisposed to develop diet-induced obesity and, further, whether this can be prevented by TEL treatment. Mas-ko mice and FVB/N wild-type (wt) animals were treated with TEL (8 mg/kg/day) or vehicle while they were fed with high-fat diet (HFD) or chow.

Influence of AT1 blockers on obesity and stress induced eating of cafeteria diet.

Based on findings that treatment with AT1 receptor blocker (ARB) prevents diet-induced obesity and that the activity of the hypothalamic-pituitary-adrenal (HPA) axis is stimulated by AngII and blocked by ARBs, we aimed to investigate whether ARB treatment can reduce stress-induced eating of cafeteria diet (CD) , thus contributing to alterations in eating behavior. Sprague Dawley rats were fed with chow or CD and treated with telmisartan (TEL, 8mg/kg/d) or vehicle. At weeks 2 and 12, rats were stressed over 5 consecutive days by restraint stress (RS, 4h) and by additional shaking at d5.

After standard dosage of piperacillin plasma concentrations of drug are subtherapeutic in burn patients.

Infections are a major problem in patients with burn diseases. Mortality is high despite antibiotic therapy as studies are controversial concerning drug underdosing. The aims of this prospective, observational study were to monitor plasma concentrations of piperacillin during standard piperacillin/tazobactam treatment in 20 burn patients and 16 controls from the intensive care unit (ICU) and to optimize doses by in silico analyses.

Telmisartan prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier in high-fat diet-fed mice.

Obesity is a global health problem and treatment options are still insufficient. When chronically treated with the angiotensin II receptor blocker telmisartan (TEL), rodents do not develop diet-induced obesity (DIO). However, the underlying mechanism for this is still unclear.

ApoA-I Mimetic Peptide 4F Reduces Age-Related Lipid Deposition in Murine Bruch's Membrane and Causes Its Structural Remodeling.

Purpose: Accumulation of lipoprotein-derived lipids including esterified and unesterified cholesterol in Bruch's membrane of human eyes is a major age-related change involved in initiating and sustaining soft drusen in age-related macular degeneration (AMD). The apolipoprotein (apo) A-I mimetic peptide 4F is a small anti-inflammatory and anti-atherogenic agent, and potent modifier of plasma membranes. We evaluated the effect of intravitreally-injected 4F on murine Bruch's membrane.

Obesity-stimulated aldosterone release is not related to an S1P-dependent mechanism.

Aldosterone has been identified as an important factor in obesity-associated hypertension. Here, we investigated whether sphingosine-1-phosphate (S1P), which has previously been linked to obesity, increases aldosterone release. S1P-induced aldosterone release was determined in NCI H295R cells in the presence of S1P receptor (S1PR) antagonists.

Glucagon increase after chronic AT blockade is more likely related to an indirect leptin-dependent than to a pancreatic α-cell-dependent mechanism.

AT blockers (ARB) prevent diabetes by improving pancreatic β cell function. Less is known about whether α cells are affected although they express angiotensin II (AngII) receptors. We aimed to investigate glucagon release upon AngII stimulation.

The brain renin-angiotensin system plays a crucial role in regulating body weight in diet-induced obesity in rats.

Background And Purpose: Reduced weight gain after treatment with AT1 receptor antagonists may involve a brain-related mechanism. Here, we investigated the role of the brain renin-angiotensin system on weight regulation and food behaviour, with or without additional treatment with telmisartan.

Methods: Transgenic rats with a brain-specific deficiency in angiotensinogen (TGR(ASrAOGEN)) and the corresponding wild-type, Sprague Dawley (SD) rats were fed (3 months) with a high-calorie cafeteria diet (CD) or standard chow.

Effect of Angiotensin(1-7) on Heart Function in an Experimental Rat Model of Obesity.

Aim: Obesity is a risk factor for the development of cardiovascular diseases. Recently it was shown that overexpression of the Mas-receptor antagonist angiotensin(1-7) could prevent from diet-induced obesity. However, it remained unclear whether diet-induced obesity and angiotensin(1-7) overexpression might also have effects on the cardiovascular system in these rats.

Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailability.

The neuraminidase (NA) inhibitor zanamivir (1) is potently active against a broad panel of influenza A and B strains, including mutant viruses, but suffers from pharmacokinetic (PK) shortcomings. Here, distinct prodrug approaches are described that aimed at overcoming zanamivir's lack of oral bioavailability. Lowering the high basicity of the 4-guanidino group in zanamivir and of a bioisosteric 4-acetamidine analog (5) by N-hydroxylation was deemed to be a plausible tactic.

Lack of weight gain after angiotensin AT1 receptor blockade in diet-induced obesity is partly mediated by an angiotensin-(1-7)/Mas-dependent pathway.

Background And Purpose: Angiotensin AT1 receptor antagonists induce weight loss; however, the mechanism underlying this phenomenon is unknown. The Mas receptor agonist angiotensin-(1-7) is a metabolite of angiotensin I and of angiotensin II . As an agonist of Mas receptors, angiotensin-(1-7) has beneficial cardiovascular and metabolic effects.

Chronic blockade of angiotensin AT₁ receptors improves cardinal symptoms of metabolic syndrome in diet-induced obesity in rats.

Background And Purpose: AT₁ receptor antagonists decrease body weight gain in models of murine obesity. However, fewer data are available concerning the anti-obesity effects of these antagonists, given as a treatment after obesity had been established.

Experimental Approach: In spontaneously hypertensive rats, obesity was established by cafeteria diet (CD) feeding for 19 weeks.