Supplementation with Highly Standardized Cranberry Extract Phytosome Achieved the Modulation of Urinary Tract Infection Episodes in Diabetic Postmenopausal Women Taking SGLT-2 Inhibitors: A RCT Study.

Urinary tract infections (UTIs) are the most common bacterial infections in postmenopausal women, and women with diabetes are possibly at a higher risk. The aim of this study is to evaluate the potential benefit on the prevention of UTI episodes, assessed by urinalysis and urine culture (primary outcome) after two, four and six months, of daily oral dietary supplement (120 mg highly standardized cranberry extract phytosome), compared to placebo, in diabetic postmenopausal women taking SGLT-2 inhibitors. Forty-six subjects (mean age 72.

Favorable Preclinical Pharmacological Profile of a Novel Antimalarial Pyrrolizidinylmethyl Derivative of 4-amino-7-chloroquinoline with Potent In Vitro and In Vivo Activities.

The 4-aminoquinoline drugs, such as chloroquine (CQ), amodiaquine or piperaquine, are still commonly used for malaria treatment, either alone (CQ) or in combination with artemisinin derivatives. We previously described the excellent in vitro activity of a novel pyrrolizidinylmethyl derivative of 4-amino-7-chloroquinoline, named against drug-resistant parasites. Here, we report the optimized and safer synthesis of , now suitable for a scale-up, and its additional in vitro and in vivo characterization.

A rapid spectrophotometric method to identify inhibitors of human erythropoiesis.

Erythropoiesis is a complex physiological process by which erythroid progenitors proliferate and differentiate into nonnucleated red blood cells. Several methods can be used to monitor in vitro the differentiation of erythroid precursors, and hence the toxic effects of drugs, chemicals, or pollutants. One of the most commonly available assay of erythropoiesis is the microscopic observation of differentiated cells after benzidine staining, which forms a blue complex with hemoglobin.

Phagocytosis and activation of bone marrow-derived macrophages by Plasmodium falciparum gametocytes.

Background: The innate immune response against various life cycle stages of the malaria parasite plays an important role in protection against the disease and regulation of its severity. Phagocytosis of asexual erythrocytic stages is well documented, but little and contrasting results are available about phagocytic clearance of sexual stages, the gametocytes, which are responsible for the transmission of the parasites from humans to mosquitoes. Similarly, activation of host macrophages by gametocytes has not yet been carefully addressed.

Facile Preparation of -Glycosylated 10-Piperazinyl Artemisinin Derivatives and Evaluation of Their Antimalarial and Cytotoxic Activities.

According to the precepts that C-10 amino-artemisinins display optimum biological activities for the artemisinin drug class, and that attachment of a sugar enhances specificity of drug delivery, polarity and solubility so as to attenuate toxicity, we assessed the effects of attaching sugars to N-4 of the dihydroartemisinin (DHA)-piperazine derivative prepared in one step from DHA and piperazine. -Glycosylated DHA-piperazine derivatives were obtained according to the Kotchetkov reaction by heating the DHA-piperazine with the sugar in a polar solvent. Structure of the D-glucose derivative is secured by X-ray crystallography.

In Vivo and In Vitro Activities and ADME-Tox Profile of a Quinolizidine-Modified 4-Aminoquinoline: A Potent Anti-P. falciparum and Anti-P. vivax Blood-Stage Antimalarial.

Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1) between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (). The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia), proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication.

Malaria pigment stimulates chemokine production by human microvascular endothelium.

Severe falciparum malaria is characterized by the sequestration of infected erythrocytes and leukocyte recruitment in the microvasculature, resulting in impaired blood flow and metabolic disturbances. Which parasite products cause chemokine production, thus contributing to the strong host inflammatory response and cellular recruitment are not well characterized. Here, we studied haemozoin (Hz), the end-product of haem, a ferriprotoporphyrin-IX crystal bound to host and parasite lipids, DNA, and proteins.

Salinomycin and other ionophores as a new class of antimalarial drugs with transmission-blocking activity.

The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P.

Broad spectrum and prolonged efficacy of dimiracetam in models of neuropathic pain.

Dimiracetam, a bicyclic 2-pyrrolidinone derivative originally developed as cognition enhancer, is a member of the nootropic family for which anecdotal efficacy in models of neuropathic pain has been reported. Its antineuropathic activity was evaluated in established models of neuropathic pain induced by nerve injury, chemotherapy or MIA-induced osteoarthritis. Acutely, dimiracetam was very effective in models of antiretroviral drug induced painful neuropathy, oxaliplatin-induced hyperalgesia and in the MIA-osteoarthritis.

Inhibition of Plasmodium falciparum pH regulation by small molecule indole derivatives results in rapid parasite death.

The V-type H+ATPase is critical during the intraerythrocytic stage of the human malaria parasite Plasmodium falciparum. It is responsible for maintaining a near-neutral cytosolic pH (pH 7.3), an acidic digestive vacuole (pH 4.

Biological effects of a new vacuolar-H,-ATPase inhibitor in colon carcinoma cell lines.

Vacuolar-H(+)-ATPase plays a critical role in the cellular balance of protons, thus regulating intracellular pH and contributing to apoptosis resistance, drug resistance, and invasive and metastatic behavior of cells. NiK-12192, a vacuolar-H(+)-ATPase inhibitor, caused a reduction in the volume and/or acidity of lysosomes, a polarization of alphavbeta5 integrin distribution, and a number of floating live cells, whereas signs of apoptosis appeared only after 72 h of treatment. In conclusion, NiK-12192, by affecting vacuolar- H(+)-ATPase activity (and intracellular pH), causes a modification of structures crucial for cell adhesion and induces cell death, likely by a modality involving an anoikis-mediated apoptosis.

Antimetastatic effect of a small-molecule vacuolar H+-ATPase inhibitor in in vitro and in vivo preclinical studies.

On the basis of the evidence that vacuolar H(+)-ATPase is implicated in the development of the metastatic phenotype, we have explored the possibility to target the enzyme function in an attempt to control the metastatic behavior of tumor cells. In this study, we used an indole derivative, NiK-12192 [4-(5,6-dichloro-1H-indol-2-yl)-3-ethoxy-N-(2,2,6,6-tetramethyl-piperidin-4-yl)-benzamide], recently identified as an effective inhibitor of vacuolar H(+)-ATPase, as a potential antimetastatic agent in the treatment of NSCLC H460 xenograft, which is able to induce lung metastases in mice. Oral administration of NiK-12192 caused a significant inhibition of formation of spontaneous metastases.

Evaluation of in vitro brain penetration: optimized PAMPA and MDCKII-MDR1 assay comparison.

Parallel artificial membrane permeability assay (PAMPA) is arising in ADMET screening as a powerful tool to determine the passive permeability of new potential chemical entities. In an attempt to set up a sensitive high throughput method to assess passive blood-brain barrier (BBB) penetration we focused our attention on the effect of solvent and the influence of phospholipids on the permeability in PAMPA. Moreover, the high throughput nature of the assay was maximized by decreasing the incubation time and performing the assay in a cassette mode.

Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1).

Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives.

New perspectives in bio-analytical techniques for preclinical characterization of a drug candidate: UPLC-MS/MS in in vitro metabolism and pharmacokinetic studies.

Lead optimization requires rapid bio-analytical turnover for the generation of early absorption, distribution, metabolism, excretion (ADME) and pharmacokinetics (PK) data maintaining a high quality level. Therefore, one of the major challenges in the bio-analytical field is to achieve faster and more sensitive quantification protocols. In the present communication, a comparison between HPLC and ultra performance liquid chromatography (UPLC) performances in terms of sensitivity and resolution is shown using a pharmakokinetic study and a metabolism study as models.

Effect of a novel vacuolar-H+-ATPase inhibitor on cell and tumor response to camptothecins.

The vacuolar-H(+)-ATPase, functionally expressed in cell membranes, is known to play a relevant role in intracellular pH regulatory mechanisms, because it is implicated in pumping protons into the extracellular environment or in sequestrating excess protons into acidic vacuolar compartments. Because tumor cells exist in a hypoxic microenvironment and produce acidic metabolites, this regulatory mechanism is recognized as a protective function. This study was designed to investigate the effect of NiK-12192 [4-(5,6-dichloro-1H-indol-2-yl)-3-ethoxy-N-(2,2,6,6-tetramethyl-piperidin-4-yl)-benzamide], an indole derivative identified as an effective inhibitor of vacuolar-H(+)-ATPase, on the cytotoxic activity of two camptothecins, i.

Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid(1)(-)(42) secretion.

Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Abeta42 inhibitory potency while removing anti-COX activity.

Antagonism between the anti-inflammatory activity of the cannabinoid WIN 55212-2 and SR 141716A.

The CB1/CB2 receptor agonist WIN 55212-2 (0.75 mg/kg, i.v.

PTH2 receptor-mediated inhibitory effect of parathyroid hormone and TIP39 on cell proliferation.

The parathyroid hormone (PTH) has dual mitogenic and inhibitory effects on cell proliferation, depending on the cell type and experimental conditions. PTH can signal via two different receptors, both positively coupled to the adenylyl cyclase/cyclic AMP pathway which can mimic some of the proliferative effects of PTH. We evaluated the role of the type-2 PTH (PTH2) receptor on cell proliferation in clonal human embryonic kidney HEK293 cells stably expressing the human PTH2 receptor.

A selective inhibitor of the osteoclastic V-H(+)-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats.

A potent and selective inhibitor of the osteoclastic V-H(+)-ATPase, (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6, 6-pentamethylpiperidin-4-yl)-2,4-pentadienamide (SB 242784), was evaluated in two animal models of bone resorption. SB 242784 completely prevented retinoid-induced hypercalcemia in thyroparathyroidectomized (TPTX) rats when administered orally at 10 mg/kg. SB 242784 was highly efficacious in the prevention of ovariectomy-induced bone loss in the rat when administered orally for 6 months at 10 mg/kg/d and was partially effective at 5 mg/kg/d.

Opiate receptors within the blood-brain barrier mediate kappa agonist-induced water diuresis.

Data suggest that kappa opioid agonist-induced water diuresis involves inhibition of vasopressin (AVP) secretion; however, it is not clear whether this action involves kappa receptors in the neurohypophysis or receptors behind the blood-brain barrier (BBB). We have investigated the site of action using three selective kappa agonists, BRL 52656 (S(-)-2-(1-pyrrolidinylmethyl)-1-(4-trifluoromethylphenyl) acetyl piperidine hydrochloride), BRL 53114 ((-)-1-(4-trifluoromethylphenyl) acetyl-2-(1-pyrrolidinymethyl)3,3- dimethyl piperidine hydrochloride) and BRL 52974 (4-(1-pyrrolidinylmethyl)5-(3,4-dichlorophenyl)acetyl-4,5,6,7-t etrahydroimidazo [4,5-c] pyridine), with varying abilities to cross the BBB. Chemical and functional assays indicate that BRL 52974 has limited ability to cross the BBB, whereas BRL 53114 and BRL 52656 can freely penetrate.