Flavones. 2. Synthesis and structure-activity relationship of flavodilol and its analogues, a novel class of antihypertensive agents with catecholamine depleting properties

(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple flavonoxypropanolamines was prepared to further explore the structural requirements for the antihypertensive effect of these compounds. A structure-activity relationship of these derivatives indicates that the position of the oxypropanolamine side chain, the hydroxy group of the side chain, steric bulkiness and length of N substituents, degree of the N-substitution, phenyl group at the 2-position of the chromone nucleus, and substituents of the phenyl group or B ring of the flavone play significant roles in imparting pharmacological effects. In addition, there is a good correlation between the antihypertensive activity and depletion of myocardial norepinephrine. Of these analogues tested, the most effective one was flavodilol. Only the 8-substituted analogue 6 was found to be a beta-antagonist. Flavodilol was chosen for in-depth pharmacological, toxicological, and clinical evaluation.     

Evaluation of an Automated Thermodynamic Treatment (LipiFlow®) System for Meibomian Gland Dysfunction: A Prospective,Randomized, Observer-Masked Trial

PurposeTo compare the effectiveness of a single LipiFlow^® treatment with combined lid warming and massage in patients with meibomian gland dysfunction (MGD).MethodsIn this prospective, randomized, crossover, observer-masked clinical trial, subjects were randomized to receive either a single 12-min LipiFlow-LipiFlow Thermal Pulsation (LTP) system treatment or to perform combined twice-daily lid warming and massage for 3 months. All subjects were examined before, and 1 and 3 months after initiation of treatments. Investigated parameters included subjective symptoms, lipid layer thickness, meibomian gland assessment, tear break-up time, tear osmolarity, corneal and conjunctival staining, Schirmer test values, and tear meniscus height.ResultsA total of 31 subjects completed the 3-month follow-up. At 1 and 3 months, patients in the LipiFlow treatment group had a significant reduction in Ocular Surface Disease Index (OSDI) scores compared with those in the lid-margin hygiene group. Both treatments produced a significant improvement in expressible meibomian glands compared to the baseline parameters, but no significant difference was noted between the two groups. The other investigated objective parameters did not show a significant difference.ConclusionResults of our study show that a single LipiFlow treatment is as least as effective as a 3-month, twice-daily lid margin hygiene regimen for MGD. However, the present study was observer-masked only, and therefore a placebo effect may have confounded any improvements in subjective symptoms and other parameters in both groups.     

Choroidal Neovascularization in a Patient with Crohn's Disease

Purpose

To report a case of subfoveal choroidal neovascularization (CNV) in a patient with Crohn''s disease (CD) and to discuss a possible association between these two conditions.

Methods

This is an observational case report.

Results

A 69-year-old male affected by CD was referred to our department because of sudden visual acuity drop in the left eye. A subfoveal CNV was diagnosed based on slit-lamp fundus biomicroscopy and fluorescein angiography. Color fundus photography, infrared autofluorescence and spectral-domain optical coherence tomography imaging of both eyes were also performed. Following six intravitreal ranibizumab injections, visual improvement was obtained with no related adverse events.

Conclusion

We report a case of CNV as a possible rare extraintestinal manifestation of CD. The use of ranibizumab successfully impacted on CNV, while not affecting CD, which remained quiescent.Key words: Choroidal neovascularization, Crohn''s disease, Anti-VEGF, Intravitreal ranibizumab, Fluorescein angiography, Optical coherence tomography     

Herb–Drug Interactions with St John’s Wort (Hypericum perforatum): an Update on Clinical Observations

St John’s wort (SJW) extracts, prepared from the aerial parts of Hypericum perforatum, contain numerous pharmacologically active ingredients, including naphthodianthrones (e.g., hypericin and its derivatives), phloroglucinols derivatives (e.g., hyperforin, which inhibits the reuptake of a number of neurotransmitters, including serotonin), and flavonoids. Such extracts are widely used for the treatment of mild-to-moderate depression. As a monotherapy, SJW has an encouraging safety profile. However, relevant and, in some case, life-threatening interactions have been reported, particularly with drugs which are substrate of cytochrome P450 and/or P-glycoprotein. Well-documented SJW interactions include (1) reduced blood cyclosporin concentration, as suggested by multiple case reports as well as by clinical trials, (2) serotonin syndrome or lethargy when SJW was given with serotonin reuptake inhibitors, (3) unwanted pregnancies in women while using oral contraceptives and SJW, and (4) reduced plasma drug concentration of antiretroviral (e.g., indinavir, nevirapine) and anticancer (i.e., irinotecan, imatinib) drugs. Hyperforin, which is believed to contribute to the antidepressant action of St John’s wort, is also strongly suspected to be responsible of most of the described interactions.     

Peripheral endocannabinoid dysregulation in obesity: relation to intestinal motility and energy processing induced by food deprivation and re-feeding

Background and purpose:

Endocannabinoids in tissues controlling energy homeostasis are altered in obesity, thus contributing to metabolic disorders. Here we evaluate endocannabinoid dysregulation in the small intestine of mice with diet-induced obesity (DIO) and in peripheral tissues of Zucker and lean rats following food deprivation and re-feeding.

Experimental approach:

Intestinal transit, evaluated using rhodamine-B-labelled dextran, and small intestinal endocannabinoid levels, measured by liquid chromatography mass spectrometry, were measured in mice fed normal or high-fat diets (HFDs). Endocannabinoid levels were measured also in various tissues of lean and Zucker rats fed ad libitum or following overnight food deprivation with and without subsequent re-feeding.

Key results:

After 8 weeks of HFD, baseline intestinal transit was increased in DIO mice and enhanced by cannabinoid CB₁ receptor antagonism less efficaciously than in lean mice. Small intestinal anandamide and 2-arachidonoylglycerol levels were reduced and increased respectively. In Zucker rats, endocannabinoids levels were higher in the pancreas, liver and duodenum, and lower in the subcutaneous adipose tissue. Food deprivation increased endocannabinoid levels in the duodenum and liver of both rat strains, in the pancreas of lean rats and in adipose tissues of Zucker rats.

Conclusions and implications:

Reduced anandamide levels might account for increased intestinal motility in DIO mice. Regulation of endocannabinoid levels in rat peripheral tissues, induced by food deprivation and re-feeding, might participate in food intake and energy processing and was altered in Zucker rats. These data, together with previous observations, provide further evidence for dysregulation of peripheral endocannabinoids in obesity.     

Dopamine D2 receptor knock-out mice are insensitive to the hypolocomotor and hypothermic effects of dopamine D2/D3 receptor agonists.

The dopamine (DA) D2-like family of receptors is comprised of three subtypes, the D2, D3, and D4 receptors. It has been suggested that the potency of DA receptor agonists to produce hypothermia and hypolocomotion in rodents correlates more strongly with the in vitro affinity for, or potency (mitogenesis test) at the D3 than at the D2 subtype. However, it has recently been reported that when tested in DA D3 receptor knock-out mice, several DA D2/D3 receptor agonists (7-OH-DPAT, PD 128907 and quinelorane) induced levels of hypothermia and decreases of locomotor activity similar to those obtained in control (wild-type) mice. These results do not argue in favour of an implication of DA D3 receptors in these in vivo effects. In order to investigate whether the DA D2 receptor is the subtype that mediates hypothermia and hypolocomotion produced by DA D2/D3 receptor agonists, we tested the effects of ip administration of the DA D2/D3 receptor agonists 7-OH-DPAT and PD 128907, on core temperature and locomotor activity in DA D2 receptor knock-out mice (homozygotes: D2(-/-) and heterozygotes: D2(+/-)), and in wild-type (D2(+/+)) mice. 7-OH-DPAT (0.1-3 mg/kg) and PD 128907 (1-10 mg/kg) induced hypothermia and decreased locomotion in D2(+/+) mice, but had no effects in D2(-/-) mice; the magnitude of the hypothermic and locomotor-reducing effects of these two agonists in D2(+/+) mutants was approximately half that of D2(+/+) mice. During the first 10 min in the activity chambers, the level of spontaneous locomotor activity of D2(-/-) individuals was almost 50% below that of D2(+/+) mice; basal locomotor activity of D2(+/-) mice was between that of D2(-/-) and D2(+/+) individuals. Neither type of mutant showed spontaneous catalepsy or deficits in forelimb muscle strength (grip-strength test). These results show that the presence of DA D2 receptors is necessary for the expression of the locomotor- and core temperature-decreasing effects of DA D2/D3 receptor agonists such as 7-OH-DPAT and PD 128907.     

Weight control smoking among sedentary women

This study examined characteristics associated with weight control smoking among 281 sedentary women enrolled in a smoking cessation trial. A series of regression models were developed to identify predictors of weight control smoking as measured by the Smoking Situations Questionnaire. Predictor variables included demographic variables, dietary intake, weight gain following previous quit attempts, dietary restraint, self-efficacy for weight management, smoking behavior, exercise behavior, negative affect and psychological constructs relevant to smoking cessation, and exercise adoption. In the final predictor model, anticipation of weight gain in the current quit attempt, higher dietary restraint, younger age, greater Fagerstrom scores, greater number of pounds gained in previous quit attempts, and lower levels of self-efficacy to manage weight in negative affect situations were associated with smoking for weight control. Treatment implications for women who smoke for weight control reasons are discussed.     

Rimonabant inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon

The selective CB1 receptor antagonist rimonabant (SR141716) was shown to perform a number of biological effects in several pathological conditions. Emerging findings demonstrate that rimonabant exerts antitumor action in thyroid tumors and breast cancer cells. In our study, human colorectal cancer cells (DLD‐1, CaCo‐2 and SW620) were treated with rimonabant and analyzed for markers of cell proliferation, cell viability and cell cycle progression. Rimonabant significantly reduced cell growth and induced cell death. In addition, rimonabant was able to alter cell cycle distribution in all the cell lines tested. Particularly, rimonabant produced a G2/M cell cycle arrest in DLD‐1 cells without inducing apoptosis or necrosis. The G2/M phase arrest was characterized by a parallel enhancement of the number of mitoses associated to elevated DNA double strand breaks and chromosome misjoining events, hallmarks of mitotic catastrophe. Protein expression analyses of Cyclin B1, PARP‐1, Aurora B and phosphorylated p38/MAPK and Chk1 demonstrated that rimonabant‐induced mitotic catastrophe is mediated by interfering with the spindle assembly checkpoint and the DNA damage checkpoint. Moreover, in the mouse model of azoxymethane‐induced colon carcinogenesis, rimonabant significantly decreased aberrant crypt foci (ACF) formation, which precedes colorectal cancer. Our findings suggest that rimonabant is able to inhibit colorectal cancer cell growth at different stages of colon cancer pathogenesis inducing mitotic catastrophe in vitro. © 2009 UICC.     

Impact of Structural Changes on Multifocal Electroretinography in Patients With Use of Hydroxychloroquine

PurposeTo investigate the relationship between retinal structure and macular function in eyes screened for hydroxychloroquine (HCQ) toxicity.MethodsParticipants referred for hydroxychloroquine retinopathy screening with spectral domain optical coherence tomography (SD-OCT) and multifocal electroretinogram (mfERG) testing were included in the analysis. Amplitude and implicit time of mfERG N1 and P1 responses were included in the analysis. Ring ratios were computed for amplitude values as the ratio of rings 1–3:5 (R1–3:R5). A control group of healthy participants was included for comparison of SD-OCT metrics.ResultsSixty-three eyes screened for HCQ retinopathy and 30 control eyes were analyzed. The outer nuclear layer (ONL) was significantly thinner in HCQ patients in the foveal (P = 0.008), parafoveal (P < 0.0001), and perifoveal (P < 0.0001) regions. The HCQ cohort was further divided into two subgroups according to the presence of structural clinically detectable retinopathy (i.e., structural damage as detected by multimodal imaging). HCQ eyes without retinopathy had a thinner ONL thickness in the foveal (P = 0.032), parafoveal (P < 0.0001), and perifoveal (P < 0.0001) regions and a thinner inner nuclear layer (INL) in the parafoveal region (P = 0.045 versus controls). Structural changes in HCQ patients without retinopathy were significantly associated with macular function as R2:R5 ring ratio of mfERG P1 amplitude was associated with INL (P = 0.002) and ONL (P = 0.044) thicknesses, and R3:R5 ring ratio of P1 amplitude was associated with ONL thickness (P = 0.004).ConclusionsOur results suggest that structural alterations secondary to HCQ toxicity may occur in the absence of clinically detectable retinopathy, and this may reflect in an impaired macular function.     

Benzene metabolites inhibit the release of proinflammatory mediators and cytokines from human basophils

Benzene and its metabolites have been involved in the pathogenesis of chronic lung inflammation and allergic disorders such as bronchial asthma. However, the effects of these xenobiotics on human basophils, key cells in the development of respiratory allergy, have not been investigated. We examined the effects of hydroquinone (HQ) and benzoquinone (BQ), two important chemicals implicated in benzene toxicity, on the release of preformed (histamine) and de novo synthesized mediators (cysteinyl leukotriene C4, LTC4, and IL-4) from human basophils. Preincubation of basophils purified from normal donors with HQ (3-100 microM) inhibited up to 30% histamine release induced by anti-IgE and up to 55% of that induced by the Ca2+ ionophore A23187. HQ had no effect on histamine release induced by formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe). Preincubation of basophils with BQ (3-100 microM) resulted in the concentration-dependent inhibition of histamine release (up to 70%) induced by anti-IgE, A23187 and f-Met-Leu-Phe. HQ completely suppressed the de novo synthesis of LTC4 from basophils challenged with anti-IgE or f-Met-Leu-Phe and the production of IL-4 in cells stimulated with anti-IgE. These results indicate that two major benzene metabolites, HQ and BQ, inhibit the release of proinflammatory mediators and Th2-promoting cytokines from basophils activated by different stimuli. These results suggest that benzene metabolites interfere with multiple intracellular signals involved in the activation of human basophils.