Beneficial effects of phytochemicals in diabetic retinopathy: experimental and clinical evidence.

Diabetic retinopathy (DR) is a microvascular complication of diabetes mellitus and a major preventable cause of blindness. Strict control of blood glucose, blood pressure, and lipid profiles are the pivotal criteria to reduce the risk of developing DR. Although timely intervention with laser photocoagulation therapy could mitigate the progression of DR, it may not significantly improve visual acuity. Therefore, invasive surgical interventions such as vitrectomy are sometimes the only option to treat or manage advanced stages of DR. However, the risk of intra-ocular infections outweighs the benefits of the surgery. Newer therapies such as intraocular injection of anti-vascular endothelial growth factor (VEGF) antibody and steroids serve as a viable option for the treatment of DR. However, several clinical studies that assessed the long-term efficacy and safety of this therapy have yielded inconclusive results. Therefore, there is an urgent need to develop potent and safe drugs for the effective management of DR. In this review, we discuss various plant-derived small molecules (phytochemicals) that have been investigated for retinal cytoprotective effects in pre-clinical and clinical studies. Furthermore, we highlight the caveats on using phytochemicals for the management of DR.

[Renal failure in sarcoidosis]. / L'insuffisance rénale au cours de la sarcoïdose.

Renal sarcoidosis is rare and may lead to renal failure in less than 3% of patients. It may occur as a consequence of calcium metabolism disorders or granulomatous interstitial nephritis. In this retrospective study, we present five patients with renal failure secondary to sarcoidosis diagnosed in our centre on one period of nine years. Patients were three males and two females with a mean age at the time of the diagnosis of 31,6 years. Pulmonary involvement was present in three cases. Renal biopsy revealed granulomatous interstitial nephritis lesions in all patients. Extra-membranous glomerulonephritis was present in one case. In another case, moderate interstitial fibrosis was observed. Corticosteroid therapy using prednisolone 1mg/kg per day was used in all patients. Three patients had methylprednisolone pulse before oral corticosteroid therapy. One patient required several sessions of haemodialysis. All patients were followed up for a mean period of 52,6 months (ranged from 13 to 84 months). All patients improved their renal function with normalization of creatininemia in two of them. Renal involvement in sarcoidosis is probably underestimated. Corticosteroids therapy is efficient and must be introduced early to prevent progression to chronic renal failure.

[Renal amyloidosis: uncommon complication of sickle cell disease]. / L'amylose rénale: une complication inhabituelle de la drépanocytose.

Type AA amyloidosis is a rare complication of sickle cell anemia. The purpose of this report is to describe the case of a 30-year-old man with heterozygous sickle cell disease who was referred to our unit with nephritic syndrome and microscopic hematuria. Light microscopy on a renal biopsy specimen demonstrated AA amyloidosis. After elimination of other causes, it was concluded that amyloidosis was the result of recurrent acute inflammation secondary to sickle cell disease. To our knowledge, this is the fifth that renal amyloidosis as a complication of sickle cell disease has been described in the literature.

[Pregnancy in chronic hemodialysis patients]. / Grossesse chez les patientes hémodialysées chroniques.

INTRODUCTION: Pregnancy in hemodialysis patients is a rare event, with a high risk of maternal and fetal morbidity. The aim of our study is to report our experience in management of pregnancies occurred in hemodialysis patients, and clarify the factors of good prognosis. PATIENTS AND METHODS: We identified all pregnancies occurred in patients on hemodialysis between January 2000 and July 2010, and analysed their clinical and biological characteristics. The adjustment parameters of hemodialysis sessions, and treatment adjustments have been specified. The maternal and fetal complications and pregnancy outcome have been reported. RESULTS: Over a period of 10 years and 6 months, among 23 patients of childbearing age, 14 patients were married. We observed 11 pregnancies in eight patients, with an incidence of 7,14% year, and a prevalence of 71,4%. The evolution was marked by intrauterine fetal death in one case, medical pregnancy termination in a second one and four spontaneous abortions. Only five pregnancies were completed. The average age of conception was 34 years. The average duration of dialysis prior to conception was 76 months. Pregnancy diagnosis was made on average after 10,4 weeks. The mean gestational age at delivery was 33,6 weeks, and the mean newborn weight was 2070g. Apgar score was of 10/10 in the first minute in all newborns. No maternal complication was found. One case of intrauterine growth restriction and another case of pyelo-caliceal dilatation with resolving renal insufficiency were reported. In the long term, the fetal psychomotor development was normal. DISCUSSION: The fertility chronic hemodialysis patients in childbearing age have improved together with the quality of dialysis, with an increased incidence of pregnancy and the proportion of viable children. However, treatment modalities are not clearly established, because of the absence of randomized studies and the small number of pregnancies during the playoffs. Treatment of anemia with erythropoietin and blood transfusions, and the improvement in blood urea by extensive dialysis in women on hemodialysis, may improve outcomes by reducing the incidence of prematurity and increasing gestational age. CONCLUSION: Pregnancy in hemodilalysis patient is a rare event, but desired and valuable. Its completion requires a multidisciplinary management involving the nephrologist to ensure adequate dialysis and the gynecologist to ensure good obstetrical monitoring.

Novel gemini cationic surfactants based on N, N-dimethyl fatty hydrazide and 1,3-dibromopropane: synthesis, evaluation of surface and antimicrobial properties.

A fatty hydrazide based cationic gemini surfactants, 1,3-bis (N'-acyl-N,N-dimethylhydrazinium) propane dibromide which possess hydrolyzable amido moieties in the lipophilic portions, were prepared by reacting 1,3-bromopropane with N,N-dimethyl fatty hydrazide. The surface properties were explained and discussed based on the effect of their chemical structures. The micelle-forming ability, foaming ability, and foam stability were evaluated. The prepared surfactants also showed some antimicrobial activity against gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus) but they were not active against gram negative bacteria (Escherichia coli, P. aeruginosa), yeast (Candida albicans), and molds (Aspergillus niger).

Developing and characterizing a mouse model of hepatotoxicity using oral pyrrolizidine alkaloid (monocrotaline) administration, with potentiation of the liver injury by co-administration of LPS.

Oral administration of xenobiotics is preferable for research in in vivo models because it mimics the real life situation of human subjects. Therefore, oral (po) monocrotaline (MCT) (a common contaminant of dietary supplements)/intraperitoneal (ip) lipopolysaccharides (LPS)-induced liver injury possibly imitates idiosyncratic hepatotoxicity in humans. Cytokines, for example interleukin-1beta (IL-1beta) and transforming growth factor beta (TGF-beta) are known to play a role in the development of toxicity and repair processes, respectively. The purpose of this study was to develop and characterize a model of po MCT/ip LPS hepatotoxicity which may elucidate the mechanisms of injury. ND4 male mice were given MCT (200 mg/kg) followed 4 h later by LPS (6 mg/kg). Blood samples were drawn for plasma chemistry and IL-1beta. Animals were euthanized and livers were harvested at different time points. We have shown that MCT/LPS cotreatment results in significant elevation of plasma alanine aminotransferase (ALT), CRP, IL-1beta and TGF-1beta. Histopathological evaluation revealed diffuse degenerative injury. In summary, we have established a reproducible in vivo model of hepatotoxicity by po MCT/ip LPS cotreatment that may closely mimic real life idiosyncratic hepatotoxicity.

Unexpected partial H1-receptor agonism of imidazole-type histamine H3-receptor antagonists lacking a basic side chain.

OBJECTIVE AND DESIGN: The putative partial H1-receptor agonism of some H3-receptor antagonists belonging to the proxifan series was characterized in a functional in-vitro assay using guinea-pig ileum. METHODS: Whole segments of guinea-pig ileum were mounted in Tyrode's solution under isotonic conditions in the presence of atropine (10(-7) M) and were cumulatively treated with histamine as an internal reference. After washout, the putative H1-receptor agonists were added cumulatively to determine agonist potency (pEC50) and intrinsic activity (Emax) relative to histamine. Maximal or supramaximal concentrations of partial agonists, or sufficient concentrations of H1-receptor antagonists were incubated for 3-15 min prior to construction of a second concentration-effect curve to histamine in order to calculate partial agonist or antagonist affinity for the H1 receptor (pKP or pA2 value, respectively). RESULTS: Several analogues of FUB 372 displayed low H1-receptor affinities (pA2 or pKP 4.2-5.5) except for a methyl benzoate derivative (pA2 = 6.81, Schild plot slope unity). FUB 372, four ortho-substituted derivatives (R = F, CH3, OCH3, CF3), and ciproxifan were weak contractile agents (Emax 9-38%, pEC50 4.73-5.68, histamine: 6.70) susceptible to antagonism by the H1-antihistaminergic drug mepyramine (2.10(-9)-10(-7) M). Agonist potency and H1-receptor affinity of these compounds did not correlate with the data of a set of H1-histaminergic 2-phenylhistamines bearing the same substituents. CONCLUSIONS: A specific subset of proxifans related to FUB 372 and ciproxifan represent a unique type of H1-receptor agonists lacking a basic side chain.

Benzophenone derivatives and related compounds as potent histamine H3-receptor antagonists and potential PET/SPECT ligands.

Para-substituted aromatic ethers with benzophenone or related structural elements and a 3-(1H-imidazol-4-yl)propyloxy moiety were prepared by Mitsunobu-type ether synthesis or SNAr reaction. Most of the title compounds possess high antagonist potency in histamine H3-receptor assays in vitro as well as in vivo in mouse CNS following oral administration. After defining 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl phenyl methanone as a new lead, structure-activity relationships were investigated for this new class of compounds. Substitution of the meta'-position of the benzophenone moiety with halogen atoms (e.g., iodine, fluorine) led to compounds with high antagonist potency in vitro as well as in vivo (Ki = 9.3 and 4.3 nM, ED50 = 0.7 and 0.47 mg/kg p.o., 18 and 12, respectively). A receptor profile of several functional in vitro assays for several biogenic amine receptors for the meta'-iodinated derivative demonstrated high selectivity toward the histamine H3 receptor.

Novel histamine H(3)-receptor antagonists with carbonyl-substituted 4-(3-(phenoxy)propyl)-1H-imidazole structures like ciproxifan and related compounds.

Novel histamine H(3)-receptor antagonists possessing a 4-(3-(phenoxy)propyl)-1H-imidazole structure generally substituted in the para-position of the phenyl ring have been synthesized according to Mitsunobu or S(N)Ar reactions. With in vitro and in vivo screening for H(3)-receptor antagonist potency, the carbonyl-substituted derivatives proved to be highly active compounds. A number of compounds showed in vitro affinities in the subnanomolar concentration range, and the 4-hexanoyl (10) and 4-acetyl-3-methyl (29) substituted derivatives showed in vivo antagonist potencies of about 0.1 mg/kg after po administration. Many proxifans were also tested for their affinities at other histamine receptor subtypes thereby demonstrating their pronounced H(3)-receptor subtype selectivity. Since the cyclopropyl ketone derivative 14 (ciproxifan) had high affinity in vitro as well as high potency in vivo, it was selected for further studies in monkeys. It showed good oral absorption and long-lasting, dose-dependent plasma levels making it a promising compound for drug development.

Analogues and derivatives of ciproxifan, a novel prototype for generating potent histamine H3-receptor antagonists.

Novel derivatives of the highly potent and selective histamine H3-receptor antagonist ciproxifan (3) with different chain lengths as well as with structural variants of the cyclopropyl ketone moiety have been prepared and screened for their antagonist H3-receptor potencies in vitro and in vivo. Some derivatives (2, 6-8, 12) containing other functionalities were effective in vitro in the same (sub)nanomolar concentration range and in vivo in a remarkably low oral dose.

New histamine H(3)-receptor ligands of the proxifan series: imoproxifan and other selective antagonists with high oral in vivo potency.

Histamine H(3)-receptor antagonists of the proxifan series are described. The novel compounds possess a 4-(3-(phenoxy)propyl)-1H-imidazole structure and various functional groups, e.g., an oxime moiety, on the phenyl ring. Synthesis of the novel compounds and X-ray crystallography of one highly potent oxime derivative, named imoproxifan (4-(3-(1H-imidazol-4-yl)propyloxy)phenylethanone oxime), are described. Most of the title compounds possess high antagonist potency in histamine H(3)-receptor assays in vitro as well as in vivo in mouse CNS following po administration. Structure-activity relationships are discussed. Imoproxifan displays subnanomolar potency on a functional assay on synaptosomes of rat cerebral cortex (K(i) = 0.26 nM). In vivo, imoproxifan increases the central N(tau)-methylhistamine level with an ED(50) of 0.034 mg/kg po. A receptor profile on several functional in vitro assays was determined for imoproxifan, demonstrating high selectivity toward the histamine H(3) receptor for this promising candidate for further development.