Dihydrocapsaicin (DC) protects against serum hyperlipidemia in guinea pigs fed a cholesterol-enriched diet

Juvenile guinea pigs were maintained either on a standard diet (cholesterol-free) or a 0.5% cholesterol-enriched vitamin C deficient diet for six weeks. Half of the animals of each dietary group were treated with dihydrocapsaicin (DC) at the rate of 8 mg per animal per day. DC administration significantly altered food consumption, body weight, and dry weight of feces of animals maintained on the standard diet. In addition, the mean serum triglyceride concentration of these animals was significantly decreased with DC treatment. Food consumption, body weight and (wet) fecal weight of animals maintained on the 0.5% cholesterol-enriched diet were significantly lower than the corresponding values in control animals even though the liver was much larger in proportion to the total body weight. The mean serum cholesterol concentration of the animals fed a cholesterol-enriched diet was significantly elevated. However, in animals also receiving DC, the cholesterol and triglyceride levels were comparable to controls fed a regular diet. The gross and microscopic fatty infiltration of the liver observed in the cholesterol-fed animal were minimized in those animals fed cholesterol and DC.     

Mechanisms of big endothelin-1-induced diuresis and natriuresis : role of ET(B) receptors

Endothelin-1 (ET-1) at high concentrations has marked antidiuretic and antinatriuretic activities, whereas its precursor, big endothelin-1 (big ET-1), has surprisingly potent diuretic and natriuretic actions. The mechanisms underlying the excretory effects of big ET-1 have not been fully elucidated. To explore these mechanisms, we examined the effects of a highly selective ET(B) antagonist (A-192621.1), a calcium channel blocker (verapamil), a nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]), and a cyclooxygenase inhibitor (indomethacin) on the systemic and renal actions of big ET-1 in anesthetized rats. An intravenous bolus injection of incremental doses of big ET-1 (0.3, 1. 0, and 3.0 nmol/kg) produced a significant hypertensive effect that was dose dependent and prolonged (from 113+/-7 mm Hg to a maximum of 148+/-6 mm Hg). The administration of big ET-1 induced marked diuretic and natriuretic responses (urinary flow rate increased from 8.5+/-1 to 110+/-14 microL/min, and fractional excretion of sodium increased from 0.38+/-0.13% to 7.51+/-1.24%). Glomerular filtration rate and renal plasma flow significantly decreased only at the highest dose of big ET-1. Pretreatment with A-192621.1 (3 mg/kg plus 3 mg. kg(-1). h(-1)) significantly abolished the diuretic (17+/-5 microL/min to a maximum of 19+/-3 microL/min) and natriuretic (0. 29+/-0.1% to a maximum of 1.93+/-0.37%) responses induced by big ET-1. Moreover, A-192621.1 potentiated the decline in glomerular filtration rate and renal plasma flow and the increase in mean arterial blood pressure produced by the low doses of big ET-1. Similar to A-192621.1, pretreatment with a nitric oxide synthase inhibitor (L-NAME, 10 mg/kg plus 5 mg. kg(-1). h(-1)) significantly and comparably reduced the diuretic and natriuretic actions of big ET-1 and augmented the hypoperfusion/hypofiltration and systemic vasoconstriction induced by high doses of the peptide. Pretreatment with verapamil (2 mg. kg(-1). h(-1)) slightly inhibited the diuretic/natriuretic effects of the high-dose big ET-1 and completely prevented the increase in mean arterial blood pressure provoked by the peptide. Unlike verapamil and L-NAME, only indomethacin administration was associated with significant natriuretic/diuretic responses and did not influence the pressor effect and renal actions of big ET-1. Taken together, these results suggest that big ET-1-induced diuretic and natriuretic responses are mediated mainly by stimulation of nitric oxide production coupled to ET(B) receptor subtype activation.     

Endothelin 3 (ET3) stimulates the hypothalamic-pituitary-adrenal axis mainly by corticotropin-releasing-hormone (CRH)]

Endothelin 3 (ET3) is a member of the novel vasoconstrictive peptide family, identified in the porcine central nervous system. The effect of ET3 on the hypothalamic-pituitary-adrenal axis in male rats was examined in vivo and in vitro. Intravenous bolus injection of 1000pmol/kg of ET3 in free moving rats caused significant increases in plasma ACTH and corticosterone levels, almost equivalent to those of 100pmol/kg of rat corticotropin-releasing hormone (rCRH). Since an iv bolus injection of ET3 1000pmol/kg did not cause significant changes in the blood pressure of anesthetized rats or the locomotor activity of free moving rats, it seems unlikely that ET3 1000pmol/kg acted as a nonspecific stressor. When ET3 (10(-11) greater than 10(-7)M) was added to cultured anterior pituitary cells, neither direct stimulation of ACTH release nor potentiation of rCRH action was noted. Although it has been shown that ET3 administered systemically probably does not cross the brain-blood-barrier, circulating ET3 may reach the brain tissues through regions lacking the tight barrier, circumventricular structures. The next studies included pretreatment of antagonists or blockers of ACTH stimulating hormones to elucidate the mechanisms of ET3 induced ACTH release. The action of ET3 was virtually abolished by pretreatment of CRH-antagonist alpha helical CRH (150 micrograms/rat icv). But pretreatment of catecholamine-blocker alpha methyl-tyrosine (100mg/kg iv), arginine vasopressin-antagonist dP-thy(Me)AVP (50 micrograms/rat iv) and prostaglandin-blocker indomethacin (3mg/rat iv) did not inhibit the action of ET3. The results indicate that ET3 may play the role of a neuropeptide and that the stimulation of the CRH-neurons is mainly responsible for activation of ACTH and corticosterone release.     

Effectiveness of a nonselective ET(A/B) and a selective ET(A) antagonist in rats with monocrotaline-induced pulmonary hypertension

BACKGROUND: Both nonselective ET(A/B) receptor and selective ET(A) receptor antagonists can reduce pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) in various animal models. Depending on their net effects after blockade of endothelial and smooth muscle ET(B) receptors, nonselective ET(A/B) antagonists could be more or less effective than selective ET(A) antagonists. METHODS AND RESULTS: Two weeks after injection of saline or 60 mg/kg monocrotaline (MCT), rats received 50 mg x kg(-1) x d(-1) of a selective (LU135252) or nonselective (BSF420627) antagonist for 3 weeks. This resulted in 4 groups: control (n=15), MCT (n=60), MCT+ET(A) (n=39), and MCT+ET(A/B) (n=40). Five-week survival was 35% in the MCT group; this was increased to 56% in the MCT+ET(A) group (P:=0.10) and to 67% in the MCT+ET(A/B) group (P:=0.0015). Drug administration was stopped 48 hours before hemodynamic measurements to evaluate the chronic effects of therapy: PH in the MCT group (RV systolic pressure 87+/-1 mm Hg) was improved similarly in both MCT+ET(A) and MCT+ET(A/B) groups (72+/-3 and 70+/-3 mm Hg, respectively, P:<0.05). Severe RVH in the MCT group (RV/left ventricle+septum weight ratio 73+/-1%) was not affected by the selective antagonist (70+/-2%) but was reduced to 54+/-2% in the MCT+ET(A/B) group (P:<0.01). Pulmonary resistive properties, assessed from isolated lung pressure-flow relationships, were improved similarly in survivors from both treated groups. CONCLUSIONS: Both the nonselective ET(A/B) antagonist BSF420627 and the selective ET(A) antagonist LU135252 are effective in this model of PH. Similar direct comparative studies in other models of PH and with various dosage regimens are warranted to define the optimal pharmacological approach of PH when ET receptor antagonists are used.     

Effects of sibutramine on body weight and serum lipids: a double-blind, randomized, placebo-controlled study in 322 overweight and obese patients with dyslipidemia

BACKGROUND: Cardiovascular risk factors associated with obesity, including dyslipidemia, can be improved by weight loss. The main dyslipidemia associated with obesity is elevated serum triglyceride and decreased serum high-density lipoprotein cholesterol (HDL-C) levels. METHODS: A total of 322 obese patients (body mass index > or = 27) with serum triglyceride levels > or = 250 mg/dL and < or = 1000 mg/dL and serum HDL-C levels < or = 45 mg/dL (women) and < or = 40 mg/dL (men) were placed on a step I American Heart Association diet and subsequently randomized to sibutramine 20 mg (n = 162) or placebo (n = 160) once daily for 24 weeks. RESULTS: Patients taking sibutramine had significantly greater mean weight loss than those receiving placebo (-4.9 kg vs -0.6 kg, P < or = .05). Forty-two percent of the sibutramine group lost > or = 5% of baseline weight and 12% lost > or = 10% compared with 8% and 3%, respectively, of the placebo group (P < or = .05). Mean decreases in serum triglyceride levels among 5% and 10% weight-loss responders in the sibutramine group were 33.4 mg/dL and 72.3 mg/dL, respectively, compared with an increase of 31.7 mg/dL among all patients receiving placebo (P < or = .05). Mean increases in serum HDL-C levels for 5% and 10% weight-loss responders in the sibutramine group were 4.9 mg/dL and 6.7 mg/dL, respectively, compared with an increase of 1.7 mg/dL among all patients in the placebo group (P < or = .05). Adverse events and discontinuation rates were similar in the sibutramine and placebo groups, although sibutramine-treated patients had mean increases in systolic and diastolic blood pressure of 2 to 3 mm Hg relative to placebo. CONCLUSIONS: In overweight and obese patients with high serum triglyceride levels and low serum HDL-C levels, treatment with sibutramine was associated with significant improvements in body weight and in serum triglyceride and HDL-C levels.     

Effect of an ET(B)-selective and a mixed ET(A/B) endothelin receptor antagonist on venomotor tone in deoxycorticosterone-salt hypertension

OBJECTIVES: Because the ET(B) receptor is important in venoconstriction, we examined the effects of a selective ET(B) receptor antagonist (A-1 92621) and a mixed ET(A/B) receptor antagonist (A-182086) on endogenous endothelin-1 (ET-1) contributions to elevated venomotor tone in deoxycorticosterone acetate-salt (DOCA-salt) hypertension. METHODS: Changes in venomotor tone were assessed using repeated measurements of mean circulatory filling pressure (MCFP) in awake, uninephrectomized, DOCA-salt-treated rats and uninephrectomized sham rats following intravenous (i.v.) injections of the ET(B) antagonist (12 mg/kg i.v.) or the ET(A/B) antagonist (12 mg/kg i.v.) alone, or 1 h before ganglion blockade with hexamethonium (30 mg/kg i.v.). RESULTS: DOCA-salt rats were hypertensive and exhibited higher MCFP than sham normotensive rats. The ET(A/B) receptor antagonist lowered mean arterial blood pressure (MABP) in DOCA-salt and sham rats, but MCFP fell in DOCA-salt rats only. The ET(B) antagonist produced no changes in MCFP while MABP increased in both groups. Pre-treatment of DOCA-salt rats, but not sham rats, with either antagonist produced greater declines in MCFP following hexamethonium than after hexamethonium alone. CONCLUSIONS: The present study confirms previous findings of elevated MCFP in DOCA-salt hypertensive rats compared to normotensive rats, but is the first to show that venomotor tone is affected by the actions of endogenous ET-1 acting at ET(B) receptors to modulate sympathetic input to the veins, as well as direct actions of ET-1 on vascular smooth muscle (VSM) ET(A) receptors. We also showed that mixed ET(A/B) receptor antagonism was effective in lowering MCFP and MABP in DOCA-salt hypertensive rats.     

Inhibitory effects of RRR-alpha-tocopheryl succinate on benzo(a)pyrene (B(a)P)-induced forestomach carcinogenesis in female mice

AIM: To study the inhibitory effects of VES (RRR-alpha-tocopheryl Succinate, VES),a derivative of natural Vitamin E, on benzo(a)pyrene(B(a)P)-induced forestomach tumor in female mice. METHODS: The model of B(a)P-induced forestomach tumor was established according to the methods of Wattenberg with slight modify-cations.One hundred and eighty female mice (6 weeks old) were divided into six groups equally; negative control (Succinic acid), vehicle control (Succinate+B(a)P),positive control(B(a)P), high VES(2.5 g/kg.b.w+B(a)P), low VES(1.25 g/kg.b.w+B(a)P)ig as well as VES by ip (20 mg/kg.b.w+B(a)P). Except the negative control group, the mice were administrated with B(a)P ig. and corresponding treatments for 4 weeks to study the anti-carcinogenetic effect of VES during the initiation period. The experiment lasted 29 weeks, in which the inhibitory effects of VES both on tumor incidence and tumor size were tested. RESULTS: The models of B(a)P-induced forestomach tumor in female mice were established successfully. Some were cauliflower-like, others looked like papilla, even a few were formed into the ulcer cavities.VES at 1.25 g/kg.b.w, 2.5 g/kg.b.w. by ig and 20 mg/kg.b.w. via ip could decrease the number of tumors per mouse (1.7 plus minus 0.41, 1.6 plus minus 0.34 and 1.1 +/- 0.43), being lower than that of B(a)P group (5.4 +/- 0.32, P<0.05). The tumor incidence was inhibited by 18.2%, 23.1% and 50.0%. VES at 1.25 g/kg.b.w., 2.5 g/kg.b.w. by ig and 20 mg/kg.b.w. via ip reduced the total volume of tumors per mouse (54.8 +/- 8.84, 28.4 8 +/- 8.32 and 23.9 8 +/- 16.05), being significantly lower than that of B(a)P group (150.2 8 +/- 20.93, P < 0.01). The inhibitory rates were 63.5%, 81.1% and 84.1%, respectively. CONCLUSION: VES has inhibitory effects on B(a)P-induced forestomach carcinogenesis in female mice, especially by ip and it may be a potential anti-cancer agent in vivo.     

Endotoxin treatment causes an upregulation of the endothelin system in the liver: amelioration of increased portal resistance by endothelin receptor antagonism

BACKGROUND: Mechanisms underlying hepatic microcirculatory failure during endotoxemia are incompletely understood. Because endothelin-1 (ET-1) has been implicated in endotoxin-induced liver injury, we investigated the hepatic ET-1 system in endotoxin-treated rats. METHODS: Rats were treated with endotoxin (Escherichia coli lipopolysaccharide; 3 mg/kg, i.p.), and various determinations were made 24 h later. RESULTS: Endotoxin treatment caused 11.2 +/- 1.6% weight loss, a decrease in mean arterial pressure (MAP; 96 +/- 5 mmHg vs 108 +/- 3 mmHg; P < 0.05) and an increase in portal pressure (11.6 +/- 1.3 mmHg vs 7.4 +/- 1 mmHg; P < 0.02). No significant changes in the serum levels of liver enzymes or hepatocellular necrosis were observed. Endotoxin caused increases in hepatic ET-1 (from 345 +/- 31 to 565 +/- 38 pg/g; P < 0.01), ET-1 receptor density (from 179 +/- 16 to 340 +/- 26 fmol/mg; P < 0.02), and mRNA expression of preproendothelin-1, and ET(A) and ET(B) receptors. While the serum nitric oxide (nitrite +/- nitrate) concentration was increased in endotoxin-treated rats, that of ET-1 remained unchanged. A mixed ET(A)/ET(B) receptor antagonist, TAK-044 (10 mg/kg, i.v.), reduced the weight loss from 11.2 +/- 1.6% to 5.9 +/- 2.9% (P < 0.05) and the portal pressure from 11.6 +/- 1.3 mmHg to 8.6 +/- 0.7 mmHg (P < 0.05) in endotoxin-treated rats. The mixed ET(A)/ET(B) receptor antagonist also caused an increase in serum ET-1 concentration, but did not affect serum nitric oxide and MAP in endotoxin-treated rats. CONCLUSIONS: These results suggest that the upregulated hepatic ET-1 system is an important mechanism of increased portal resistance and related complications of endotoxemia.     

Influence of glucose, alcohol and glycerol on galactose tolerance in man

Six volunteers were given 0.5 g galactose/kg body weight alone (A) or with 0.5 g glucose/kg (B) or with 0.5 g glycerol/kg body weight (C). Meals A and B were also given 15 min after ingestion of 300 mg ethanol/kg body weight. Glycerol did not influence the serum galactose response to galactose. Glucose reduced the serum galactose response as was expected. Administration of alcohol prior to a galactose test meal increased the mean area under the serum galactose response curve (p less than 0.01); when glucose was given with galactose after alcohol ingestion, the serum galactose response was significantly reduced (p less than 0.01) when compared to the serum galactose response to galactose after alcohol, but remained higher than after the galactose and glucose test meal. Glucose, therefore, can reduce the effect of alcohol on galactose levels but alcohol can abolish the effect of glucose on galactose metabolism.     

Renal endothelin ET(A)/ET(B) receptor imbalance differentiates salt-sensitive from salt-resistant spontaneous hypertension

It is unclear why a subgroup of patients with essential hypertension develop salt-sensitive hypertension with progression of target organ damage over time. We evaluated the role of the renal endothelin (ET) system in the stroke-prone spontaneously hypertensive rat (SHRSP) model of salt-sensitive spontaneous hypertension (SS-SH) compared with the spontaneously hypertensive rat (SHR) model of salt-resistant spontaneous hypertension (SR-SH). Both strains were studied after either sham-operation on a normal diet (Sham) or after unilateral nephrectomy and high NaCl loading (NX-NaCl) with 4% NaCl in diet for 6 weeks (n=10, respectively). Systolic blood pressure (SBP) increased only in SHRSP-NX-NaCl compared with SHRSP-Sham (250+/-6 versus 172+/-5 mm Hg, P:<0.0001). SBP remained unchanged in SHR-NX-NaCl compared with SHR-Sham. In SHRSP-NX-NaCl animals, urinary albumin and ET-1 excretion, renal ET-1 mRNA expression, glomerulosclerosis index, and tubulointerstitial damage index were elevated compared with SHRSP-Sham (P:<0.05, respectively), whereas no significant changes were found in SHR after NX-NaCl. Urinary sodium excretion (U(Na(+))) was significantly reduced by 38% in SHRSP-NX-NaCl compared with SHR-NX-NaCl (P:<0.005, respectively). SHR animals showed a similar increase in both renal ET(A) and ET(B) receptor densities after NX-NaCl (2.2-fold, P:<0.05). In contrast, SHRSP-NX-NaCl developed a significantly more pronounced increase in ET(A) compared with ET(B) binding (4.7-fold versus 2.4-fold, P:<0.05, compared with SHRSP-Sham, respectively), resulting in a significant 2.1-fold increase in ET(A)/ET(B) receptor ratio only in the SHRSP-NX-NaCl (P:<0.05). Thus, activation of the renal ET system together with an increased ET(A)/ET(B) receptor ratio may contribute to the development and progression of SS-SH.     

Myocardial protective effects of lidoflazine during ischemia and reperfusion

The myocardial protective effect of intravenous (i.v.) lidoflazine with potassium cardioplegia and hypothermia (28 degrees C) was investigated in 21 greyhounds. Animals were injected a single dose of cardioplegia (30 ml/kg body weight) and subjected to 120 minutes of ischaemia and 60 minutes of reperfusion. Ten dogs served as controls (Group C) and 11 dogs received i.v. lidoflazine (1.25 mg/kg b.w.) (Group L). Myocardial drill biopsies for the adenosine triphosphate (ATP) and the creatine phosphate (CP) levels were obtained. Hemodynamic measurements were made at intervals. In Group C, no dog could be weaned from bypass, whereas all 11 dogs in Group L came off bypass and maintained their circulation for 15 minutes. After a 120 minute ischemic period, the ATP and CP contents diminished significantly in both groups. Following reperfusion, the ATP level was 28% of the control level in Group C (p less than 0.005) and 38% in Group L (p less than 0.01). The CP levels showed an overshoot in both groups. There was no significant difference between the groups. In Group L animals, cardiac output (CO) and mean aortic pressure (MAP) were significantly reduced after bypass; from 5 +/- 1/min to 3.2 +/- 1, from 156 +/- 26 mmHg to 82 +/- 11 mmHg respectively (p less than 0.005). Left ventricular minute work (LVMW) also deteriorated markedly from 9.7 +/- 2 kg-m to 3.2 +/- 1 (p less than 0.005). The use of lidoflazine achieved considerable protection in terms of survival, but did not prevent the severe loss of high-energy phosphates in this experimental model.     

Heterozygous knock-Out of ET(B) receptors induces BQ-123-sensitive hypertension in the mouse

Homozygous knock-out of ET(A) or ET(B) receptor genes results in lethal developmental phenotypes in the mouse. Such deleterious phenotypes do not occur in heterozygous littermates. However, it remains to be determined whether mice partially defective in ET(A) or ET(B) receptors display significant alterations in their responses to exogenous or endogenous endothelin-1 (ET-1). Furthermore, the anesthetized ET(B) (+/-) knock-out mice showed a significantly higher mean arterial blood pressure than the ET(A) (+/-) knock-out or their wild-type littermates. The pressor response to ET-1 but not to a selective ET(B) agonist, IRL-1620, was significantly reduced in the ET(A) (+/-) knock-out mice. In ET(B) (+/-) knock-out mice, the pressor effect of IRL-1620 was more markedly altered than those induced by ET-1. In wild-type mice, both ET(A) and ET(B) receptors were found to be involved in the pressor effect of ET-1, as confirmed by the significant and specific antagonism induced by either BQ-123 (ET(A) antagonist) or BQ-788 (ET(B) antagonist). Also, ET(A)-selective or mixed ET(A)/ET(B)- but not ET(B)-selective antagonists reversed the hypertensive state of the ET(B) (+/-) knock-out mice to the level of wild-type littermates. Finally, radiolabeled ET-1 plasmatic clearance was altered in ET(B) (+/-) but not ET(A) (+/-) knock-out mice when compared with wild-type animals. Thus, heterozygous knock-out of ET(B) receptors results in a hypertensive state, suggesting an important physiological role for that particular receptorial entity in opposing the endogenous ET-1-dependent pressor effects in the mouse.     

Etoposide (VP-16) plus G-CSF mobilizes different dendritic cell subsets than does G-CSF alone

Dendritic cells (DCs) are antigen-presenting cells that are critical to the generation of immunologic tumor responses. Myeloid DCs (DC1) express myeloid antigen CD11c; lymphoid DCs (DC2) express CD123(+) and are CD11c(-). Analysis of DC subsets from peripheral blood progenitor cells (PBPC) collected from normal donors mobilized with G-CSF shows a predominance of DC2 cells. Whether PBPCs mobilization by chemotherapy yields different subsets of DCs has not been studied. We analyzed DC subsets in apheresis products from 44 patients undergoing autologous stem cell transplantation from 6/00 to 5/01. Patients received either G-CSF alone (10 microg/kg per day, n=11) or etoposide (2 g/m(2)) plus G-CSF (n=33) for progenitor cell mobilization. The patients were apheresed for 2-10 days (median 3) to reach a minimum of 2.0 x 10(6) CD34(+) cells/kg. Patients receiving G-CSF alone mobilized significantly more total DC2s than did those receiving etoposide plus G-CSF (median 6.2 x 10(6)/kg vs 2.9 x 10(6)/kg, P=0.001). The DC2/DC1 ratio was also significantly different in the two groups, with the G-CSF group having a higher ratio (median 1.2 vs 0.4, P<0.001). We conclude that the combination of chemotherapy plus G-CSF yields different mobilized dendritic cell subsets than does G-CSF alone.     

Dose-dependent inhibition by cyclosporine A of the induction of pancreatic ornithine decarboxylase (ODC) in rats

The effect of cyclosporine A (CsA) and alpha-difluoromethylornithine (DFMO) on the camostate-induced increase in pancreatic ornithine decarboxylase (ODC) activity and polyamine biosynthesis has been studied in vivo. Six hours after application of the synthetic trypsin inhibitor camostate (200 mg/kg b wt orally) pancreatic ODC activity increased about 140-fold and putrescine concentration about ninefold. CsA inhibited the elevation of both parameters in a dose-dependent manner. CsA pretreatment for 3 d with doses of 7.5, 10.0, and 12.5 mg/kg b wt orally once a day and consecutive CsA blood levels 24 h after the last CsA application of 751 +/- 62, 968 +/- 70, and 1,395 +/- 79 ng/mL, respectively, resulted in a complete inhibition of the camostate-stimulated increase in pancreatic ODC activity and putrescine concentration in vivo. DFMO (2% in drinking water and additionally 300 mg/kg b wt intraperitoneally at 8 AM, 12 noon, and 4 PM) inhibited the increase in both, ODC activity, and putrescine, significantly in an equipotent degree as 2.5 mg CsA/kg b wt, whereas higher doses of CsA proved to be more effective than DFMO in the chosen subtoxic dose. In all cases, no significant changes in pancreatic spermidine and spermine concentration, DNA and protein content, or pancreatic and body weight were observed. It is concluded that CsA in doses used for immunosuppression in clinical practice is a very potent and more effective inhibitor of ODC activity and polyamine synthesis in vivo than DFMO. This ODC inhibitory effect of CsA is a further detail to elucidate the up to now incompletely understood mechanisms of action of this immunosuppressive agent.     

Antioxidant and diuretic activity of co-administration of Capparis spinosa honey and propolis in comparison to furosemide

Objective: To study the antioxidant properties of Capparis spinosa(C.spinosa) honey and propolis and the effect of combined honey and propolis administration on urine volume and electrolytes in rats.Methods: C.spinosa honey [1 000 mg/kg body weight(b.wt)], propolis(100 mg/kg b.wt), honey/propolis mixture(C.spinosa honey 1 000 mg/kg b.wt/propolis extract 100 mg/kg b.wt), distilled water(1 mL/kg b.wt) and furosemide(10 mg/kg b.wt) were orally administered to fi ve groups of rats for 21 d.Urine volume, blood and urine sodium,potassium and chloride were measured.The antioxidant activity of propolis and honey was assessed and their total phenols and flavonoids were determined.Results: Propolis and C.spinosa honey contain polyphenols including flavonoids and propolis demonstrated higher antioxidant activities than honey.Honey significantly increased urine volume and urine electrolyte excretion.Propolis had no significant effect on urine volume, but co-administration of propolis and honey caused significant diuresis.No major changes were observed in plasma electrolytes with the use of honey, propolis or their combination.Conclusions: Honey and propolis have antioxidant activity and contain polyphenols including flavonoids that are more pronounced in propolis.Honey has a significant diuretic activity alone or in combination with propolis.This is the first study comparing the diuretic effect of co-administration of propolis and C.spinosa honey with furosemide.     

Achillea fragrantissima,rich in flavonoids and tannins,potentiates the activity of diminazine aceturate against Trypanosoma evansi in rats

Objective:To evaluate activity of methanol extract of Achillea fragrantissima(meth)(A.fragrantissima) alone or in combination with diminazine aceturate(DA) against Trypanosoma evansi in experimentally infected rats.Methods:Sixty adult male Wister albino rats were divided equally into 6 groups(A-F).Rats in groups A-E were experimentally infected with T.evansi and those in group F were uninfected.The groups were treated respectively as follows:group A- with 3.5 mg/kg DA;group B- with 1 000 mg/kg meth,A.fragrantissima;group C-3.5mg/kg DA plus 500 mg/kg meth A.fragrantissima;group D-3.5 mg/kg DA plus 1 000 mg/kg meth A.fragrantissima.Group E was left untreated.Parasitaemia,survivability,packed cell volume,hemoglobin concentration,total leucocytes count,lymphocyte count,and serum malondialdehyde and reduced glutathione(GSH) levels were estimated.Phytochemical screening of meth A.fragrantissima was also performed.Results:The phytochemical analysis of the meth A.fragrantissima indicated a higher content from polyphenols tannins and non tannins and flavonoids.The efficacy percentage against trypanosomiasis in groups A to E was respectively as follows 80,40,90.100,0.The administration of meth-A.fragrantissima(1000)mg/kg b.wt.) produced a moderate efficacy against trypanosomiasis.Untreated rats in group E died between 25 and 30 d post infection.The rats given DA and meth A.fragrantissima combinations(C and D) showed faster and higher recovery rates than the uninfected control and groups A and B.The initial reduction in packed cell volume,hemoglobin,total leucocytes count,increases in serum malondialdehyde and decreases in GSH levels were reversed by the treatments.C onclusions:The administration of the methanol extracts of A.fragrantissima and DA combination therapy was more effective than each product alone in the treatment of rats infected with Trypanosoma evansi and further studies are required to isolate more active ingredients.     

Plasma amino acid concentrations in normal adults ingesting aspartame and monosodium L-glutamate as part of a soup/beverage meal

We tested the hypothesis that ingestion of monosodium L-glutamate with aspartame produces a marked increase in plasma glutamate and aspartate concentrations. Twelve normal adults (6 males, 6 females) ingested three different soup/beverage meals in a balanced Latin square design. One meal (A) provided no aspartame (APM) or monosodium L-glutamate (MSG); a second (B) provided 50 mg MSG/kg body weight; while the third (C) provided 50 mg MSG and 34 mg APM per kg body weight. Plasma glutamate (Glu) concentrations were not significantly affected by meal A but increased significantly after meals B and C (no significant difference between B and C). Plasma aspartate (Asp) concentrations were not significantly affected by meal A but increased significantly after meals B and C (values significantly higher after meal C than meal B). Plasma Glu + Asp concentrations were not significantly affected by meal A but increased significantly from a mean (+/- SD) baseline value of 5.64 +/- 2.62 mumol/dL to high mean values of 23.1 +/- 7.29 and 26.8 +/- 9.74 mumol/dL after ingestion of meals B and C, respectively (no significant difference between meals B and C). Similarly, the area under the plasma Glu + Asp concentration-time curve did not differ significantly between meals B and C (624 +/- 197 v 763 +/- 277 mumol/dL x min, respectively). Peak plasma Glu + Asp concentrations for each subject (ignoring time) were also examined. The mean peak plasma Glu + Asp concentrations were 7.39 +/- 2.77, 23.0 +/- 6.61, and 27.3 +/- 9.07 mumol/dL, respectively after meals A, B, and C.     

Management of type IV hyperlipoproteinemia. Evaluation of practical clinical approaches.

A lipid intervention clinic screened 4000 employees (89% participation) and identified 150 type IV subjects (top 5 percentile triglyceride values, 100% initial participation, 6% drop out). The 150 healthy type IV subjects, ages 20 to 49, were randomly divided into treatment subgroups: A, treatment by clinic nutritionist and physician with the National Heart and Lung Institute's type IV diet for 6 weeks, then diet plus clofibrate for 18 weeks; B, same treatment by private physician; C, no intervention for 24 weeks, subjects advised of abnormality. The group A mean fasting serum triglyceride of 407 mg/dl declined 50% at 6 weeks, 61% at 12 weeks, and was unchanged at 24 weeks (P less than 0.0005 at 6, 12, 24 weeks). Group B triglyceride decreased 42%, 50%, 41% (P less than 0.0005 at 6, 12, 24 weeks). Group C triglyceride declined 20%, 1st to 24th week. Body weight decreased 8% (A) and 4% (B) at 6 weeks (P less than 0.0005) and was unchanged at 24 weeks. The maximum cholesterol decrease (A) was 11% (P less than 0.0005). Type IV hyperlipoproteinemia can readily be identified in a working population; treatment by clinic or private physician will markedly lower fasting serum triglyceride values in apparently healthy type IV subjects for at least 24 weeks.     

Effects of carbohydrate-containing and carbohydrate-restricted hypocaloric and eucaloric diets on serum concentrations of retinol-binding protein, thyroxine-binding prealbumin and transferrin

The effects of diet on the serum concentrations of albumin, transferrin, thyroxine-binding prealbumin (TBPA) and retinol-binding protein (RBP) were studied in 3 groups of obese subjects (Groups I-III) and 1 group of normal weight subjects (Group IV). Group I subjects ate either a 830 kcal carbohydrate-containing diet (CCD) or carbohydrate-restricted diet (CRD), Group II and III subjects ate a hypocaloric CRD. Subjects in Group IV ate a eucaloric CRD. Serum albumin concentrations did not change in any of the 4 groups. Only the subjects in Group II had a statistically significant decrease in serum transferrin concentration 6 wk after starting the hypocaloric, CRD. Group I individuals eating the CRD and the subjects in Groups II, III and IV had significant decreases in the serum concentrations of TBPA and RBP after 1 wk which persisted without further change during the remaining 3-5 wk of the diets. Group I subjects eating the CCD had a significant decrease in TBPA concentration at 1 and 6 wk. The RBP serum concentration was significantly decreased after 1 wk on the diet, but was not significantly different from the control diet period at 6 wk. The magnitude of the decreases in serum concentrations of TBPA and RBP in the Group I subjects eating the CRD were significantly greater than in the Group I subjects eating the CCD. Thus, ingestion of a hypocaloric, CRD by obese individuals results in decreased serum concentrations of TBPA and RBP. Isocaloric substitution of carbohydrate for fat reduces this effect. Dietary carbohydrate apparently modulates the serum concentrations of TBPA and RBP, independently of caloric intake, since ingestion of a eucaloric CRD by normal weight individuals also decreased the serum concentration of the two visceral proteins.     

Role of NF-κB and cytokine in experimental cancer cachexia

AIM: To assess the putative involvement of NF-κB and pronflammatory cytokines in the pathogenesis of cancer cachexia and the therapeutic efficacy of indomethadn (IND)on cachexia. METHODS: Thirty young male BABL/c mice were divided randomly into five groups: (a) control, (b) tumor-bearingplus saline, (c) tumor-bearing plus IND (0.25 mg.kg-1), (d)tumor-bearing plus IND (0.5 mg.kg-1), and (e) tumor-bearingplus IND (2 mg.kg-1). Colon 26 adenocarcinoma cells of murine were inoculated subcutaneously to induce cachexia. Saline and IND were given intraperitoneally daily for 7 days from the onset of cachexia to sacrifice. Food intake and body composition were documented, serum levels of TNF-α and IL-6 and activity of NF-κB in the spleen wereinvestigated in all animals .RESULTS: Weight loss was observed in all tumor-bearingmice. By day 16, body weights of non-tumor mice were about 72 % of healthy controls (P&lt;0.01), and the weight of gastrocnemius was decreased by 28.7 % (P&lt;0.01). No difference was found between groups in food intake (P&gt;0.05). Gastrocnemius weight was increased markedly (P&lt;0.01) after treatment of IND (0.5 mg.kg-1), while the non-tumor body weights were not significantly elevated. Tumor-bearing caused a 2-3 fold increase in serum levels of both TNF-α and IL-6 (P&lt;0.01). The concentration of TNF-α (P&lt;0.05)and IL-6 (P&lt;0.01) in tumor-bearing mice was reduced after administration of 0.5 mg.kg-1 IND for 7 days. But the level of IL-6 was slightly elevated following treatment of IND 2.0mg-kg-1. NF-κB activation in the spleen was increased in tumor-bearing mice in comparison with controls in electrophoretic mobility shift assay (EMSA). NF-κB activity was reduced in mice treated with 0.5 mg.kg-2 of IND, whereas a hiaher NF-κB activity was observed in mice treated with 2.0 mg,kg-1 of IND . CONCLUSION: Colon 26 adenocarcinoma cells can induce severe cancer cachexia experimentally, and the mechanism may be partially due to the enhanced TNF-α and IL-6 in tumor-bearing animals, which is controlled by NF-κB, Low dose of indomethacin alleviates the cachexia,decreases the activation of NF-κB and the serum levelsof TNF-α and IL-6, and prevents body weight loss andmuscle atrophy, while no further effect is gained by ahigher dosage,