Effect of rosiglitazone in sodium arsenite-induced experimental vascular endothelial dysfunction

The present study has been designed to investigate the effect of rosiglitazone, a peroxisome proliferator activated receptor γ agonist in sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. The rats were administered sodium arsenite (1.5 mg/kg/day, i.p., 2 weeks) to induce VED. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum nitrite/nitrate concentration. Further, the integrity of the aortic endothelium was assessed histologically using haematoxylin-eosin staining. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances, aortic reactive oxygen species and reduced form of glutathione. The administration of sodium arsenite produced VED by impairing acetylcholine-induced endothelium dependent relaxation, diminishing the integrity of vascular endothelium and decreasing the serum nitrite/nitrate concentration. In addition, sodium arsenite was noted to produce oxidative stress as it increased serum thiobarbituric acid reactive substances and aortic reactive oxygen species and consequently decreased glutathione. Treatment with rosiglitazone (3 mg/kg/day, p.o., 2 weeks and 5 mg/kg/day, p.o., 2 weeks) significantly prevented sodium arsenite-induced VED by enhancing acetylcholine-induced endothelium dependent relaxation, improving the integrity of vascular endothelium, increasing the nitrite/nitrate concentration and decreasing the oxidative stress. However, the vascular protective effect of rosiglitazone was markedly abolished by co-administration of nitric oxide synthase inhibitor, N-Omega-Nitro-L-Arginine Methyl Ester (L-NAME) (25 mg/kg/day, i.p., 2 weeks). Thus, it may be concluded that rosiglitazone reduces oxidative stress, activates eNOS and enhances the generation of nitric oxide to prevent sodium arsenite-induced VED in rats.     

Dietary intake of organophosphorus pesticide residues through vegetables from Kumasi, Ghana

Contamination and health risk hazards of organophosphorus pesticides residues in vegetables were studied. Ethyl-chlorpyrifos, observed at an average level of 0.211 ± 0.010 mg kg⁻¹ in 42% of tomato, 0.096 ± 0.035 mg kg⁻¹ in 10% of eggplant and 0.021 ± 0.013 mg kg⁻¹ in 16% of pepper was below the 0.5 mg kg⁻¹ MRL. Dichlorvos was the most frequently detected residue in all the samples analyzed. Levels of malathion in tomatoes (0.120 ± 0.101 mg kg⁻¹) and pepper (0.143 ± 0.042 mg kg⁻¹) exceeded the MRL of 0.1 mg kg⁻¹. Health risks were found to be associated with methyl-chlorpyrifos, ethyl-chlorpyrifos, and omethioate in tomatoes and methyl-chlorpyrifos, ethyl-chlorpyrifos, dichlorvos, monocrotophos and omethioate in eggplant. Routine monitoring of these pollutants in food items is required to prevent, control and reduce the pollution and to minimize health risks.     

Chronic nicotine treatment enhances vascular smooth muscle relaxation in rats

Aim:

To investigate the effect of chronic nicotine treatment on vascular function and to identify the underlying mechanisms.

Methods:

Adult rats were treated with nicotine (3 mg·kg⁻¹·d⁻¹, sc) for 6 weeks. After the rats were sacrificed, aortic rings were prepared for detecting vascular reactivity, and thoracic aorta and periaortic fat samples were collected for histological and molecular biology studies.

Results:

Chronic nicotine treatment significantly reduced periaortic fat, and specifically enhanced smooth muscle relaxation without altering the aortic adventitial fat and endothelium function. Pretreatment with the soluble guanylyl cyclase inhibitor ODQ (3 μmol/L) or PKG inhibitor Rp-8-Br-PET-cGMP (30 μmol/L) abolished the nicotine-induced enhancement of smooth muscle relaxation, whereas the cGMP analogue 8-Br-cGMP could mimic the nicotine-induced enhancement of smooth muscle relaxation. However, the chronic nicotine treatment did not alter PKG protein expression and activity in aortic media.

Conclusion:

Chronic nicotine treatment enhances vascular smooth muscle relaxation of rats via activation of PKG pathway.     

Effect of bis(maltolato) oxovanadium on experimental vascular endothelial dysfunction

The study has been designed to investigate the effect of bis(maltolato) oxovanadium (BMOV), a protein tyrosine phosphatase inhibitor, on hypercholesterolemia and hypertension-induced vascular endothelial dysfunction. High fat diet (8 weeks) and deoxycorticosterone acetate (DOCA; 40 mg kg⁻¹, s.c.) were administered to rats to produce hypercholesterolemia and hypertension (mean arterial blood pressure >120 mmHg) respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) were estimated to assess oxidative stress. BMOV (0.2 mg/ml in drinking water) or atorvastatin (30 mg kg⁻¹, p.o.) markedly improved acetylcholine-evoked endothelium-dependent relaxation, lining of vascular endothelium, serum nitrite/nitrate concentration, and serum TBARS in hypercholesterolemic and hypertensive rats. However, this ameliorative effect of BMOV has been prevented by L-NAME (25 mg kg⁻¹, i.p.), an inhibitor of NOS, or by glibenclamide (5 mg kg⁻¹, i.p.), a blocker of ATP-sensitive K⁺ channels. It may be concluded that BMOV-induced inhibition of PTPase may improve vascular endothelial dysfunction.     

Alginate oligosaccharide alleviates senile osteoporosis via the RANKL–RANK pathway in D-galactose-induced C57BL/6J mice

Osteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density (BMD) and bone quality and increased bone porosity, which increase the risk of bone fracture. Inflammation, one of the important mechanisms related to aging, is associated with osteoporosis. Treatment with anti-inflammatory agents is effective for alleviating senile osteoporosis. Alginate oligosaccharide (AOS) can prevent and treat diseases related to inflammation, oxidative stress, and immunity. This study evaluates the effect of AOS on osteoporosis and investigates the underlying mechanism. Osteoporosis model was induced by D-galactose (D-gal) (200 mg kg^?1 day^?1) for eight weeks. Three groups were administered via AOS (50, 100, and 150 mg kg^?1 day^?1) for four weeks, while a control group received sterile water (5 ml kg^?1 day^?1) for 8 weeks. The results showed that AOS improved bone density and bone microstructure in D-gal-induced osteoporosis mice. AOS inhibited osteoclast proliferation, probably through the suppression of receptor activator of nuclear factor-kappa B ligand (RANKL)-associated nuclear factor kappa B (NF-κB) and c-Fos signaling pathway. AOS also increased osteoprotegerin (OPG) expression and competitively inhibited the binding between RANK and RANKL in senile osteoporosis. Further, AOS decreased the secretion of serum osteocalcin and reduced bone conversion. Together, these results demonstrate the anti-osteoporosis activity of AOS in mice with osteoporosis.     

Influence of vitamin C on bisphenol A,nonylphenol and octylphenol induced oxidative damages in liver of male rats

The purpose of this study was to investigate whether bisphenol A (BPA), nonylphenol (NP) and octylphenol (OP) induce oxidative stress in the liver of male rats and co-administration of vitamin C can prevent any possible oxidative stress. Wistar male rats were divided into seven groups (vehicle, BPA, NP, OP, BPA + C, NP + C, OP + C). BPA, OP and NP groups (25 mg kg⁻¹ day⁻¹) were administered orally to rats three times a week for 50 days. In BPA + C, NP + C, OP + C groups, vitamin C (60 mg kg⁻¹ day⁻¹) was administered along with BPA, OP and NP (25 mg kg⁻¹ day⁻¹) treatments. Aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), thiobarbituric acid-reactive substances (TBARS) were increased, glutathione (GSH) levels were decreased in treatment groups. AST, ALT, LDH and TBARS levels were increased whereas GSH levels were decreased in BPA + C, NP + C and OP + C groups compared to BPA, NP, and OP groups, respectively. Hepatic necrosis and congestion were observed in livers of rats treated. In conclusion, the present results demonstrate that BPA, NP, and OP cause oxidative damage by disturbing the balance between ROS and antioxidant defenses system in liver of male rats. Vitamin C co-administration along with BPA, NP, OP aggravates the damage in liver of male rats.     

Embryo–fetal toxicity assessment of vonoprazan in rats and rabbits

Vonoprazan is a new potassium‐competitive acid blocker to treat acid‐related diseases. However, its safety during pregnancy is unclear. The aim of the study was to investigate the potential reproductive toxicity on the embryo–fetal development of vonoprazan. Vonoprazan acetate was administered by intravenous injection to pregnant rats (0, 2, 6 and 20 mg kg^–1 day^–1) and rabbits (0, 1.2, 3.6 and 12 mg kg^–1 day^–1) during the organogenetic period (gestation day 6–15 [rats] and 6–18 [rabbits]). Maternal reproductive endpoints were evaluated, together with effects on fetal growth and morphological development. In rats, no treatment‐related effects were found in the highest dose group (20 mg kg^–1) and the maternal plasma exposure was ≥50‐fold the expected clinical human exposure. However, in rabbits, dose‐related clinical signs (soft or liquid feces) occurred in the 12 mg kg^–1 group, which was regarded as a maternal toxicity. Besides, decreased maternal weight gain also was considered as a minimal maternal toxicity. At 12 mg kg^–1, delayed fetal ossification was found as evidence of embryo–fetal growth retardation, which was related to decreased fetal and placental weights. There was no maternal and developmental toxicity in the 1.2 and 3.6 mg kg^–1 groups. Thus, the no‐observed‐adverse‐effect levels of vonoprazan acetate in rabbits are considered 3.6 mg kg^–1 day^–1, which produced plasma exposure that was about 18‐fold human clinical exposure.     

Drug monitoring of quinine by HPLC in cerebral malaria with acute renal failure treated by haemofiltration

Summary The monitoring of quinine by HPLC in 3 patients suffering from cerebral malaria with acute renal failure and treated by haemofiltration is reported.The recommended dose of quinine in this situation is reduced to 10 to 15 mg·kg^–1·day^–1. However, in the first patient, when given quinine 10 mg kg^–1·day^–1 the plasma concentration was mainly below the recommended therapeutic range of 5 to 15 mg/l. In consequence, the dose of quinine in the second patient was elevated to quinine dihydrochloride 15.1 mg·kg^–1·day^–1 which produced plasma concentrations in the low therapeutic range. In the third patient, an unreduced dose of quinine dihydrochloride 25.7 mg·kg^–1·day^–1 was employed, resulting in plasma concentrations above 15 mg/l, which is generally assumed to be toxic, although, no sign of acute quinine toxicity was seen.The antimalarial effect in all three patients was satisfactory. Quinine was estimated in the haemofiltrate in two patients and was found to be below the limit of sensitivity (0.25 mg/l). Plasma quinine did not change during or shortly after haemofiltration.It is concluded that in case of acute renal failure in cerebral malaria the dose of quinine should be reduced, but that the common recommendation of 10 to 15 mg·kg^–1·day^–1 may be too low, and that haemofiltration has no marked influence on the total body clearance of quinine.     

Antidepressants but not antipsychotics have antiepileptogenic effects with limited effects on comorbid depressive-like behaviour in the WAG/Rij rat model of absence epilepsy

Background and Purpose

Two of the most relevant unmet needs in epilepsy are represented by the development of disease-modifying drugs able to affect epileptogenesis and/or the study of related neuropsychiatric comorbidities. No systematic study has investigated the effects of chronic treatment with antipsychotics or antidepressants on epileptogenesis. However, such drugs are known to influence seizure threshold.

Experimental Approach

We evaluated the effects of an early long-term treatment (ELTT; 17 weeks), started before seizure onset (P45), with fluoxetine (selective 5-HT-reuptake inhibitor), duloxetine (dual-acting 5-HT-noradrenaline reuptake inhibitor), haloperidol (typical antipsychotic drug), risperidone and quetiapine (atypical antipsychotic drugs) on the development of absence seizures and comorbid depressive-like behaviour in the WAG/Rij rat model. Furthermore, we studied the effects of these drugs on established absence seizures in adult (6-month-old) rats after a chronic 7 weeks treatment.

Key Results

ELTT with all antipsychotics did not affect the development of seizures, whereas, both ELTT haloperidol (1 mg·kg⁻¹ day⁻¹) and risperidone (0.5 mg·kg⁻¹ day⁻¹) increased immobility time in the forced swimming test and increased absence seizures only in adult rats (7 weeks treatment). In contrast, both fluoxetine (30 mg·kg⁻¹ day⁻¹) and duloxetine (10–30 mg·kg⁻¹ day⁻¹) exhibited clear antiepileptogenic effects. Duloxetine decreased and fluoxetine increased absence seizures in adult rats. Duloxetine did not affect immobility time; fluoxetine 30 mg·kg⁻¹ day⁻¹ reduced immobility time while at 10 mg·kg⁻¹ day⁻¹ an increase was observed.

Conclusions and Implications

In this animal model, antipsychotics had no antiepileptogenic effects and might worsen depressive-like comorbidity, while antidepressants have potential antiepileptogenic effects even though they have limited effects on comorbid depressive-like behaviour.     

Toxicokinetics of glyphosate and its metabolite aminomethyl phosphonic acid in rats

The toxicokinetics of glyphosate after single 100 mg kg⁻¹ intravenous (i.v.) and 400 mg kg⁻¹ oral doses were studied in rats. Serial blood samples were obtained after i.v. and oral administration. Plasma concentrations of glyphosate and its metabolite amiomethyl phosphonic acid (AMPA) were determined by HPLC method. After i.v. and oral administration, plasma concentration–time curves were best described by a two-compartment open model. For glyphosate, the elimination half-lives (T_1/2β) from plasma were 9.99 h after i.v. and 14.38 h after oral administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.995 l h⁻¹ kg⁻¹. After i.v. administration, the apparent volume of distribution in the second compartment (V₂) and volume of distribution at steady state (V_ss) were 2.39 and 2.99 l kg⁻¹, respectively, suggesting a considerable diffusion of the herbicide into tissues. After oral administration, glyphosate was partially and slowly absorbed with a T_max of 5.16 h. The oral bioavailability of glyphosate was found to be 23.21%. Glyphosate was converted to AMPA. The metabolite AMPA represented 6.49% of the parent drug plasma concentrations. The maximum plasma concentrations of glyphosate and AMPA were 4.62 and 0.416 μg ml⁻¹, respectively. The maximum plasma concentration of AMPA was achieved at 2.42 h. For AMPA, the elimination half-life (T_1/2β) was 15.08 h after oral administration of glyphosate parent compound.     

Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension

Background and Purpose

Toll-like receptor 4 (TLR4) signalling contributes to inflammatory cardiovascular diseases, but its role in hypertension and the associated vascular damage is not known. We investigated whether TLR4 activation contributed to angiotensin II (AngII)-induced hypertension and the associated vascular structural, mechanical and functional alterations.

Experimental Approach

AngII was infused (1.44 mg·kg⁻¹·day⁻¹, s.c.) for 2 weeks in C57BL6 mice, treated with a neutralizing anti-TLR4 antibody or IgG (1 μg·day⁻¹); systolic BP (SBP) and aortic cytokine levels were measured. Structural, mechanical and contractile properties of aortic and mesenteric arterial segments were measured with myography and histology. RT-PCR and Western blotting were used to analyse these tissues and cultured vascular smooth muscle cells (VSMC) from hypertensive rats (SHR).

Key Results

Aortic TLR4 mRNA levels were raised by AngII infusion. Anti-TLR4 antibody treatment of AngII-treated mice normalised: (i) increased SBP and TNF-α, IL-6 and CCL2 levels; (ii) vascular structural and mechanical changes; (iii) altered aortic phenylephrine- and ACh-induced responses; (iv) increased NOX-1 mRNA levels, superoxide anion production and NAD(P)H oxidase activity and effects of catalase, apocynin, ML-171 and Mito-TEMPO on vascular responses; and (v) reduced NO release and effects of L-NAME on phenylephrine-induced contraction. In VSMC, the MyD88 inhibitor ST-2825 reduced AngII-induced NAD(P)H oxidase activity. The TLR4 inhibitor CLI-095 reduced AngII-induced increased phospho-JNK1/2 and p65 NF-κB subunit nuclear protein expression.

Conclusions and Implications

TLR4 up-regulation by AngII contributed to the inflammation, endothelial dysfunction, vascular remodelling and stiffness associated with hypertension by mechanisms involving oxidative stress. MyD88-dependent activation and JNK/NF-κB signalling pathways participated in these alterations.     

T-type and L-type calcium channel blockers exert opposite effects on renin secretion and renin gene expression in conscious rats

1. This study aimed to investigate and to compare the effects of pharmacological T-type calcium channel and of L-type calcium channel blockade on the renin system. To this end, male healthy Sprague-Dawley rats were treated with the T-channel blocker mibefradil or with the L-channel blocker amlodipine at doses of 5 mg kg⁻¹, 15 mg kg⁻¹ and 45 mg kg⁻¹ per day for four days and their effects on plasma renin activity (PRA) and kidney renin mRNA levels were determined.
2. Whilst amlodipine lowered basal systolic blood pressure at 5 mg kg⁻¹, mibefradil had no effect on basal blood pressure in the whole dose range examined. Amlodipine dose-dependently induced up to 7 fold elevation of PRA and renin mRNA levels. Mibefradil significantly lowered PRA and renin mRNA levels at 5 mg kg⁻¹ and moderately increased both parameters at a dose of 45 mg kg⁻¹, when PRA and renin mRNA levels were increased by 100% and 30%, respectively. In primary cultures of renal juxtaglomerular cells neither amlodipine nor mibefradil (0.1–10 μM) changed renin secretion.
3. In rats unilateral renal artery clips (2K-1C) mibefradil and amlodipine at doses of 15 mg kg⁻¹ day⁻¹ were equally effective in lowering blood pressure. In contrast mibefradil (5 mg kg⁻¹ and 15 mg  kg⁻¹ day⁻¹) significantly attenuated the rise of PRA and renin mRNA levels, whilst amlodipine (15 mg kg⁻¹) additionally elevated the rise of PRA and renin mRNA levels in response to renal artery clipping.
4. These findings suggest that T-type calcium channel blockers can inhibit renin secretion and renin gene expression in vivo, whilst L-type calcium channel blockers act as stimulators of the renin system. Since the inhibitory effect of T-type antagonists is apparent in vivo but not in vitro, one may infer that the effect on the renin system is indirect rather than directly mediated at the level of renal juxtaglomerular cells.

     

Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats

Background and purpose:

The association between torcetrapib and its off-target effects on blood pressure suggested a possible class-specific effect. The effects of dalcetrapib (RO4607381/JTT-705) and torcetrapib on haemodynamics and the renin-angiotensin-aldosterone system (RAAS) were therefore assessed in a rat model.

Experimental approach:

Arterial pressure (AP) and heart rate were measured by telemetry in normotensive and spontaneously hypertensive rats (SHR) receiving torcetrapib 10, 40 or 80 mg·kg⁻¹·day⁻¹; dalcetrapib 100, 300 or 500 mg⁻¹·kg·day⁻¹; or vehicle (placebo) for 5 days. Expression of RAAS genes in adrenal gland, kidney, aorta and lung from normotensive rats following 5 days'' treatment with torcetrapib 40 mg·kg⁻¹·day⁻¹, dalcetrapib 500 mg·kg⁻¹·day⁻¹ or vehicle was measured by quantitative polymerase chain reaction.

Key results:

Torcetrapib transiently increased mean AP in normotensive rats (+3.7 ± 0.1 mmHg), whereas treatment in SHR resulted in a dose-dependent and sustained increase [+6.5 ± 0.6 mmHg with 40 mg·kg⁻¹·day⁻¹ at day 1 (P < 0.05 versus placebo)], which lasted over the treatment period. No changes in AP or heart rate were observed with dalcetrapib. Torcetrapib, but not dalcetrapib, increased RAAS-related mRNAs in adrenal glands and aortas.

Conclusions and implications:

In contrast to torcetrapib, dalcetrapib did not increase blood pressure or RAAS-related gene expression in rats, suggesting that the off-target effects of torcetrapib are not a common feature of all compounds acting on cholesteryl ester transfer protein.     

Long-term treatment with supraphysiological doses of nandrolone decanoate reduces the sensitivity of Bezold–Jarisch reflex control of heart rate and blood pressure

We investigated the influence of long-term treatment with supraphysiological doses of an anabolic-androgenic steroid on the Bezold–Jarisch reflex (BJR) control of heart rate (HR) and diastolic arterial pressure (DAP), and whether this treatment induced cardiac hypertrophy. Male rats were treated with nandrolone decanoate (ND) (10 mg kg⁻¹ body weight for 8 weeks; DECA) or vehicle (control animals; CON). After 8 weeks of treatment, the BJR was evaluated by bradycardia and hypotension responses that were elicited by serotonin administration (2–32 μg kg⁻¹). Mean arterial pressure (MAP) was assessed and cardiac hypertrophy was determined by the ratio of the left and right ventricle weight/body weight (LVW/BW and RVW/BW, respectively) and by histological analysis. Total body protein (TBP) content was also evaluated. Nandrolone decanoate treatment increased MAP (CON = 99 ± 1 mmHg; DECA = 109 ± 2 mmHg; p < 0.01) but did not change the mean basal HR (CON = 356 ± 13 bpm; DECA = 367 ± 11 bpm). The treatment also induced LV and RV hypertrophy (LVW/BW: CON = 1.86 ± 0.04 mg g⁻¹, DECA = 2.17 ± 0.04 mg g⁻¹, p < 0.01; RVW/BW: CON = 0.42 ± 0.02 mg g⁻¹, DECA = 0.53 ± 0.03 mg g⁻¹, p < 0.05) and reduced the number of myocyte nuclei/high-power field (CON = 23.0 ± 2; DECA = 9.4 ± 1.0; p < 0.01). ND treatment blunted the HR and DAP decreases induced by serotonin. ND determines an increase in the TBP content in DECA group (35 ± 3%; p < 0.01) compared with control animals (18 ± 1%). We conclude that 8 weeks of ND treatment induces anabolic effect, cardiac hypertrophy and an elevation of MAP. This treatment also reduces the sensitivity of the BJR control of bradycardia and blood pressure, possibly due to cardiac hypertrophy. The blunted BJR response could contribute to the MAP elevation in DECA animals.     

An updated weight of evidence approach for deriving a health‐based guidance value for 4‐nonylphenol

4‐Nonylphenol (NP) is a persistent estrogen‐active compound. Human exposure to NP is primarily through water and food. Although risk assessments of NP have been conducted by the European Union and a few other countries, only the Danish Veterinary and Food Administration, in 2000, proposed a tolerable daily intake of 0.005 mg kg^?1 body weight (bw) day^?1. New data have been accumulated since then, prompting an update on the risk assessment of NP. A weight of evidence approach is recommended for use in scientific assessments by several agencies, e.g., European Food Safety Authority, etc. Based on the results of a weight of evidence approach, two methods were used to derive the health‐based guidance value (HBGV) for NP in this study, namely a no observed adverse effects level/lowest observable adverse effect level method, and a benchmark dose method. Considering the considerable uncertainty of benchmark dose model fitting of the available data, a tolerable daily intake value of 0.025 mg kg^?1 bw day^?1 was derived as a provisional HBGV for NP based on the lowest observable adverse effect level value of 15 mg kg^?1 bw day^?1 of the renal toxicity in rats, together with the uncertainty factor of 600. However, the HBGV of NP still needs further investigation.     

虾青素对大鼠乙酸性胃溃疡的治疗作用

This study is to investigate therapeutic effect of astaxanthin on acetic acid-induced gastric ulcer in rats.  Rats were divided into control group, ulcer control group, and astaxanthin (5, 10, and 25 mg·kg^-1) groups at random, 8 rats in each group.  After administered for 10 days consecutively, all the rats were sacrificed.  The area of ulcer and the levels of MDA, SOD, CAT and GSH-Px in gastric mucosa were measured.  Compared with ulcer control group, in astaxanthin (5, 10, and 25 mg·kg^-1) groups, the area of ulcer was decreased significantly.  Level of MDA decreased while activities of SOD, CAT and GSH-Px increased (P < 0.05).  Astaxanthin has good therapeutic effect on acetic acid-induced gastric ulcer in rats.  Eliminating free radical and improving local blood circulation of the ulcer may be the mechanism of action.     

Influence of dietary salts on the cardiovascular effects of low-dose combination of ramipril and felodipine in spontaneously hypertensive rats

1. In spontaneously hypertensive rat (SHR) we examined over a 4-week period the influence of control low sodium diet, common salt-enriched diet (sodium chloride 6% of the dry weight of the chow) and a novel mineral salt-enriched diet (potassium-, magnesium-, and l-lysine-enriched mineral salt added at a 75% higher level of 10.5% to produce the same sodium chloride concentration of 6%) on the cardiovascular effects produced by a low-dose combination of an angiotensin converting enzyme inhibitor ramipril (0.25 mg kg⁻¹ day⁻¹ in the food) and a calcium channel blocker felodipine (0.4 mg kg⁻¹ day⁻¹ subcutaneously via an osmotic minipump).
2. Common salt, but not the mineral salt, accelerated the development of hypertension and induced left ventricular and renal hypertrophy in SHR. Neither common salt nor mineral salt significantly affected heart rate.
3. The combination of ramipril and felodipine decreased systolic blood pressure and prevented the development of left ventricular hypertrophy effectively during the common salt diet without any significant effect on the heart rate. The cardiovascular effects of the drug combination were improved by the low sodium diet or by replacement of high common salt in the diet by mineral salt.
4. Responses of endothelium-intact mesenteric arterial rings in vitro were examined at the end of the four-week study. The combination of ramipril and felodipine markedly improved the endothelium-dependent vascular relaxation responses to acetylcholine and enhanced the endothelium-independent vascular relaxation responses to sodium nitroprusside in SHR on control and common salt diets. Replacement of common salt in the diet by mineral salt improved the endothelium-dependent vascular relaxation responses to acetylcholine. The drug combination attenuated the α-adrenoceptor-mediated vascular contractile responses to noradrenaline during the common salt diet.
5. Ramipril and felodipine in combination increased plasma renin activity by 1.9–3.2 fold without affecting serum aldosterone levels.
6. Our findings suggest that the cardiovascular effect of the low-dose combination of ramipril and felodipine was maintained during high salt intake. However, salt restriction or replacement of common salt in the diet by the potassium- and magnesium-enriched mineral salt improved the cardiovascular effects of the drug combination. In the face of a high intake of sodium, a part of the beneficial cardiovascular effects of the drug combination is apparently mediated by improved endothelium-dependent and endothelium-independent vascular relaxation responses and attenuated α-adrenoceptor-mediated vascular contractile responses.

     

Determination of dysprosium in monkey serum by inductively-coupled plasma atomic emission spectrometry (ICP-AES) after the administration of Sprodiamide Injection, a new contrast medium for magnetic resonance imaging

Sprodiamide Injection (S-043 Injection, Nycomed Salutar; WIN 59080, Sterling Winthrop) is a magnetic susceptibility-based MRI contrast agent which contains 500 mM dysprosium diethylenetriaminepentaacetic acid bis(methylamide) (DyDTPA-BMA), and 25 mM caldiamide sodium (CaNaDTPA-BMA). A study was conducted to evaluate clearance of drug in cynomolgus monkeys. Eighteen cynomolgus monkeys, divided into three groups of six animals each, were administered Sprodiamide Injection intravenously at dose levels of 0.25, 0.5 and 2.5 mmol kg⁻¹ respectively. The concentration of dysprosium in serum was determined in a monkey serum—hydrochloric acid matrix by inductively-coupled plasma atomic emission spectrometry (ICP-AES). The ICP-AES method was demonstrated to be valid for sensitivity, precision, accuracy and specificity. The dynamic range was linear from 0 to 50 μg ml⁻¹ and the limit of quantification was 24 ng ml⁻¹. The measured dysprosium concentration in monkey serum ranged from 0 to 339 μg ml⁻¹ for the 0.25 mmol kg⁻¹ Sprodiamide Injection dose group, from 0 to 633 μg ml⁻¹ for the 0.5 mmol kg⁻¹ and from 0 to 2920 μg ml⁻¹ for 2.5 mmol kg⁻¹ dose groups. Dysprosium was not detected after 480 min in any of the serum samples from the 0.25 and 0.5 mmol kg⁻¹ dose groups after the administration of Sprodiamide Injection. All the monkeys in the 2.5 mmol kg⁻¹ dose group, with one exception, required 720 min for clearance of the drug from the serum. The drug was completely cleared from serum in all monkeys within 24 h.     

Meta-analytic review of the clinical effectiveness of oral deferiprone (L1)

Objective: To summarize efficacy and effectiveness in iron overloaded patients treated with the orally active iron chelator deferiprone also known as L₁ or, using meta-analysis of the literature. Methods: We reviewed the literature, searching Medline and Embase databases, as well as reviews and other literature on the topic. Inclusion criteria were: original clinical trials reporting results for serum ferritin concentration (SF), hepatic iron concentration or urinary iron excretion (UIE). Efficacy data had to have been reported after ≥3 months of treatment. Data were combined using a random effects model (Cochrane) modified for use with single groups to produce a point estimate and a 95% confidence interval. To summarize the clinical effectiveness, overall proportion of patients where deferiprone was able to reduce serum ferritin was calculated. We also examined average (mg · l⁻¹) serum ferritin levels over the reported time (mean) and absolute decrease from the baseline after therapy. To summarize efficacy, success was defined as the proportion of patients who achieved UIE of 25 mg per day or 0.5 mg · kg⁻¹ · day⁻¹, which equals the average amount received from monthly blood transfusions. We also calculated the overall average level (mg per day) of UIE over the reported time of therapy (mean). As part of a sensitivity analysis, data were analyzed for two ranges of deferiprone dosage: ≤50 mg · kg⁻¹ · day⁻¹ and ≥75 mg · kg⁻¹ · day⁻¹. Results: Of 83 identified references, nine clinical trials met our inclusion criteria, providing data for 129 iron overloaded patients. After a mean of 16 months of therapy (range 6.4–36 months) with 66.4 mg · kg⁻¹ · day⁻¹ (mean) of deferiprone, 75.5% of highly iron overloaded patients had a decrease in serum ferritin from baseline. The average drop in serum ferritin of 0.8 mg · l⁻¹ was 23.5% from baseline. The overall average UIE for therapy was 28.8 mg per day in patients receiving ≥75 mg · kg⁻¹ · day⁻¹ over 8.5 months of therapy. At the same dosage, more than half of the patients (51.8%) achieved negative iron balance. When studies with patients receiving lower dosage (≤50 mg · kg⁻¹ · day⁻¹) were included, the success rate was 45.1%. Conclusion: Overall, deferiprone has clinical efficacy in achieving negative iron balance and reducing body iron burden in highly iron overloaded patients. After an average of 16 months of deferiprone in doses ≥75 mg · kg⁻¹ · day⁻¹, most patients had a decrease in ferritine concentration. Received: 1 July 1998 / Accepted in revised form: 17 November 1998