Influence of arginase polymorphisms and arginase levels/activity on the response to erectile dysfunction therapy with sildenafil.

Arginase 1 (ARG1) and arginase 2 (ARG2) compete with nitric oxide synthases for the substrate l-arginine. Here we aim to assess whether arginase 1 and 2 plasma levels, plasma arginase activity or genetic factors are associated with altered responsiveness to sildenafil. We studied 71 post-prostatectomy erectile dysfunction (ED) patients (PED group) and 72 clinical ED patients (CED). Patients responded to the International Index of Erectile Function questionnaire before and after the treatment. We found positive and negative correlations between plasma levels of arginase 1 and sildenafil responsiveness in the PED and CED groups, respectively. PED group also presented negative correlation between plasma arginase activity and sildenafil responsiveness. Sildenafil poor responders have shown higher plasma arginase activity in PED and higher arginase 1 levels on CED groups. In addition, variant genotypes for the rs2781659, rs2781667 and rs17599586 polymorphisms were associated with reduced arginase activity, as well as the GTTT ARG1 haplotype in CED group.

Gene-gene interactions in the NAMPT pathway, plasma visfatin/NAMPT levels, and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy.

Nicotinamide phosphorybosil transferase (NAMPT) polymorphisms affect visfatin/NAMPT levels and may affect the responsiveness to therapy in hypertensive disorders of pregnancy. We examined whether NAMPT polymorphisms (rs1319501 T>C and rs3801266 A>G), or haplotypes, and gene-gene interactions in the NAMPT pathway affect plasma visfatin/NAMPT levels and the response to antihypertensive therapy in 205 patients with preeclampsia (PE) and 174 patients with gestational hypertension. We also studied 207 healthy pregnant controls. Plasma visfatin/NAMPT levels were measured by ELISA. Non-responsive PE patients with the TC+CC genotypes for the rs1319501 T>C, and with the AG+GG genotypes for the rs3801266 A>G polymorphism had lower and higher visfatin/NAMPT levels, respectively. The 'C, A' haplotype was associated with response to antihypertensive therapy, and with lower visfatin/NAMPT levels in PE. Interactions among NAMPT, TIMP-1 and MMP-2 genotypes were associated with PE and with lack of response to antihypertensive therapy in PE. Our results suggest that NAMPT polymorphisms affect plasma visfatin/NAMPT levels in nonresponsive PE patients, and that gene-gene interactions in the NAMPT pathway not only promote PE but also decrease the response to antihypertensive therapy in PE.

Polymorphisms in VEGFA gene affect the antihypertensive responses to enalapril.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that affects blood pressure by promoting vasodilation mediated by nitric oxide. Angiotensin-converting enzyme inhibitors (ACEi) up-regulate the VEGF expression; thus, genetic polymorphisms in the VEGFA gene could affect the antihypertensive responses to these drugs. METHODS: Hypertensive patients (n = 102) were prospectively treated only with the ACEi enalapril for 60 days. We compared the effect of VEGFA polymorphisms on changes in blood pressure after enalapril treatment. In addition, multiple linear regression analysis was carried out to assess the effect of covariates on blood pressure. Genotypes for g.-2578C>A (rs699947), g.-1154G>A (rs1570360), and g.-634G>C (rs2010963) VEGFA polymorphisms were determined, and haplotype frequencies were estimated. RESULTS: Individuals carrying the CA and AA genotypes for the g.-2578C>A polymorphism and the AGG haplotype showed more intense decrease in blood pressure in response to enalapril 20 mg/day. A multiple linear regression analysis showed that the AA genotype for the g.-2578C>A polymorphism and the AGG haplotype are associated with more intense decrease in blood pressure in response to enalapril 20 mg/day, while the CC genotype for the g.-2578C>A polymorphism and the CGG haplotype are associated with the opposite effect. CONCLUSIONS: These findings suggest that polymorphisms in VEGFA gene may affect the antihypertensive responses to enalapril.

The effects of NAMPT haplotypes and metabolic risk factors on circulating visfatin/NAMPT levels in childhood obesity.

OBJECTIVE: Polymorphisms in the NAMPT gene, which encodes the adipocytokine visfatin/nicotinamide phosphorybosil transferase (NAMPT), affect the circulating visfatin/NAMPT levels and are associated with obesity and cardiovascular diseases. However, no study has tested the hypothesis that NAMPT haplotypes could affect visfatin/NAMPT levels in case of childhood obesity. We investigated the effects of traditional metabolic risk factors (MRFs) and NAMPT polymorphisms T/C (rs1319501) and A/G (rs3801266) or haplotypes on visfatin/NAMPT levels in obese children and adolescents, and whether NAMPT polymorphisms and/or haplotypes are associated with susceptibility to childhood obesity. METHODS: We studied 175 control, 99 obese and 82 obese with ⩾ 3 MRFs children and adolescents. Genotypes were determined by a Taqman allele discrimination assay and real-time PCR. The plasma visfatin/NAMPT level was measured using an enzyme immunoassay. RESULTS: Obese children and adolescents with ⩾ 3 MRFs had higher plasma visfatin/NAMPT levels in comparison with control children and adolescents (P<0.05). Although positive associations were observed between visfatin/NAMPT and body mass index (rs = 0.157; P = 0.034) as well as visfatin/NAMPT and waist circumference (rs = 0.192; P = 0.011), visfatin/NAMPT and high-density lipoprotein cholesterol were inversely associated (rs = -0.162; P = 0.031). No significant differences in genotype, allele or haplotype frequency distributions for the studied polymorphisms were found when the three groups were compared. However, higher plasma visfatin/NAMPT levels were found in control and obese subjects carrying the GG genotype for the A/G (rs3801266) polymorphism (P<0.05) but not in obese children with ⩾ 3 MRFs. Moreover, control subjects carrying the 'T-G' haplotype showed higher plasma visfatin/NAMPT levels. NAMPT genotypes or haplotypes were not associated with childhood obesity. CONCLUSIONS: Obesity in children with ⩾ 3 MRFs increases plasma visfatin/NAMPT levels, and this marker was associated with body mass index and waist circumference. The A/G polymorphism and NAMPT haplotypes affect plasma visfatin/NAMPT levels in controls but not in obese children with ⩾ 3 MRFs. These results suggest that obesity and MRFs are more influential than genetic polymorphisms in the determination of visfatin/NAMPT levels in obese children. Further research is necessary to explain why the GG genotype is not associated with increased visfatin/NAMPT levels in obese children with ⩾ 3 MRFs.

The effects of endothelial nitric oxide synthase tagSNPs on nitrite levels and risk of hypertension and obesity in children and adolescents.

Obesity and the nitric oxide synthase 3 (NOS3) gene polymorphisms are associated with nitrite levels and hypertension. However, no study has tested the hypothesis that NOS3 tagSNPs rs3918226, rs3918188, rs743506 and rs7830 affect nitrite levels and are associated with hypertension in childhood obesity. We investigated the association of these NOS3 tagSNPs and the haplotypes formed by them with hypertension and with nitrite levels in children and adolescents with obesity and with obesity plus hypertension. We studied 355 subjects: 174 healthy (controls), 109 normotensive obese, and 72 obese children and adolescents with obesity plus hypertension. Genotypes were determined by Taqman allele discrimination assay and real-time PCR. We compared the distribution of NOS3 tagSNP genotypes, alleles and haplotypes in the three groups of subjects. Nitrite levels were determined by ozone-based chemiluminescence. Nitrite levels were affected by the rs3918226 polymorphism (P<0.05) but not by NOS3 haplotypes. There was no association between the tagSNPs studied and hypertension in children and adolescents. Our findings show that the NOS3 tagSNP rs3918226 is associated with NO production in children and adolescents, and suggest that this polymorphism may have an impact on cardiovascular health. Further studies are needed to better clarify the effects of this polymorphism on cardiovascular risk.

Tissue inhibitor of matrix metalloproteinase-1 polymorphism, plasma TIMP-1 levels, and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy.

Tissue inhibitor of metalloproteinase (TIMP)-1 is a major endogenous inhibitor of matrix metalloproteinase (MMP)-9, which may affect the responsiveness to therapy in hypertensive disorders of pregnancy. We examined whether TIMP-1 polymorphism (g.-9830T>G, rs2070584) modifies plasma MMP-9 and TIMP-1 levels and the response to antihypertensive therapy in 596 pregnant: 206 patients with preeclampsia (PE), 183 patients with gestational hypertension (GH) and 207 healthy pregnant controls. We also studied the TIMP-3 polymorphism (g.-1296T>C, rs9619311). Plasma MMP-9 and TIMP-1 levels were measured by ELISA. GH patients with the GG genotype for the TIMP-1 polymorphism had lower MMP-9 levels and MMP-9/TIMP-1 ratios than those with the TT genotype. PE patients with the TG genotype had higher TIMP-1 levels. The G allele and the GG genotype were associated with PE and responsiveness to antihypertensive therapy in PE, but not in GH. Our results suggest that the TIMP-1 g.-9830T>G polymorphism not only promotes PE but also decreases the responses to antihypertensive therapy.

VEGF genetic polymorphisms affect the responsiveness to sildenafil in clinical and postoperative erectile dysfunction.

Vascular endothelial growth factor (VEGF) is a cytokine involved in angiogenesis and is closely related to the nitric oxide-cyclic guanosine monophosphate pathway, a target for sildenafil. We investigated for the first time whether three clinically relevant polymorphisms in the VEGF gene are associated with altered responsiveness to sildenafil treatment in postoperative erectile dysfunction (PED) and clinical erectile dysfunction (CED). We determined VEGF genotypes for three polymorphisms in VEGF promoter: -2578C>A (rs699947), -1154G>A (rs1570360) and -634G>C (rs2010963) in 126 patients with erectile dysfunction (ED; 66 patients with PED and 60 patients with CED). The patients were classified as good or poor responders to sildenafil (GR and PR groups, respectively) according to their responses with basis on the changes in five-item version of the International Index for Erectile Function (5-IIEF). We found an association of the -1154AA genotype with PR in both PED and CED patients (P<0.05), whereas the -2578AA and the -2578CA genotypes were associated with PR only in the CED group (P<0.05). The AAG haplotype was more common in PR than in GR patients (38% versus 20%, respectively; P=0.032) in the CED group, thus increasing the risk for a worse response to sildenafil (odds ratio, OR=2.33, 95% confidence interval, CI=1.07-5.09). However, this finding does not resist to Bonferroni's correction (P>0.0125). Our results indicate that VEGF polymorphisms affect the responsiveness of PED and CED patients to sildenafil. These findings may help to improve the therapy of patients with ED.

eNOS and BDKRB2 genotypes affect the antihypertensive responses to enalapril.

PURPOSE: The antihypertensive effect of angiotensin-converting enzyme inhibitors (ACEi) is attributed partially to increased nitric oxide bioavailability. It is possible that functional polymorphisms in endothelial nitric oxide synthase (eNOS) and bradykinin receptor B2 (BDKRB2) genes may affect the antihypertensive response to enalapril. METHODS: We evaluated 106 hypertensive patients treated only with enalapril for 60 days. The difference between the mean arterial pressure (MAP) before and after the antihypertensive treatment was defined as ΔMAP. If ΔMAP were below or above the median value, the patients were classified as poor responders (PR) or good responders (GR), respectively. eNOS genotypes for the T(-786)C, G894T and 4b/4a polymorphisms were determined and haplotype frequencies were estimated by PHASE and Haplo.stats programs. The C(-58)T and BE1 +9/-9 polymorphisms of BDKRB2 genes and their haplotypes were determined by DNA sequencing. Robust multifactor dimensionality reduction analysis was used to characterize gene-gene interactions. RESULTS: The TC/CC genotypes and the C allele for the eNOS T(-786)C polymorphism were more frequent in GR than in PR. Furthermore, the TT genotype for the BDKRB2 C(-58)T polymorphism was more frequent in PR than GR. No other significant differences in genotypes or haplotypes were found. However, we found significant gene-gene interactions: the CC genotype for the BDKRB2 C(-58)T polymorphism was associated with response to enalapril depending on eNOS T(-786)C genotypes. CONCLUSIONS: These findings suggest that eNOS T(-786)C and BDKRB2 C(-58)T polymorphisms may synergically affect the antihypertensive response to enalapril.

Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction.

Erectile dysfunction (ED) is usually treated with sildenafil. Although genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may impair endogenous NO formation, there is little information about how eNOS polymorphisms and haplotypes affect the responses to sildenafil. We studied 118 patients; 63 patients had ED secondary to radical prostatectomy (PED) and 55 had organic, clinical ED. eNOS genotypes for three eNOS polymorphisms (T(-786)C, rs2070744; a variable number of tandem repeats (VNTR) in intron 4; and Glu298Asp, rs1799983) were determined, and eNOS haplotypes were estimated using PHASE 2.1. The clinical responses to sildenafil were evaluated and the patients were classified as good responders (GR) or poor responders (PR) when their changes in five-item version of International Index for Erectile Function questionnaire were above or below the median value. The TC/CC genotypes and the C allele for the T(-786)C polymorphism were more common in GR, compared with PR patients with PED. However, the 4b4a/4a4a genotypes and the 4a allele for the VNTR polymorphism in intron 4 were more common in GR, compared with PR patients with clinical ED. The C-4a-Glu haplotype was more common in GR than in PR patients with PED. Conversely, the T-4b-Asp haplotype was less common in GR than in PR patients with PED. No other significant differences were found. Our findings show evidence that eNOS polymorphisms affect the responses of PED and clinical ED patients to sildenafil.

Haptoglobin polymorphism affects nitric oxide bioavailability in preeclampsia.

Studies showed elevated cell-free hemoglobin (Hb) in preeclampsia (PE), and Hb reacts with nitric oxide (NO), decreasing its bioavailability. Haptoglobin (Hp) is a polymorphic protein (Hp1-1, Hp2-1 and Hp2-2) that binds Hb to form a complex that is removed from circulation, thus preventing Hb-driven oxidative stress and NO scavenging. Hp protein products differ in biochemical and biophysical properties, which reflects on the Hb-Hp complex clearance rate. We hypothesized that Hp phenotypes modulate NO bioavailability by influencing NO consumption in PE. We studied 92 PE subjects and 105 normal pregnant women (NP). Hp genotypes were determined using real-time PCR. To assess NO bioavailability, we measured plasma nitrite using an ozone-based chemiluminescence assay. Plasma Hb and Hp were assessed with commercial immunoassays. A NO consumption assay was used to measure NO consumption. We found no differences in Hp genotype frequencies between PE and NP groups. Hp genotypes had no effects on plasma heme levels, NO consumption and plasma nitrite in NP. However, in PE, Hp2-1 and Hp2-2 were associated with higher plasma heme levels (48 and 55% higher, respectively; P<0.05), increased NO consumption (42 and 44% more, respectively; P<0.05) and lower plasma nitrite (39% less for Hp2-2; P<0.05) compared with Hp1-1. These findings indicate that although Hp genotype does not affect the risk of PE, Hp1-1 genotype may exert a protective role in PE by reducing NO scavenging, whereas Hp2-1 and Hp2-2 further may aggravate PE by reducing NO bioavailability.

Adiponectin associates positively with nitrite levels in children and adolescents.

OBJECTIVE: To compare the circulating levels of adiponectin and nitric oxide (NO) bioavailability in eutrophic, eutrophic hypertensive, obese, and obese hypertensive children and adolescents, and to assess whether adiponectin is associated with increased NO bioavailability in these children and adolescents. METHODS: We studied 129 eutrophic, 8 eutrophic hypertensive, 91 obese, and 44 obese hypertensive children and adolescents in this cross-sectional study. Adiponectin concentrations were measured in plasma samples by enzyme-linked immunosorbent assay. To assess NO bioavailability, nitrite concentrations were measured in whole-blood samples by chemiluminescence. Multiple linear regression analysis was carried out to assess the effects of adiponectin on NO bioavailability. RESULTS: We found no significant differences in nitrite levels among groups (P>0.05). The obese hypertensive group had the lowest adiponectin levels among groups (P<0.05). Additionally, obese subjects had lower adiponectin levels than eutrophic individuals (P<0.05). A multiple linear regression analysis showed that NO bioavailability was positively associated with adiponectin concentrations (P<0.05). CONCLUSIONS: Our findings suggest that adiponectin increases NO bioavailability in children and adolescents. Further studies are needed to assess the cardiovascular protective role for this adipokine in childhood obesity.

Circulating matrix metalloproteinases and their endogenous inhibitors in patients with erectile dysfunction.

Erectile dysfunction (ED) may reflect vascular alterations associated with imbalanced matrix metalloproteinases (MMPs) activities. However, no previous study has compared MMPs levels in ED patients with those found in healthy subjects. We measured the circulating MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in ED patients, with or without diabetes mellitus (DM), and in healthy controls. We studied 28 healthy men (control group), 35 men with ED (ED group), and 33 men with ED and DM (ED/DM group). MMP-2, MMP-9, TIMP-1 and TIMP-2 plasma levels were measured by enzyme-linked immunosorbent assay and zymography. We found no differences in MMP-9 levels (P>0.05) among groups. However, while patients in the ED group had similar TIMP-1 levels compared with those found in the control group, we found higher TIMP-1 levels and lower MMP-9/TIMP-1 ratios in the ED/DM group compared with controls (P<0.05). While both groups of patients (ED and ED/DM) had slightly lower MMP-2 levels compared with controls (P<0.05), we found no differences in TIMP-2 levels among the study groups (P>0.05), and no differences in MMP-2/TIMP-2 ratios (P>0.05). We found evidence indicating lack of significant alterations in circulating net MMP-9 and MMP-2 activities in patients with ED, and lower net MMP-9 activity in diabetic patients with ED.

Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients.

Matrix metalloproteinases (MMPs) are involved in cardiac remodelling. We examined whether MMP-2 genetic polymorphisms are associated with hypertension and left ventricular (LV) remodelling in hypertensive patients. We studied 160 hypertensive patients and 123 healthy controls. Echocardiography was performed in all patients and the C(-1306)T (rs243865) and C(-735)T (rs 2285053) MMP-2 polymorphisms were analysed. Haplo.stats analysis was used to evaluate whether MMP-2 haplotypes are associated with hypertension and with extremes in LV mass index (LVMI). Multiple linear regression analysis was performed to assess whether MMP-2 genotypes or haplotypes affect LVMI and other echocardiography parameters. The C(-1306)T 'CC' genotype was associated with reduced LVMI and LV end-diastolic diameter (EDD) (P=0.0365 and P=0.0438, respectively). The haplotype 'C, C' was associated with reduced LVMI and EDD (P=0.0278 and P=0.0322, respectively). The comparison of upper and lower extremes of the LVMI phenotype showed that the 'C, C' haplotype was more common in the lower LVMI group (P=0.0060), whereas the 'T, C' haplotype was more common in the higher quartile of LVMI (P=0.0187), and this haplotype was associated with increased risk of higher LVMI values (odds ratio=3.5121, 95% confidence interval=1.3193-9.3494). The findings suggest that MMP-2 polymorphisms affect hypertension-induced LV remodelling.

Matrix metalloproteinase-9 polymorphisms affect plasma MMP-9 levels and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy.

Abnormal matrix metalloproteinase (MMP)-9 levels may have a role in hypertensive disorders of pregnancy. We examined whether MMP-9 genetic polymorphisms (g.-1562C >T and g.-90(CA)13-25) modify plasma MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 levels and the responses to antihypertensive therapy in 214 patients with preeclampsia (PE), 185 patients with gestational hypertension (GH) and a control group of 214 healthy pregnant (HP). Alleles for the g.-90(CA)13-25 polymorphism were grouped L (low) (< 21 CA repeats) or H (high) (≥ 21 CA repeats). Plasma MMP-9 and TIMP-1 concentrations were measured by enzyme-linked immunosorbent assay. Plasma MMP-9 concentrations were not affected by genotypes or haplotypes in HP and PE groups, except for the g.-90(CA)13-25 polymorphism: GH patients with the LH genotype for this polymorphism have higher MMP-9 levels than those with other genotypes. The T allele for the g.-1562C > T polymorphism and the H4 haplotype (combining T and H alleles) are associated with GH and lack of responsiveness to antihypertensive therapy in GH. The H2 haplotype (combining C and H alleles) was associated with lack of responsiveness to antihypertensive therapy in PE, but not in GH. In conclusion, our results show that MMP-9 genetic variants are associated with GH and suggest that MMP-9 haplotypes affect the responsiveness to antihypertensive therapy in hypertensive disorders of pregnancy.

PP130. ENOS tagging SNP haplotypes in hypertensive disorders of pregnancy.

INTRODUCTION: Haplotypes formed by polymorphisms (T-786C, rs2070744; a variable number of tandem repeats in intron 4, and Glu298Asp, rs1799983) of eNOS gene were associated previously with gestational hypertension (GH) and preeclampsia (PE). However, no study has explored the tagging SNPs rs743506 and rs7830 in these disorders. OBJECTIVES: The aim of the current study was to compare the distribution of the genotypes and haplotypes formed by the two tagging SNPs or by the five eNOS polymorphisms mentioned among healthy pregnant GH and PE. METHODS: We recruited 122 HP, 138 GH and 157 PE. Genotypes for the T-786C, the Glu298Asp and rs743506 polymorphisms were determined by Taqmanâ Allele Discrimination assays and fluorescence signals were measured on Chromo 4 Detector (Bio-Rad Laboratories, USA). Genotypes for the VNTR polymorphism in intron 4 and rs7830, however, were determined by PCR and fragment separation by electrophoresis in 8% polyacrylamide gels. Plasma aliquots were analyzed in triplicate for their nitrite content using an ozone-based chemiluminescence assay. RESULTS: The haplotype formed by the most common variants in each polymorphism "T b G A C" was more frequent in PE group compared to HP (P=0.00004), which may be explained by the higher linkage disequilibrium found in PE compared to GH and HP. Conversely, the haplotype "C b G G C" was more frequent in HP compared to PE (P=0.00113), which is supported by previous findings that demonstrated the association of the combination "C b G" with higher level of nitrite (NO marker). CONCLUSION: Our results suggest a protective effect of the haplotype "C b G G C" against the development of PE. This study was funded by the Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG-Brazil), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP-Brazil).

Pharmacokinetics of ceftazidime administered to lactating and non-lactating goats.

The aim of this work was to determine the pharmacokinetics of intravenous (i.v.) and intramuscular (i.m.) ceftazidime administered to lactating (LTG; n=6) and non-lactating (NLTG; n=6) healthy Creole goats in 2 trials (T1 and T2). During T1 and T2, goats randomly received a single dose of i.m. or i.v. ceftazidime (10 mg/kg). Serum concentration of iv ceftazidime in NLTG and LTG goats is best described by 2 and 3 compartment models, respectively. The pharmacokinetic parameters of iv and im ceftazidime administered to LTG and NLTG showed statistically significant differences (P < 0.05) in the constants (lamda(z), T1 vs. T2 [i.v.] 0.5 +/- 0.1 vs. 0.3 +/- 0.1/h; T1 vs. T2 [i.m.] 0.5 +/- 0.2 vs. 0.3 +/- 0.1/h) and in the mean times (t(1/2), T1 vs. T2 [i.v.] 1.6 +/- 0.3 vs. 2.3 +/- 0.6 h; T1 vs. T2 [i.m.] 1.6 +/- 0.7 vs. 2.6 +/- 0.9 h) of elimination. The bioavailability of ceftazidime in LTG and NLTG was 113.0 +/- 17.8 and 96.0 +/- 18.0%, respectively. Ceftazidime concentration in milk at 2 h was: i.v. = 1.9 +/- 0.2 and i.m. = 2.4 +/- 0.5 microg/ml; the penetration in milk was i.v. = 18.3 +/- 13.5 and im = 14.3 +/- 10.6%. Ninety-six hours after i.v. and i.m. administration, residues of the drug were not found in milk. In conclusion, ceftazidime, when administered to goats, showed high concentration times in serum, good penetration into milk and a bioavailability that makes it suitable to be used by the i.m. route.

Evaluation of cefepime kinetic variables and milk production volume in goats

Avaliaram-se as variáveis cinéticas da cefepime e a produção de leite de cabras após a administração parenteral (intravenosa e intramuscular) de cefepime, com e sem reação inflamatória na região implantada. Dez cabras em lactação, implantadas com caixas de material sem reação imunológica para colher o fluido de tecido (FT) foram usadas em dois experimentos. No primeiro a aplicação de cefepime foi feita na primeira semana após a implantação e no segundo na oitava semana. Na primeira semana após a implantação observou-se elevação dos níveis de proteína no fluido do tecido após uma simples dose de 20mg/kg de cefepime via endovenosa ou intramuscular. Amostras do sangue e do leite foram obtidas e as variáveis cinéticas foram avaliadas.

Pharmacokinetics and penetration into tissue fluid of ceftizoxime in normal and hyperthermic sheep.

The pharmacokinetics of ceftizoxime was studied in six sheep before and after inducing hyperthermia using Escherichia coli endotoxin. Sheep implanted subcutaneously with cages of non-reactive material for collecting tissue cage fluid (TCF) were used to conduct two trials. In Trial 1 animals with normal basal temperature (normal sheep (NS)) were given intravenous (i.v.) and intramuscular (i.m.) monodoses of ceftizoxime (20mg/kg BW) at 1 week interval. One and 5 weeks later (Trial 2) each sheep were injected 1µg/kg BW of endotoxin to produce hyperthermia (hyperthermic sheep (HS)) previously to i.v. administration (HSi.v.) and i.m. (HSi.m.) of ceftizoxime (20mg/kg BW), respectively. Serum and TCF samples were collected over 6h post-administration. Ceftizoxime concentrations in serum and TCF were determined by a microbiological assay. The concentrations in serum and TCF of ceftizoxime were analyzed through compartmental and non-compartmental models.Rectal temperature were significantly incremented in all animals during Trial 2. The half-time and constant of elimination in serum of ceftizoxime in NSi.v. (t(1/2)=1.1+/-0.4h; lambda(z)=0.7+/-0.2h(-1)) were statistically different those observed in HSi.v. (t(1/2)=1.4+/-0.4h; lambda(z)=0.5+/-0.2h(-1)). The constants of distribution in NSi.v. and HSIV were 5.1+/-4.6 and 4.1+/-3.4h(-1), respectively. The time to reach the maximum concentrations in TCF was latter (p<0.05) in NS (t(max)=2.3+/-0.7h) than in HS (t(max)=1.3+/-0.6 h). After i.m. administration in NS the absorption half-life (0.12+/-0.19h) was latter (p<0.05) than in HS (0.06+/-0.007h) with greater areas under the curve (AUC in NS=65.4+/-20.8 and AUC in HS=34.7+/-7.5 (µg/ml) h). The maximum value of concentration in serum (C(max)) and AUC in TCF were greater (p<0.05) in NS (C(max)=46.1+/-10.6µg/ml and AUC=84.4+/-17.4 (µg/ml) h) as compared to same HS (C(max)=27.0+/-12.9µg/ml and AUC=47.9+/-3.9 (µg/ml) h). The concentrations of ceftizoxime in TCF after i.v. and i.m. in NS and HS were elevated during a 6h period after administration. The bioavailability of ceftizoxime in NS (101.6+/-59.9%) and HS (87.4+/-63.3%) was suitable for its use by the i.m. route.