Coronary flow velocity and coronary flow velocity reserve in children with ventricular septal defect

To assess coronary flow characteristics in congenital heart defect with left ventricular (LV) volume overload, we examined 24 children (mean 12.1 +/- 7.1 months) with ventricular septal defect. The pulmonary to systemic flow ratio ranged from 1.1 to 3.0. Control group consisted of 10 age-matched children who had a history of Kawasaki disease with angiographically normal coronary artery in the acute phase. LV end-diastolic volume and LV mass were measured by left ventriculogram. With Doppler flow guide wire (0.014-inch), average peak flow velocity (APV) in left anterior descending coronary artery was recorded at rest and during hyperemia (0.16 mg/kg/min adenosine infusion intravenously). Coronary flow velocity reserve (CFVR) was calculated as the ratio of hyperemic/baseline APV. Seven patients were also studied 5-7 months after surgery. Compared with control subjects, CFVR was significantly reduced in patients with LVvolume overload (1.78 +/- 0.24 vs. 2.66 +/- 0.42, p < .0001) because baseline APV was significantly greater (30 +/- 8 vs. 23 +/- 5 cm/sec, p = 0.0027). Significant correlations were observed between CFVR and Qp/Qs, baseline APV, LV end-diastolic volume, or LVmass. Stepwise regression analysis showed that baseline APV and Qp/Qs were important determinants of CFVR (CFVR = 2.64-0.202 [Qp/Qs]-0.015 [APV] r = 0.83, p < 0.0001). In 7 patients with LVvolume overload, CFVR improved significantly after surgery because of reduction of baseline APV. CFVR is limited in patients with LV volume overload because of the elevation of baseline resting APV. LAD flow pattern is dependent on LV volume overload level and its changes after surgery.     

Positive impact of HIV-1 gag cleavage site mutations on the virological response to darunavir boosted with ritonavir

We assessed the roles of baseline gag and gag-pol cleavage site mutations (CSM) on the virological outcome of a darunavir-based regimen in highly antiretroviral-experienced patients. We showed the association, in multivariate analysis, between the A431V gag CSM and the virological response, defined as a reduction in plasma HIV-1 RNA to <50 copies/ml at month 3 (P = 0.028). Our results suggest that a specific gag CSM might have a role on protease inhibitor susceptibility in an inhibitor-specific manner.     

Possible prognostic value of leukotriene B(4) in acute respiratory distress syndrome

OBJECTIVE: To study the major eicosanoids implicated in the pathophysiology of acute respiratory distress syndrome (ARDS) in order to estimate their relative prognostic values. METHODS: We conducted a prospective study in a consecutive series of patients with ARDS admitted to a university hospital intensive care unit. We measured the plasma concentrations of 3 inflammatory mediators (thromboxane B(2), 6-keto prostaglandin F(1alpha), and leukotriene B(4)) in peripheral arterial and mixed venous plasma samples. RESULTS: We studied 16 patients with ARDS, who had a mean alpha SD baseline ratio of P(aO(2)) to fraction of inspired oxygen (P(aO(2))/F(IO(2))) of 147 +/- 37 mm Hg and a mean +/- SD baseline lung injury score of 2.9 +/- 0.37. The plasma concentrations of thromboxane B(2), 6-keto prostaglandin F(1alpha), and leukotriene B(4) were greater than the general-population reference levels in both arterial and mixed venous plasma, but only leukotriene B(4) was higher in arterial plasma than in mixed venous plasma (401 +/- 297 pg/mL vs 316 +/- 206 pg/mL, p = 0.04). When we correlated the eicosanoid concentrations with specific indicators of clinical severity, we found correlations only between the baseline P((aO2))/F(IO(2)) and the arterial thromboxane B(2) level (r = -0.57, p = 0.02), the arterial leukotriene B(4) level (r = -0.59, p = 0.01), and the transpulmonary gradient of leukotriene B(4) level (r = -0.59, p = 0.01). We also found a correlation between the transpulmonary gradient of leukotriene B(4) and the lung injury score (r = 0.51, p = 0.04). The thromboxane B(2) concentration in arterial plasma and the leukotriene B(4) concentration in both arterial and mixed venous plasma were the only baseline plasma eicosanoid concentrations that predicted significant differences in outcome. When looking at the transpulmonary gradient of the eicosanoids studied, we found that only the gradient of leukotriene B(4) showed significant differences of clinical interest. Among survivors we observed practically no gradient (-4.9%), whereas among nonsurvivors we found a substantial positive gradient of 41.6% for the elevated arterial (post-pulmonary) values, compared with the pulmonary-artery (pre-pulmonary) values, and this difference was statistically significant (p = 0.02). CONCLUSIONS: The pro-inflammatory eicosanoid leukotriene B(4) showed the best correlation with lung-injury severity and outcome in patients with ARDS.     

Systemic and intraperitoneal interleukin-6 system during the first year of peritoneal dialysis.

OBJECTIVE: To investigate if intraperitoneal and systemic interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) are related to each other and to peritoneal solute transport rate (PSTR). DESIGN: Longitudinal study in retrospectively selected patients. SETTING: Peritoneal dialysis (PD) unit of a university-based hospital. PATIENTS AND METHODS: 31 PD patients on treatment with conventional glucose-based solutions participated in a longitudinal study. IL-6 and sIL-6R were measured in plasma and overnight effluent, both at baseline and after 12 +/- 2 months on PD. C-reactive protein (CRP) and serum albumin were used as surrogate markers of inflammation. PSTR of small solutes was evaluated using the dialysate-to-plasma ratio (D/P) of creatinine after a 4-hour dwell; PSTR of large solutes was evaluated using the 24-hour D/P ratio of albumin. RESULTS: D/P creat increased over time (0.67 +/- 0.15 vs 0.80 +/- 0.11, p < 0.0001) and correlated to D/P albumin only at the baseline evaluation. Patients with plasma IL-6 > or = median had higher (p < 0.005) D/P creat at baseline [0.74 (0.62 - 0.87)] compared to patients with IL-6 < median [0.57 (0.47 - 0.66)]. Dialysate IL-6 at baseline was also higher (p < 0.05) in patients with plasma IL-6 > or = median [24.7 (16.5 - 38.5) pg/mL] compared to patients with IL-6 < median [14.1 (10 - 25.7) pg/mL]. Neither CRP nor albumin changed over time on PD, although they were closely linked to plasma IL-6 levels. A strong positive correlation was found between D/P creat and dialysate IL-6 (rho = 0.77, p < 0.0001) at baseline, but not at 1 year. In contrast, there was a significant correlation between D/P creat and dialysate sIL-6R (rho = 0.39, p < 0.05) at 1 year, but not at baseline. At 1 year, 17 patients with increasing PSTR had higher increases in dialysate IL-6 (28 +/- 26 vs -21 +/- 78 pg/mL, p < 0.05) and levels of dialysate sIL-6R (693 +/- 392 vs 394 +/- 274 pg/mL, p = 0.05) compared to patients with stable PSTR (n = 11). Patients who had peritonitis presented higher baseline serum IL-6 concentration (6.8 +/- 1.0 pg/mL) compared with patients without peritonitis (4.0 +/- 0.6 pg/mL, p < 0.05). Finally, both at baseline and after 1 year, there were significant correlations between plasma and dialysate IL-6 (rho = 0.46, p < 0.05, and rho = 0.40, p < 0.05) respectively. CONCLUSIONS: These findings indicate that, (1) intraperitoneal and systemic inflammation increase in PD patients during the first year of therapy; (2) intraperitoneal and systemic inflammation may be interrelated and the IL-6 system may be the link; (3) the IL-6 system (both intraperitoneal and systemic) is associated with PSTR, particularly in the early phase of PD treatment, in which small and large solute transport are linked. Signs of a transition between acute and chronic inflammation were observed in the follow-up evaluation. Inflammation may, at least in part, be responsible for the development of a high PSTR, and this could be one reason for the high mortality in patients with high PSTR.     

A pilot study to assess the use of protein a immunoadsorption for chronic dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a leading cause of end-stage heart failure and cardiac transplantation. Anticardiac antibodies are common and removal of these through immunoadsorption (IA) is associated with improvement in global cardiac function. The effect of IA on regional function and quality of life (QOL) without intravenous immunoglobulin (IVIG) substitution has not been described. We performed a pilot trial using Immunosorba columns in four patients with chronic DCM and NYHA Class II-III congestive heart failure. Subjects were followed for 6 months with serial echocardiograms and validated QOL assessments. Regional and global left ventricular (LV) end-systolic deformations were assessed by two-dimensional strain echocardiography. Total IgG decreased 95% (from 1,210 +/- 274 mg/dl to 57 +/- 16 mg/dl, P = 0.003) and IgG3 decreased 61% (from 33 +/- 16 mg/dl to 13 +/- 7 mg/dl, P = 0.024). QOL improved from baseline to 6 months as assessed by the Living with Heart Failure questionnaire (from 54 +/- 18 to 19 +/- 7, P = 0.029). Mean LV ejection fraction improved from 35 to 40% at Day 5 and to 44% at 6 months (P = NS). The LV end diastolic and end systolic volumes decreased (220-202 ml, 159-130 ml, P = NS) at 6 months. Global end-systolic strain improved from -7.3% at baseline to -8.5% at Day 5 and -8.8% at 6 months (P = NS). Regional LV function and response to IA was not uniform. Even without IVIG substitution, IA for the treatment of chronic DCM is associated with improved QOL up to 6 months after treatment. A randomized, sham-controlled trial is required to confirm the benefits of IA for DCM.     

Combination of thiotropium bromide with almitrine and pulmonary rehabilitation in the treatment of patients with chronic obstructive pulmonary disease

AIM: To elucidate efficacy of a combination almitrine+thiotropium bromide (TB)+pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) of stage II-III complicated with chronic respiratory failure (CRF). MATERIAL AND METHODS: Efficacy of therapy was compared in two groups of patients: group 1 (n = 22) received TB in a dose 18 mcg/day for one year, almitrine in a dose 10 mg/kg/day for 3 months, an 8 week course of PR, group 2 (n = 17) received TB and PR. The treatment efficacy was determined by spirometric parameters of external respiration function, blood gases, dyspnea indices, exercise tolerance assessed by 6-min walk test, quality of life (St. George Hospital Respiratory Questionnaire). RESULTS: Group 1 patients walked longer distance after a course of PR and 1 year later (by 90.5 +/- 25.4 and 44.5 +/- 10.2 m, respectively, p < 0.05), had reduced desaturation measured by pulsoxym-etry at the end of 6-min walk test, increased PaO2 in baseline under 70 mmHg (by 5.8 +/- 1.2 mmHg, p > 0.05), decreased exacerbation rate per 1 patient a year (by 25%). CONCLUSION: Combination treatment with TB, almitrine and PR is indicated for COPD patients with moderate hypoxemia.     

Natural polymorphisms in the human immunodeficiency virus type 2 protease can accelerate time to development of resistance to protease inhibitors

Human immunodeficiency virus type 2 (HIV-2) contains numerous natural polymorphisms in its protease (PR) gene that are implicated in drug resistance in the case of HIV-1. This study evaluated emergent PR resistance in HIV-2. Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture. Genotypic analysis determined the time to the appearance of protease inhibitor (PI)-associated mutations compared to HIV-1. Phenotypic drug susceptibility assays were used to determine the levels of drug resistance. Within 10 to 15 weeks of serial passage, three major mutations--I54M, I82F, and L90M--arose in HIV-2 viral cultures exposed to APV, NFV, and IDV, whereas I82L was selected with TPV. After 25 weeks, other cultures had developed I50V and I84V mutations. In contrast, no major PI mutations were selected in HIV-1 over this period except for D30N in the context of NFV selective pressure. The baseline phenotypes of wild-type HIV-2 isolates were in the range observed for HIV-1, except for APV and NFV for which a lower degree of sensitivity was seen. The acquisition of the I54M, I84V, L90M, and L99F mutations resulted in multi-PI-resistant viruses, conferring 10-fold to more than 100-fold resistance. Of note, we observed a 62A/99F mutational motif that conferred high-level resistance to PIs, as well as novel secondary mutations, including 6F, 12A, and 21K. Thus, natural polymorphisms in HIV-2 may facilitate the selection of PI resistance. The increasing incidence of such polymorphisms in drug-naive HIV-1- and HIV-2-infected persons is of concern.     

Prevalence and clinical implications of insertions in the HIV-1 p6Gag N-terminal region in drug-naive individuals initiating antiretroviral therapy

We assessed the prevalence and clinical impact of insertions within the HIV-1 p6Gag proline-rich (PTAP) region on initial antiretroviral therapy response in 461 HIV-infected, drug-naive individuals initiating therapy in British Columbia, Canada between June 1996 and August 1998. HIV p6Gag insertions were detected by nested RT-PCR of extracted patient plasma followed by direct DNA sequencing. Insertions were observed in 70 of 423 successfully genotyped samples (16.5%). HIV p6Gag insertions were significantly associated with a lower baseline CD4 cell count (P<0.05) and the presence of basic amino acids at key positions in the HIV envelope V3 loop linked to a syncytium-inducing phenotype (P<0.05). After adjusting for baseline factors, no effect of HIV p6Gag insertions was observed on time to virological success (pVL < or = 500 copies/ml), virological failure (subsequent confirmed pVL > or = 500 copies/ml) or immunological failure (confirmed CD4 count below baseline), as evaluated by Kaplan-Meier methods and Cox proportional hazard regression (P>0.1). The data suggest that HIV p6Gag insertions are not exclusively related to drug resistance and may not influence response to antiretroviral therapy, but may be linked to sequence variations in the HIV envelope.     

Relationship between whole plasma calcitonin levels, calcitonin secretory capacity, and plasma levels of estrone in healthy women and postmenopausal osteoporotics.

The exact role of calcitonin (CT) in the pathogenesis of postmenopausal osteoporosis remains unknown. Whole plasma calcitonin (iCT) basal levels, metabolic clearance rate (MCR), and production rate (PR) of CT were measured in 9 premenopausal and 16 postmenopausal women, including 11 osteoporotics (OP). Basal iCT levels were statistically lower in postmenopausal women than in the premenopausal group (P less than 0.01) and strongly correlated (r = 0.72; P less than 0.001) with estrone circulating levels (E1). MCR were similar in all groups. PR were similar in eugonadal women between 22 (mean +/- SD = 30.9 +/- 9.9 micrograms/d) and 37 yr (mean +/- SD = 25.5 +/- 11.1 micrograms/d) premenopausal women. In healthy postmenopausal women PR were reduced, but not significantly (mean +/- SD = 19.5 +/- 6.95 micrograms/d), whereas osteoporotic patients presented a highly significant reduction of CT PR (mean +/- SD = 9.8 +/- 4 micrograms/d) (P less than 0.01). Because there is a strong relationship between E1 and PR (r = 0.64; P less than 0.001), CT secretory capacity appears to be modulated by estrogen circulating levels. This modulation leads to a menopause-related decrease in iCT. In osteoporotics, an independent impairment of CT production drastically lowers PR and basal iCT levels. CT might be one of the determining factors in the pathogenesis of postmenopausal osteoporosis.     

Peritoneal ultrafiltration and serum icodextrin concentration during dialysis with 7.5% icodextrin solution in Japanese patients.

OBJECTIVES: To assess the efficacy and safety of icodextrin in Japanese patients and to investigate the relationship between net ultrafiltration (UF) during the long dwell and plasma oligosaccharides. DESIGN: Open-labeled clinical trial involving patients on continuous ambulatory peritoneal dialysis (CAPD) receiving icodextrin during the 12-hour long dwell for 6 weeks, preceded by and followed by a 2-week baseline period and a follow-up period during which 1.36% glucose was used for the 8-hour long dwell. SETTING: A prospective, randomized multicenter study done in tertiary medical centers. PATIENTS: 18 stable patients on CAPD for 3 months or longer. MAIN OUTCOMES MEASURES: Net UF (in milliliters), UF rate (in milliliters per hour), plasma oligosaccharides, serum osmolarity (in milliosmoles per liter), peritoneal absorption of icodextrin, and peritoneal clearances of icodextrin, creatinine, and urea were assessed. Adverse events, laboratory findings, and vital signs were also monitored. RESULTS: Long-dwell net UF (544.4 +/- 96.7 mL at day 3, p < 0.001; 309.4 +/- 60.7 mL at week 4, p < 0.001; and 391.7 +/- 61.1 mL at week 6, p < 0.001) and UF rate (48.2 +/- 38.8 mL/ hour at day 3, p < 0.001; 26.9 +/- 22.1 mL/hr at week 4, p < 0.002; and 35.3 +/- 22.9 mL/hr at week 6, p = 0.0002) were significantly greater during the icodextrin period than at baseline (-25.9 +/- 46.0 mL and -2.2 +/- 22.1 mL/hr, respectively). Plasma oligosaccharides reached steady state within 2 weeks, remained stable during the treatment period, and returned to baseline level 2 weeks after discontinuation of icodextrin. Serum osmolarity increased during the use of icodextrin by approximately 5 mOsm/L. No statistically significant relationship was found between plasma oligosaccharides and net UF. Peritoneal absorption of icodextrin (36.3% +/- 5.1% at day 3, 42.2% +/- 5.9% at week 4, and 38.0% +/- 6.3% at week 6) and peritoneal clearance of icodextrin (10.1 mL/minute at day 3, 10.1 mL/min at week 4, and 10.3 mL/min at week 6) showed no major change over time. Serum sodium and serum chloride both decreased by 5 mEq/L with icodextrin but remained within the normal range during the treatment period and returned to baseline levels immediately after discontinuation. No serious adverse events were observed during the study. CONCLUSION: The results of this study do not support the hypothesis that an increased blood oligosaccharide level and the concomitant elevation in serum osmolarity have a negative impact on peritoneal UF. Therefore, the increase in plasma oligosaccharides appears to be too small to be of clinical significance.     

Renal and cardiovascular effects of exogenous insulin in healthy volunteers.

1. Renal and cardiovascular effects of three dosages of insulin [50 (Ins I), 300 (Ins II) and 500 (Ins III) m-units h-1 kg-1] were investigated in healthy males by using a euglycaemic clamp technique. On separate days, control experiments were carried out to correct for any circadian variation in the variables studied. 2. All three insulin dosages resulted in a marked decline in fractional sodium excretion (actual experiments: basal, 0.95 +/- 0.15%, Ins I, 0.79 +/- 0.10%, Ins II, 0.80 +/- 0.12%, Ins III, 0.84 +/- 0.08%; control experiments: basal, 0.96 +/- 0.10%, Ins I, 1.20 +/- 0.12%, Ins II, 1.53 +/- 0.15%, Ins III, 1.43 +/- 0.10%; means +/- SEM, P less than 0.005, analysis of variance). With the highest insulin dosage, the reduction in fractional sodium excretion tended to be less striking. This coincided with a rise in heart rate, pulse pressure and pulse rate-systolic blood pressure product (double product). Although blood pressure itself did not change, systolic blood pressure also tended to increase (actual experiments: basal, 133 +/- 5 mmHg, Ins I, 132 +/- 5 mmHg, Ins II, 139 +/- 5 mmHg, Ins III, 143 +/- 4 mmHg; control experiments: basal, 128 +/- 3 mmHg, Ins I, 129 +/- 3 mmHg, Ins II, 130 +/- 3 mmHg, Ins III, 133 +/- 3 mmHg; means +/- SEM, P = 0.09, analysis of variance). There was a positive correlation between the change in fractional sodium excretion and the change in systolic blood pressure over control values (r = 0.696, P less than 0.028).(ABSTRACT TRUNCATED AT 250 WORDS)     

Longitudinal study of cardiac electrical activity in anesthetized guinea pigs by contactless magnetocardiography

Guinea pigs (GPs) are used for preclinical evaluation of electrophysiologic effects of new drugs, because their myocytes have human-like action potentials and ventricular repolarization's (VR) ion currents. This study was aimed to assess the reliability of magnetocardiographic (MCG) mapping for longitudinal studies of GP cardiac electrical activity. Eighteen anesthetized GPs were investigated with an unshielded 36-channel MCG instrumentation, at the age of 5 months (268.1 +/- 19 g). Twelve GPs survived and were restudied when 14 months old (595.6 +/- 90.5 g). RR, PR, QRS, QT(peak), QT(end), JT(peak), JT(end) and T(peak-end) intervals were measured from MCG waveforms. Magnetic field (MF) maps, equivalent current dipole (ECD) parameters and current density imaging were also analyzed. A significant prolongation of the PR (p < 0.05) and QRS (p < 0.001) intervals was found at 14 months. Gender-related differences of VR intervals were not significant. P(peak) and QRS(peak) MFs were similar in all animals, while T(peak) MF varied interindividually at 5 months and showed a rotation in some animals, at 14 months. The ECD strengths, measured at the P(peak), QRS(peak) and T(peak) were stronger (p < 0.01) at the age of 14 months than at 5 months. In contrast to findings in Wistar rats, age-related and gender-related differences of MCG VR parameters were not significant in GPs. Further work is necessary to clarify the variability of VR MF observed in healthy GPs.     

Endogenous anti-inflammatory response after coronary injury in a porcine model

BACKGROUND: Corticotropin-releasing hormone (CRH)/adrenocorticotropic hormone (ACTH)/cortisol is the major anti-inflammatory system. After percutaneous translumenal angioplasty, an inflammatory process is triggered. We investigate whether CRH/ACTH/cortisol axis is activated after deep vessel wall injury (DVWI). MATERIALS AND METHODS: Plasma and leukocyte CRH and ACTH, serum cortisol and IL-1beta, and leukocyte cAMP were measured (ELISA) in 16 pigs after anaesthesia (baseline), 60 min into anaesthesia without causing vascular injury and 90 min after DVWI of the left anterior descending (LAD) coronary artery induced by percutaneous directional atherectomy (Atherocath GTO 7F; DVI, Inc., Temecula, USA). Biochemical variables were also measured at baseline, 60 and 180 min into anaesthesia in six additional pigs without coronary intervention. RESULTS: MANOVA showed that CRH/ACTH/Cortisol, cAMP and IL-1beta production was not modified during anaesthesia. Post-DVWI plasma CRH (0.077 +/- 0.046 ng mL-1), and cellular cAMP (0.14 +/- 0.067 pmol 10(-6) cells) increased significantly (P = 0.001) with respect to their baseline values (CRH = 0.036 +/- 0.013 ng mL-1; cAMP = 0.081 +/- 0.034 pmol 10-6). There was also a statistically significant increase (P = 0.02) in post-DVWI IL-1beta (from 46.6 +/- 12.8 to 64.05 +/- 13.5 pg mL-1), and in serum cortisol (P = 0.05) compared to its baseline values (8.98 +/- 3.2 microgr dL-1 vs. 6.57 +/- 2.3 microgr dL-1, respectively). CONCLUSION: In our experimental model, coronary vessel wall injury-activated CRH/ACTH/cortisol axis caused a significant increase in plasma CRH, cortisol and cellular cAMP levels, which may influence the response of coronary arteries to injury.     

Baseline resistance and virological outcome in patients with virological failure who start a regimen containing abacavir: EuroSIDA study

OBJECTIVES: To investigate the ability of several HIV-1 drug-resistance interpretation systems, as well as the number of pre-specified combinations of abacavir-related mutations, to predict virological response to abacavir-containing regimens in antiretroviral therapy-experienced, abacavir-naive patients starting an abacavir-containing regimen in the EuroSIDA cohort. PATIENTS AND METHODS: A total of 100 HIV-infected patients with viral load (VL) >500 copies/ml who had a plasma sample available at the time of starting abacavir (baseline) were included. Resistance to abacavir was interpreted by using eight different commonly used systems that consisted of rules-based algorithms or tables of mutations. Correlation between baseline abacavir-resistance mutations and month 6 virological response was performed on this population using a multivariable linear regression model accounting for censored data. RESULTS: The baseline VL was 4.36 log10 RNA copies/ml [interquartile range (IQR): 3.65-4.99 log10 RNA copies/ml] and the median CD4 cell count was 210 cells/microl (IQR: 67-305 cells/microl). Our patients were pre-exposed to a median of seven antiretrovirals (2-12) before starting abacavir therapy. The median (range) number of abacavir mutations (according to the International AIDS Society-USA) detected at baseline was 3.5 (0-8). Overall, the Kaplan-Meier estimate of the median month 6 VL decline was 0.86 log10 RNA copies/ml [95% confidence intervals (95% CI): 0.45-1.24]. The VL in those patients (n=31) who intensified treatment by adding only abacavir decreased by a median 0.20 log10 RNA copies/ml (95% CI: -0.18; +0.94). The proportion of patients who harboured viruses fully resistant to abacavir among the eight genotypic resistance interpretation algorithms ranged from 12% [Agence Nationale de Recherches sur le SIDA (ANRS)] to 79% [Stanford HIV RT and PR Sequence Database (HIVdb)]. Some interpretation systems showed statistically significant associations between the predicted resistance status and the virological response while others showed no consistent association. The number of active drugs in the regimen was associated with greater virological suppression (additional month 6 VL reduction per additional sensitive drug=0.51, 95% CI: 0.15-0.88, P=0.006); baseline VL was also weakly associated (additional month 6 VL reduction per log10 higher=0.30, 95% CI: -0.02; +0.62, P=0.06). In contrast, the number of drugs previously received was associated with diminished viral reduction (additional month 6 VL reduction per additional drug=-0.14, 95% CI: -0.28; 0.00, P=0.05). CONCLUSIONS: Our results revealed a high degree of variability among several genotypic resistance interpretation algorithms currently in use for abacavir. Therefore, the interpretation of genotypic resistance for predicting response to regimens containing abacavir remains a major challenge.     

Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with ritonavir

BACKGROUND AND OBJECTIVES: Acute ingestion of usual quantities of grapefruit juice produces inhibition of enteric cytochrome P450 (CYP) 3A enzymes, causing pharmacokinetic interactions with a number of drugs. However, the effect of extended exposure to grapefruit juice on CYP3A activity is not established. METHODS: Triazolam, a CYP3A index compound, was administered to 3 cohorts of volunteers (n = 6-7 per group) on 4 occasions (trials 1-4), as follows: 1 day prior to cotreatment initiation, at the beginning and end of cotreatment, and 3 days after cotreatment discontinuation. The 3 cotreatments (daily administration for 10 consecutive days) were: 300 mL grapefruit juice, 400 mg ritonavir, or 300 mL water. RESULTS: Grapefruit juice cotreatment (trial 2) increased the triazolam area under the plasma concentration curve by 50% compared to the trial 1 control (15.1 +/- 7.6 ng/mL.h versus 10.0 +/- 3.5 ng/mL.h, P < .05), but the half-life was not changed. Effects of acute and extended exposure to grapefruit juice (trials 2 and 3) were similar, and produced augmentation in benzodiazepine agonist effects measured by the Digit Symbol Substitution Test and electroencephalographic beta amplitude. Kinetic and dynamic effects reverted to baseline (trial 1) values at 3 days after grapefruit juice discontinuation (trial 4). Ritonavir caused a more than 20-fold increase in the triazolam area under the plasma concentration curve during trial 2 (553 +/- 422 ng/mL.h) and trial 3 (287 +/- 299 ng/mL.h) compared to the trial 1 control (13.3 +/- 16.3 ng/mL.h) (P < .05 for both comparisons); Digit Symbol Substitution Test and electroencephalographic pharmacodynamics increased in parallel. During trial 4, triazolam kinetics reverted close to trial 1 values, with no evidence of induction. Triazolam kinetics were not altered by water cotreatment. CONCLUSION: Acute and extended exposure to grapefruit juice produces quantitatively similar inhibition of enteric, but not hepatic, CYP3A. Recovery is complete within 3 days after grapefruit juice discontinuation. Ritonavir greatly inhibits both enteric and hepatic CYP3A. With extended exposure to ritonavir, inhibition is the predominant effect, and recovery to baseline is nearly complete 3 days after ritonavir discontinuation.     

The effect of angiotensin-l converting enzyme inhibition on insulin action in healthy volunteers

Acute hyperinsulinaemia, achieving insulin levels within the physiological range, induces sodium retention. At the same time an activation of the renin-angiotensin system occurs, with a rise in plasma renin activity (PRA) and angiotensin-II level but no change in plasma aldosterone. After administration of higher, pharmacological doses of insulin an increase in systolic blood pressure and heart rate can also be observed, while further increases in PRA and angiotensin-II are noted. To determine whether angiotensin-II is involved in observed insulin actions, we studied the renal and cardiovascular effects of three dosages of insulin (50 (Ins I), 300 (Ins II) and 500 (Ins III) mU kg-1 h-1) in healthy subjects after one week of treatment with the angiotensin-I converting enzyme inhibitor enalapril (10 mg twice a day), using the euglycaemic clamp technique. Control data were obtained from two previously conducted experiments in the same subjects, one with infusion of insulin and one with the insulin solvent only. The effect of insulin on fractional sodium excretion, blood pressure and heart rate was unaffected by enalapril, which precludes any involvement of the renin-angiotensin system with regard to these aspects of insulin action. Insulin sensitivity increased significantly during treatment with enalapril (with enalapril: Ins I: 11.3 +/- 3.0, Ins II: 20.0 +/- 3.4 and Ins III: 20.6 +/- 3.9 mg kg-1 min-1 glucose (mean +/- SD); without enalapril: Ins I: 8.7 +/- 2.3, Ins II: 13.7 +/- 3.0 and Ins III: 15.5 +/- 3.1 mg kg-1 min-1 glucose; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic clearance and production rates of prolactin in man.

Metabolic clearance rates (MCR) and production rates (PR) of prolactin (PRL) have been determined by the constant infusion to equilibrium technique in 11 normal subjects, 6 patients with hyperthyroidism, 4 patients with hypothyroidism, and 9 patients with hyperprolactinemia. PRL MCR was also determined tin four patients during dopamine infusion. Mean PRL MCR was 46 +/- 1 ml/min per m2 in women and 44 +/- 3 ml/min per m2 in men, and was significantly correlated with body mass (r = 0.84, P less than 0.001). In contrast with controls, PRL MCR was higher in hyperthyroidism (MCR = 52 +/- 8 ml/min per m2, P less than 0.05), was slightly lower in hypothyroidism (MCR = 38 +/- 10 ml/min per m2, P = NS), and was significantly correlated with serum thyroxine (r = 0.46, P less than 0.02). PRL MCR was lower than controls in hyperprolactinemia (MCR = 40 +/- 5 ml/min per m2, P less than 0.01) and was inversely correlated with serum PRL (r = -0.72, P less than 0.001). PRL MCR was not significantly changed by dopamine infusion. Mean PRL PR for women and men was 211 +/- 74 and 187 +/- 44 micrograms/d per m2, respectively (P = NS). In hyperthyroidism the PRL PR was elevated (PR = 335 +/- 68 micrograms/d per m2, P less than 0.02), but in hypothyroidism the increase (PR = 233 +/- 159 micrograms/d per m2) was not significant. In hyperprolactinemia the PRL PR was extremely high (PR = 31,000 +/- 29,000 micrograms/d per m2). Dopamine infusion decreased RPL PR from 270 to 66 micrograms/d per m2 indicating that its effect was on pituitary PRL secretion and not PRL metabolism. To evaluate possible circulating PRL heterogeneity that might arise during infusion, gel filtration of infusate and serum obtained during the MCR procedure was performed. Labeled monomeric PRL (peak III, Kav (partition coefficient) = 0.4) was partially converted to two larger forms (peaks I and II) in vivo. Peak I (Kav = 0) was 30--40% immunoprecipitable, although peak II (Kav = 0.2) was not immunoprecipitable. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of peak I resulted in greater than or equal to 90% conversion to peak III and restoration of full immunoactivity. Thus, peak I is a noncovalently linked aggregate that is partially immunoactive, and therefore able to alter MCR determinations. These studies demonstrate the impact of hormone heterogeneity on MCR estimations and suggest that gel filtration of immunoprecipitable material be an integral part of future MCR measurements.     

Effect of pinitol treatment on insulin action in subjects with insulin resistance

OBJECTIVE: Endogenous low-molecular-weight glycans containing pinitol (3-O-methyl-D-chiro-inositol) and D-chiro-inositol are thought to mediate certain actions of insulin. We tested the hypothesis that oral administration of soybean-derived pinitol would improve insulin sensitivity in obese subjects (BMI = 36.6 kg/m2) with diet-treated type 2 diabetes or glucose intolerance (HbA1c = 6.8%). RESEARCH DESIGN AND METHODS: There were 22 subjects randomized to receive either pinitol 20 mg x kg(-1) x day(-1) (n = 12) or placebo (n = 10) in a 28-day double-blinded trial. RESULTS: No toxicity due to the pinitol was observed during the study The sensitivity of glucose and lipid metabolism to insulin were assessed by measurement of whole-body glucose, palmitate, and glycerol kinetics during basal conditions and a hyperinsulinemic-euglycemic clamp. Metabolic measurements were made at baseline and again at the end of the study Final plasma levels of pinitol were 48-fold (1.06 +/- 0.15 vs. 0.02 +/- 0.01 micromol/l, P < 0.0001) and D-chiro-inositol levels 14-fold (0.56 +/- 0.08 vs. 0.04 +/- 0.02 micromol/l, P < 0.0001) greater in the pinitol group compared with placebo. CONCLUSIONS: Four weeks of pinitol treatment did not alter baseline glucose production, insulin-mediated glucose disposal, or rates of appearance of free fatty acids and glycerol in plasma. We conclude that plasma levels of both pinitol and D-chiro-inositol are very responsive to pinitol ingestion, but insulin sensitivity does not increase after pinitol treatment in individuals with obesity and mild type 2 diabetes.     

Comparison of cisapride and metoclopramide for facilitating gastric emptying and improving tolerance to intragastric enteral nutrition in critically III, mechanically ventilated adults.

BACKGROUND: Placebo-controlled studies have indicated that both cisapride and metoclopramide promote gastric motility in critically ill patients. Objective: This study was conducted to compare cisapride and metoclopramide for facilitating gastric emptying and improving tolerance to intragastric enteral nutrition (EN) and to evaluate the relationship between aspirated gastric residual volume and gastric emptying function in this patient population. METHODS: In this double-blind study, critically ill, mechanically ventilated patients with an aspirated gastric residual volume > or = 150 mL while receiving intragastric EN were randomized to receive enteral cisapride 10 mg or metoclopramide 10 mg every 6 hours for a total of 7 doses. The acetaminophen-absorption method was used to assess gastric emptying at baseline and 30 minutes after the seventh dose by determining the area under the plasma concentration-time curve at 240 minutes (AUC240), maximum concentration (Cmax), and time to Cmax (Tmax). Gastric residual volume was measured every 6 hours before dosing. RESULTS: Fourteen patients were included in the study, 7 in each group. Patient characteristics were similar in the 2 groups. Compared with baseline, metoclopramide significantly accelerated Tmax (39.00 +/- 15.56 min with metoclopramide vs 103.71 +/- 47.35 min at baseline; P = 0.018) and increased Cmax (12.94 +/- 6.68 mg/L vs 6.97 +/- 4.78 mg/L; P = 0.018) and AUC240 (1,421.43 +/- 780.31 mg/L x min vs 839.00 +/- 545.58 mg/L x min; P = 0.043). Cisapride increased Cmax from baseline (12.27 +/- 8.95 mg/L vs 4.53 +/- 2.37 mg/L, respectively), but the difference was not statistically significant. Gastric residual volume was significantly reduced from baseline after 3 doses of metoclopramide (from 268.7 +/- 112.3 mL to 57.0 +/- 23.1 mL; P < 0.05) and was significantly lower after the seventh dose of metoclopramide than after the seventh dose of cisapride (5.3 +/- 8.2 mL vs 41.4 +/- 39.7 mL, respectively; P = 0.05). Cmax at baseline and residual volume at study entry were inversely correlated (r = -0.50; P = 0.049). Conclusions: Both cisapride and metoclopramide enhanced gastric motility and improved tolerance to intragastric EN. Metoclopramide reduced gastric residual volume to a significantly greater extent than did cisapride. Only Cmax at baseline was inversely associated with residual volume.     

Long-term virological outcome and resistance mutations at virological rebound in HIV-infected adults on protease inhibitor-sparing highly active antiretroviral therapy

OBJECTIVE: To assess the durability of the undetectability of HIV plasma viraemia (pV) and to determine the factors associated with virological rebound (VR) in HIV-infected adults on protease inhibitor (PI)-sparing highly active antiretroviral therapy (HAART). The development of resistance mutations during virologically successful therapy and VR was also analysed. MATERIALS AND METHODS: One hundred and twenty-six HIV-infected adults on PI-sparing HAART were prospectively followed from April 1998 to December 2002: Group 1, naive for antiretroviral drugs (n = 26); Group 2, previously PI-HAART-exposed patients (n = 19); Group 3, previously exposed to suboptimal therapy (n = 81). Genotypic resistance tests on peripheral blood mononuclear cells or on plasma RNA (when feasible) were carried out when undetectable HIV pV was demonstrated for at least 48 weeks. Additionally, patients showing a therapy adherence >95% developing VR were also tested at rebound, at simplification and during previous suboptimal therapy exposure. RESULTS: The median follow-up time was 630 [329-903] days. VR was considered as two consecutive pV levels >50 copies/mL. Twenty-two (17.5%) patients developed VR. Only therapy adherence <95% was independently associated with VR (adjusted hazard ratio: 8.42; 95% CI: 3.33-21.27). Twenty (40%) of the 50 patients with pV < 50 copies/mL for at least 48 weeks showed at least one thymidine-associated mutation (TAM) but none had NNRTI-resistance mutations. Ten (83.3%) of 12 available adherent patients showing VR harboured NNRTI-resistance-associated mutations; 50% of them were considered as wild-type strains at simplification time. However, the TAM number and resistance mutations profile found on suboptimal exposure were very similar to those found at VR on simplification therapy. CONCLUSIONS: PI-sparing HAART allows maintenance of successful long-term control of HIV replication, adherence to therapy being the main factor associated with VR. However, a small proportion of patients on simplification regimen may develop VR regardless of therapy compliance. VR on PI-sparing HAART is characterized by the emergence of NNRTI cross-resistance mutations. Finally, TAMs 'archived' during previous suboptimal exposures are partially involved in subsequent VR on simplification HAART.