A Comparative Study of the Pharmacokinetics of Clozapine N-Oxide and Clozapine N-Oxide Hydrochloride Salt in Rhesus Macaques.

Translating chemogenetic techniques from nonhuman primates to potential clinical applications has been complicated in part due to in vivo conversion of the chemogenetic actuator, clozapine N-oxide (CNO), to its pharmacologically active parent compound, clozapine, a ligand with known side effects, including five boxed warnings from the Food and Drug Administration. Additionally, the limited solubility of CNO requires high concentrations of potentially toxic detergents such as dimethylsulfoxide (DMSO). To address these concerns, pharmacokinetic profiling of commercially available CNO in DMSO (CNO-DMSO, 10% v/v DMSO in saline) and a water-soluble salt preparation (CNO-HCl, saline) was conducted in rhesus macaques. A time course of blood plasma and cerebrospinal fluid (CSF) concentrations of CNO and clozapine was conducted (30-240 minutes post-administration) following a range of doses (3-10 mg/kg, i.m. and/or i.v.) of CNO-DMSO or CNO-HCl. CNO-HCl resulted in 6- to 7-fold higher plasma concentrations of CNO compared to CNO-DMSO, and relatively less clozapine (3%-5% clozapine/CNO in the CNO-DMSO group and 0.5%-1.5% clozapine/CNO in the CNO-HCl group). Both groups had large between-subjects variability, pointing to the necessity of performing individual CNO pharmacokinetic studies prior to further experimentation. The ratio of CNO measured in the CSF was between 2% and 6% of that measured in the plasma and did not differ across drug preparation, indicating that CSF concentrations may be approximated from plasma samples. In conclusion, CNO-HCl demonstrated improved bioavailability compared with CNO-DMSO with less conversion to clozapine. Further investigation is needed to determine if brain concentrations of clozapine following CNO-HCl administration are pharmacologically active at off-target monoaminergic receptor systems in the primate brain.

The Basic Metabolic Profile in Heart Failure-Marker and Modifier.

PURPOSE OF REVIEW: The physiologic determinants of each of the components of the basic metabolic profile in patients with heart failure will be explored. Additionally, the review will discuss the prognostic value of alterations in the basic metabolic profile as well as their effects on management. RECENT FINDINGS: Abnormalities in the basic metabolic profile have significant correlation with clinical outcomes and can modify treatment in heart failure. Hypochloremia has recently received increased attention for these reasons. Elevated creatinine, increased blood urea nitrogen, hyponatremia, and hypochloremia correlate with worse mortality and diuretic resistance in heart failure. Hypokalemia, even when mild, has proven to be a worse clinical indicator than modest elevations in serum potassium. Hypochloremia is mechanistically linked to hyponatremia and metabolic alkalosis, but recent compelling data suggests that it can provide more discriminating prognostic information. Knowledge of the physiologic basis for each of these alterations informs their management.

Cambios clínicos y analíticos al sustituir el líquido de diálisis convencional por uno sin acetato / Clinical and analytical changes in hemodialysis without acetate

Introducción: El objetivo de dicho estudio fue evaluar los cambios en la acetatemia durante la hemodiálisis (HD) en pacientes con líquido de diálisis (LD) convencional con acetato y en pacientes con LD con clorhídrico (HCl) y analizar sus efectos sobre la clínica y sobre distintos parámetros analíticos. Material y métodos: 14 pacientes en programa de HD estable (11 hombres) de 61 ± 15 años de edad fuerondializados durante 1 mes con el LD convencional con acetato y durante el segundo mes con el LD con HCl (sin acetato). Se obtuvieron análisis pre y post-diálisisla tercera sesión de las semanas 1 y 4 en cada uno de los períodos (con y sin acetato).Resultados: Las medias de los acetatos pre-diálisis fueron similares en ambos grupos, mientras que las medias de los acetatos post-diálisis fueron significativamente superiores en el grupo tratado con el LD convencional (0,48 ± 0,64 vs 0,18 ±0,23 mmol/L, p = 0,024). Tampoco hallamos diferencias significativas entre los 2 grupos en cuanto a la presencia de valores de acetato pre-diálisis patológicos, mientras sí hallamos un mayor porcentaje valores patológicos de acetato post-diálisis enel grupo tratado con LD convencional respecto al grupo del HCl (67% vs 21%, p = 0,001). Los niveles plasmáticos de IL-6 fueron significativamente superiores en el periodo de diálisis con acetato (31,7 ± 24,7 vs 18,7 ± 10,3 pg/ml, p = 0,014), aunque no se acompañaron de un aumento de otros marcadores inflamatorios como la LBP,el TNF-alfa o la PCR dializante el mismo periodo. No hallamos diferencias estadísticamente significativas en los otros parámetros evaluados excepto en la variación de las concentraciones de sodio, cloro y bicarbonato. Conclusiones: El LD sin acetato no expone a los pacientes a concentraciones elevadas de acetato consiguiendo que la mayoría de pacientes (79%) termine la HD con una acetatemia dentro del rango fisiológico.El uso de LD sin acetato es seguro y bien tolerado por los pacientes en hemodiálisis, aunque su traducción clínica debe ser evaluada en estudios prospectivosa más largo plazo (AU)

Background: the purpose of this study was to evaluate blood acetate levels and its correlation with clinical and analytical changes in hemodialysis patients treated with standard bicarbonate dialysate compared to treatment with acetate-free bicarbonate dialysate. Methods: Fourteen patients on hemodialysis (11 male) with mean age of 61 ± 15 years were treated with conventional bicarbonate dialysate for 1 month andthen switched to acetate-free bicarbonate dialysate for another month. Blood samples were drawn at the third session of first and fourth week of each type of dialysis.Results: Pre-dialysis blood acetate levels were similar in both groups, whereas postdialysis blood acetate levels were higher in patients treated with conventional bicarbonate dialysate (0.48 ± 0.64 vs 0.18 ± 0.23 mmol/L, p = 0.024). Moreover, both periods had similar percentage of patients with pre-dialysis blood acetate levels in the pathologic range, whereas this percentage was higher in post-dialysis samples from patients treated with conventional bicarbonate dialysate respect to acetate-free dialysate (67% vs 21%, p = 0.001). Serum levels of interleukin-6 were statistically higher in the period with conventional bicarbonate dialysate (31.7 ± 24.7 vs 18,7 ± 10,3 pg/ml, p = 0,014), even though other inflammatory markers such as LBP, TNF-alfa and CRP failed to increase in the same period. We didn’t found significant differences in the other parameters studied except for the changes in serum concentrationsof sodium, chloride and bicarbonate. Conclusions: Acetate-free bicarbonate dialysate does not expose patients to a big amount of acetate and allows that the majority of patients finished hemodialysis with blood acetate levels in the physiologic ranges. Acetate-free dialysate was safe and well tolerated by our hemodialysis patients, although clinical advantages derived from its use should be evaluated in long-termprospective studies (AU)

Arterial acid-base status during digestion and following vascular infusion of NaHCO(3) and HCl in the South American rattlesnake, Crotalus durissus.

Digestion is associated with gastric secretion that leads to an alkalinisation of the blood, termed the "alkaline tide". Numerous studies on different reptiles and amphibians show that while plasma bicarbonate concentration ([HCO(3)(-)](pl)) increases substantially during digestion, arterial pH (pHa) remains virtually unchanged, due to a concurrent rise in arterial PCO(2) (PaCO(2)) caused by a relative hypoventilation. This has led to the suggestion that postprandial amphibians and reptiles regulate pHa rather than PaCO(2). Here we characterize blood gases in the South American rattlesnake (Crotalus durissus) during digestion and following systemic infusions of NaHCO(3) and HCl in fasting animals to induce a metabolic alkalosis or acidosis in fasting animals. The magnitude of these acid-base disturbances were similar in magnitude to that mediated by digestion and exercise. Plasma [HCO(3)(-)] increased from 18.4+/-1.5 to 23.7+/-1.0 mmol L(-1) during digestion and was accompanied by a respiratory compensation where PaCO(2) increased from 13.0+/-0.7 to 19.1+/-1.4 mm Hg at 24 h. As a result, pHa decreased slightly, but were significantly below fasting levels 36 h into digestion. Infusion of NaHCO(3) (7 mmol kg(-1)) resulted in a 10 mmol L(-1) increase in plasma [HCO(3)(-)] within 1 h and was accompanied by a rapid elevation of pHa (from 7.58+/-0.01 to 7.78+/-0.02). PaCO(2), however, did not change following HCO(3)(-) infusion, which indicates a lack of respiratory compensation. Following infusion of HCl (4 mmol kg(-1)), plasma pHa decreased by 0.07 units and [HCO(3)(-)](pl) was reduced by 4.6 mmol L(-1) within the first 3 h. PaCO(2), however, was not affected and there was no evidence for respiratory compensation. Our data show that digesting rattlesnakes exhibit respiratory compensations to the alkaline tide, whereas artificially induced metabolic acid-base disturbances of same magnitude remain uncompensated. It seems difficult to envision that the central and peripheral chemoreceptors would experience different stimuli during these conditions. One explanation for the different ventilatory responses could be that digestion induces a more relaxed state with low responsiveness to ventilatory stimuli.

Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis.

STUDY OBJECTIVE: To determine the effects of hyperchloremic acidosis, induced by dilute HCl infusion, on BP and circulating inflammatory mediators in an experimental model of severe sepsis in the rat. DESIGN: Randomized, open-label, controlled experiment. SETTING: University research laboratory. PARTICIPANTS: Twenty-four adult, male, Sprague-Dawley rats. INTERVENTION: Eighteen hours after inducing lethal sepsis by cecal ligation and puncture, animals were randomized and classified into three groups. In groups 2 and 3, we began an IV infusion of 0.1 N HCl to reduce the standard base excess (SBE) by 5 to 10 mEq/L and 10 to 15 mEq/L, respectively. In group 1, we infused a similar volume of lactated Ringer solution. In all groups, infusions were continued for 8 h or until the animals died. MEASUREMENTS: We measured mean arterial pressure (MAP), arterial blood gases, electrolytes, plasma nitrate/nitrite, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10 levels at 0 h, 3 h, 6 h, and 8 h. RESULTS: MAP remained stable in group 1 but decreased in groups 2 and 3 (p < 0.001), such that at 8 h MAP was much higher in group 1 (94 +/- 9.2 mm Hg) [+/- SD] compared to either group 2 (71.6 +/- 20.1 mm Hg) or group 3 (49.4 +/- 33.2 mm Hg) [p = 0.01]. This change in MAP correlated with the increase in plasma Cl(-) (R(2) = 0.50, p < 0.0001) and less well with the decrease in pH (R(2) = 0.24, p < 0.001). After 6 h of acidosis, plasma nitrite levels were significantly higher in group 2 animals compared to either group 1 or group 3 animals (p < 0.05). Plasma TNF-alpha, IL-6, or IL-10 levels were not significantly different from control animals. CONCLUSION: Moderate acidosis (SBE of 5 to 10 mEq/L), induced by HCl infusion, worsened BP and increased plasma nitrate/nitrite levels but had no effect on circulating cytokines in septic rats. However, severe acidosis (SBE of 10 to 15 mEq/L), while still causing hypotension, did not affect plasma nitrate/nitrite levels.

Effect of acidotic blood reperfusion on reperfusion injury after coronary artery occlusion in the dog heart.

A prolongation of the intracellular acidosis after myocardial ischemia can protect the myocardium against reperfusion injury. In isolated hearts, this was achieved by prolongation of the extracellular acidosis. The aim of this study was to investigate whether regional reperfusion with acidotic blood after coronary artery occlusion can reduce infarct size and improve myocardial function in vivo. Anesthetized open-chest dogs were instrumented for measurement of regional myocardial function, assessed by sonomicrometry as systolic wall thickening (sWT). Infarct size was determined by triphenyltetrazolium staining after 3 h of reperfusion. The left anterior descending coronary artery (LAD) was perfused through a bypass from the left carotid artery. The animals underwent 1 h of LAD occlusion and subsequent bypass-reperfusion with normal blood (control, n = 6) or blood equilibrated to pH = 6.8 by using 0.1 mM HCl during the first 30 min of reperfusion (HCl, n = 5). Regional collateral blood flow (RCBF) at 30-min occlusion was measured by using colored microspheres. There was no difference in recovery of sWT in the LAD-perfused area between the two groups at the end of the experiments [-2.8+/-1.2% (HCl) vs. -4.4+/-2.5% (control); mean +/- SEM; p = NS]. RCBF was comparable in both groups. Infarct size (percentage of area at risk) was reduced in the treatment group (12.8+/-2.8%) compared with the control group (26.2+/-4.8%; p < 0.05). These results indicate that reperfusion injury after coronary artery occlusion can be reduced by a prolonged local extracellular acidosis in vivo.

Bupivacaine carbonate and bupivacaine hydrochloride: a comparison of blood concentrations during epidural blockade for vaginal surgery.

Carbonated bupivacaine, plain bupivacaine hydrochloride, and bupivacaine hydrochloride with adrenaline were used to provide epidural analgesia for patients undergoing vaginal hysterectomy. Following injection to the blood concentrations of bupivacaine were measured at intervals over a period of 30 minutes. All three preparations produced satisfactory analgesia at a bupivacaine dose of 1.5 mg/kg body weight. The highest group mean blood concentrations were just outside the toxic dose range. Carbonated bupivacaine was absorbed most rapidly producing significantly higher blood concentrations up to 12 minutes after injection.

Renal regulation of acid-base equilibrium during chronic administration of mineral acid.

Previous studies in metabolic alkalosis have demonstrated that two factors are the prime determinants of acid excretion and bicarbonate reabsorption; first, the diversion to distal exchange sites of sodium previously reabsorbed in the proximal tubule and loop of Henle; and, second, a stimulus to sodium-cation exchange greater than that produced by a low-salt diet alone. In the present study we have examined the hypothesis that these two factors are also the prime determinants of acid excretion during the administration of mineral acid loads. To test this hypothesis, we have administered to dogs ingesting a low NaCl diet a daily dose of 7 meq/kg of H+ with anions (chloride, sulfate, or nitrate) whose differing degrees of reabsorbability influence the speed and completeness with which each is delivered to the distal nephron with its accompanying Na+. After 2-3 wk of acid administration, and after an initial urinary loss of Na+ and K+, the steady-state value for plasma [HCO3-] was 8.6 meq/liter below control in the HCl group, 3.7 meq/liter below control in the H2SO4 group, and unchanged from control in the HNO3 group; all of these values were significantly different from each other. We would propose the following explanation for our findings: when HCl is administered chronically, marked acidosis occurs because distal delivery of Cl- is restricted by the ease with which the Cl- can be reabsorbed in the proximal portions of the nephron. Only when Cl- retention produces sufficient hyperchloremia to insure delivery of Na+ (previously reabsorbed in proximal tubule and loop of Henle) to the distal nephron in quantities equal to ingested Cl is this primary constraint removed. In the case of sulfuric and nitric acids, there is no constraint on distal delivery, the nonreabsorbability of the administered anion causing prompt, total delivery of Na+ to exchange sites in quantities equal to administered hydrogen. Thus, with H2SO4 and HNO3 the sole constraint on removal of the acid load is the inability of the distal exchange mechanism to conserve the Na+ increment fully by means of H+ exchange. Escape of Na+ and K+ into the urine and the resulting stimulus to Na(+)-H+ exchange remove this constraint and are responsible for establishment of a new steady-state of acid-base equilibrium at plasma [HCO3-] levels significantly higher than those seen with HCl. The feeding of HCl in the presence of a normal salt intake led to a degree of metabolic acidosis not significantly different from that seen in dogs ingesting a low-salt diet. We suggest that the presence of dietary sodium at distal exchange sites did not enhance acid excretion because it is only after a loss of body sodium stores that sodium avidity is increased sufficiently to allow full removal of the acid load. The present findings indicate that the fundamental factors controlling acid excretion and bicarbonate reabsorption in metabolic acidosis are closely similar to those operative in metabolic alkalosis.