Relationship between urinary concentrating ability, arginine vasopressin in plasma and blood pressure after renal transplantation

Arginine vasopressin (AVP) and serum osmolality (Sosm) were determined in plasma before and after a 24-h period of water deprivation in 19 patients with post-renal-transplant hypertension (group I), 14 patients with normal blood pressure after renal transplantation (group II), and 16 healthy control subjects (group III). Urine was collected in four periods of 6 h each for measurement of urine volume (V), urine osmolality (Uosm) and tubular capacity for reabsorption of water (Tc water). AVP and Sosm increased significantly in all groups. The AVP levels were the same in groups I and II, but higher in group I than III both before and after water deprivation. In group II, AVP was higher than in group III only after water deprivation; V was significantly reduced in all groups. In groups I and II, V, Tc water and Uosm were the same. In group III, V was significantly lower than in groups I and II in the last three 6-h periods, and in group III, Tc water was higher in the first 6-h period than in groups I and II. There was a significant positive correlation between AVP and Sosm in all groups. In conclusion, renal water excretion cannot be reduced as rapidly and to the same degree in renal transplant recipients as in control subjects because of a decreased renal capacity for reabsorption of water. The higher AVP level in the transplant recipients may be a compensatory phenomenon for the decreased responsiveness of the renal collecting ducts in the transplanted kidneys. The sensitivity of the osmoreceptors to changes in osmotic stimuli was normal.     

Radioimmunoassay of Vasopressin in Unextracted Plasma

A radioimmunoassay (RIA) for arg₈-vasopressin (AVP) in unextracted human plasma was based on a sensitive anti-AVP rabbit antiserum, inhibition of enzymatic damage to [¹²⁵I]AVP and AVP, and the use of an individual plasma blank, to correct for interference of plasma factors with the RIA. Sensitivity was 0.4 pg of synthetic AVP detected, corresponding to 1.2 pg/ml of AVP in human plasma. Recovery of AVP added to pooled plasma was 94 ± 9.3% (mean± S.D.) in the low range (AVP, 2.8 pg/ml added) and 106 ± 11.7% in the high range (45.0 pg/ml added). In 26 healthy, ambulatory subjects on ad lib. water intake, plasma AVP concentration was 2.0 ± 1.22 pg/ml in the supine position and in 28 healthy subjects, 6.2 ± 4.3 pg/ml in the upright position. Water loading suppressed the plasma AVP concentration. Smoking caused increased plasma AVP in 3 subjects despite water loading.     

比较PET/CT显像中肝脏18F-FDG摄取半定量分析方法

目的 探讨PET/CT显像中影响肝脏¹⁸F-FDG摄取的因素,分析常规体质量（BM）、瘦体质量（LBM）及体表面积（BSA）校正最大标准化摄取值（SUV_max-B、SUV_max-L、SUV_max-S）的应用价值。方法 回顾性分析行¹⁸F-FDG PET/CT显像的67名健康受检者。测量肝脏SUV_max-B、SUV_max-L及SUV_max-S,分析年龄、空腹血糖水平、体质量指数（BMI）、肝脏CT值、性别、脂肪肝对上述参数的影响。结果 空腹血糖水平与肝脏SUV_max-B、SUV_max-L、SUV_max-S均呈正相关（r=0.329、0.336、0.353,P=0.012、0.010、0.007）。BMI与肝脏SUV_max-B （r=0.543,P<0.01）、SUV_max-L （r=0.328,P=0.07）呈正相关BMI与SUV_max-S无相关性（r=0.026,P=0.833）。受检者年龄、肝脏CT值与肝脏SUV_max-B、SUV_max-L、SUV_max-S均无相关性（P均>0.05）。男性肝脏SUV_max-B （t=2.608,P=0.011）、SUV_max-L （t=5.272,P<0.001）明显高于女性,男性与女性肝脏SUV_max-S无统计学差异（t=0.759,P=0.450）。脂肪肝受检者与非脂肪肝受检者肝脏SUV_max-B、SUV_max-L、SUV_max-S均无统计学差异（P=0.646、0.775、0.068）。结论 空腹血糖水平、BMI、性别是PET/CT显像中影响肝脏摄取¹⁸F-FDG的因素。BMI较大的受检者可采用SUV_max-L或SUV_max-S代替SUV_max-B,此外SUV_max-S可弥补性别间的差异,但校正技术无法减弱血糖水平对肝脏SUV_max的影响。     

Vascular Effects of Arginine Vasopressin during Fluid Deprivation in the Rat

The vascular effects of arginine vasopressin (AVP) were examined in conscious Sprague-Dawley rats. In six control rats, synthetic AVP at a dose of 40 ng/kg, injected as an intravenous bolus, resulted in a rise in mean arterial blood pressure (BP) from 127 to 149 mm Hg (P < 0.005). No tachyphylaxis was observed after a second AVP bolus administered 30 min later, as BP increased from 125 to 150 mm Hg, P < 0.005. In a second group of six rats, 1-deamino penicillamine, 2-(O-methyl) tyrosine AVP ([dPTyr (Me)]AVP), was administered intravenously at a dose of 10 μg/kg, just before the second AVP bolus. In this group of studies BP rose from 124 to 150 mm Hg (P < 0.01) after the first AVP bolus, but not after the second AVP bolus, which was administered after [dPTyr (Me)]AVP (129 vs. 129 mm Hg, NS). To assess the effect of this AVP pressor antagonist on BP in rats with suppressed endogenous vasopressin, six water-diuresing rats (mean urinary osmolality, 99 mosmol/kg H₂O) were administered the analogue at the same dose as the first group of rats. The analogue exerted no demonstrable effect on mean BP (128 before vs. 129 mm Hg after [dPTyr (Me)]AVP, NS). In these rats, mean radioimmunoassayable levels of AVP were at or below the detectable limits of our assay (0.5 pg/ml). In contrast, six rats in which endogenous AVP was stimulated by fluid deprivation for 24 h (mean urinary osmolality, 2,489 mosmol/kg H₂O and mean AVP level of 21.6 pg/ml) had a marked fall in BP when administered the AVP analogue. In these animals [dPTyr (Me)]AVP caused a fall in BP from 124 to 110 mm Hg (P < 0.005). This fall in blood pressure was due to a fall in peripheral vascular resistance (0.35 vs. 0.30 mm Hg/ml per min per kg, P < 0.02) after [dPTyr (Me)]AVP, as cardiac index remained unchanged.     

Effects of alpha-thalassemia and sickle polymerization tendency on the urine-concentrating defect of individuals with sickle cell trait.

A defect in urine concentrating ability occurs in individuals with sickle cell trait (HbAS). This may result from intracellular polymerization of sickle hemoglobin (HbS) in erythrocytes, leading to microvascular occlusion, in the vasa recta of the renal medulla. To test the hypothesis that the severity of the concentrating defect is related to the percentage of sickle hemoglobin present in erythrocytes, urinary concentrating ability was examined after overnight water deprivation, and intranasal desmopressin acetate (dDAVP) in 27 individuals with HbAS. The HbAS individuals were separated into those who had a normal alpha-globin genotype (alpha alpha/alpha alpha), and those who were either heterozygous (-alpha/alpha alpha) or homozygous (-alpha/-alpha) for gene-deletion alpha-thalassemia, because alpha-thalassemia modulates the HbS concentration in HbAS. The urinary concentrating ability was less in the alpha alpha/alpha alpha genotype than in the -alpha/alpha alpha or -alpha/-alpha genotypes (P less than 0.05). After dDAVP, the urine osmolality was greater in patients with the -alpha/-alpha genotype than with the -alpha/alpha alpha genotype (882 +/- 37 vs. 672 +/- 38 mOsm/kg H2O) (P less than 0.05); patients with the -alpha/alpha alpha genotype had greater concentrating ability than individuals with a normal alpha-globin gene arrangement. There was an inverse linear correlation between urinary osmolality after dDAVP and the percentage HbS in all patients studied (r = -0.654; P less than 0.05). A linear correlation also existed for urine concentrating ability and the calculated polymerization tendencies for an oxygen saturation of 0.4 and O (r = -0.62 and 0.69, respectively). We conclude that the severity of hyposthenuria in HbAS is heterogeneous. It is determined by the amount of HbS polymer, that in turn is dependent upon the percentage HbS, which is itself related to the alpha-globin genotype.     

Evidence for a Role of Opioid Peptides in the Release of Arginine Vasopressin in the Conscious Rat

Recent reports have suggested that opioid peptides may be involved in renal water excretion. The present in vivo experiments, therefore, were undertaken to determine the effect of opioid peptides on the osmotic and nonosmotic release of arginine vasopressin (AVP) in the conscious rat. Experimental animals were infused intravenously with naloxone (20 μg/kg per min) or oxilorphan (40 μg/kg per min), chemically dissimilar opioid antagonists. Control rats were infused with normal saline, the vehicle for the opioid antagonists. In all three groups the osmotic release of AVP was examined during an acute hypertonic saline (3%) infusion (2 ml/100 g body wt). The antidiuresis following the hypertonic saline infusion was significantly attenuated in naloxone- and oxilorphan-treated rats, as the peak urinary osmolality (Uosm) rose to 581.4±22.4 and 558.2±27.6 mosmol/kg H₂O in naloxone- and oxilorphan-treated rats as compared with the value in control rats of 735.3±24.2 mosmol/kg H₂O (both P < 0.001 vs. control). At the same time the plasma AVP levels of 5.4±1.3 and 5.2±1.1 pg/ml in naloxone- and oxilorphan-treated rats, respectively, were significantly lower than the plasma AVP in control rats of 16.9±2.5 pg/ml (P < 0.001). In another three groups of rats the nonosmotic release of AVP was examined during hypovolemia induced by intraperitoneal 6% dextran (1.8 ml/100 g body wt). Following intraperitoneal administration of dextran the peak Uosm of 703.0±87.8 and 734.8±99.1 mosmol/kg H₂O in naloxone- and oxilorphan-treated rats, respectively, was significantly less than the value in control rats of 1,169.3±135.5 mosmol/kg H₂O (both P < 0.02 vs. control). A comparable decrease in blood volume of 13% occurred in all three groups of animals. During the dextran administration plasma AVP levels in naloxone- and oxilorphan-treated rats increased to 4.3±1.0 and 6.0±2.0 pg/ml, respectively; both of these values were significantly lower than the plasma AVP of 12.9±1.4 pg/ml in control rats (P < 0.02). The effect of opioid antagonists to impair the osmotic and nonosmotic release of AVP occurred in the absence of differences in mean arterial pressure, glomerular filtration rate and the renal response to AVP. These results, therefore, indicate that opioid peptides are involved in renal water excretion primarily by modulating the central release of AVP.     

Propofol-Containing Sedatives Increase Levels of Parathyroid Hormone

Objective: To evaluate the effects of propofol and propofol containing disodium edetate (ethylenediaminetetraacetic acid [EDTA]) on the parathyroid-calcium axis in normal subjects. Design: Randomised, double-blind, age-stratified, crossover trial. Setting: Single centre. Patients: A total of 50 healthy subjects. Interventions: Each subject was randomised to receive propofol or propofol containing EDTA on day 1 and the alternate treatment between days 15 and 29, with a 2-week washout period in between. On the day of treatment, subjects received a bolus of trial medication (1 or 2 mg/kg) followed by a 60-minute observation period. At the end of 60 minutes, subjects received trial medication infused for 60 minutes at 1 of 4 randomised infusion rates (25, 50, 100, or 200 wg/kg per min). Subjects were monitored for an additional 60 minutes following the infusion. Measurements and Results: Blood pressure, heart rate, respiratory rate, oxygen saturation, blood ionised calcium concentration, serum total magnesium concentration, serum intact parathyroid hormone (PTH) level, and plasma EDTA level were assessed at periodic intervals during and following the bolus and continuous infusion of trial medication. Mean arterial pressure significantly decreased (p < 0.05) following the bolus injection of both trial medications and returned to baseline at 60 minutes; it significantly decreased again during the continuous infusion and returned to baseline during recovery. Heart rate and respiratory rate fluctuated in both groups with significant increases and decreases throughout the study period following the bolus injection; both returned to baseline during the recovery period in each group. Ionised calcium and total magnesium concentrations remained within normal limits and were unchanged in response to both study medications. PTH levels significantly increased following the bolus injection of both study drugs. The increase in PTH levels was greater with higher doses of study medication during the infusion period. There was no difference in the response of blood pressure, heart rate, respiratory rate, or PTH levels between propofol and propofol with EDTA. EDTA levels increased significantly during the infusion of propofol with EDTA, reaching mean levels of 240 ng/mL. Conclusions: The results of this study indicate that propofol increases PTH levels in normal subjects; however, propofol with EDTA does not alter ionised calcium or total magnesium concentrations.     

Effects of intracerebroventricular administration of adrenoceptor-agonists on the regulation of renal water and electrolytes handling through endocrine, renal and hemodynamic function

In order to assess the roles of central adrenoceptors in the release of atrial natriuretic peptide (ANP), aldosterone (ALD), vasopressin (AVP) and renin as well as in the regulation of renal and cardiovascular functions, either norepinephrine (NE; 0.07 microgram/kg/min), guanabenz (GB; alpha 2-agonist; 0.4 microgram/kg/min), methoxamine (MET; alpha 1-agonist; 0.4 microgram/kg/min), or isoproterenol (ISO; beta-agonist; 0.07 microgram/kg/min), dissolved in the artificial cerebrospinal fluid (ACSF), was intracerebroventricularly (i.c.v.) administered at a rate of 10 microliters/min for 30 min in anesthetized dogs. In the control study, the drugs were omitted. NE decreased mean arterial pressure (MAP), urinary osmolality (Uosm) and plasma ALD and AVP concentrations, and increased urine flow (UF). GB increased UF and urinary K excretion without any changes in urinary Na excretion, but decreased plasma ALD and AVP, heart rate, and Uosm without changes in MAP. ISO decreased MAP and plasma ALD, and increased Na and K output, renal plasma flow and UF with decreased Uosm. MET and ACSF failed to affect any of these parameters. Glomerular filtration rate, plasma ANP concentration and renin activity did not change in any of the studies. The present results suggest that central alpha 2- and beta-adrenoceptors may attenuate ALD and/or AVP release without changes in ANP and renin release, and decrease blood pressure, thereby causing a diuresis and natriuresis.     

Vasopressin vs. terlipressinin the treatmentof cardiovascular failure in sepsis

Background Arginine vasopressin (AVP) and terlipressin (TP) are increasingly used as adjunct vasopressors in the treatment of septic shock. Despite important pharmacological differences between the two drugs (e.g., receptor selectivity, effective half-life) the use of either substance is determined mainly by local availability and institutional inventory. We briefly describe the pathophysiology and pharmacology of septic shock relevant to the treatment with vasopressin analogues. In addition, differences in pharmacokinetics and pharmacodynamics between AVP and TP are discussed. Discussion The current literature suggests that neither AVP nor TP should be administered in high doses in patients with septic shock. Furthermore, increasing evidence indicates that early administration of vasopressin analogues may improve outcome as compared to a last-resort treatment. Low-dose infusion of AVP (0.6–2.4 U/h) has been demonstrated to be a safe adjunct in the management of septic shock. The V₂ agonistic effects of AVP may exert favorable effects on hepatosplanchnic, renal, pulmonary, and coronary perfusion. However, the higher V₁ receptor selectivity of TP may prove more potent in restoring arterial blood pressure and avoiding rebound hypotension, while carrying the risk of sustained global and regional vasoconstriction after bolus injection. Conclusions Evidence from experimental studies and initial clinical reports suggests that continuous low-dose infusion of TP may stabilize hemodynamics in septic shock with reduced side effects. However, randomized, controlled trials are necessary to determine the role of bolus or continuous infusion of TP in the treatment of septic shock before this approach can be recommended for routine clinical use.     

Haemodynamic effects of low and high doses of insulin during beta receptor blockade in dogs

Summary. Haemodynamic effects of small and high doses of insulin during beta receptor blockade were studied in nine dogs. Beta receptor blockade was induced by 0.5 mg/kg propranolol and caused depression of cardiac performance with a significant increase in left ventricular end-diastolic pressure (LVEDP) and a significant decrease in heart rate; maximum rate of left ventricular (LV) pressure rise (LVdP/dt_max), stroke volume and cardiac output. At 15 min, after beta receptor blockade, a bolus injection of 0.5 IU/kg of insulin, free of glucagon and calcium, was given followed by a continuous infusion of 0.5 IU/kg/h. After 30 min another bolus dose of 300 IU insulin was injected. Glucose and potassium were given to maintain physiological levels of these factors. Five minutes after a low dose of insulin there was a significant decrease in LVEDP (P<0.01), and a significant increase in LVdP/dt_max (P<0.01), in stroke volume (P<0.01) and in cardiac output (P<0.01). The other haemodynamic variables were not significantly changed. Administration of a high dose of insulin further, significantly, improved performance of the beta receptor blocked heart and caused a significant reduction in total peripheral resistance. In conclusion, insulin exerts inotropic and vasodilator effects which are dose-dependent and not related to adrenergic mechanisms.     

Arginine vasopressin gene regulation in the homozygous Brattleboro rat.

The Brattleboro rat, which has an autosomally recessive form of diabetes insipidus, has been reported to have a marked defect in the regulation of arginine vasopressin (AVP) gene expression. However, it is not known whether this is a primary genetic defect or occurs secondary to the urinary water losses which occur in the absence of circulating AVP in the Brattleboro rat. This present study was therefore undertaken to study AVP gene regulation in the Brattleboro rat after chronic AVP treatment by osmotic minipump for 2 wk. In Brattleboro rats without AVP treatment, neither urinary osmolality (Uosm) nor hypothalamic AVP mRNA was significantly changed after 24 h of fluid deprivation (Uosm, 413 +/- 33 to 588 +/- 44, NS; AVP mRNA, 39.33 +/- 2.95 to 46.39 +/- 2.71 pg/micrograms total RNA, NS). In contrast, when Brattleboro rats were treated with AVP for 2 wk, the regulation of AVP gene occurred in response to 24 h of fluid deprivation. In these studies, hypothalamic AVP mRNA was significantly increased compared with the Brattleboro rats still receiving AVP with free access of water (28.9 +/- 3.5 vs. 65.0 +/- 3.3 pg/micrograms total RNA, P less than 0.001). Further studies in Long-Evans rats demonstrate a similar response to a comparable degree of fluid deprivation as Uosm and AVP mRNA were significantly increased after 72 h of fluid deprivation (Uosm, 1,505 +/- 186 to 5,460 +/- 560 mosmol/kg, P less than 0.001; AVP mRNA, 31.7 +/- 3.9 to 77.5 +/- 4.6 pg/micrograms total RNA, P less than 0.001). These results indicate that AVP-replaced homozygous Brattleboro rats can regulate AVP gene expression normally in response to fluid deprivation. This finding indicates that the defect in AVP gene regulation in the Brattleboro rat not receiving AVP replacement is a secondary phenomenon rather than a primary genetic defect.     

Urinary excretion of aquaporin‐2 after furosemide and felodipine in healthy humans

Objective. Furosemide inhibits renal sodium and chloride reabsorption in the loop of Henle. A compensatory increased reabsorption of sodium and water takes place in the collecting duct. It is not known whether aquaporin‐2 (AQP2) renal water channels are involved in this compensatory reabsorption. In animals, dihydropyridine derivatives of calcium channel blockers down‐regulate AQP2 in the collecting duct, but the effect has not been studied in humans. We sought to test the hypotheses that urinary excretion of aquaporin‐2 (U‐AQP2) increases after a single intravenous dose of furosemide, and that U‐AQP2 decreases after a single oral dose of felodipine. Material and methods. In two randomized, single‐blind, placebo‐controlled, cross‐over studies, we measured the effect of furosemide and felodipine on U‐AQP2, urine volume, free water clearance (C_H2O), and fractional excretion of sodium (FE_Na) in 13 healthy subjects in each study. Plasma concentrations of vasopressin (AVP), renin (PRC), angiotensin II (ang II), aldosterone (aldo), atrial (ANP), and brain natriuretic peptides (BNP) were measured during the study. Glomerular filtration rate (GFR) was measured by constant infusion technique. U‐AQP2 and hormones were determined by radioimmunoassay. Results. Furosemide treatment increased U‐AQP2 (202%), urine volume (214%), and FE_Na by a factor of 11, (p<0.001 for all), whereas C_H2O and GFR were unchanged. After treatment with placebo, no differences were seen. Furosemide treatment increased AVP (18%), PRC (60%), ang II (100%), and aldo (98%) (p<0.032); ANP was decreased by 29% (p<0.001), whereas there was no change in BNP. The hormones were unchanged after placebo except for a minor decrease in ANP after placebo. Felodipine tended to increase U‐AQP2, to decrease C_H2O and urine volume and GFR, and to increase FE_Na, but the effect was not significantly different from placebo. Felodipine increased PRC (82%) (p<0.003) and ang II, but decreased aldo, and increased AVP. After placebo, PRC was unchanged, whereas ang II, aldo and AVP were changed as after felodipine. Conclusions. Furosemide treatment increased U‐AQP2, AVP, and the activity of the renin‐angiotensin‐aldosterone system. These changes are most likely compensatory phenomena, which prevent an excess loss of sodium and water. Felodipine tended to increase U‐AQP2.     

The pharmacokinetics of fluconazole in healthy Chinese adult volunteers: influence of ethnicity and gender

Objective: The purpose of the present study was to investigate and compare the influence of ethnicity (including Han, Mongolian, Korean, Hui and Uygur) and gender on the pharmacokinetics of fluconazole in healthy adult volunteers after administration of 200‐mg fluconazole tablet. Methods: Ten healthy subjects (five males and five females) of each ethnicity were recruited and given a single 200‐mg dose of fluconazole in tablet form. Blood samples were obtained before dosing and at various predetermined time points after administration up to 96 h. Drug levels were measured by high‐performance liquid chromatography. The blood concentration–time profiles were analyzed using a non‐compartmental approach to estimate the absorption parameters (AUC_(0–96), C_max and t_max), the distribution parameter (V_d) and the disposition parameters (t_1/2 and CL). Results: Ethnicity did not affect the parameter estimates, but gender did. However, the gender differences in pharmacokinetic parameter could be accounted for by differences in weight. There was a high linear correlation between weight and ln C_max, ln AUC (ln means natural logarithmic transformation), V_d and CL. Conclusions: Ethnicity (Chinese Han, Mongolian, Korean, Hui and Uygur) influences the pharmacokinetics of fluconazole tablet. However, there were statistically significant gender differences in AUC, C_max, V_d and CL. But these could be accounted for by weight differences. If fluconazole dose‐adjustment is deemed necessary, this can be done on a weight basis rather than gender basis.     

Decreased reuptake of serotonin in human platelets after surgery

We have documented earlier a decrease in platelet serotonin and a concurrent increase in plasma serotonin, 5‐hydroxytryptamin (5‐HT) after various forms of stress, suggesting a disturbed platelet 5‐HT reuptake mechanism following stress. In order to further elucidate these findings, we have studied platelet 5‐HT reuptake kinetics (V_max and K_m) in nine patients before and 4 days after major, uncomplicated abdominal surgery. We found a significant decrease in the maximal 5‐HT reuptake velocity (V_max) after surgery and changes in K_m, verifying alterations in the affinity of the platelet 5‐HT transport system. The present results thus confirm the hypothesis that 5‐HT reuptake kinetics are altered following adrenergic hyperactivity. A decrease in platelet 5‐HT reuptake may bear implications for our understanding of poststress adaptive changes in the cardiovascular system as well as in the central nervous system (CNS) serotonergic neurones following stressful stimulation.     

Plasma endorphin species during dynamic exercise in humans

Summary. β-Endorphin is metabolized to γ- and α-endorphin. In order to evaluate endorphin metabolism during exercise, radioimmunoassay blood levels of α, β- and γ-endorphins were recorded during exercise for 2 h on a cycling ergometer in 12 endurance-trained and 11 untrained male subjects. In untrained subjects, mild exercise (49±4%VO_2max, mean±SD) did not show an increase in plasma β-endorphin, while the levels of its metabolites rose. No changes were noted in the endurance-trained subjects. More intensive exercise (66±6%VO₂max in untrained and 57±7%VO_2max in trained subjects) resulted in an increase in p-endorphin concentration in association with elevation of the a-endorphin level. While before and during exercise the β-endorphin levels did not differ significantly between athletes and untrained subjects, the levels of γ- and α-endorphins, as well as the molar ratios α/β and γ/β, were significantly higher in untrained subjects. In conclusion, blood levels of β-endorphin metabolites in the resting state and during exercise are dependent on previous training. In untrained subjects, mild exercise may result in accumulation of γ- and α-endorphins in blood without a concomitant change in β-endorphin level.     

The Critical Importance of Urinary Concentrating Ability in the Generation of Urinary Carbon Dioxide Tension

Measurement of urine to blood (U-B) carbon dioxide tension (P_CO2) gradient during alkalinization of the urine has been suggested to assess distal H⁺ secretion. A fact that has not been considered in previous studies dealing with urinary P_CO2 is that dissolution of HCO₃ in water results in elevation of P_CO2 which is directly proportional to the HCO₃ concentration. To investigate the interrelationship of urinary HCO₃ and urinary acidification, we measured U-B P_CO2 in (a) the presence of enhanced H⁺ secretion and decreased concentrating ability i.e., chronic renal failure (CRF), (b) animals with normal H⁺ secretion and decreased concentrating ability, Brattleboro (BB) rats, and (c) the presence of both impaired H⁺ secretion and concentrating ability (LiCl treatment and after release of unilateral ureteral obstruction). At moderately elevated plasma HCO₃ levels (30-40 meq/liter), normal rats achieved a highly alkaline urine (urine pH > 7.8) and raised urine HCO₃ concentration and U-B P_CO2. At similar plasma HCO₃ levels, BB rats had a much higher fractional water excretion and failed to raise urine pH, urine HCO₃ concentration, and U-B P_CO2 normally. At a very high plasma HCO₃ (>50 meq/liter), BB rats raised urine pH, urine HCO₃ concentration, and U-B P_CO2 to the same levels seen in normals. CRF rats failed to raise urine pH, urine HCO₃, and U-B P_CO2 normally at moderately elevated plasma HCO₃ levels; at very high plasma HCO₃ levels, CRF rats achieved a highly alkaline urine but failed to raise U-B P_CO2. Dogs and patients with CRF were also unable to raise urine pH, urine HCO₃ concentration, and U-B P_CO2 normally at moderately elevated plasma HCO₃ levels. In rats, dogs, and man, U-B P_CO2 was directly related to urine HCO₃ concentration and inversely related to fractional water excretion. At moderately elevated plasma HCO₃ levels, animals with a distal acidification defect failed to raise U-B P_CO2; increasing the plasma HCO₃ to very high levels resulted in a significant increase in urine HCO₃ concentration and U-B P_CO2. The observed urinary P_CO2 was very close to the P_CO2 which would be expected by simple dissolution of a comparable amount of HCO₃ in water. These data demonstrate that, in highly alkaline urine, urinary P_CO2 is largely determined by concentration of urinary HCO₃ and cannot be used as solely indicating distal H⁺ secretion.     

Increased activity of serotonin uptake in platelets in medication overuse headache following regular intake of analgesics and triptans

We investigated the effect of chronic administration of different pain medications on the activity of the serotonin transporter (SERT) in patients with medication overuse headache (MOH). We measured the kinetic of platelet 5-HT uptake (maximal velocity, V _max and the Michaelis–Menten constant, K _m) in patients with overuse of triptans (tMOH, n = 15) or analgesics (aMOH, n = 14) before and after drug withdrawal, as well as in headache-free healthy subjects (n = 15) and patients with episodic migraine (EM, n = 16). V _max was increased similarly in both, tMOH and aMOH compared to healthy subjects and patients with EM and normalized after withdrawal in parallel to the improvement of headache frequency. Average K _m was similar in all groups at baseline and not affected by the withdrawal. The data demonstrate a transient increase of SERT activity in patients with analgesic and triptan induced MOH but do not allow to differentiate whether the increase of serotonin uptake is caused by regular intake of analgesics or triptans or is a consequence of frequent headache attacks. An erratum to this article can be found at     

The Pharmacokinetics,Efficacy, Safety,and Ease of Use of a Novel Portable Metered-Dose Cannabis Inhaler in Patients With Chronic Neuropathic Pain: A Phase 1a Study

ABSTRACT

Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a “main stream” pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ⁹-tetrahydrocannabinol (THC) and 11-hydroxy-Δ⁹-THC were taken at baseline and up to 120 minutes. Pain intensity (0–10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ⁹-THC plasma C_max ± SD was 38 ± 10 ng/mL, T_max ± SD was 3 ± 1 minutes, AUC_0→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma C_max increase per mg Δ⁹-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of C_max (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15–30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ⁹-THC pharmacokinetic profile with low interindividual variation of C_max, achieving pharmaceutical standards for inhaled drugs.     

Alkalinization Is Ineffective for Severe Hyperkalemia in Nonnephrectomized Dogs

Objective : To determine whether alkalinization with sodium bicarbonate (NaHCO₃) in near-lethal hyperkalemia either lowers potassium (K) rapidly or shortens duration of cardiac conduction disturbances. Methods : A controlled canine laboratory investigation of 3 treatments for severe hyperkalemia. Conditioned dogs (n = 8; 17–30 kg) received, in random order, 2 mmol/kg of each of 3 treatments (matched in sodium and water) in separate experiments ≥1 week apart: 1.05% NaHCO₃ over 60 minutes (infusion therapy); 8.4% NaHCO₃ over 5 minutes, then 14 mL/kg sterile water over 55 minutes (bolus therapy); 8.4% NaCl over 5 minutes, then 14 mL/kg sterile water over 55 minutes (saline therapy). Prior to administering one of the above therapies, the animals were anesthetized with 0.5–2.5% isoflurane and ventilated to maintain a normal Pco₂. After 30 minutes of equilibration, 2 mmol/kg/hr (loading dose) of a 2-mmol/mL KCl solution was given until idioventricular or relative junctional bradycardic dysrhythmias were sustained for 15 minutes. Then KCl was decreased to 1 mmol/kg/hr (maintenance dose) for 2 hours and 45 minutes. Treatment was begun after 45 minutes of maintenance KCl infusion. Results : The pretreatment K level (all studies) was 9.06 ± 0.82 mmol/L (mean ± SD). Although the mean K level decreased more after saline therapy than after bolus therapy at every time, differences were neither statistically significant nor clinically important during the first 30 minutes. The means of the differences in decreases (saline minus bolus) were small, 0.26 (95% CI, -0.48 to 1.00) at 15 minutes, 0.16 (95% CI, -0.67 to 0.98) at 30 minutes. Dysrhythmia duration was shorter with bolus therapy than for saline therapy in only 1 of 5 dogs (p = 0.38). Conclusions : Hypertonic saline bolus lowered plasma K as effectively as NaHCO₃ bolus in this animal model within the first 30 minutes. Clinically meaningful decreases due to alkalinization alone within 30 minutes are unlikely.     

Pharmacokinetics of losartan and its active carboxylic acid metabolite E-3174 in five ethnic populations of China

What is known and Objective: Interethnic variability in drug pharmacokinetics is well known. Our aim was to investigate whether the pharmacokinetics of losartan and its active carboxylic acid metabolite E‐3174 vary between subjects of five Chinese ethnicities (Han, Mongolian, Korean, Hui and Uigur). Methods: Fifty healthy subjects (five men and five women of each ethnicity) were recruited, and each received 50‐mg dose of losartan in tablet form. Fourteen blood samples were collected for each subject over a 24‐h period after drug administration. The concentrations of losartan and its active carboxylic acid metabolite E‐3174 in plasma were determined by high‐performance liquid chromatography/fluorescence (HPLC/FLU) method, and the pharmacokinetic parameters were calculated by DAS 2.0 software and compared by SPSS 16.0 software. Pharmacokinetic parameters, including area under the curve from 0 h to the last measured point 24 h [AUC_(0–24)], area under the curve from 0 h to infinite time [AUC_(0–∞)], peak plasma concentration (C_max), time to reach C_max (t_max), oral clearance (CL), oral volume of distribution (V_d) and elimination half‐life (t_1/2), were determined following a single oral dose of losartan. Results and Discussion: The t_1/2 values of losartan and its active carboxylic acid metabolite E‐3174 showed significant differences across the five ethnicities. After normalization by weight, no ethnicity‐based difference was noted in the pharmacokinetic parameters of losartan. However, there were significant differences in C_max and V_d of the active carboxylic acid metabolite E‐3174 for Han and Mongolian subjects, compared with the other three ethnic groups. There was a high linear correlation between weight and C_max, AUC_(0–24), AUC_(0–∞), CL and V_d. What is new and Conclusion: Ethnicity was associated with significant differences in the single‐dose pharmacokinetics of losartan’s active carboxylic acid metabolite E‐3174 in healthy subjects of the five main ethnic groups in China.