Comparison of loop diuretics in patients with chronic renal insufficiency

Furosemide and bumetanide share a number of characteristics including reduced natriuretic effects in azotemic patients. It has been presumed that this condition affects each drug equally. Previous studies, however, suggest dissimilar pathways of delivery to their sites of action. Though not rigorously tested, this potential disparity might cause them to differ when used in azotemia. We, therefore, assessed the pharmacokinetic and pharmacodynamic characteristics of intravenously administered furosemide and bumetanide in ten adult patients with stable, chronic renal insufficiency (mean creatinine clearance = 14.1 +/- 2.0 ml/min/1.73 m2) in a randomized, cross-over study during controlled sodium intake. Our goals were to assess differences in diuretic effectiveness and in so doing to determine the dose required to produce a maximal response. The mean diuretic doses of 172 and 4.3 mg for furosemide and bumetanide, respectively (ratio = 40:1) were sufficient to produce a maximum response. Despite similarities in maximal fractional excretion of sodium (18.2 +/- 2.6% with furosemide vs. 19.4 +/- 4.5% with bumetanide, P = 0.687) demonstrating an equal tubular responsiveness to both drugs, overall response as quantified by cumulative natriuresis in the initial eight hour period was 52% greater with furosemide (108 +/- 17 vs. 71 +/- 7 mEq; P = 0.042). The difference in total excreted sodium was accounted for by a preserved nonrenal clearance of bumetanide (113 +/- 12 compared to 53 +/- 5 ml/min for furosemide, P = 0.001) which resulted in relatively less bumetanide in serum available to be delivered into the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

表小檗碱对α受体的作用

表小檗碱(epiberberine,EB)是从湖北产黄连(Coptis chinensis Franch)中提取的一种生物碱,属苯喹嗪类原小檗碱,对其药理作用的研究资料甚少,未见其对α肾上腺素体作用的报道。资料表明,许多原小檗碱类化合物有α受体阻滞作用,为从该类化合物中选择     

In vitro evidence that urine composition affects the fraction of active furosemide in the nephrotic syndrome

Diuretic resistance to furosemide in the nephrotic syndrome (NS) may result from binding of drug to filtered albumin within the renal tubule. In buffer solutions intended to partially mimic the luminal environment of the distal nephron during the NS, we examined several chemical properties to determine their effect on furosemide-albumin binding equilibria. Dissociation constants were obtained by measuring furosemide's quenching of human serum albumin's intrinsic tryptophan fluorescence over ranges of pH, ionic strength (IS) and osmolarity. Neither pH nor osmolarity significantly affected binding; however, incremental increases in IS between 0.0 and 1.0 produced increases in Kd from 0.65 +/- 0.05 to 34.38 +/- 1.72 microM, resulting in a 5- and 28-fold increase in the unbound furosemide fraction when the furosemide-albumin concentrations were 3.0:5.0 and 10.0:45.0 microM, respectively. Our results indicate that human serum albumin contains one high affinity binding site for furosemide that is sensitive to IS. Because of changes in the concentrations of reactants as well as IS that can occur in nephron segments distal to furosemide's site of action, we conclude that the amount of unbound (i.e., pharmacologically active) drug in voided urine will not necessarily correspond to the amount at the active site. To clinically assess the pharmacodynamic consequence of protein binding in the NS, changes in the concentration of the reactants and IS in the distal nephron must be minimized so that the unbound furosemide measured in voided urine will accurately reflect the amount at the drug's active site.     

Pain and faulty breathing: a pilot study

The purpose of this pilot study was to observe both relaxed and deep breathing patterns in a convenience sample to determine the incidence of normal versus faulty patterns of respiration. These observations were then combined with respondent answers to a survey on pain history to determine if there is any correlation between faulty breathing and musculo-skeletal pain patterns. If such a correlation can be made, then we propose that clinicians working with chronic pain patients may have improved outcomes if they address and correct faulty breathing patterns. Based on this study, it is suggested to include the evaluation and treatment of faulty respiration in the rehabilitation of chronic musculo-skeletal conditions, most notably cervical pain.     

Profile of etodolac: Pharmacokinetic evaluation in special populations

The pharmacokinetics of etodolac, a new nonsteroidal anti-inflammatory drug, were compared in normal subjects, in patients with renal and hepatic disease, and in elderly patients. In 28 normal subjects, orally administered etodolac was rapidly absorbed. By 1.2 hours after ingestion of a 200 mg dose, the maximum serum concentration (C_max) averaged 15.9 g/ml, with more than 99% of the drug bound to serum protein. Clearance was primarily hepatic. The mean half-life (t_1/2) was 6 to 7 hours. There were no apparent differences in C_max, the time at which C_max occurred (t_max), area under the serum concentration/time curve (AUC_0–24), or t_1/2 between groups of young men (n=20), elderly men (n=24), and elderly men with osteoarthritis (n=20), after a single dose of etodolac or after 7 days of subchronic administration. Moreover there was no evidence of accumulation. There also were no differences in C_max, t_max, AUC_0–24 or t_1/2 between groups of normal subjects (n=10) and patients with mild-to-moderate renal impairment (n=10). Patients with end-stage renal disease who were receiving chronic hemodialysis had the same mean serum concentration of free drug as normal subjects, even though mean serum levels of protein-bound etodolac were slightly lower than those in the normal subjects. The only significant (p<0.05) difference between patients with stable hepatic cirrhosis and normal, age-matched subjects was a slightly shorter t_max in the cirrhotic subjects (1.1 vs. 1.4 hours). These findings suggest that no alteration of etodolac dosage would be necessary in these high-risk groups.Die pharmakokinetischen Parameter von Etodolac, einem neuen, nichtsteroidalen entzündungshemmenden Therapeutikum, wurden an gesunden Probanden, an Patienten mit Leber- und Nierenleiden und an Älteren Patienten untersucht. Orale Etodolac Gaben wurden von den 28 gesunden Probanden schnell resorbiert. Nach einer einmaligen Dosis von 200 mg betrug nach 1,2 Stunden die durchschnittliche maximum Serumkonzentration (C_max) 15,9 g/ml, wobei mehr als 99% des Medikaments an das Serumprotein gebunden war. Clearance erfolgte hauptsÄchlich über die Niere. Die mittlere Eliminationshalbwertszeit (t_1/2) variierte zwischen 6 und 7 Stunden. In Bezug auf C_max, dem Zeitpunkt an dem C_max auftrat (t_max), FlÄche unter der Serumkonzentrationskurve (AUC_0–24) und t_1/2 wurden keine offensichtliche Unterschiede festgestellt zwischen der Gruppe junger MÄnnern (n=20), Älterer MÄnner (n=24) und Älteren MÄnnern mit Osteoarthritis (n=20) nach einer einmaligen Etodolac-Gabe oder nach 7 tÄgiger subchronischer Dosierung. Es bestanden auch keine Anzeichen einer Kumulation. ZusÄtzlich wurden auch keine Unterschiede in C_max, t_max, AUC_0–24 und t_1/2 zwischen der Gruppe gesunder Probanden (n=10) und der Patientengruppe mit leichten bis mÄigen NierenfunktionsschÄden (n=10) beobachtet. Im mittleren Serumspiegel des nicht gebundenen Medikaments in Patienten im Endstadium der Nierenerkrankung, die mit Langzeitdialyse behandelt wurden, konnte kein Unterschied im Vergleich zu gesunden Probanden festgestellt werden, obwohl der mittlere Serumspiegel für proteingebundenes Etodolac in den Patienten etwas niedriger lag als in gesunden Probanden. Der einzige signifikante Unterschied (p<0.05) zwischen Patienten mit stabilisierter Leberzirrhose und gleichaltrigen Probanden war eine etwas kürzere t_max in den Zirrhosepatienten (1,1 versus 1,4 Stunden). Diese Ergebnisse beweisen, dakeine Notwendigkeit vorliegt, die Etodolac-Dosierung für diese Risikogruppen zu modifizieren.Se comparó la farmacocinética de etodolac, un fármaco antiinflamatorio no esteroide nuevo, en sujetos normales y en pacientes con enfermedad renal y hepática y en pacientes ancianos. Etodolac administrado por vía oral a 28 sujetos normales fue rápidamente absorbido. A las 1,2 horas siguientes a la administración de una dosis de 200 mg, la concentración sérica máxima (C_max) alcanzó un promedio de 15,9 g/ml, con más del 99% del fármaco unido a la proteína sérica. La eliminación fue principalmente hepática. La vida media (t_1/2) fue 6–7 horas. No se observaron diferencias en C_max, en el tiempo en el cual se produjo C_max, en el área bajo la curva de concentración sérica/tiempo (ABC_0–24) ni en t_1/2 entre los grupos de hombres jóvenes (n=20), de hombres ancianos (n=24) y de hombres ancianos con osteoartritis (n=20), después de la administración de una dosis Única o después de 7 días de administración subcrónica de etodolac. Además, no hubo evidencia de acumulación. Tampoco se registraron diferencias en C_max, t_max, ABC_0–24 o t_1/2 entre los grupos de sujetos normales (n=10) y los pacientes con insuficiencia renal leve a moderada (n=10). Los pacientes con nefropatía terminal que estaban recibiendo hemodiálisis crónica tuvieron las mismas concentraciones séricas medias de fármaco libre que los sujetos normales, a pesar de que las concentraciones séricas medias de etodolac unido a proteina fueron levemente inferiores que en los sujetos normales. La Única diferencia significativa (p<0,05) entre los pacientes con cirrosis hepática estable y los sujetos normales de edad similar fue t_max ligeramente inferior en los sujetos cirróticos (1,1 vs 1,4 horas). Estos hallazgos sugieren que no es necesario modificar la dosis de etodolac para su uso en estos grupos de alto riesgo.La pharmacocinétique de l'étodolac, un anti-inflammatoire non stéroÏdien, a été comparé chez des sujets normaux et des patients présentant des affections rénales et hépatiques, et chez des malades âgés. Chez 28 sujets normaux, la résorption d'étodolac administré par voie orale a été rapide. Dès 1,2 heure suivant l'absorption d'une dose de 200 mg, la moyenne des concentration sériques maximales (C_max) était de 15,9 g/ml, plus de 99% pour cent du médicament étant liés aux protéines sériques. La clairance se fait surtout par voie hépatique. La demivie moyenne (t_1/2) était de 6 à 7 heures. Il n'y avait aucune différence apparente en ce qui concerne C_max, le temps d'apparition de C_max (t_max), l'aire sous la courbe concentration sérique/temps (AUC_0–24) ni t_1/2 entre les groupes d'hommes jeunes (n=20), d'hommes âgés (n=24), et d'hommes âgés atteints d'arthrose (n=20) à la suite d'une dose unique d'étodolac ou après 7 jours d'administration subchronique. De plus, aucune accumulation n'a été constatée. D'autre part, aucune différence de C_max, t_max, AUC_0–24 ni t_1/2 n'a été notée entre les groupes de sujets normaux (n=10) et de malades présentent des altérations rénales légères ou modérées (n=10). Les malades en insuffisance rénale terminale soumis à l'hémodialyse chronique ont présenté une concentration sérique moyenne de médicament libre analogue à celle des sujets normaux, mais la moyenne des taux sériques d'étodolac lié aux protéines était légèrement inférieure à celle observée chez les sujets normaux. La seule différence significative (p<0.05) entre les malades présentant une cirrhose hépatique stable et des sujets normaux appariés quant à l'âge était représentée par un t_max légèrement plus court chez les cirrhotiques (1,1 contre 1,4 heure). Ces données permettent de penser qu'aucune modification posologique de l'étodolac ne serait nécessaire pour ces groupes à haut risque.La farmacocinetica dell'etodolac, un nuovo farmaco anti-infiammatorio non steroidale è stata messa a confronto in gruppi normali, in pazienti affetti da malattia rénale ed epatica ed in pazienti anziani. In 28 soggetti normali l'etodolac somministrato oralmente è stato rapidamente assorbito. Dopo 1.2 ore dall'ingestione di una dose di 200 mg la massima concentrazione di siero (Cmax) presentava un valore medio di 15,9 mg/ml, con più del 99% del farmaco legato alla proteina del siero. La clearance era soprattutto a livello epatico. L'emivita media (t1/2) era di 6–7 ore. Non vi sono state evidenti differenze medie nei valori di concentrazione massima (Cmax), tempo (Tmax) al quale si aveva la Cmax, nella curva dell'area sotto concentrazione di siero/tempo (AUCo-24) oppure nel valore dell'emivita media (t1/2) tra gruppi di uomini giovani (n=20), uomini anziani (n=24) e anziani con osteoartrite (n=20), dopo una dose singola di etodolac o dopo 7 giorni di somministrazione subcronica. Inoltre non vi sono stati segni di accumulo. Per di più non vi sono state differenze nei valori di Cmax, tmax, AUCo-24 o t1/2 tra gruppi di soggetti normali (n=10) e pazienti con alterazioni renali da leggere a moderate (n=10). I pazienti con malattia renale all'ultimo stadio che ricevevano emodialisi cronica presentavano la stessa concentrazione media di siero di farmaco libero dei soggetti normali, anche se i livelli medi di siero di etodolac legato alle proteine erano leggermente inferiori a quelli di soggetti normali. L'unica differenza significativa (p<0.05) tra pazienti con cirrosi epatica stabile e soggetti normali della stessa età era nei tmax leggermente più brevi nei soggetti cirrotici (1.1. contro 1.4 ore). Questi risultati suggeriscono che nessuna alterazione del dosaggio di etodolac sarebbe necessaria in questi gruppi ad alto rischio.     

Anatomic basis of venous drainage in donor flaps

Summary The venous architecture in donor flaps was observed in 17 fresh cadavers by injection of latex or ink into the vessels or by making corrosion-cast specimens. The pattern of the veins resembles that of the arteries, with the difference that there is another set of venous trunks which do not accompany the arteries. Because these trunks are of larger caliber, they are the main drainage route for flaps. There are three types of drainage based on the anatomical architecture: 1) the superficial trunk is the main drainage path; 2) the deep trunk is the main path; 3) both superficial and deep veins are involved. These morphological considerations are the basis for selection of veins for anastomosis in microsurgery. The axial veins in temporal, frontal and facial flaps on the dorsum of the hand and the foot usually loosely accompany the axial arteries. The characteristics of these vascular pedicules should be studied in transplant operation.

---

Bases anatomiques du drainage veineux des lambeaux cutanés libres

Résumé Le drainage veineux des lambeaux cutanés libres a été étudié sur 17 cadavres frais par injection de latex ou d'encre dans les vaisseaux, ou en réalisant des moulages par injection-corrosion. La distribution des veines ressemble à celle des artères à la différence près qu'il existe des troncs veineux qui n'accompagnent pas les artères. Ces troncs ont un calibre plus important et représentent une voie de drainage principale pour les lambeaux. On peut individualiser trois types de drainages basés sur l'architecture veineuse : 1. Le tronc superficiel est la principale voie de drainage ; 2. le tronc profond est la principale voie; 3. les veines superficielles et profondes sont impliquées simultanément. Ces considérations morphologiques sont les bases de la sélection des axes veineux pour les anastomoses en micro-chirurgie. Les veines axiales au niveau temporal, frontal et facial et pour les lambeaux de la face dorsale de la main et du pied sont habituellement relativement éloignées du trajet artériel. Les caractéristiques de ces pédicules veineux doivent être précisées pour la réalisation des lambeaux.

     

Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction

Y chromosome deletions encompassing the AZFc region have been reported in 13% of azoospermic men and 7% of severely oligozoospermic men. We examined the impact of these Y deletions on the severity of testicular defects in 51 azoospermic men undergoing intracytoplasmic sperm injection (ICSI) after testicular sperm extraction (TESE) and 30 men with severe oligozoospermia undergoing ICSI after ejaculation of spermatozoa. In addition, five azoospermic patients shown previously to have Y chromosome deletions underwent histological evaluation of their previously obtained testis biopsy specimens. A further 27 azoospermic men underwent TESE-ICSI, but not Y chromosome DNA testing. Ten of 51 azoospermic men (20%) who underwent TESE-ICSI and Y-DNA testing were found to be deleted for portions of the Y chromosome AZFc region. Of these 10, five had spermatozoa retrievable from the testis, and in two cases the wives became pregnant. Of the 41 azoospermic men with no Y chromosome deletion, 22 (54%) had spermatozoa retrievable from the testis, and in 12 cases (29%) the wives became pregnant. Four of 30 (13%) severely oligozoospermic patients were found to be deleted for AZFc and in three (75%) of these pregnancy was achieved. The other 26 severely oligozoospermic couples who had no AZFc deletions underwent ICSI, and 12 (46%) have an ongoing or delivered pregnancy. The embryo implantation rate was not significantly different for azoospermic (22%), oligozoospermic (16%), Y-deleted (14%) or Y-intact (18%) men. Of the total of 19 infertile men who had Y chromosome deletions, 14 had deletions within Y chromosome intervals 6D-6F, in the AZFc region. Twelve of those 14 had some spermatozoa (however few in number) in the ejaculate or testis. Five of the Y-deleted men had deletions that extended more proximally on the Y chromosome, and in none of these could any spermatozoa be observed in either ejaculate or testis. These results support the concept that, in azoospermic or oligozoospermic men with Y chromosome deletions limited to intervals 6D-6F (AZFc), there are generally very small numbers of testicular or ejaculated spermatozoa. Larger Y deletions, including and extending beyond the AZFc region and encompassing more Y genes, tend to be associated with a total absence of testicular spermatozoa. In those cases where spermatozoa were retrieved, the presence of Y deletions had no obvious impact on fertilization or pregnancy rate.      

The Influence of Misoprostol on the Adverse Renal Effects and Stereospecific Pharmacokinetics of Ibuprofen in Chronic Renal Insufficiency

The use of nonsteroidal anti-inflammatory drugs in patients with chronic renal insufficiency (CRI) may be complicated by renal functional abnormalities due to the inhibition of renal prostaglandins. We tested the hypothesis that administration of the oral PGE1 analog, misoprostol, could attenuate the adverse renal effects of ibuprofen in patients with CRI. Because the metabolism of misoprostol and the stereoinversion of R- to S-ibuprofen involve the same metabolic pathway, the stereospecific pharmacokinetics of ibuprofen were also evaluated. In a randomized, crossover trial of six stable CRI patients (Clcr 25--67 ml min(minus sign1)), in sodium balance on a 150 mEq Na(+) per day metabolic diet, we compared the effects of ibuprofen 600 mg qid with and without misoprostol 200 &mgr;g qid upon Clcr, Clinulin, Clpah, Na(+), and K(+) excretion during 4-h clearance studies. We also assessed stereospecific ibuprofen kinetics following single dose (acute) and after 7 days on drug(s) (chronic). Daily weights, supine blood pressures, electrolytes, osmolality, BUN, creatinine and 24-h urine collections for Clcr and Na(+) and K(+) excretions were obtained during chronic dosing. Supine and upright plasma renin activities were obtained prior to dosing and during chronic dosing for both treatment limbs. Ibuprofen alone resulted in an approximately 20% transient reduction in GFR, occurring 2--2.5 h following dosing in both the acute and chronic clearance studies. This was not affected by misoprostol. There was a greater degree of stimulation of PRA with the upright posture with misoprostol plus ibuprofen than with ibuprofen alone. There was a significant weight gain in both study limbs, but no effect of misoprostol (1.2 plus minus 0.2 kg ibuprofen alone and 1.0 plus minus 0.2 kg ibuprofen plus misoprostol, p = 0.13). Otherwise no clinically significant alteration in renal function occurred in either treatment limb. The presence of misoprostol did not alter the stereospecific pharmacokinetics of ibuprofen. We conclude that misoprostol does not significantly alter the renal effects of ibuprofen in patients with mild to moderate CRI.