Effect of intranasal histamine on nasal mucosal blood flow and the antidiuretic activity of desmopressin.

The effects of exogenous histamine on nasal mucosal blood flow and the systemic activity of intranasally administered desmopressin, a vasopressin analogue, were studied in normal volunteers. Ten subjects received either saline or histamine (1, 20, 100, and 500 micrograms) by intranasal spray. Maximal nasal mucosal blood flow response, determined by laser doppler velocimetry, demonstrated a significant (P less than 0.05) linear relationship to histamine dose. Eight additional subjects received each of the following intranasal treatments: 20 micrograms histamine followed by 10 micrograms desmopressin; normal saline followed by 10 micrograms desmopressin; 20 micrograms histamine followed by vehicle; or normal saline and vehicle. Nasal blood flow was determined before and after each treatment. Desmopressin activity was assessed by measuring urine osmolality, flow rate, electrolyte, and creatinine concentration for 24 h after each treatment. The effect of histamine and desmopressin was greater than desmopressin alone, with respect to nasal blood flow response (103 +/- 24 vs. 4 +/- 17%, mean +/- SEM, P less than 0.02), initial urine osmolality (520 +/- 123 vs. 333 +/- 75 mosM, P less than 0.03), urine electrolyte (potassium, 45 +/- 11 vs. 28 +/- 7 meq/liter; sodium, 68 +/- 21 vs. 36 +/- 8 meq/liter, P less than 0.03) and creatinine concentrations (95 +/- 23 vs. 60 +/- 13 mg/dl, P less than 0.03), and the duration of decrease in urine flow rate compared with saline and vehicle. These results suggest that the systemic activity of intranasal desmopressin is enhanced by increasing local nasal blood flow and are consistent with increased transnasal absorption of the peptide.

Etoposide pharmacokinetics in patients with normal and abnormal organ function.

Precise guidelines for dose modification of etoposide in patients with hepatic dysfunction have not been determined. Etoposide pharmacokinetics were determined in 17 patients. Nine patients had bilirubin less than or equal to 1 mg/dL and eight had bilirubin ranging from 1.9 to 23 mg/dL. Twelve patients received etoposide 100 mg/m2 days 1, 3, and 5, in combination with cisplatin 70 mg/m2 or iproplatin 225 mg/m2 on day 1. Five patients received only one dose of etoposide. Etoposide was measured using a published high pressure liquid chromatography (HPLC) method which also quantitates picro etoposide and its hydroxy acid. Systemic clearance, Vdss and t1/2 beta averaged (+/- SD) 21.4 (+/- 7.4) mL/min/m2, 10.7 (+/- 4.1) L/m2, and 8.1 (+/- 2.8) hours in the nine patients with bilirubin less than or equal to 1 mg/dL, and 22.4 (+/- 9.6) mL/min/m2, 13.6 (+/- 11.3) L/m2, and 8.4 (+/- 3.9) hours in the eight patients with bilirubin 1.9 to 23.0 mg/dL. Stepwise multiple linear regression analysis of liver and renal function tests and other patient-specific variables identified creatinine clearance as the strongest predictor of etoposide systemic clearance (r2 = 40.8). Serum albumin was identified as the next strongest predictor, improving the r2 to 57.3%. Cumulative biliary excretion of unchanged etoposide and glucuronide or sulfate conjugates over 48 hours accounted for less than 3% of the dose in six patients studied. Toxicity occurred in patients with normal and abnormal bilirubin and was unrelated to etoposide clearance. Patients with total bilirubin 1.9 to 23 mg/dL, but creatinine clearance greater than 30 mL/min/m2 had etoposide clearance within the range for patients with normal liver function (16.8 to 35 mL/min/m2). Although these patients did not have reduced etoposide clearance, the major routes of etoposide non-renal elimination remain to be clearly defined. Additional patients should be evaluated to establish more precise guidelines for dosing etoposide in patients with abnormal liver function.

Measurement of glomerular filtration rate: single injection plasma clearance method without urine collection.

Glomerular filtration rate (GFR) can be calculated from the plasma clearance of any of several radiopharmaceuticals that are excreted by glomerular filtration. Simplified methods have been proposed that require only one or two plasma samples in lieu of a more complete clearance curve. We examined the error introduced by this simplification. Forty patients were studied using a dual-isotope technique employing [99mTc]DTPA and [169Yb]DTPA, obtaining eight plasma samples for each clearance curve at intervals from 10 to 240 min after injection. Data were fit to several empirical or semiempirical formulae and also to a two-compartment computer model that permitted GFR estimation from only one or two data points. The computer model gave good fit, but so did several simpler methods. The error that results from replacing the complete clearance curve by a single 3-hr sample was about 8 ml/min (residual s.d.). By using two samples (at 1 and 3 hr), the error could be reduced to 4 ml/min. Recommended one- and two-sample methods are presented.

Prostaglandin A2 at low rates of infusion restores the antidiuretic effect of vasopressin in lithium-treated rats.

To test the effect of prostaglandin A2 (PGA2) on renal function, infusions of PGA2 (0-7 ng/kg/min), arginine-vasopressin (AVP) (1-25 ng/kg/min) and PGA2 plus AVP were administered to male rats made resistant to the antidiuretic effect of AVP by pre-treatment with lithium. In non-lithium-treated control rats, AVP had its expected antidiuretic action but in lithium-treated rats neither urinary volume nor osmolarity was changed. Prostaglandin A2 alone had no effect on urine output in lithium-treated rats; AVP plus PGA2 infused together evoked a near normal antidiuretic response. This antidiuretic action of PGA2 contrasts with the diuretic action reported by others. However, our infusion rates were 300-4000 times lower than those of other workers and it is suggested that PGs may have opposite actions on the kidney depending on their concentration. The effect of indomethacin (a blocker of prostaglandin synthesis) on urine flow was tested in five groups of rats on different régimes of liquid intake. Urine flow was reduced in the three groups with the highest urine volumes before treatment, and increased in the two groups with the lowest urinary volumes, again indicating that PGs may have both diuretic and antidiuretic actions.

Bicarbonate and chloride transport in relation to the acidification or alkalinization of the urine.

Although the electrogenicity of the active reabsorption of sodium and bicarbonate (or secretion of protons) has been well-established in the short-circuited turtle bladder preparation, the nature of the active reabsorption of chloride and secretion of bicarbonate has been controversial. These processes have been ascribed to the separate actions of two discrete electrogenic pumps or to the single action of a metabolically driven electroneutral anion exchange mechanism. The present report deals with these transport processes per se; with the relations among serosal bicarbonate,glucose, and the reabsorption of Na and Cl; and finally with the application of the Heinz model for inversion of an active transport as a tentative single mechanism for the alkalinization and acidification of the urine.

The significane of measurement of osmolality in critically ill patients.

The plasma and urine osmolality and their ratios were measured in 774 patients in critical care. We found that changes in osmolality were related to the alterations of ratios of sodium ion, glucose, blood urea nitrogen and unknown metabolites, and this knowledge may be of therapeutic and prognostic value.

The role of the sympathetic nervous system in the regulation of ultradian rhythms in urine excretions.

The effects of alpha and beta adrenoreceptors blockade and surgical kidney denervation on ultradian rhythmicity in urine excretion were investigated in four dogs. Pharmacological treatments and surgical denervation of the kidneys suppressed the ultradian rhythmicity in urine flow but did not completely eliminate the ultradian rhythms in urinary osmolality and in electrolyte concentrations. These findings suggest that the autonomic nervous system plays a major role in the regulation of the ultradian rhythms in water excretion in dogs. The partial persistence of ultradian rhythms in urine osmolality and electrolyte concentrations after autonomic denervation supports the assertion that the ultradian rhythms in solute concentrations are regulated by different mechanisms to those of water excretion, suggesting the possible involvement of a multioscillatory system.

Mutagenicity induced by lyophilization or storage of urine from isoniazid-treated rats.

Urine collected during 24 h after treatment of rats with 90--550 mg/kg isonicotinic acid hydrazide (isoniazid, INH) was after lyophilization, mutagenic for Salmonella typhimurium TA1535. Urine collected directly from bladders of INH-treated rats was not mutagenic, and solutions of INH in water or urine became mutagenic only after lyophilization. In the absence of lyophilization, sterile urine from INH-treated rats became mutagenic after 8--14 days' storage at room temperature.

Body fluid concentrations of ampicillin trihydrate in 6 horses after a single intramuscular dose.

Six adult mares were given a single dose of ampicillin trihydrate (250 mg/ml) intramuscularly at a dosage of 20 mg/kg body weight. Serum, synovial fluid, peritoneal fluid and urine ampicillin concentrations were measured serially over a 48 h period. The mean peak serum ampicillin concentration was 2.49 micrograms/ml at 6 h. Ampicillin was found in synovial fluid and peritoneal fluid, which obtained mean peak ampicillin concentrations of 1.65 micrograms/ml and 1.81 micrograms/ml at 6 h and 4 h respectively. These concentrations declined in parallel with serum concentrations and were still detectable at 48 h. Urine concentration of ampicillin was relatively high, with a mean peak concentration of 1364.9 micrograms/ml at 4 h.

Electrolyte changes at 3500 m in males with and without high-altitude pulmonary edema.

Ten normal healthy male subjects between 20-30 years of age were initially examined at Delhi (200 m) and thereafter air-lifted to an altitude of 3,500 m. Excretion of sodium, potassium and chloride in urine and their plasma level were determined at sea level (SL) and daily at high altitude (HA) for 4 d. At HA, four subjects developed high-altitude pulmonary edema (HAPE), four remained normal, and two suffered from acute mountain sickness. The results on normals and HAPE are presented. There was increased excretion of potassium at HA in both groups resulting in reduction of plasma level. The sodium and chloride excretion was also increased in normals at HA irrespective of urine volume. In HAPE cases, the sodium and chloride excretion was related to urine output. With the retention of fluid, the excretion of these ions in urine was diminished without a parallel change in plasma levels.

Kidney stones. Medical management and newer options for stone 'removal'.

Patients with recurrent kidney stone disease or stone formers at increased risk of recurrence deserve a thorough metabolic workup. This should be based on a careful history and include urinalysis, serum chemistry studies, and analysis of 24-hour urine collections. Measures to prevent recurrent stone formation are aimed at correcting the metabolic imbalances detected in the workup. A variety of drugs are available that target one or more of the metabolic abnormalities that may be involved. For "surgically active" renal and ureteral stone disease, newer techniques make surgery unnecessary in most cases. Extracorporeal shock wave lithotripsy is becoming the preferred technique for disintegration of upper urinary tract stones. Percutaneous ultrasonic lithotripsy and electrohydraulic disintegration also are widely used. For lower urinary tract stones, the ureteroscope permits either extraction under visualization or ultrasonic disintegration.

Metabolism of [14C]2-aminobiphenyl in vivo by different species.

[14C] 2-Aminobiphenyl is predominantly metabolised in vivo to 3- and 5-hydroxy conjugated derivatives in all species. In some species, 2-aminobiphenyl is also excreted to a small extent as N-conjugated derivatives. Renal excretion accounts for about 30-40% of the administered dose during the first 24 hours. The 5-O-sulphate and 5-O-glucuronide of 2-amino-5-hydroxybiphenyl have been found as major metabolites with all species; 2-amino-3-hydroxybiphenyl-O-sulphate is also a significant metabolite. There were metabolic differences observed between species in this study. HPLC and TLC analytical techniques were used for separation and detection of [14C] 2-aminobiphenyl and its metabolites. Formation of different isomeric metabolites may be explained by electronic Hückel molecular orbital calculations and stereochemical factors.

[Renal and circulatory function under ketamine anesthesia. An experimental study on animals (author's transl)]. / Nieren- und Kreislauffunktion unter Ketaminnarkose. Eine tierexperimentelle Studie

Cardiac output, glomerular filtration rate, stroke volume, heart rate, and urinary output were determined in 10 mongrel dogs. Under the conditions of the experiment it was observed that in contrast to man cardiac and renal output as well as stroke volume declined significantly. Heart rate showed no significant change. With diminished urinary output a differential excretion of individual electrolytes was noted. To carry the results of these experiments over to humans is, in the author's view, not warranted unreservedly.