Study of in vivo tumor state and response to therapy by analysis of DNA distribution

Comparative studies of cefamandole and cephalothin were carried out in 32 cancer patients. After rapid intravenous injection of 1 gm cefamandole or cephalothin, the peak mean serum concentrations in 11 patients achieved at 0.25 hr were 103.4 mcg/ml and 56.7 mcg/ml, respectively. Except at 6 hr, the serum concentration of cefamandole was higher (p less than 0.05) at all times. The terminal half-lives (t 1/2) were similar, being 1.2 hr for cefamandole and 1.0 hr for cephalothin. Cefamandole, 1 gm intramuscularly, induced a peak mean serum concentration of 26.6 mcg/ml at 1 hr, with a slow decay. Intermittent cefamandole (2 gm intravenously every 6 hr) induced very high mean serum concentrations (7 patients), but at 4 hr the concentrations were similar to those after 1 gm intravenously. Per cent of urinary excretion was similar for both drugs regardless of dose and mode of administration. Continuous-infusion cefamandole or cephalothin (2 gm loading followed by 2 gm every 6 hr) in 14 patients showed consistently higher serum concentrations for cefamandole (p less than 0.05) over a 5-day period. There was no evidence of drug accumulation in the multiple-dose studies. Both the single- and multiple-dose schedules were well tolerated.     

Naltrexone: disposition, metabolism, and effects after acute and chronic dosing

The disposition of naltrexone during acute and chronic administration of 100-mg oral dose was studied in 4 subjects. Following an acute dose the mean (X) peak naltrexone plasma level was 43.6 +/- 29.9 ng/ml at 1 hr and for the major biotransformation product, beta-naltrexol, was 87.2 +/- 25.0 ng/ml at 2 hr. Twenty-four hours after the dose the X levels of naltrexone and beta-naltrexol declined to 2.1 +/- 0.47 and 17.6 +/- 5.0 ng/ml, respectively. Following chronic administration and X peak plasma levels of naltrexone and beta-naltrexol rose to 46.4 +/- 18.5 and 158.4 +/- 89.9 ng/ml at 1 hr, but by 24 hr both compounds declined to levels of the same order as in the acute state at 24 hr. Plasma levels of naltrexone and beta-naltrexol measured 24 hr after the daily doses of naltrexone throughout the study indicated that steady-state equilibrium was rapidly attained and that there was no accumulation of naltrexone and beta naltrexol in the plasma after chronic treatment on 100 mg oral doses. Biexponential kinetics were observed for naltrexone and beta-naltrexol in the first 24 hr. The half-life of naltrexone and beta-naltrexol decreased slightly from the acute to thechronic study from 10.3 +/- 3.3 to 9.7 +/- 1.1 hr and from 12.7 +/- 2.6 to 11.4 +/- 2.0 hr. The plasma levels of naltrexone declined slowly from 24 through 72 hr from 2.4 to 1.7 ng/ml, with an apparent half-life of 96 hr. The renal clearance data indicate that naltrexone is partially reabsorbed while beta naltrexol is actively secreted by the kidney. During acute and chronic naltrexone administration the mean fecal excretion was 2.1% and 3.6% while urinary excretion was 38% and 70% of the dose in a 24-hr period. Opiate antagonism to 25 mg heroin challenges was nearly complete through 48 hr after naltrexone. At 72 hr the objective responses reappeared to a greater extent than the subjective ones. Correlation coefficient (r) between naltrexone plasma levels and opiate antagonism was 0.91 and between individual half-life of naltrexone and opiate antagonism it was 0.99.     

Paracetamol disposition in normal subjects and in patients treated with antiepileptic drugs

1 The serum concentration profile of paracetamol has been determined after administration of single 1000 mg intravenous and oral doses in six normal subjects and six epileptic patients on chronic antiepileptic drug therapy. The urinary excretion of free and conjugated paracetamol has also been determined. 2 Following intravenous administration, serum paracetamol concentration declined with first-order kinetics. Both elimination rate and total body clearance were higher in the epileptic patients, although in neither case was the difference statistically significant. 3 The oral bioavailability (mean +/- s.e. mean) was significantly lower in the epileptic patients than in the normal subjects (0.77 +/- 0.03 and 0.89 +/- 0.02 respectively, P less than 0.01), whereas the urinary excretion total (free+conjugated) paracetamol was almost identical in the two groups. 4 It is suggested that the lower bioavailability of paracetamol in the epileptic patients results from enhancement of first-pass metabolism, secondary to enzyme induction.     

Effect of furosemide on the renal excretion of digoxin

Digoxin serum and urine levels were determined by radioimmunoassay in 6 subjects (4 patients with heart disease and 2 volunteers without heart disease) who had been maintained on oral digoxin (0.25 or 0.5 mg daily). Observations were made during a 3-day control period and then during 8 days of concomitant digoxin and oral furosemide (40 mg daily) therapy. Serum digoxin levels determined 10 and 24 hr after each dose of digoxin averaged 1.2+/-0.1 ng/ml (M+/-SE) during control and 1.3+/-0.1 during the last 3 days on digoxin and furosemide. The daily urinary excretion of digoxine averaged 51+/-6% of the oral dose during control and 52+/-6 during the entire period of furosemide administration. The renal clearance of digoxin and creatinine averaged 94+/-7 and 87+/-11 ml/min, respectively, during control; corresponding values were 88+/-8 and 85+/-9 for urine collections demonstrating a distinct diuretic effect of furosemide and 87+/-8 and 75+/-10 for urine collections not demonstrating such an effect during diuretic therapy. The results suggest that the diuretic effect of furosemide does not significantly affect the excretion of digoxin     

Cephacetrile--application of pharmacokinetic data to dosage determination

This pharmacokinetic investigation was based on the determination of serum and urinary levles of cephacetrile in 50 subjects given single intramuscular or intravenous doses of 0.5 or 1 gm of the antibiotic; 30 normal subjects, 10 patients with renal insufficiency, and 10 patients with chronic nephritis undergoing maintenance haemodialysis were included in this study. In normal subjects, mean serum half-life was 1.09 hours (Ke = 0.6337) after intramuscular injection of 0.5 gm cephacetrile, 1.31 hours (Ke = 0.5276) after intramuscular injection of 1 gm, and 0.89 hours (Ke = 0.7806) after intravenous injection of 1 gm. Absorption half-life was 0.45 hours after intramuscular injection of 1 gm cephacetrile. The urinary elimination of cephacetrile over the first 6 hours after injection was on the average 72.7% of the administered dose. After intravenous injection of 1 gm of the antibiotic, the plasma clearance of cephacetrile was 407 ml/min., and its renal clearance 313 ml/min. A linear correlation was found between the values of overall elimination rate constant (Ke) and creatinine clearance in the subjects under investigation (Ke = 0.0080 + 0.0061 ClCr). The established pharmacokinetic characteristics were used to calculate the maintenance and loading doses as well as the intervals between injections adjusted to creatinine clearance. These data constitute true dosage schemes adapted to the particular case of each patient according to his kidney function.     

Urinary kallikrein: a marker of blood pressure sensitivity to salt

We evaluated if a rat strain inbred for low urinary kallikrein excretion differs from normal-kallikrein Wistar rats regarding blood pressure levels in basal conditions and during alterations in sodium balance. Blood pressure was measured in unanesthetized rats on normal sodium intake. Then, blood pressure sensitivity to salt was evaluated over a period of 20 days of high sodium diet (0.84 mmol per g chow). Low-kallikrein rats showed greater systolic blood pressure levels (125 +/- 3 vs. 114 +/- 2 mm Hg in controls, P < 0.01) at nine weeks of age. Systolic blood pressure was increased after sodium loading in the low-kallikrein group and remained unchanged in controls (150 +/- 6 vs. 112 +/- 2 mm Hg, P < 0.01). This effect was associated with a reduced cumulative urinary excretion of sodium in the low-kallikrein rats. No group difference was found in the clearance of endogenous creatinine in basal conditions. Urinary creatinine excretion decreased during sodium loading, particularly in the low-kallikrein group. The group-difference in urinary kallikrein excretion found in basal conditions (6.85 +/- 0.31 vs. 20.74 +/- 1.71 nkat/24 hr in controls, P < 0.01) was enhanced by high salt diet (2.96 +/- 0.67 vs. 22.07 +/- 2.47 nkat/24 hr in controls, P < 0.01). In addition, renal kallikrein activity and content were reduced in low-kallikrein rats. The latter group showed a greater ratio of heart weight to body wt both in basal conditions and after sodium loading. The ratio of kidney weight to body wt was reduced after sodium loading. These results indicate that a genetically-determined defect in urinary kallikrein excretion is associated with a greater blood pressure sensitivity to salt, possibly due to altered renal sodium handling.     

Effects of hyperinsulinemia under the euglycemic condition on calcium and phosphate metabolism in non-obese normotensive subjects

The effect of acute insulin infusion on the metabolism of calcium (Ca) and phosphate (P) was examined in 17 healthy subjects. They were hospitalized and kept on a constant diet for 5 days, and an euglycemic hyperinsulinemic glucose clamp was applied. Synthetic human insulin was infused at the rate of 40 mU/m2/min for 2 hr, and glucose was also infused to maintain basal glucose levels of each subject. The control study was performed in 8 of the 17 subjects, into whom 10% xylitol was infused for 2 hr at the rate of 100 ml/hr. The plasma insulin concentrations were 7.94 +/- 0.35 and 62.3 +/- 14.3 mU/liter before and after the glucose clamp technique, but serum free Ca ion was increased significantly (p < 0.05), and serum P and serum parathyroid hormone (PTH) were decreased significantly (p < 0.001). Creatinine clearance did not change during the glucose clamp technique. Urinary excretion of Ca (UCaV) was significantly higher after the glucose clamp than the control study. Fractional excretion of Ca (FECa) was increased significantly (p < 0.05), and urinary excretion of P (UPV) and fractional excretion of P (FEP) were decreased significantly (p < 0.05) under the hyperinsulinemic condition. The results suggested that, under the conditions of euglycemic hyperinsulinemia by glucose clamp technique, insulin increased the serum free Ca ion, and as a result, PTH was suppressed. Decreased PTH might induce calciuresis and enhance tubular P reabsorption under hyperinsulinemia. Insulin increased serum free Ca ion might relate to the vasodilating action of insulin by its decrease of intracellular free Ca ion in vascular smooth muscle.     

Human leucocyte antigen-DQA1, -DQB1 polymorphism distribution in Shanghai Chinese women with pregnancy induced hypertension]

Our objective was to determine if maternal urinary calcium excretion is altered during treatment of mild preeclampsia remote from term with the calcium channel blocker nifedipine. One hundred forty-eight women with mild preeclampsia were randomly allocated to treatment with either bed rest alone (n=64) or in combination with nifedipine (n=84) at 26-36 weeks' gestation. All women had 24 hr urine samples collected for creatinine clearance and calcium excretion determination prior to therapy and during treatment. There was no difference in gestational age at the time of urine collection between the two groups. There were no differences in 24-hr creatinine clearance and calcium excretion between the groups prior to therapy. When followed longitudinally, there was a significant reduction in calcium excretion within each group (p=0.0005 control group, p <0.0001 nifedipine group). Further, a significant reduction in calcium excretion was noted following nifedipine therapy (62+/-94 mg Ca/24 hr) compared to the control group (143+/-153 mg Ca/24 hr), p <0.001. Consistent with previous studies, we have shown that progressive hypocalciuria is a feature of preeclampsia. Further, urinary calcium excretion decreased despite nifedipine therapy. Altered urinary calcium excretion may be less reflective of the progression in severity of preeclampsia in patients treated with nifedipine.     

Serum and urinary boron levels in rats after single administration of sodium tetraborate

The pharmacokinetics of boron was studied in rats by administering a 1 ml oral dose of sodium tetraborate solution to several groups of rats (n=20) at eleven different dose levels ranging from 0 to 0.4 mg/100 g body weight as boron. Twenty-four-hour urine samples were collected after boron administration. After 24 h the average urinary recovery rate for this element was 99.6+/-7.9. The relationship between boron dose and excretion was linear (r=0.999) with a regression coefficient of 0.954. This result suggests that the oral bioavailability (F) of boron was complete. Another group of rats (n=10) was given a single oral injection of 2 ml of sodium tetraborate solution containing 0.4 mg of boron/100 g body wt. The serum decay of boron was followed and found to be monophasic. The data were interpreted according to a one-compartment open model. The appropriate pharmacokinetic parameters were estimated as follows: absorption half-life, t1/2a=0.608+/-0.432 h; elimination half-life, t1/2=4.64+/-1.19 h; volume of distribution, Vd = 142.0+/-30.2 ml/100 g body wt.; total clearance, Ctot=0.359+/-0.0285 ml/min per 100 g body wt. The maximum boron concentration in serum after administration (Cmax) was 2.13+/-0.270 mg/l, and the time needed to reach this maximum concentration (Tmax) was 1.76+/-0.887 h. Our results suggest that orally administered boric acid is rapidly and completely absorbed from the gastrointestinal tract into the blood stream. Boric acid in the intravascular space does not have a strong affinity to serum proteins, and rapidly diffuses to the extravascular space in proportion to blood flow without massive accumulation or binding in tissues. The main route of boron excretion from the body is via glomerular filtration. It may be inferred that there is partial tubular resorption at low plasma levels. The animal model is proposed as a useful tool to approach the problem of environmental or industrial exposure to boron or in cases of accidental acute boron intoxication.     

Segregation and integration of cytoplasmic and nuclear materials during cleavage and induced fusion of blastomeres of mouse early embryos

Phenylbutazone was administered intravenously (i.v.) to a group of four lactating cows at a dosage of 6 mg/kg body weight. Whole plasma, protein-free plasma and milk were analysed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a non compartmental method. In regards to whole plasma data, the mean volume of distribution at steady state (Vss), was 147 mL/kg body weight, with a mean (+/-SEM) terminal elimination half-life (t1/2) of 40+/-6 h. The mean clearance (Cl) was 3 mL/h/kg body weight. The Vss as determined from the protein-free plasma fraction was 50021 mL/kg body weight. This larger Vss of free phenylbutazone compared to total plasma phenylbutazone was attributed to a high degree of plasma protein binding, as well as the greater penetration of free phenylbutazone into tissues. The mean t1/2 of free phenylbutazone was 39+/-5 h. This similarity to the t1/2 estimated from total plasma phenylbutazone data is attributed to an equilibrium between free and plasma phenylbutazone during the terminal elimination phase. Mean t1/2 as determined from milk, applying a urinary excretion rate model, was 47+/-4 h. Milk clearance of phenylbutazone was 0.009 mL/h/kg body weight, or about 0.34% of total body clearance. Furthermore, evidence suggests that phenylbutazone either binds to milk proteins, or is actively transported into milk, as its concentration in milk was greater than that predicted due to a simple partitioning from plasma into milk.     

Renal glomerular and tubular function following acute insulin deprivation in juvenile diabetes mellitus

The effects of acute deprivation of insulin on renal glomerular and tubular functions were studied in 10 children with juvenile diabetes mellitus. Serum glucose concentrations were similar when insulin was administered (251 +/- 112 mg/dl) and when it was withheld (306 +/- 130 mg/dl; 0.5 greater than 0.2). Acute insulin deprivation was associated with a significant reduction in glomerular filtration rate, from 151 +/- 48 ml/min/1.73 m2 to 114 +/- 41 ml/min/1.73 m2 (p less than 0.01). The fractional excretion of sodium rose from 0.45 +/- 0.43 to 0.85 +/- 0.54% (p less than 0.05) and was associated with an enhanced natriuresis; the urinary excretion of sodium increased from 1.67 +/- 1.23 to 2.43 +/- 1.72 microEq/min/kg body weight (p less than 0.05), whereas the urinary excretion of phosphate was not significantly altered from control values. During insulin deprivation a drop occurred in the serum concentration of calcium from 10.37 +/- 0.52 to 9.73 +/- 0.61 mg/dl (p less than 0.01) as well as in its urinary excretion from 0.34 +/- 0.24 to 0.24 +/- 0.20 microgram/min/kg body weight (p less than 0.01). The serum concentration of potassium rose from 4.44 +/- 0.41 to 4.96 +/- 0.51 mEq/l, but its urinary excretion was not significantly different from control values. These data suggest that in juvenile diabetes mellitus the acute deprivation of insulin, dissociated from fluctuations in serum glucose concentration, is associated with a fall in glomerular filtration rate, an increased natriuresis, and a modified calcium and potassium homeostasis.     

Minimal daily variations of plasma and urinary endothelin-1 in healthy subjects

The daily profiles of both the plasma level and the urinary excretion rate of endothelin-1 were examined in 13 healthy volunteers (9 males and 4 females, aged 22 +/- 1 [SEM]). Plasma endothelin-1 (PET) was measured after a one-hour recumbency every 6 hours at 8 a.m., 2 p.m., 8 p.m. and 2 a.m. and the urinary excretion rate of endothelin-1 (UET) was determined in the urine collected every 6 hours. PET was found to be quite stable throughout the day, being 1.57 +/- 0.25 pg/ml at 8 a.m., 1.88 +/- 0.21 at 2 p.m., 2.2 +/- 0.24 at 8 p.m. and 1.90 +/- 0.20 at 2 a.m. After a one-hour ambulation, PET showed no statistical difference. UET also remained unchanged for each 6-hour collecting period, measuring 4.61 +/- 0.69, 3.98 +/- 0.46, 4.63 +/- 0.73 and 3.42 +/- 0.49 ng/hr, respectively. The absence of any daily variations in either PET or UET thus suggests that apparently no specific considerations need be applied regarding the time of taking samples to measure the plasma and urinary endothelin-1.     

Geophagy, iron status and anaemia among pregnant women on the coast of Kenya

OBJECTIVE: To report a case of methemoglobinemia in a patient receiving dapsone for prophylaxis of Pneumocystis carinii pneumonia (PCP). CASE SUMMARY: A 69-year-old white woman was hospitalized to rule out sepsis. Two years prior to this admission, the patient received an orthotopic liver transplant after which she required hemodialysis three times weekly. Because of intolerance to trimethoprim/ sulfamethoxazole and aerosolized pentamidine, she was prescribed dapsone therapy on hospital day 13, that was continued for 11 days. On hospital day 45 the patient received a cadaveric kidney transplant, and dialysis treatments were scheduled only as needed. One week after the transplant, dapsone therapy was resumed. Nine days into this course of dapsone, the patient developed dyspnea and oxygen desaturation of unknown etiology. The patient was evaluated for and diagnosed with methemoglobinemia. She received two doses of intravenous methylene blue and one dose of oral activated charcoal due to fluctuating methemoglobin concentrations. DISCUSSION: The elimination of dapsone is not completely understood. Several case reports of dapsone-induced methemoglobinemia are present in the literature. Most have occurred in patients who have accidentally or deliberately overdosed. Cases of methemoglobinemia in patients receiving therapeutic doses of dapsone are discussed. CONCLUSIONS: The growing numbers of immunosuppressed patients due to transplantation of HIV may result in increased dapsone use for the prevention of PCP. Clinicians should be aware of the adverse effects associated with dapsone therapy, and patients with dyspnea and hypoxemia of unclear etiology should be evaluated for methemoglobinemia.     

Circulating angiotensin II and renal sodium handling in man: a dose-response study

1. Animal studies have shown that angiotensin II has a biphasic effect on urinary sodium excretion. To examine whether this is also true in man, we studied seven salt-replete male subjects in a single-blind placebo-controlled manner. 2. While undergoing maximum diuresis, subjects were infused with 0, 1, 2, 5 or 10 ng of angiotensin II min-1 kg-1 over 80 min. Subjects were studied while seated, and stood every 20 min for urine collection. 3. Angiotensin II produced a dose-dependent antidiuretic effect. The urine flow rate, in ml/min expressed as the change from baseline with increasing dose of angiotensin, was: +3.4 +/- 1.77, -1.26 +/- 0.49 (P < 0.05), -2.75 +/- 1.23 (P < 0.05), -4.21 +/- 0.82 (P < 0.05) and -6.51 +/- 1.07 (P < 0.01). 4. In contrast, the effect of angiotensin II on sodium excretion showed a flat dose-response curve beyond 5 ng min-1 kg-1. The urinary sodium excretion, in mumol/min expressed as the change from baseline with increasing dose of angiotensin, was: 9.5 +/- 21.2, -18.9 +/- 29.6, -37.0 +/- 11.6 (P < 0.05), -67.7 +/- 19.6 (P < 0.01) and -63.8 +/- 14.3 (P < 0.01). 5. The fractional distal reabsorption of sodium, determined by using the lithium clearance technique, showed a rise with all doses of angiotensin II used and reached statistical significance with the top two doses. 6. Unlike antidiuresis, antinatriuresis after graded doses of angiotensin II in human subjects showed a flat dose-response curve beyond 5 ng min-1 kg-1. Pressor doses of angiotensin II also have a significant effect on the distal tubule in promoting sodium reabsorption.     

Refractory ascites in cirrhosis: roles of volume expansion and plasma atrial natriuretic factor level elevation

Cirrhotic patients with ascites refractory to diuretics also have blunted response to marked elevations of plasma atrial natriuretic factor levels alone or to moderate intravascular volume expansion by head-out water immersion. However, these patients usually undergo natriuresis after peritoneovenous shunting. To dissect the factors responsible for this response, we studied the effects on separate days of moderate intravascular volume expansion and highly elevated plasma atrial natriuretic factor levels (head-out water immersion and atrial natriuretic factor infusion) or marked volume expansion and moderate plasma atrial natriuretic factor level elevation (head-out water immersion and albumin infusion) in 13 alcoholic cirrhotic patients with massive ascites. Three of these patients, who responded to initial head-out water immersion with a negative sodium balance, served as controls. Unresponsiveness to head-out water immersion was confirmed in the remaining 10 patients on both days on the basis of blunted natriuretic response (urinary sodium excretion < 0.8 mmol/hr after 2 hr). In contrast, these 10 refractory patients were able to achieve negative sodium balance with both combinations. Mean urinary sodium excretion increased from a baseline level of 0.13 +/- 0.10 mmol/hr to a peak level of 2.29 +/- 0.61 mmol/hr after head-out water immersion and atrial natriuretic factor infusion and from 0.10 +/- 0.3 mmol/hr to 1.61 +/- 0.62 mmol/hr after head-out water immersion and albumin infusion. Both maneuvers were associated with suppression of plasma renin activity and serum aldosterone levels. With head-out water immersion and atrial natriuretic factor infusion, we noted a significant increase in 5' cyclic GMP levels, a second messenger of atrial natriuretic factor, indicating possible activation of atrial natriuretic factor receptors at the inner medullary collecting ducts. In contrast, with head-out water immersion and albumin infusion no such increase in levels occurred, indicating that the increase in urinary sodium excretion was mainly due to increased delivery of sodium to the cortical distal nephron, as indicated by a disproportionate increase in urinary potassium excretion. In conclusion, massive (as opposed to moderate) volume expansion or greatly elevated levels of plasma atrial natriuretic factor associated with moderate volume expansion can improve blunted atrial natriuretic factor responsiveness in cirrhotic patients with refractory ascites. This appears to be achieved by way of a marked increase in distal delivery of filtrate in the kidney, with or without activation of distal atrial natriuretic factor receptors in the inner medullary collecting ducts.     

In vivo proliferation of oligodendrocyte progenitors expressing PDGFalphaR during early remyelination

2,4-Pentanedione (2,4-PD; CAS No. 123-54-6), an industrial chemical, was investigated for its comparative pharmacokinetics in male Fischer 344 rats by a single intravenous (i.v.) injection of (4.3, 43, 148.5, and 430 mg/kg), or a 6-hr nose-only inhalation exposure (400 ppm) to 14C-2,4-PD. For the i.v. route, the plasma concentration of 14C-2,4-PD-derived radioactivity declined in a biexponential fashion. The overall form of the 14C plasma concentration-time curves and derived pharmacokinetic parameters indicated that dose-linear kinetics occurred in the i.v. dose range 4.3-148.5 mg/kg, but not with 430 mg/kg. Metabolism of 2,4-PD was quite rapid as the concentration of unmetabolized 2,4-PD declined steadily to undetectable after 8 hr. 14C-2,4-PD derived radioactivity was eliminated mainly as 14CO2 and in urine. For the 4.3, 43 and 148.5 mg/kg doses 14CO2 elimination was relatively constant (36.8, 38.8 and 42.3% in 48 hr samples respectively) and greater than urinary excretion (17.9, 14.3 and 29.6%; 48 hr specimens). At 430 mg/kg i.v. there was a reversal of the excretion pattern, with urine 14C excretion (54.7%) becoming greater than that for 14CO2 (27.3%). Excretion in expired volatiles and feces was small. Radiochromatograms of urine showed free 2,4-PD in the 12 hr sample, together with 7 other metabolites. Free 2,4-PD and 6 of the metabolites decreased or were not detectable in a 24 or 48 hr urine sample, but one peak (retention 7.9 min) increased progressively to become the major fraction (97%). Nose-only exposure to 400 ppm 14C-2, 4-PD produced a mean decrease in breathing rate of 20.1%, which was constant and sustained throughout exposure, due to a lengthening of the expiratory phase of the respiratory cycle. 14C-2,4-PD was rapidly absorbed during the first 3 hr of exposure, then began to plateau, but did not reach a steady state. Postexposure elimination of 14C from plasma followed a biexponential form with a t1/2 for the terminal disposition phase of 30.72 hr. Plasma unmetabolized 2,4-PD was present throughout the whole of the exposure phase, but was significantly less than total 14C. Postexposure, plasma unmetabolized 2,4-PD declined rapidly to undetectable concentrations by 12 hr. Radiolabel excretion was approximately equivalent in urine (37.6%) and expired 14CO2 (36.3%). Urine radiochromatograms showed a minor 2,4-PD contaminant (0.6-5.9% over 48 hr), along with 7 other peaks probably representing metabolites. As with the 148.5 mg/kg i.v. dose, the major metabolite peak was at 7.8 min retention, increasing from 41.1% (12 hr) to 62.8% (48 hr). Immediately postexposure, radioactivity was present in all tissues examined, but on a concentration basis (microgram equiv/g) there was no preferential accumulation of 14C in any tissue or organ. On a total organ basis, highest contents were in liver and kidney, presumably related to the metabolism and excretion of 2,4-PD. By 48 hr postexposure, concentrations had decreased in all tissues except fat, presumably due to the lipophilicity of 14C residues. The profile of the plasma-time radioactivity curves, and the presence of residual radioactivity in tissues at 48 hr postexposure, suggests that a cumulative process could occur with frequent repeated exposures.     

Intermittent intraperitoneal ceftazidime dosing in end-stage renal disease

Infections are a common problem in dialysis patients. As hospital stay shortens, many require outpatient antibiotic therapy. Parenteral administration may pose considerable logistic and financial burdens, whereas daily intraperitoneal dosing increases the risk of contamination. Ceftazidime, with its long half-life, may provide adequate dosing when administered intraperitoneally thrice weekly. The authors therefore studied the kinetics of a 2 g loading dose followed by a 1.5 g dose every 48 hr in seven stable chronic peritoneal dialysis patients. In vitro stability at 4 degrees C (measured by high performance liquid chromatography) was 91% at 120 hr. Peak serum concentration (60 +/- 22 microg/ml) was reached at 4.9 +/- 2.2 hr. Serum values were 25 +/- 9 and 8 +/- 3 microg/ml at 24 and 48 hr, respectively. However, median trough levels at 48 hr in dialysate were significantly lower than in serum (2.8 vs 8.5 microg/ml, respectively; p = 0.0425). Pharmacokinetic parameters were as follows: bioavailability (F), 88% +/- 8%; volume of distribution at steady state (VDss), 20 +/- 8 L; absorption half-life (T1/2(abs)), 1.8 +/- 1.3 hr; elimination half-life (T1/2(el)), 11.4 +/- 4.5 hr; and clearance (CL), 22 +/- 10 ml/min. Intraperitoneal ceftazidime every 48 hr is a practical alternative to parenteral therapy of nonperitoneal infections. In peritonitis, whether increased permeability results in improved dialysate levels remains to be defined.     

Effect of detergents on the electrophoretic behaviour of plasma apolipoproteins in capillary electrophoresis

The effects of anatomical site and occlusion on the percutaneous absorption and residue pattern of total 14C were investigated following topical application of 2,6-[ring-14C]parathion onto four skin sites (300 micrograms/10 microCi; 40 micrograms/cm2) in weanling swine using occluded and nonoccluded dosing systems. The excretion profile was examined after iv administration. After dosing onto the abdomen, buttocks, back, and shoulder (N = 4/site), total urinary and fecal excretion (%dose) by 168 hr were, for the occluded system, 43.94 +/- 2.24, 48.47 +/- 7.85, 48.82 +/- 4.49, and 29.28 +/- 5.70%, and for the nonoccluded system, 7.47 +/- 2.16, 15.60 +/- 3.71, 25.00 +/- 8.75, and 17.41 +/- 1.76%, respectively. After iv dosing, 98.44 +/- 2.83% of the applied dose was excreted primarily via urine. The total recoveries for different sites ranged from 90.09 +/- 7.10 to 94.62 +/- 1.98% in the occluded system, 77.84 +/- 5.75 to 88.18 +/- 3.34% in the nonoccluded system, and 99.03 +/- 2.89% in the iv experiments. Time of maximal excretion rate was determined in the occluded system as abdomen (7.9 +/- 3.6 hr) < buttocks (9.4 +/- 2.6 hr) < shoulder (10.5 +/- 3.8 hr) < back (13.3 +/- 7.7 hr), but in the nonoccluded system as buttocks (11.9 +/- 3.6 hr) < shoulder (12.6 +/- 4.1 hr) < back (14.3 +/- 6.4 hr) < abdomen (16.9 +/- 7.1 hr). The percutaneous absorption from the shoulder was much lower than that from the other three sites under occluded conditions. However, if nonoccluded dosing was employed, absorption from the abdomen became the lowest, with shoulder and buttocks being similar, and the back the highest. Occlusion conceals the site difference and enhances both the extent and the rate of parathion percutaneous absorption in vivo. 14C residue pattern in tissues and dosing materials was site and dosing method dependent, all of which are factors which must be considered when assessing the risk of exposure to topically applied compounds.     

Iron-balance and dose-response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in iron-loaded patients with sickle cell disease

Several life-threatening complications of the common disorder sickle cell disease require management with red blood cell transfusions and, hence, long-term iron-chelating therapy. The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) has not previously been determined in patients with sickle cell disease. We compared the efficacy of L1 to that of standard-dose subcutaneous deferoxamine in four regularly transfused patients with homozygous sickle cell disease, who had evidence of severe iron overload and a history of poor compliance with deferoxamine. Determination of 24-hour urinary iron excretion conducted over 5 days immediately after transfusion showed that the mean daily urinary iron excretion induced by L1 at 75 mg/kg/d (0.48 +/- 0.23 mg/kg) was equivalent to that induced by deferoxamine at 50 mg/kg/d (0.39 +/- 0.06 mg/kg). In two of three patients studied, a significant (P < .025) increase in mean daily urinary iron excretion was achieved when the dose of L1 was increased to 100 mg/kg/d. Total iron balance studies, which quantitated both urinary and stool iron excretion on L1 and deferoxamine, determined that mean total daily iron excretion induced by deferoxamine (0.88 +/- 0.05 mg/kg) was significantly greater (P < .05) than that induced by L1 (0.53 +/- 0.17 mg/kg), attributable to the significantly greater stool iron excretion during deferoxamine treatment (0.50 +/- 0.16 mg/kg/d) compared with that measured during L1 treatment (0.12 +/- 0.08 mg/kg/d, P < .01). Stool iron excretion accounted for a significantly greater percentage of total iron excretion during deferoxamine treatment (59% +/- 20%) than during L1 treatment (23% +/- 14%, P < .01). These iron balance studies are the first to compare total iron excretion induced by L1 with that achieved by deferoxamine. They demonstrate that the mean total daily iron excretion during L1 treatment (0.53 +/- 0.17 mg/kg) is sufficient to maintain net negative iron balance in most regularly transfused patients with sickle cell disease. Because long-term compliance with L1 has been shown previously to be superior to that with deferoxamine in patients with homozygous beta-thalassemia, the use of L1 should increase the long-term effectiveness of iron chelation in patients with sickle cell disease.     

Interaction of a thrombin inhibitor and a platelet GP IIb/IIIa antagonist in vivo: evidence that thrombin mediates platelet aggregation and subsequent thromboxane A2 formation during coronary thrombolysis

We examined the effect of a specific thrombin inhibitor, Ro 46-6240, alone and combined with an antagonist of the platelet GP IIb/IIIa, Ro44-9883, on the response to tissue-type plasminogen activator in a canine model of thrombolysis. Platelet activity was determined by measuring the excretion of 2,3-dinorthromboxane (TX)B2, an enzymatic metabolite of TXA2. Ro 46-6240 administered before tissue-type plasminogen activator induced a dose-dependent prolongation of the activated partial thromboplastin time and prothrombin time. The time to reperfusion decreased dose-dependently (P < .01) to 10 +/- 6 min vs. 52 +/- 5 min in controls. Ro 46-6240 also prevented reocclusion, which occurred in every case in control experiments. Urinary excretion of 2,3-dinor-TXB2 increased from 3 +/- 1 to 37 +/- 9 ng/mg creatinine in controls after reperfusion. This increase was reduced in a dose-dependent fashion by Ro 46-6240, such that at the highest dose, urinary 2,3-dinor-TXB2 after reperfusion was 5.6 +/- 1 ng/mg creatinine. Similar functional and biochemical effects were seen when a subthreshold dose of Ro 46-6240 was combined with Ro 44-9883. At the dose used, Ro 44-9883 alone abolished platelet aggregation ex vivo but failed to modify the response to tissue-type plasminogen activator or the excretion of 2,3-dinor-TXB2 after reperfusion (51 +/- 6 ng/mg creatinine, n = 3). However, the combination of Ro 44-9883 and Ro 46-6240 reduced the time to reperfusion (40 +/- 8 vs. 68 +/- 15 min; n = 7, P < .05), prevented reocclusion and abolished the rise in urinary 2,3-dinor-TXB2 (5 +/- 1 ng/mg creatinine, n = 4). These findings suggest that thrombin mediates platelet activation during coronary thrombolysis. The increased platelet activity results in platelet aggregation and a subsequent increase in TXA2 formation.