Earlier studies suggested that the dose of 6-mercaptopurine (6-MP) can be reduced substantially when the drug is given with allopurinol. We studied the effect of allopurinol on the kinetics of oral and intravenous 6-MP. Studies conducted initially in rhesus monkeys and subsequently in man with 6-MP doses of 100 mg/m2 and 75 mg/m2, demonstrated that allopurinol pretreatment resulted in a nearly 400% increase in peak plasma concentration of oral 6-MP in monkeys (from a mean of 0.54 microM to a mean of 2.1 microM) and a 500% increase in man (0.74 microM to 3.7 microM). Allopurinol pretreatment also led to a 300% increase in plasma AUC in monkeys after oral 6-MP (from a mean of 121 microM/min to a mean of 391 microM/min) and a 500% increase in AUC in man (from a mean of 142 microM/min to a mean of 716 microM/min). In contrast, allopurinol pretreatment had no effect on the kinetics of intravenous 6-MP. This difference was found to be due to inhibition of first-pass metabolism of oral 6-MP as the result of the action of allopurinol on liver or intestinal xanthine oxidase. Our results indicate that, although dose reduction of oral 6-MP given in conjunction with allopurinol is appropriate, it is not necessary when 6-MP is injected intravenously.
The function of the hypothalamic-adenohypophyseal unit was tested in 2 groups of rhesus monkeys before and at periodic intervals after the administration of 2400 and 4000 rads cranial radiation. This therapy was given in 10 fractions over a 2-week period. Plasma TSH, basally and after TRH administration, and LH and FSH, before and after gonadotropin-releasing hormone stimulation, were normal up to 1 yr after radiation. Plasma GH at the basal state and after arginine and L-dopa stimulation was also normal. An insulin tolerance test, however, demonstrated a blunted GH response at a dose (0.1 U/kg) that caused brisk stimulation of GH secretion in normal control monkeys. A larger dose of insulin (0.2 U/kg) resulted in ample secretion of GH in these animals, suggesting decreased hypothalamic sensitivity to insulin in treated animals. The measurement of GH every 20 min for 24 h in animals treated with 4000 rads showed a dramatically altered secretory pattern of GH 1 yr after radiation. GH secretory spikes were markedly decreased in both frequency and amplitude, suggesting a reduction in the normal daily production of GH.
Interferons are currently undergoing clinical testing in patients with cancer and other diseases. A variety of routes of administration are being utilized, and there is particular interest in delivery of interferon to the central nervous system. A biphasic decline in plasma concentrations was observed in monkeys following an i.v. bolus, with initial half-times of 15 to 33 min and terminal half-times of 1.7 to 4.6 hours. Total body clearance ranged from 24 to 39 ml/sq. m/min and steady-state volume of distribution was similar to extracellular space. CSF exposure was 1% or less than that of plasma. Intramuscular injections produced lower peak concentrations and more sustained levels, but there was substantial variation in bioavailability (range 19-103%). Levels in the CSF were not detectable for the i.m. route. For intraventricular doses, CSF exposure was 3,000-fold greater than for i.v. doses, despite a 20-fold lower dose.
Intracerebroventricular injection of corticotropin-releasing factor (CRF) in animals activates behavioral, motor, metabolic and sympathetic responses similar to those seen with stress. To explore the pharmacokinetics of this peptide in the primate ventricular CSF, we determined the clearance of ovine 125I-CRF from the CSF and compared it to that of 111In-DTPA, a substance cleared by bulk flow. 125I-CRF was cleared from the ventricular fluid sixfold more rapidly than bulk flow. This suggests that the CSF may be a pathway for physiological distribution of this releasing factor to active sites within the central nervous system, and that a mechanism exists for active removal of CRF from the ventricular CSF.
~e i . & C a r d i o . Res. I n s t . , Univ. C a l i f . , S a n F r a n c i s c o .To e x a m i n e t h e o n t o g e n y a n d r e g u l a t i o n o f CBG i n t h e p e r i n a t a l p e r i o d , we d e t e r m i n e d p l a s m a c o r t i s o l b i n d i n g c a p a c i t y u s i n g a c h a r c o a l a b s o r p t i o n a s s a y .CBG c a p a ci t y i n c r e a s e d p r o g r e s s i v e l y f r o m 1 . 6 p g / d l a t 75 d a y s t o 7 . 1 u g / d l a t 1 4 1 d a y s ( n = 2 4 9 ) , w i t h t h e g r e a t e s t i n c r e a s e f r o m 1 2 1 d a y s t o t e r m .T h e r e was a s i m i l a r i n c r e a s e i n CBG ( + 4 1 . 1 % ) a n d t o t a l p r o t e i n s ( + 3 6 . 7 % ) i n 6 f e t u s e s d u r i n g t h e 4-6 d a y s b e f o r e s p o n t a n e o u s d e l i ve r y .A f t e r b i r t h , b o t h CBG a n d p r o t e i n s d e c r e a s e d d u ri n g t h e f i r s t h a l f d a y ; t h e r e a f t e r CBG d e c r e a s e d ( t + = 5 d a y s ) t o 1 . 0 p g / d l a t 1 4 d a y s w h i l e p r o t e i n s d i d n o t c h a n g e . I n 7 f e t u s e s w i t h l o s s o f p i t u i t a r y f u n c t i o n t h e r e was n o i n c r e a s e i n C B G d u r i n g t h e 22-35 d a y s a ft e r s u r g e r y . I n f u s i o n s o f h y d r o c o r t i s o n e f o r 2 d a y s , e s t r a d i o l f o r 5 d a y s , p r o l a c t i n f o r 5-8 d a y s a n d ACTH f o r 3 d a y s t o i n t a c t f e t u s e s d i d n o t a f f e c t CBG l e v e l s . We, c o n c l u d e t h a t t h e p i t u i t a r y c o n t r o l s t h e m a j o r i n c r e a s e i n CBG a f t e r 1 2 1 d a y s ; t h e r e i s a n a d d i t i o n a l p r e p a r t u m i n c r e a s e i n a l l s e r u m p r o t e i n s w i t h l a b o r . The p i t u i t a r y h o r m o n e ( s ) w h i c h s t i m u l a t e C B G p r o d u c t i o n a r e n o t i d e n t i f i e d , b u t t h i s h o r m o n a l i n f l u e n c e a p p a re n t l y c e a s e s w i t h b i r t h .
4'-(9-Acridinylamino)-methanesulfon-m-anisidide (m-AMSA) is an acridine compound that has been found useful in the systemic treatment of acute leukemia. This paper specifically investigates the CSF pharmacokinetics of m-AMSA following both intravenous and intraventricular administration in a subhuman primate model. Following intravenous administration, m-AMSA crossed the blood-brain barrier poorly; cerebrospinal fluid (CSF) concentrations were only 1-3% of systemic concentrations. Intraventricular administration of drug achieved high initial ventricular fluid concentrations, but the drug was rapidly cleared with a half-life of 115 min. Following 500 micrograms of intraventricular drug, CSF concentrations of m-AMSA remained above 1 microM for only 6 h. These data suggest that m-AMSA has potential as an intrathecal agent against meningeal leukemia refractory to more conventional therapy, but detailed toxicology and neurohistopathology will be required before intra-CSF m-AMSA can be considered for human use.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.