Concomitant Dosing Research Articles

The effect of ageing on the disposition of nifedipine and atenolol.

1. Healthy young and elderly volunteers received 20 mg nifedipine (slow release) orally for 2 weeks with concomitant dosing of atenolol 50 mg orally during the second week. 2. Drug kinetics and dynamics were compared between the groups after a single dose of nifedipine (day 1), after chronic dosing for 1 week (day 8), and following concomitant daily dosing of atenolol (day 15). 3. Plasma profiles of nifedipine were similar within each group on each of the 3 sampling days. The elderly group had higher plasma concentrations from about 6 h but there was no difference in the maximum concentrations achieved. The half-life in the elderly was significantly longer (8.8 +/- 0.9 h) compared with that in the young (5.8 +/- 1.1 h) (P less than 0.01). 4. Blood concentrations of atenolol were higher in the elderly at 12 and 24 h post-dose (P less than 0.001) and the AUC was greater than in the young (P less than 0.001). 5. Systolic blood pressure was reduced by nifedipine in both groups but to a greater extent in the elderly (P less than 0.01); differences in diastolic blood pressure were not significant. Blood pressure was reduced further by the addition of atenolol. Atenolol reduced the heart rate in all subjects.

Attenuation of 2-methoxyethanol and methoxyacetic acid-induced digit malformations in mice by simple physiological compounds: implications for the role of further metabolism of methoxyacetic acid in developmental toxicity.

The ethylene glycol ether 2-methoxyethanol (ME) and its oxidation product methoxyacetic acid (MAA) are selective embryotoxins and equipotent as inducers of digit malformations when given by gavage to pregnant Crl:CD-1 ICR BR mice on gestation day 11. Earlier observations showed that the teratogenic effects were attenuated by delayed administrations of ethanol given at a time when all ME is already converted to MAA. That outcome suggested that acetate from ethanol catabolism might compete with methoxy-acetate in biosynthetic reactions relevant to MAA-induced malformations. Furthermore, 14C derived from [1,2-14C]-ME or [1-14C]-MAA is incorporated into all macromolecular fractions of the embryo, and 14C is exhaled by the dam in 14CO2. Those data indicate that 14C derived from 14C-ME catabolism enters into many metabolic reactions. The present study examined acetate and other simple physiological compounds with close relationships to carbon and one-carbon moiety metabolic pathways for their ability to attenuate digit malformations upon concomitant dosing with ME. All of the agents examined reduced the teratogenic effect significantly with a potency rank order of formate much greater than acetate = glycine much greater than D-glucose. The common link for their efficacy may be the one-carbon moiety oxidation pathway that involves tetrahydrofolic acid as a catalyst of one-carbon transfer into purines and thymidylate. Carbon from all of the attenuators administered is incorporated into those bases and then into DNA. It appears as if methoxyacetate enters into biochemical reactions analogous to those of acetate. This speculation is supported by the metabolic fate of 14C from 14C-ME in dam and embryo. Based on the indirect evidence obtained with all of the simple compounds that attenuate the ME-induced digit malformations, we postulate that abnormal macromolecules are generated by anabolic reactions and that those products disrupt normal paw development.

Nocturnal Doses of Ranitidine and Nizatidine Do not Affect the Disposition of Diazepam

The disposition of diazepam (D) after a single oral dose of 10 mg was evaluated in nine healthy male volunteers under the following conditions (randomized, double-blind, crossover design): D + comedication of placebo and D + nocturnal dosing with 300 mg ranitidine or 300 mg nizatidine. Plasma concentrations of D and its major active metabolite, desmethyldiazepam (DD), were monitored by a gas-liquid chromatography-electron-capture detection assay for 84 hours. Neither ranitidine nor nizatidine had any significant effect on the hepatic elimination of D as characterized by its terminal half-life (mean +/- SD) of 35.3 +/- 24.2 hours (+ ranitidine: 30.1 +/- 9.9 hr; + nizatidine: 37.3 +/- 18.3 hr) or total plasma clearance of 28.2 +/- 12.0 mL/min (+ ranitidine: 26.5 +/- 7.9 mL/min; + nizatidine: 26.7 +/- 10.4 mL/min). Likewise, the formation of DD as measured by its AUC was not affected by ranitidine or nizatidine. Thus, it can be concluded that concomitant once-daily dosing (300 mg nocturnally) with ranitidine or nizatidine does not impair hepatic drug metabolism.

Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the active S-enantiomer.

Six healthy men received single oral doses of 1500 mg of vigabatrin [(R,S)-gamma-vinyl-GABA] and 750 mg of S(+)-gamma-vinyl-GABA on two occasions. Concentrations of the individual enantiomers were assayed by a stereoselective procedure based on combined GC/MS. At peak, concentrations of the R(-)-enantiomer exceeded concentrations of the S(+)-enantiomer, with an approximate ratio of 2:1. The mean terminal t1/2 ranged from 6 to 8 hours for both enantiomers. Mean urinary recovery of the S(+)-enantiomer was 49% after both doses and was 65% for the R(-)-enantiomer. Plasma concentration values obtained for the S(+)-enantiomer after a dose of the pure S(+)-enantiomer and an equivalent dose of the racemate showed good agreement for both the concentrations observed at any time point and the elimination characteristics, demonstrating bioequivalence. Renal clearance values for the S(+)-enantiomer are not affected by concomitant dosing with the pharmacologically inactive R(-)-enantiomer. No chiral inversion was detected after dosing with the pure S(+)-enantiomer.

The warfarin-sulfinpyrazone interaction: stereochemical considerations.

To allow the simultaneous evaluation of the interaction between sulfinpyrazone and each enantiomer of racemic warfarin, pseudoracemic warfarin (1:1 12C-R(+) and 13C-S(-)warfarin) was given to six normal subjects both before and during oral sulfinpyrazone dosing. Serial blood and urine samples were analyzed for unchanged warfarin and its metabolic products by GC/MS. A mass balance of an oral dose of pseudoracemic warfarin, containing a tracer quantity of 14C-warfarin, was carried out in one of the subjects by monitoring 14C levels in urine and feces for 15 days. Concomitant sulfinpyrazone dosing markedly increased hypoprothrombinemia, decreased clearance of (S)-warfarin, and increased clearance of (R)-warfarin. Sulfinpyrazone also decreased the urinary excretion of warfarin-related products but increased their fecal excretion by an equivalent amount. Virtually all of the administered warfarin dose could be accounted for either as unchanged drug or known metabolites. Pharmacokinetic analysis of the data suggests the following: At least four distinct enzymes (two oxidases and two reductases) are involved in the metabolism of warfarin. Sulfinpyrazone increases the hypoprothrombinemia caused by warfarin primarily by inhibition of the cytochrome P-450-mediated oxidation of (S)-warfarin, the biologically more potent enantiomer. The increased clearance of (R)-warfarin results not from induction, but from its selective displacement from plasma protein binding sites.

Effects of verapamil, diltiazem, and nifedipine on plasma levels and renal excretion of digitoxin

To determine whether verapamil, diltiazem, or nifedipine affect digitoxin kinetics, glycoside plasma concentrations and renal excretion were measured before and during steady-state dosing in 30 patients with cardiac insufficiency. The mean (+/- SD) digitoxin plasma concentration was 14.27 +/- 3.66 ng/ml before and 18.15 +/- 5.33 ng/ml during verapamil dosing in 10 patients over a period of 4 to 6 weeks. Renal digitoxin clearance was not influenced by verapamil, but total body clearance and extrarenal clearance of digitoxin were reduced by 27% and 29%, respectively. Diltiazem resulted in a 6% to 31% (mean = 21%) increase in plasma digitoxin concentrations in five of 10 patients because of reduced extrarenal clearance of digitoxin. In contrast to verapamil, the concomitant dosing of nifedipine over 4 to 6 weeks did not alter digitoxin plasma levels or daily renal excretion. Based on these observations, the risk of digitalis intoxication after combined dosing with verapamil and digitoxin is much less pronounced than that after digoxin, and thus this glycoside is a valuable alternative.

Remission induction of meningeal leukemia with high-dose intravenous methotrexate.

Twenty children with acute lymphoblastic leukemia who developed meningeal disease were treated with a high-dose intravenous methotrexate regimen that was designed to achieve and maintain CSF methotrexate concentrations of 10(-5) mol/L without the need for concomitant intrathecal dosing. The methotrexate was administered as a loading dose of 6,000 mg/m2 for a period of one hour followed by an infusion of 1,200 mg/m2/h for 23 hours. Leucovorin rescue was initiated 12 hours after the end of the infusion with a loading dose of 200 mg/m2 followed by 12 mg/m2 every three hours for six doses and then every six hours until the plasma methotrexate level decreased to less than 1 X 10(-7) mol/L. The mean steady-state plasma and CSF methotrexate concentrations achieved were 1.1 X 10(-3) mol/L and 3.6 X 10(-5) mol/L, respectively. All 20 patients responded to this regimen, 16/20 (80%) achieved a complete remission, and 20% obtained a partial remission. The most common toxicities encountered were transient serum transaminase and bilirubin elevations, neutropenia, and mucositis. One patient had focal seizures and transient hemiparesis but recovered completely. High-dose intravenous methotrexate is an effective treatment for the induction of remission after meningeal relapse in acute lymphoblastic leukemia.

EFFECTS OF L-GLUTAMINE ON ACETYLSALYCYLIC ACID INDUCED GASTRIC LESIONS AND ACID BACK DIFFUSION IN DOGS

Effects of l-glutamine on acetylsalicylic acid (ASA)-induced gastric mucosal lesions were studied in mongrel dogs. It was confirmed that when oral ASA at 1.0 or 2.0 g per dog is given in two divided doses, there is severe and consistent dose-dependent mucosal damage in the glandular portion of the stomach in fasted dogs. However, when l-glutamine 2.0 or 4.0 g per dog in two divided doses is given concomitantly with ASA 2.0 g per dog orally, the gastric irritation is significantly inhibited. Instillation of 20 mM of ASA in 100 mM HCl solution into the Heidenhain pouch of Beagle dogs produced a significant loss of H+ from the pouch and a gain of Na+ in the lumen compared with ASA-free controls. When l-glutamine (100 mM) was given concomitantly with ASA (20mM) into the pouch, changes of electrolyte fluxes in response to ASA alone were significantly suppressed. However, 50 mM of l-glutamine had no appreciable effect on acid back diffusion caused by ASA 20 mM. The amino acid itself had little effect on the ionic movement in the pouch. Gross bleeding from the pouch treated with ASA was never observed with the concomitant dosing of ASA and l-glutamine 50 or 100 mM.

Biochemical aspects of the protective action of propyl gallate on liver injury in rats poisoned with carbon tetrachloride

Liver injury in rats intoxicated with a high dose of CCl 4 (2.5 ml/kg, po) is partially prevented by propyl gallate. The accumulation of hepatic triglycerides and the release of liver enzymes into the plasma are more effectively inhibited by this antioxidant in rats given a smaller dose of the hepatotoxin (0.25 ml/kg, po). The antioxidant activity of propyl gallate, administered in vivo, estimated by means of the production of malonyl dialdehyde in liver homogenates in vitro, has been found to decrease progressively after treatment. The concentration of nonesterified fatty acids in the serum is not affected by dosing with propyl gallate. However, propyl gallate releases the block in triglyceride secretion from the liver that occurs after administration of CCl 4. Furthermore, both the uptake of CCl 4 by the liver and the early steps of the free radical reaction (incorporation of labeled metabolites of 14CCl 4 and double bond shifting in microsomal unsaturated lipids) are unchanged by concomitant dosing with propyl gallate. This free radical scavenger, when administered in discrete doses, more markedly influences both CCl 4 liver damage and the efficiency of the hepatic drug metabolizing enzyme system. This effect in vivo is consistent with the reported in vitro interaction of propyl gallate with microsomal electron transport. These findings indicate that propyl gallate partially interferes with the enzymes bound to the endoplasmic reticulum, but affects the secondary phenomena of lipid peroxidation at the level where lipoproteins are secreted and/or the permeability of plasma membrane is altered.

Antacids and Anticholinergics

Comments and Correction1 August 1975Antacids and AnticholinergicsROBERT C. BARGER, M.S., R.PH., JOHN F. MITCHELL, PHARM.D.ROBERT C. BARGER, M.S., R.PH.Search for more papers by this author, JOHN F. MITCHELL, PHARM.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-83-2-280_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: In their recent paper, Littman and Pine (1) stated that "anticholinergics should not be combined with antacids because absorption of the anticholinergic is reduced. . . ." This remark was not referenced, which led to our investigating the clinical significance of this drug interaction.Dotevall and Walan (2) studied the effect of 1-hyoscyamine on duration of antacid action. Antacid administration alone produced a duration of pH ≥ 3 for 28.9 ± 6.1 minutes, while concomitant dosing with the anticholinergic increased this pH limit to 71.1 ± 12.0 minutes (P< 0.01). Morrissey and associates (3), using a...

The mechanism of anti-muricidal effects of chlordiazepoxide

Muricidal activity of rats is suppressed by chlordiazepoxide (CDP). At appropriate doses the CDP effect is reversed by repeated testing, by pretreatment with CDP, and by concomitant dosing with caffeine. This points to the general behavioral depressant action of CDP which undergoes tolerance as being primarily responsible for the anti-muricidal activity of CDP.

The effects of carbon tetrachloride on rat liver microsomes during the first hour of poisoning in vivo, and the modifying actions of promethazine.

The effects of an oral administration of carbon tetrachloride on various liver microsomal and supernatant components were studied 1hr. and 2hr. after dosing. The modifications of such early changes resulting from a concomitant administration of promethazine together with the carbon tetrachloride were also investigated. The microsomal components studied were: cytochromes P-450 and b(5); inorganic pyrophosphatase; NADH- and NADPH-cytochrome c reductases; NADH- and NADPH-neotetrazolium reductases; a lipid-peroxidation system associated with the oxidation of NADPH and stimulated by ADP and Fe(2+). NAD- and NADP- DT-diaphorases were measured in the supernatant solution remaining after isolation of liver microsomes, and the distribution of RNA phosphorus between the microsomes and supernatant solution was also determined. Carbon tetrachloride produced a rapid fall in inorganic pyrophosphatase activity, a rather slower decrease in cytochrome P-450 content of the microsomes and small increases in the activities of NADH-cytochrome c reductase and neotetrazolium reductases. The activities of NADPH-cytochrome c reductase, the NADPH-ADP/Fe(2+)-linked lipid-peroxidation system, DT-diaphorases and the content of cytochrome b(5) in the microsomes were unchanged. There was also a loss of RNA phosphorus from the microsomes into the supernatant solution. The RNA phosphorus redistribution, the decrease in inorganic pyrophosphatase and the increases in neotetrazolium reductase activities were at least partially prevented by a concomitant dosing with promethazine. However, the decrease in cytochrome P-450 was not affected by promethazine treatment. These early changes are discussed in terms of the liver necrosis produced by carbon tetrachloride and which is greatly retarded in its onset by the administration of promethazine.