Search PubMed⌕ Search

Biomedical subjects

M J Berg

Publications and source records attributed to M J Berg.

At least 73 records · Page 4Linked to original sources
PubMed1983

Enhancement of theophylline clearance by oral activated charcoal.

A randomized crossover trial of the effect of oral activated charcoal on the kinetics of intravenous theophylline was carried out in six normal male subjects. After intravenous aminophylline (6 mg/kg), subjects received water or water with activated charcoal (140 gm) in divided doses over 12 hr. Serum theophylline concentrations were measured from 0 to 24 hr after the aminophylline infusion. Treatment with activated charcoal decreased the serum t 1/2 from 6.4 +/- 1.2 to 3.3 +/- 0.4 (SEM) hr and the serum AUC from 78 +/- 14 to 42 +/- 4 mg . hr/l. Percent decrease in AUC after treatment with charcoal correlated positively with the endogenous theophylline serum t 1/2 (r = 0.94). These results suggest that oral activated charcoal (1) enhanced the total body clearance of theophylline and (2) may be efficacious in the treatment of theophylline poisoning, especially in patients with prolonged serum t 1/2s of theophylline.

Adult↗
PubMed1983

Optimization of pharmacokinetic monitoring: I. Linear pharmacokinetics.

To reach and maintain therapeutic drug concentrations, reliable estimates of the parameters describing the pharmacokinetic behavior of the drug are required. The accuracy and precision of the pharmacokinetic parameters are dependent upon the error associated with the time of specimen collection and the laboratory assay error. In this report, the determinate error and random error are analyzed independently and incorporated in calculations of regimens of two drugs, gentamicin and theophylline. The calculations show that, within a particular concentration range, there are better times for sampling to determine the elimination rate constant and, consequently, the dose. From the generalized, first-order equation for a one-compartment pharmacokinetic model, ln Ct = ln C0 - Kt, where C = plasma drug concentration, t = time, C0 = C at zero time, and the elimination rate constant, K = 0.693/t1/2, the determinate error, epsilon K, in K is epsilon = (1/C0t)epsilon C0 - (In C0/C)t-2 epsilon t, and the random error, assuming a gaussian distribution, is (formula; see text) where S2x is variance of parameter x. Therefore, the variances of the calculated quantity, C0, the measured quantity, C, and the time of sample collection, t, are initially of equal importance. However, with increasing t, the effect of S2t becomes small. In both random and determinate error cases, increased time of sampling after dose reduces the error in K, thus t1/2, as do recognized biological factors. However, increased relative analytical error may obliterate this advantage if analyses are not modified to obtain best quantitation at low, even subtherapeutic concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1983

Phenytoin and folic acid interaction: a preliminary report.

The effect of folic acid (1 mg/day orally) on phenytoin steady-state pharmacokinetics was studied in four male folate-deficient epileptic patients who were treated with only one anticonvulsant. Each patient served as his own control before and after starting folic acid replacement therapy. The Michaelis-Menten parameters, Vmax and Km, were calculated for each patient, and compliance with the single anticonvulsant drug (phenytoin) regimen was documented. Blood and urine samples were collected just before (day 1) and after 180 or 300 days of vitamin administration. Total and free phenytoin were measured in plasma; and phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin (DHD) were measured in 24-h urine. After the addition of folic acid, total phenytoin plasma concentration decreased 7.5-47.6% in three of the four patients, and the extent of this change correlated with Km (r2 = 0.99). Ratios of urinary metabolites to parent drug increased in those patients showing a decrease in plasma phenytoin caused by folic acid supplementation. This indicated that a folic acid-associated increase in phenytoin oxidative metabolism had occurred.

Adult↗
PubMed1983

Phenytoin and folic acid: individualized drug-drug interaction.

The effect of folic acid supplementation on the disposition of phenytoin and the resultant loss of seizure control in a male folate-deficient epileptic is reported. Due to the increase in tonic-clonic seizures after the initiation of folic acid (1 mg, orally) the sodium phenytoin dosage was increased by 130 mg until control was achieved. Because of these dosage changes, the Vmax and Km were calculated before and after initiation of the folic acid. The Vmax remained relatively the same, but the Km decreased after folate supplementation.

Drug Interactions↗
PubMed1982

Acceleration of the body clearance of phenobarbital by oral activated charcoal.

We investigated the effect of multiple oral doses of activated charcoal on the pharmacokinetics of intravenously administered phenobarbital in a randomized crossover trial. Six healthy men volunteered to take 200 mg of phenobarbital sodium per 70 kg of body weight intravenously on two separate occasions. On one occasion, each subject received oral activated charcoal (180 g) in divided doses over three days after the infusion of phenobarbital. Serum levels of phenobarbital were measured in all subjects up to 96 hours after the infusion, and urinary excretion of phenobarbital was measured in two subjects 24 to 96 hours after the infusion. A pharmacokinetic analysis showed that the charcoal decreased the serum half-life of phenobarbital form 110 +/- 8 to 45 +/- 6 hours (S.E.M.) (P less than 0.01), increased the total body clearance of phenobarbital from 4.4 +/- 0.2 to 12.0 +/- 1.6 ml per kilogram per hour (P less than 0.01), and increased the nonrenal clearance from 52 to 80 per cent of the total body clearance. We conclude that oral administration of activated charcoal enhances the nonrenal clearance of phenobarbital.

Administration, Oral↗
PubMed1981

Lithium kinetics in single daily dosing.

The feasibility of single daily dosing of lithium carbonate was tested in eight recurrent manic-depressives being treated with lithium prophylaxis. The patients received their entire 24-h maintenance dose at 8:00 p.m. for 12 consecutive days. The suitability of single daily dosing was determined by comparing 1) lithium through levels; 2) lithium kinetic parameters of half-life, clearance, and volume of distribution; and 3) renal function parameters of serum creatinine, creatinine clearance, and mean 24-h urine output during the initial divided daily dosage trial and the subsequent single daily dosage trial. The observation of no significant changes in either serum half-lives or renal lithium clearance levels supports the conclusion that the average steady-state lithium serum concentration (Cpss) is unchanged by conversion to single daily doses. No significant changes were observed in either serum creatinine or creatinine clearance. However, a significant decrease in the 24-h urine output was noted on the single daily dose.

Adult↗
PubMed1981

Cimetidine in systemic mastocytosis.

54-year-old caucasian women with systemic mastocytosis manifested by gastrointestinal and dermatological symptoms that were treated with cyproheptadine, Lomotil (diphenoxylate-atropine), and cimetidine was studied. The patient consented to discontinue the H2-receptor antagonist, and to have the following values measured: serum and urine concentrations of cimetidine: complete blood count (CBC) with differential, serum chemistry, and urinalysis; and systemic mastocytosis symptomatology. The patient experienced prompt recurrence of gastrointestinal and dermatological symptoms after stopping the cimetidine; the drug was restarted in three days and the symptoms subsided. The preceding laboratory and symptomatological values were recorded for 11 days after the reinstitution of cimetidine therapy. Histamine, gastrin, CBC, serum chemistry, and urinalysis remained normal, with and without cimetidine. Exacerbations of her symptoms were worst when no drug was detected in the serum. Therefore, it appears that cimetidine has a role in treating the symptoms of systemic mastocytosis.

Adult↗
PubMed1980

Dose and serum concentration relationships in cimetidine-associated mental confusion.

A patient with severe liver disease and mildly obnormal but stable renal function was given cimetidine on two occasions for gastrointestinal hemorrhage. In each course, dosing was initiated at half the recommended dosage of 600 mg daily, and mental status deteriorated shortly after dosing began. A further dosage decrease to 300 mg daily allowed continuation of cimetidine therapy in absence of mental status alterations. In this patient, mental status changes occurred at lower serum concentrations than we have previously reported. This discrepancy was explained by analysis of cimetidine CSF concentrations, as this patient had abnormally high cimetidine blood to CSF permeability. Although the cause of increased CSF concentrations is unclear, cimetidine-associated mental confusion was dose related and completely reversible upon a decrease in dosage. Patients who develop cimetidine-associated mental status changes and who cannot have treatment stopped may be safely treated by individualizing the dosing rate.

Blood-Brain Barrier↗
PubMedDate not supplied

Metabolism of a heptapeptide opioid by rat brain and cardiac tissue.

Met-enkephalin-Arg6-Phe7 (E7) is converted to Met-enkephalin by rat striatal membranes; in contrast, Leu-enkephalin (E5) is inactivated by cleavage at the Tyr-Gly (aminopeptidase) and Gly-Phe sites (metalloendopeptidase). Conversion of E7 is inhibited by MK-421, and inactivation of E5 is inhibited by bestatin and Thiorphan. Purified brain angiotensin converting enzyme (EC 3.4.15.1) also converts E7 but a purified metalloendopeptidase acts on both E5 and E7 at the Gly-Phe site. Cleavage of E7-amide by metalloendopeptidase leads to release of Phe-Met-Arg-Phe-amide, a cardioactive neuropeptide. Rat heart, a potential target organ, does not convert E7-amide to release the cardioactive peptide but cleaves the Met5-Arg6 bond to release Met-enkephalin by an enzyme sensitive to MK-421.

Animals↗
PubMedDate not supplied

Enkephalin analogs as substrates for the assay of brain cysteine proteinase (Cathepsin L) and its endogenous inhibitors.

A series of enkephalin-like peptides (X-Tyr-Gly-Gly-R-Pro) were synthesized for assay of cathepsin L and papain. Enzymes acted only at the Gly-Gly bond to release N-terminal dipeptides. When X = dansyl and R = Phe(NO2) the substrate was suited for continuous fluorimetric assay of rat brain cathepsin L (Km 45 microM, kcat/Km 1333 mM-1 sec-1). The substituted pentapeptides provided information on the influence of P2, P2' residues on rates of Gly-Gly cleavage. The synthetic substrate provided rapid and sensitive assays for the brain cathepsin L and its interaction with 13-14 kDa (cerebrocystatin) and 70 kDa (T-kininogen) rat brain inhibitors. The suppression of cathepsin L- or papain-mediated hydrolysis of substrates by inhibitors may be the result of competition between their binding domains at the enzyme catalytic center.

Animals↗
PubMedDate not supplied

Synthetic domains of cystatins linked to enkephalins are novel inhibitors of brain cathepsins L/B.

Cystatin domains or homologous sequences were synthesized and tested as inhibitors of papain, and rat brain cathepsins B and L. These domains included: I, an enzyme substrate binding site containing a -GG- cleavage site (YGGFL); II, known cystatin consensus sequences (-QVVAG- or -QLVSG-); and III, the proposed ancillary site for binding of chicken cystatin to papain (-IPWLN-). A Domain II analog QVVAG(K-NH2) inhibited cathepsin L and papain with Ki 1-4 X 10(-4) M but was inactive towards cathepsin B. A peptide containing Domains I and II, YGGFL-QVVAG(K-NH2), inhibited papain and cathepsin B with Ki 10(-4)-10(-5) M, and cathepsin L with Ki 10(-6) M. The presence of Domain III in the analog YGGFL-QVVAG-IPWLN(K-NH2) resulted in a 10-fold increase in potency towards papain. These data demonstrated that putative cystatin domains are: 1) probably proximal in the intact cystatins; 2) can be linked directly to each other to yield smaller peptides active as inhibitors; 3) showed some specificity towards the three cysteine proteinases.

Amino Acid Sequence↗
PubMedDate not supplied

Status of research on gender differences.

Gender bias persists in the use of women in clinical trials, but the situation is improving. Pharmacokinetics is an obvious area in which to examine gender differences in the absorption, distribution, metabolism, and elimination of drugs. Pharmacokinetics change during pregnancy and during the different phases of woman's life cycle. The federal government has undertaken a long-range study of the diseases, disorders, and conditions of women: the Women's Health Initiative.

Adolescent↗
PubMedDate not supplied

Brain cathepsin B but not metalloendopeptidases degrade rAPP751 with production of amyloidogenic fragments. Comparison with synthetic peptides emulating beta- and gamma-secretase sites.

Lysosomal cathepsin B but not L degraded rAPP751 to yield C-terminal 19-25 kDa fragments containing beta A4, reinforcing the view that acidic proteases participate in endosomal-lysosomal processing to yield amyloidogenic fragments in situ. This mechanism is consistent with fragmentation of endogenous APPs within clathrin-coated vesicles (CVs) by vesicular hydrolases, with the appearance of C-terminal amyloidogenic fragments following incubation at pH 6.5. A neutral endopeptidase resembling NEP 24.11 (PS-NEP) purified from detergent extracts of human brain degraded rAPP751; however, breakdown was not blocked robustly by metal chelators or phosphoramidon, suggesting the presence of an alternative processing enzyme. Effects of other inhibitors showed that breakdown was mediated by serine-protease-like component(s). A phosphoramidon-insensitive metalloendopeptidase (PI-NEP) partially purified from rat brain P2 using detergents, and resembling NEP 24.15, showed no activity towards rAPP751. Peptides containing putative beta- or gamma-secretase sites were synthesized for purposes of examining their metabolism by the brain enzymes. Those containing beta-secretase sites were hydrolysed at one or more sites by the four enzymes, but only PI- and PS-NEP acted at the Met-Asp site of Ac-Val-Lys-Met-Asp-Ala-Glu-Phe-Arg.NH2. In the case of substrates containing the gamma-site, these two categories of enzymes were the only ones degrading N-Ac-Ile-Ala.NH2. These data imply that the brain metalloendopeptidases, while inactive towards intact precursors, may be involved in turnover of intermediates containing beta- or gamma-sites.

Amino Acid Sequence↗