Initial Serum Levels Research Articles

Effects of atropine on pharmacokinetics of theophylline

The effects of atropine in serum concentration and pharmacokinetic parameter of theophylline (Theo) in rabbits were studied. The Theo level in serum was determined by. ultraviolet spectrophotometry (UV). After administration of aminophylline (Amin, 12.5 mg/kg iv), atropine (1mg/kg im) decreased significantly the initial serum level of Theo from 23.6+1.1 μg/ml to 19.6+1.1 μg/ml. The calculation of pharmacokinetic parameter of Theo was based on one compartment open model. In case of Amin injection without or with atropine, the pharmacokinetic parameters of Theo were: K=0.23±0.03, 0.19±0.02/h, T1/2=3.04±0.40, 3.66±0.40h, C1=0.26± 0.04, 0.23±0.03 L/(kg.h), respectively.The results showed that the atropine decrease the elimination of Theo.

Failure of cavh to remove digoxin-fab complex in piglets

Digoxin toxicity may be associated with renal failure and an inability to excrete the digoxin-Fab (antibody fragment) complex used in detoxification. We are unaware of any previous reports regarding the removal of digoxin-Fab fragment complex by continuous arteriovenous hemofiltration. Continuous arteriovenous hemofiltration allows ultrafiltration of molecules less than 50,000 daltons. Because the digoxin-Fab fragment complex has a molecular weight of 45 - 50,000 daltons, we evaluated the efficiency of continuous arteriovenous hemofiltration in removing the digoxin-Fab fragment complex. Three piglets were given 100 mcg/kg digoxin IM, in divided doses. Animals were anesthetized and continuous arteriovenous hemofiltration was begun using a Diafilter 10 cartridge. A mean ultrafiltration rate of 3.6 +/- 0.4 ml/min was obtained. The system equilibrated for 30 minutes and initial serum and ultrafiltrate digoxin levels were obtained. Mean serum values were total 6.20 +/- 1.74 ng/ml and free 3.72 +/- 0.88 ng/ml. Digibind 40 mg IV was given and then samples of serum and ultrafiltrate were obtained at 30, 60 and 90 minutes for digoxin levels. Mean values were as follows: 30 min serum total 54.23 +/- 26.13 ng/ml and free 0.08 +/- 0.08 ng/ml; 60 min serum total 61.24 +/- 27.31 ng/ml and free 0.07 +/- 0.04 ng/ml; and 90 min serum total 67.63 +/- 26.78 ng/ml and free 0.10 +/- 0.10 ng/ml. Ultrafiltrate levels throughout the experiment were negligible (less than or equal to 0.04 ng/ml). Continuous arteriovenous hemofiltration appears to be ineffective in removing the digoxin-Fab fragment complex.

Choriocarcinoma Presenting with Cerebral Metastases After Full‐Term Pregnancy

Choriocarcinoma is a rare malignancy in Scandinavia. We present a case of a young primigravida who experienced an uneventful pregnancy and gave birth to a healthy baby. Six days after delivery she underwent neurosurgery for intracranial hemorrhage. Pathological examination of the evacuated hematoma revealed metastatic choriocarcinoma. Further work-up exposed additional metastases in the lungs and liver. The initial serum level of human chorionic gonadotropin (beta-HCG) was 350,000 IU/I. Chemotherapy was given both intravenously and intrathecally. At 10 weeks, beta-HCG had returned to normal. Treatment was continued for another 10 weeks. Two years after cessation of therapy the patient is still in complete remission. In the discussion we review a scoring system to be used in selecting the mode of treatment, and briefly mention diagnosis and prognosis.

Germ Cell Tumours of Testis: Prognostic Factors and Results

Prognostic features regarding the outcome of 232 patients with testicular germ cell tumours treated from 1980 to 1987 in Sheffield are reviewed. Delay in diagnosis was a constant feature. The majority had a swelling for over 3 months. After 6 months mortality doubled, compared with patients with a shorter history. Initial serum levels of alpha-fetoprotein and beta-human chorionic gondadotropin, particularly if both were elevated over 100, and more so 500 IU/l, indicated a subsequent mortality in non-seminomatous tumours of 24 and 37%, respectively, while only 1.5% died if both values were below 100. The overall survival rate was 97% in seminomas and 78% in non-seminomas; no patients with well or moderately differentiated tumours died. There were no deaths after the 3rd year. Surveillance treatment in stage-I tumours was safe and mortality-free.

Progression to AIDS in patients with lymphadenopathy or AIDS-related complex: reappraisal of risk and predictive factors

purpose: In 1985, we reported that acquired immunodeficiency syndrome (AIDS) developed in 14 of 81 (17%) men with generalized lymphadenopathy followed prospectively for an average of 13 months. The presence of oral thrush or constitutional symptoms, or both, or severely impaired T4 + cell responses to specific antigen (interferon-gamma production) accurately identified patients at immediate risk for AIDS. The purpose of the current report is to describe the progress of these 81 patients during the three and a half years since enrollment and to include new data on initial serum levels of beta 2 microglobulin and human immunodeficiency virus (HIV) p24 antigen. patients and methods: The mean age of the 81 patients was 35.4 years; 79 were homosexuals and two were drug abusers. Immunologic testing was performed once at the time of enrollment in all patients. Seventy-seven of the 81 patients were sero-positive for HIV antibody. Frozen samples of serum, also obtained at initial study, were assayed in 1988 for beta 2 microglobulin and HIV p24 antigen. The clinical status of patients was determined six, 14, and 36 months after enrollment was closed (June 1984) by either interview and examination or telephone contact with private physicians. results: After three and a half years of follow-up, 42 patients have developed AIDS, including (1) 77% who had had thrush or symptoms, or both, (2) 80% to 88% of those who originally demonstrated marked immunologic abnormalities (skin test anergy, less than 200 T4 + cells/mm 3, T4/T8 cell ratio of less than 0.5, severely impaired interferon-gamma production [less than 25 U/mL], or elevated serum beta 2 microglobulin level [greater than 3.0 mg/L], and (3) 95% of patients with HIV p24 antigenemia. However, AIDS also developed in 51% of patients who had had more apparently benign initial manifestations (lymphadenopathy alone, herpes zoster), in 41% to 54% despite normal initial results for either T4 + cell number, interferon-gamma secretion, beta 2 microglobulin, or skin testing, and in 44% of those whose sera did not contain HIV antigen. conclusion: These updated results demonstrate the remarkably poor prognosis of patients with generalized lymphadenopathy or AIDS-related complex irrespective of initial clinical, immunologic, and serologic findings, and suggest that essentially all such persons may be candidates for antiviral therapy.

Transient kinetics of hybridoma growth and monoclonal antibody production in serum‐limited cultures

A quantitative study of the influence of initial serum concentration on hybridoma growth rate, maximum viable and total cell yield, and specific antibody production rate is presented. The specific growth rate varied in a Monod fashion with initial serum levels (2-10% FCS), giving K(m) = 1.6 v/v% and mu(max) = 0.92 d(-1). The maximum cell yields (total and viable) were linear with initial serum level, indicating stoichiometric as well as kinetic limitation by serum component(s). The specific antibody production rate for each individual run fitted well to a non-growth-associated model. However, the non-growth-associated parameter varied monotonically with initial serum concentration, suggesting the catalytic role of serum component(s) in antibody production. Also, glutamine was utilized inefficiently, with at least a third of it secreted back into the culture supernate in the form of glutamate. While very simple model equations describe the specific growth and product formation rate for an individual batch run, the larger picture indicates need for a more detailed unstructured or structured model.

Aminoglycoside pharmacokinetics

We evaluated prospectively gentamicin and tobramycin pharmacokinetics in 37 patients with multiple system trauma and seven patients with isolated closed head trauma. The mean apparent volume of distribution (Vd) was 0.38 ± 0.10 and 0.27 ± 0.04 L/kg actual body weight (ABW) in patients with multiple trauma and closed head trauma, respectively. The difference in Vd between the two groups of patients was significant (p < .002). Vd was not predictable on the basis of age, sex, weight, trauma score, or hospital day that therapy was initiated. Mean aminoglycoside clearance (Cl) was 123 ± 46 ml/min. Neither serum creatinine nor estimated creatinine Cl predicted aminoglycoside Cl with sufficient accuracy to be clinically useful (r = .33 and .67, respectively). The mean daily dose was 6.1 ± 1.6 ing/kg. The mean peak serum level was 5.8 ± 1.3 μg/ml. Only one patient developed clinically significant renal dysfunction. Our data indicate that a loading dose of gentamicin or tobramycin of 3 mg/kg ABW in patients with multiple trauma and 2.5 mg/kg ABW in patients with isolated head trauma will obtain a mean initial peak serum level of 6.6 Ag/ml. Although adequate maintenance dosing requires individualization based on pharmacokinetic analyses, large aminoglycoside doses can be used safely in patients with blunt trauma if appropriate monitoring is employed.

5-Fluorouracil, doxorubicin (adriamycin) and mitomycin-C (FAM) in advanced gastric cancer: observations on response, patient characteristics, myelosuppression and delivered dosage.

Forty-four patients with advanced gastric adenocarcinoma were treated with the fluorouracil, adriamycin and mitomycin-C (FAM) regimen. One was excluded from response evaluation. Partial (PR) and minor (MR) response rates were 7 and 9% respectively. These patients enjoyed remission for a median of 7.0 months. Stabilization (S) occurred in 25% and lasted a median of 6.0 months. No response (NR) was associated with a median survival of 3 months (p less than 0.001). The predominant pretreatment factors to affect survival were diagnosis to treatment interval and initial CEA serum level. Performance status influenced survival less markedly. Toxicity was mainly myelosuppression, which resulted in death of one patient. 'Responders' had marrow suppression more frequently than NR. Comparison of PR + MR, PR + MR + S and NR patient groups showed median minimum WBC counts of 1.4 x 10(3), 2.6 x 10(3) and 4.3 x 10(3) per mm3 respectively. Leukopenia (less than 3,000/mm3) was associated with a median survival advantage of 9.5 versus 3.5 months (p less than 0.05) and did not depend significantly on given FAM dosage. The median dosage of FAM agents delivered to nonresponders was reduced. A trend of dose-response (including dose-survival) relationship was found but was inconclusive statistically.

Pharmacokinetics of bestatin and oral activity for treatment of experimental metastases.

Bestatin is a low molecular weight aminopeptidase inhibitor originally isolated from culture filtrates of Streptomyces olivoreticuli. The serum pharmacokinetics in mice are dependent on route of administration, with a short t1/2 (1.69 min t1/2 alpha and 12.8 min t1/2 beta), but a high initial serum level following i.v. administration. When administered via the i.p., s.c., i.m., or p.o. routes of administration, bestatin had serum t1/2 beta s of 8.56, 16.91, 19.25, or 15.4 min, respectively. The maximum area under the curve (concentration X time) occurred following i.v. and i.m. administration, with a lower level following p.o. or i.p. administration. Bestatin had therapeutic activity for experimental metastases, not only following i.v., i.p., and i.m. routes of administration but also following oral administration. Because of its brief serum t1/2, bestatin's therapeutic activity depends on aggressive (either daily or twice daily injection, especially following p.o. administration) and high-dose administration. Thus, the rate-limiting aspect of bestatin's therapeutic activity appears to be associated with its pharmacokinetics.

Relation between bone erosions and rheumatoid factor IgA and IgM isotypes in recent onset rheumatoid arthritis.

In this prospective study 58 patients with early rheumatoid arthritis were followed up for two years with six-monthly assessments including rheumatoid factors (RF) of IgA and IgM subtypes. Initial and mean serum levels of IgA-RFs were raised in patients with an erosive disease course in comparison to non erosive disease. The cases with initially increased serum levels of RFs of both isotypes developed more eroded joints in their hands and feet during the study period than the rest of the patients. None of the differences, however, were statistically significant. Of the tested parameters only clinical rheumatoid activity (Mallya-index) was significantly related to the number of eroded joints during the follow-up. We conclude that serum IgA-type RFs are raised in erosive RA, but the determination of RFs of any kind cannot be used to prognosticate erosiveness.

AMINOGLYCOSIDE PHARMACOKINETICS, DOSAGE REQUIREMENTS, AND NEPHROTOXICITY IN TRAUMA PATIENTS

We evaluated prospectively gentamicin and tobramycin pharmacokinetics in 37 patients with multiple system trauma and seven patients with isolated closed head trauma. The mean apparent volume of distribution (Vd) was 0.38 +/- 0.10 and 0.27 +/- 0.04 L/kg actual body weight (ABW) in patients with multiple trauma and closed head trauma, respectively. The difference in Vd between the two groups of patients was significant (p less than .002). Vd was not predictable on the basis of age, sex, weight, trauma score, or hospital day that therapy was initiated. Mean aminoglycoside clearance (Cl) was 123 +/- 46 ml/min. Neither serum creatinine nor estimated creatinine Cl predicted aminoglycoside Cl with sufficient accuracy to be clinically useful (r = .33 and .67, respectively). The mean daily dose was 6.1 +/- 1.6 mg/kg. The mean peak serum level was 5.8 +/- 1.3 micrograms/ml. Only one patient developed clinically significant renal dysfunction. Our data indicate that a loading dose of gentamicin or tobramycin of 3 mg/kg ABW in patients with multiple trauma and 2.5 mg/kg ABW in patients with isolated head trauma will obtain a mean initial peak serum level of 6.6 micrograms/ml. Although adequate maintenance dosing requires individualization based on pharmacokinetic analyses, large aminoglycoside doses can be used safely in patients with blunt trauma if appropriate monitoring is employed.

Metabolic and hormonal factors as predictors of nitrogen retention in obese men consuming very low calorie diets

The ability to conserve body protein during very low calorie diets in ten obese men was observed to correlate with plasma free amino acid concentrations, urinary N τ-methylhistidine:creatinine ratios, resting oxygen consumption, and serum triiodothyronine levels. A diet consisting of only protein, 1.3 g/kg ideal body weight/24 h, was given for 40 days. Cumulative nitrogen deficit ranged from −64 g to −227 g. Nitrogen balance on days 36 to 40 ranged from +1.37 g 24 h to −3.30 g 24 h . Nitrogen balance during this period had a significant direct correlation with prediet concentrations of branched-chain amino acids ( r = 0.69 to 0.89), methionine ( r = 0.85), histidine ( r = 0.66), alanine ( r = 0.73), arginine ( r = 0.70), ornithine ( r = 0.66), total essential ( r = 0.87), and nonessential ( r = 0.68) amino acids, with initial serum levels of triiodothyronine ( r = 0.66) and with the fall in triiodothyronine over the 40 days ( r = 0.79). Initial resting oxygen consumption was directly correlated ( r = 0.78) with final nitrogen balance and inversely with total nitrogen loss ( r = −0.81). On day 0, triiodothyronine levels also correlated positively ( r ranging from 0.71 to 0.93) with plasma concentrations of several essential and nonessential amino acids. These correlations suggest that individuals who ultimately will or will not achieve nitrogen equilibrium during very low calorie diets can be identified prior to dieting. These data are consistent with the hypothesis that individuals with higher initial protein flux and triiodothyronine levels are better able to adjust the balance between synthesis and degradation to attain nitrogen equilibrium during hypocaloric dieting.

Spontaneous abortion among insulin-dependent diabetic women

A prospective study was undertaken to evaluate the frequency of spontaneous abortion in clinically apparent pregnancies among insulin-dependent diabetic women evaluated prior to pregnancy. The study was done in 132 pregnancies occurring in 91 diabetic women. The spontaneous abortion rate was 30%; 70% of the pregnancies progressed beyond 20 weeks. The abortion rates for Classes B, C, D, and F through RT were 0%, 25%, 44%, and 22%, respectively. Initial serum levels of the beta-subunit of human chorionic gonadotropin above 6000 mIU were usually associated with favorable outcome while levels below 6000 mIU were not predictive of outcome. Data from this study suggest that the risk of spontaneous abortion among insulin-dependent diabetic women may be substantially higher than for the general population. Higher abortion rates were generally associated with more advanced White classification of diabetes. Age at diagnosis was the only factor which showed a significant contribution to the risk of abortion.

Equation Error

In Reply.— We thank McCormick for pointing out the error in equation 1. The correct term should be: Cpo e-Ke(t + t'). The term (t) should be considered to be the elapsed time from the beginning of the maintenance infusion. The assumptions in the program are based upon theoretically ideal circumstances, that is, the loading dose is delivered precisely over 30 minutes beginning immediately after the initial serum level is drawn. The instant the loading dose is delivered, the maintenance infusion is initiated.

Russell's viper venom levels in serum of snake bite victims in Burma

Serum levels of venom antigen were measured using enzyme-linked immunosorbent assay (ELISA) in 38 Russell's viper bite victims before and after administration of 40 ml of monovalent liquid antivenom. Initial serum levels ranged from one with less than 10·0 ng to 290 ng/ml and in one case a level of 75 ng/ml was detected 27 hours after the bite. Serum venom levels after liquid monospecific antivenom therapy indicated that venom clearance was similar in each case to the natural clearance of venom in the absence of antivenom therapy. In one case a venom level of 11·5 ng/ml was detected 66 hours after liquid antivenom therapy whereas in two fatal cases, serum venom levels of 95 ng/ml and 185 ng/ml were detected after the same interval. Failure of complete neutralization of venom is probably the result of loss of potency of antivenom during improper storage. The amount of venom excreted in the urine was not related to initial serum levels.

Changes of serum magnesium ions in open heart surgery.

The changes of magnesium in the serum were studied in 20 patients undergoing cardiac valve substitution procedures in extracorporeal circulation. The serum magnesium ions were determined before the onset of the anesthesia, at the beginning and at the end of the extracorporeal circulation, at the end of surgery and during the first post-operative day. A slight magnesium ion deficiency was observed even in the initial serum levels, probably due to the pre-operative diuretic therapy. The hypomagnesemia observed during the bypass was related to haemodilution and urinary losses. A limited increase in magnesemia, probably caused by the diffusion of the ion towards the vascular compartment, was observed at the end of the extracorporeal circulation. A new decrease was found during the post-operative stage, perhaps caused by the action of diuretics, which were administered.

Correlation of initial thiothixene serum levels and clinical response. Comparison of fluorometric, gas chromatographic, and RBC assays.

A series of three experiments addressed major problems concerning the use of serum levels as predictors of clinical response to thiothixene (Navane) hydrochloride in schizophrenia: correlation of initial test doses with clinical response; comparison of fluorescence spectrophotometry with gas chromatography in relation to clinical response; and comparison of serum levels with RBC levels in relation to clinical response. All assays correlated (near r = .5) with Brief Psychiatric Rating Scale improvement during hospitalization, except RBC levels seemed to have superior correlations (.64) in patients with lower serum levels. These correlations are similar to those obtained with steady state levels. The different methods of determining thiothixene concentrations were highly intercorrelated as well. Thus, single-dose serum levels give important clinical correlations regardless of which assay is used for thiothixene determination.

Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients.

We studied 201 critically ill patients during 267 courses of gentamicin (139 courses) or tobramycin (128 courses) therapy. Clinical and pharmacokinetic data were obtained on 240 of 267 courses (120 courses each of gentamicin and tobramycin). Two judgments of nephrotoxicity and its cause were made independently in this study, using a clinical and a pharmacokinetic definition of nephrotoxicity. The two sets of criteria were generally in good agreement, as all but 10 of 41 patients who were judged nephrotoxic by pharmacokinetic criteria were independently judged nephrotoxic by the clinical definition. Groups of patients judged nontoxic did not differ from groups judged nephrotoxic in age, sex, weight, initial creatinine clearance, total dose given, duration of treatment, initial aminoglycoside trough serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Prior aminoglycosides (usually gentamicin) had been used more frequently in the nontoxic group (P less than 0.05). Two major conclusions of this study are at variance with those of previous investigators; (i) we found no clinical parameters of value in predicting nephrotoxicity in critically ill patients; and (ii) aminoglycoside serum concentrations, once in the therapeutic range, were of limited value in prevention of aminoglycoside nephrotoxicity in our patients.

Metabolic and renal clearance rates of purified human chorionic gonadotropin.

The metabolic clearance rate (MCR) and renal clearance rate (RCR) of human chorionic gonadotropin (hCG) were measured in healthy young men and women using techniques of continuous intravenous infusion and rapid intravenous injection of unlabeled, highly purified hCG. Seven subjects received 4 d of infusion at a rate of 0.2 microgram/min, followed by an additional 4 d of infusion at 0.8 microgram/min. Mean serum levels of hCG established at these rates of infusion were 61.1 +/- 3.3 and 237 +/- 16 ng/ml, respectively (mean +/- SEM). The MCR determined at the low infusion rate was not significantly different from that determined at the higher infusion rate (1.83 +/- 0.09 vs. 1.95 +/- 0.14 ml/min per m2). The mean MCR for all subjects was 1.88 +/- 0.08 ml/min per m2. The MCR was not significantly different between men amd women (2.04 +/- 0.13 vs. 1.76 +/- 0.07 ml/min per m2). The RCR also did not vary between low and high infusion rates (0.40 +/- 0.03 vs. 0.40 +/- 0.04 ml/min per m2). The mean RCR for all subjects was 0.40 +/- 0.02 ml/min per m2. There was no difference in RCR between men and women (0.42 +/- 0.05 vs. 0.39 +/- 0.03 ml/min per m2). Six subjects were given 1.0 mg of highly purified hCG by rapid intravenous injection. Initial serum levels of hCG were 300-400 ng/ml, and the subsequent disappearance curve was multiexponential over 8-10 d. The disappearance curve of hCG in each subject was fitted to a biexponential equation. The rapid component t1/2 was 5.97 +/- 0.63 h and the slow component t1/2 was 35.6 +/- 8.0 h. We conclude that the MCR of purified hCG in man is about 2 ml/min per m2 and the RCR is 0.4 ml/min per m2; these parameters are concentration independent and do not differ significantly between healthy young men and women.

The beta-subunit of chorionic gonadotrophin as a tumour marker in gestational trophoblastic disease.

The clinical usefulness of the serum level of the beta subunit by radioimmunoassay was evaluated in 96 patients with gestational trophoblastic disease. The measurement of the hormone-specific beta subunit has allowed a better understanding of the activity of the various types of disease, with a correlation between the initial serum levels and the different subtypes of hydatidiform mole, and the ability to predict the development of malignant sequelae. The phenomenon of trophoblastic persistence after uterine evacuation was confirmed: although the half-life of the beta subunit was 4 days during the early phase, there was an average period of 8 weeks before levels fell to negative and 12 weeks was the limit for spontaneous regression. The serial beta subunit levels were found to provide an accurate indication of the clinical course of the disease in untreated and treated patients, and treatment could be withheld after 3 consecutive weekly negative values.