Lidocaine elimination: effects of metoprolol and of propranolol.

The effects of administration of metoprolol and propranolol on lidocaine elimination were studied in six healthy young men who did not smoke. Each received three single intravenous doses of lidocaine (2.5 to 3.0 mg/kg injected over 10 min): one alone, one after 1 day pretreatment with propranolol (40 mg orally every 6 hr), and one after 1 day pretreatment with metoprolol (50 mg orally every 6 hr). Lidocaine clearance was 0.88 +/- 0.28 l X hr-1 X kg-1 before beta blockade, 0.61 +/- 0.20 l X hr-1 X kg-1 during metoprolol dosing, and 0.47 +/- 0.16 l X hr-1 X kg-1 during propranolol dosing. There was no correlation between the change in lidocaine elimination and the steady-state concentrations of metoprolol or propranolol, nor between the change in lidocaine clearance and the change in resting heart rate produced by either beta blocker. Metoprolol and propranolol reduce lidocaine elimination significantly.

Kinetics of the digoxin-aspirin combination.

Digoxin interacts kinetically with many drugs in man. These interactions may result in digoxin toxicity. Aspirin has been shown to raise serum digoxin levels in the dog. We evaluated the effect of aspirin on digoxin single-dose kinetics in eight healthy adults. Aspirin induced no change in digoxin total body clearance, volume of distribution, elimination half-life, or renal or creatinine clearance. Trough serum salicylate levels ranged from 93 to 163 microgram/ml. We conclude that no alteration is required in digoxin dosing when aspirin is used.

Measurement of prostaglandin E2 in rectal mucosa in human subjects: a method study.

It has been demonstrated and confirmed that certain nonsteroidal anti-inflammatory drugs which inhibit cyclooxygenase and the synthesis of prostaglandins and other eicosanoids, can reduce the formation of both colon polyps and cancers in experimental animals given known carcinogens. Additionally, the results of several epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs may reduce the risk of colon polyp occurrence and/or colon cancer mortality. We have carried out a study to evaluate the methodology of the measurement of prostaglandin E2 (PGE2) in human colonic mucosa because its concentration may serve as a valuable intermediate marker of the pharmacological activity in Phase II studies of nonsteroidal anti-inflammatory drugs as colon cancer preventive agents. We studied all aspects of the actual measurement of PGE2 including the extraction efficiency of the PGE2 from the mucosa, the precision of the assay and calculation of the PGE2 content in terms of milligrams of protein in the sample, the inhibition of PGE2 by indomethacin over time, the reproducibility of the measurement within one homogenate, the rate of PGE2 production over time, the effect of adding indomethacin versus snap freezing on PGE2 production, the stability of PGE2 in tissues over time stored in liquid nitrogen, and the variability of the measurement of PGE2 in separate biopsies from one individual. Our studies indicated that the most reliable method for accurate and consistent measurements of PGE2 was to add the mucosal tissue instantly after biopsy to an indomethacin buffer that effectively inhibited the in vitro formation of PGE2.

Clinical relevance of drug interactions with lithium.

Although lithium continues to be regarded as the treatment of choice for bipolar disorders, the clinical use of this mood stabiliser is associated with an extremely narrow therapeutic range. Relatively minor increases in serum concentrations may induce serious adverse sequelae, and concentrations within the therapeutic range may result in toxic reactions. The safety of combining lithium with other medications, therefore, is a major concern, and extensive clinical experience has served to identify several significant drug interactions. Lithium removal from the body is achieved almost exclusively via renal means. As a result, any medication that alters glomerular filtration rates or affects electrolyte exchange in the nephron may influence the pharmacokinetic disposition of lithium. Concomitant use of diuretics has long been associated with the development of lithium toxicity, but the risk of significant interactions varies with the site of pharmacological action of the diuretic in the renal tubule. Thiazide diuretics have demonstrated the greatest potential to increase lithium concentrations, with a 25 to 40% increase in concentrations often evident after initiation of therapy. Osmotic diuretics and methyl xanthines appear to have the opposite effect on lithium clearance and have been advocated historically as antidotes for lithium toxicity. Loop diuretics and potassium-sparing agents have minor variable effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been associated with lithium toxicity, although the relative interactive potential of specific NSAIDs is difficult to determine. Small prospective studies have demonstrated large interindividual differences in lithium clearance values associated with different NSAIDs. A growing body of evidence also suggests that ACE inhibitors may impair lithium elimination, but further investigations are needed to identify patients at risk. Anecdotal reports have linked numerous medications with the development of neurotoxicity without an apparent effect on the pharmacokinetic disposition of lithium. Antipsychotics, anticonvulsants and calcium antagonists have all be implicated in a sufficient number of case reports to warrant concern. As these medications have all been commonly coadministered with lithium, the relative risk of serious interactions appears to be quite low, but caution is advised.

Transient elevation of serum activity of MB isoenzyme of creatine phosphokinase in drivers involved in automobile accidents.

Drivers involved in automobile accidents were screened for the presence of occult cardiac injury without regard for apparent severity of the accident or injury. An electrocardiogram was recorded, and serum levels of total creatine phosphokinase and the MB isoenzyme of creatine phosphokinase (myocardial form) were measured as soon as possible after the accident and subsequently during admission (or on the following day in patients treated and discharged from the emergency room). Electrocardiographic abnormalities were observed in 18 of 82 patients but correlated poorly with other evidence of the severity or location of injury. Of the 22 drivers admitted to the hospital (for any cause), nine demonstrated significant early elevations of the activity of the MB isoenzyme of creatine phosphokinase. We conclude that blunt cardiac trauma is a clinical subtlety; to be found, it must be sought. The ECG is of limited value. Measurement of the serum activity of the MB isoenzyme of creatine phosphokinase early after injury would appear to offer the best evidence of cardiac trauma.

Prospective study of the safety and financial benefit of ketoconazole as adjunctive therapy to cyclosporine after heart transplantation.

In a prospective study of the relative safety and potential benefit of concomitant ketoconazole and cyclosporine after heart transplantation, 15 transplant recipients were followed up for up to 1 year (mean, 10.7 months) after ketoconazole was added to their immunosuppressive regimen of cyclosporine, prednisone, and azathioprine, and these patients were compared with a matched cohort over the same time. There was an 88% reduction in the mean (+/- SD) dose of cyclosporine, from 394 (115) mg/day to 47 (21) mg/day (p less than 0.0005) in the ketoconazole group, compared with an insignificant change in the control group. The projected annual cost of cyclosporine was reduced by 88%, with a 72% reduction in the projected cost of immunosuppressive drugs and prophylactic antifungal therapy, from a mean of $6800 to $1862 per year per transplant recipient in the ketoconazole-treated group. Other beneficial effects found over the study period included a significant reduction in the mean and diastolic systemic arterial pressure and a significant reduction in serum cholesterol. The mean total serum cholesterol fell from 265 (44) to 204 (38) mg/dl in the ketoconazole group but did not change significantly in the control group (p less than 0.005). Low-density lipoprotein cholesterol also fell from a mean of 167 (32) mg/dl to 112 (28) mg/dl (p less than 0.005). Renal function was not significantly affected by ketoconazole when compared with the control group. Ketoconazole and other drugs of potential use in organ transplant recipients should be evaluated for financial as well as for other potential clinical benefits in the long-term management of these patients.

A modified ion-selective electrode method for measurement of chloride in sweat.

A modified method of analysis of sweat chloride concentration with an ion-selective electrode is presented. The original method of sweat chloride analysis proposed by the Orion Research Corporation (Cambridge, Massachusetts 02139) is inadequate because it produces erratic and misleading results. The modified method was compared with the reference quantitative method of Gibson and Cooke. In the modified method, individual electrode pads are cut and placed in the electrodes rather than using the pads supplied by the company; pilocarpine nitrate (2,000 mg/l) is used in place of pilocarpine HCl (640 mg/l); sodium bicarbonate as the weak electrolyte is used instead of K2SO4. A 10-minute period for sweat accumulation is employed rather than a zero-time collection as in the original Orion method. The modification has been studied for reproducibility in individuals, reproducibility between right and left arm in individuals; it has been compared extensively with the quantitative method of Gibson and Cooke, both in normal individuals and in patients with cystic fibrosis. There is excellent agreement between the modified method and the quantitative reference method. There appears to be a slight bias toward higher concentrations of chloride from the right arm compared with the left arm, but this difference is not medically significant.

Phagocytic, lambda light chain, plasma cell myeloma.

A case of phagocytic, lambda light chain, plasma cell myeloma was characterized by its clinical, morphologic, cytochemical, immunologic, and cell kinetic features. A 40-year-old man presented with Coombs-negative hemolytic anemia, hepatosplenomegaly, lytic bone lesions, lambda light chain monoclonal gammopathy, and infiltration of the bone marrow by dysplastic plasma cells, 10% of which demonstrated phagocytosis of erythroid cells. Electron microscopy demonstrated myeloma cells with prominent cytoplasmic microfilaments and erythroid cells in intracytoplasmic vacuoles. The myeloma cells did not phagocytose staphylococci in vitro. Phagocytic and nonphagocytic myeloma cells were tartrate-sensitive, acid-phosphatase positive, alpha-napthyl butyrate esterase negative, and did not form E rosettes or EAox(IgG) rosettes. The tumor cells were Tdt, Ia antigen, and SIg negative. Immunofluorescent staining for cytoplasmic light chains showed a monoclonal lambda pattern in nonphagocytic myeloma cells, and a probable monoclonal lambda pattern in phagocytic myeloma cells. These findings characterize the neoplasm as a monoclonal proliferation of differentiated plasma cells with the capability of erythrophagocytosis. Erythrophagocytosis by myeloma cells may have been responsible for the hemolytic anemia. The tritiated thymidine labeling index (LI%) was high (8%), suggesting a poor prognosis, despite a dramatic initial response to chemotherapy.

Immunochemical assays for IgG, IgA, IgM and transferrin compared.

We compared immunochemical methods for determining IgG, IgA, IgM, and transferrin in serum by studying calibrator crossover, patient comparison, and, for a newly developed technology, normal reference intervals. For the immunoglobulins, we compared radial immunodiffusion (RID), rate nephelometry using the Beckman ICS, and a new nephelometric method adapted to the Abbott TDx; for transferrin we compared the ICS, TDx, and immunoturbiditry. The methods examined for quantifying IgA and transferrin showed good agreement in calibrator crossover and patient comparison studies. In studies comparing IgG methods, the ICS and TDx demonstrated acceptable agreement, although neither showed accordance with RID. For IgM determination, crossover studies and patients having less than 4300 mg/L in this protein showed good agreement, even though more elevated samples, run on the TDx, showed a discrepancy in proportionally compared to the other two methods. Normal reference intervals (95% confidence limits) determined on the TDx agreed well with those established for the other immunochemical methods.

Alterations in creatine kinase, ornithine decarboxylase, and transglutaminase during muscle regeneration.

Creatine kinase (CK), transglutaminase (TGase) and ornithine decarboxylase (ODC), enzymes implicated in the regulation of growth processes, were studied during muscle regeneration subsequent to the injection of bupivacaine into rat tibialis anterior. Within 2 days, the percent BB isozyme of CK detected in the muscle was elevated 70-fold coincident with a marked decrease in total CK activity. The MB isozyme also increased and was 15-fold of control at 4-5 days postinjection. TGase activity was increased significantly to greater than 2-fold of control within 2 days of injection and significantly decreased at days 3 through 7 compared to controls. ODC activity was elevated significantly to 2- to 3-fold of control from 2-7 days after injection. These results suggest an early alteration in the expression of a coordinated battery of genes in this model of muscle degeneration-regeneration. The increased expression of MB and BB isozymes of CK in various human neuromuscular diseases may be a manifestation of an ongoing process of degeneration-regeneration.

Circulating levels of tumor necrosis factor and interleukin-1 in cystic fibrosis.

To assess the role of tumor necrosis factor (TNF) and interleukin-1 (IL-1) in the pathophysiology of cystic fibrosis (CF)-associated growth failure/cachexia and lung disease we measured height, weight, triceps skin fold, forced vital capacity, forced expiratory volume in 1 second, and plasma levels of TNF, interleukin-1-alpha (IL-1 alpha), interleukin-1-beta (IL-1 beta), and alpha-1-antitrypsin (A1AT) in 12 patients with CF, and in 12 age- and gender-matched healthy controls. The patients as a group had significantly lower values for the anthropomorphic measurements and lung function parameters as compared to controls. They also had higher circulating levels of A1AT than controls. TNF, however, was detected less frequently in patients than in controls. Neither group had detectable levels of circulating IL-1 alpha or IL-1 beta, which is consistent with the observation that CF patients infrequently present with fever. Potential explanations for these findings include compartmentalization of secreted TNF/IL-1, altered regulation of TNF/IL-1 secretion as a result of the chronic inflammatory state seen in CF, or increased degradation of TNF/IL-1, also a result of chronic inflammation. The role of these cytokines in the pathophysiology of CF remains unclear, but should be explored further; however it seems unlikely that circulating TNF plays a role in the growth failure/cachexia associated with CF.

Effect of interleukin-2 on microvascular liquid and protein transport in the rat small intestine.

Interleukin-2 (IL-2), a glycoprotein lymphokine derived from activated T-lymphocytes displays potent anti-cancer properties but its therapeutic use has been limited by generalized tissue swelling. To shed light on the mechanism underlying this potentially life-threatening edematogenic syndrome, recombinant IL-2 or an equal volume of control solution (excipient or 5% dextrose) was administered to 88 adult, male Sprague-Dawley rats. Initially, rats were injected with 50,000 Cetus units (equal to 300,000 I.U.) of IL-2 intraperitoneally, either one-time ("acute" rats) or every eight hours for two or seven days ("chronic" rats). Thereafter, under pentobarbital anesthesia, the main mesenteric lymph duct was isolated, incised, and measurements made of intestinal lymph flow (JV) and the total protein content and protein fractions in lymph (L) and plasma (P) (refractometry and agarose gel electrophoresis, respectively). Final measurements were also carried out after superior mesenteric vein constriction to assess filtration-independent L/P total protein "washdown." After IL-2, JV and protein clearance (JV x L/P) were increased (p less than 0.001) while lymph and plasma total protein content and protein fractionation were unchanged. Protein washdown was also maintained. These data are not only inconsistent with bulk "plasma leak" from damaged capillaries, but in conjunction with previously demonstrated increased cardiac output and reduced systemic vascular resistance after IL-2 administration, the findings favor augmented microvascular surface exchange area from increased capillary perfusion as the primary mechanism underlying increased transcapillary liquid and protein flux. This conclusion conforms to the rapid reversal of edema in patients after cessation of IL-2 therapy.

Selective serotonin reuptake inhibitors: pharmacologic profiles and potential therapeutic distinctions.

OBJECTIVE: To review the respective pharmacologic profiles of the selective serotonin reuptake inhibitors (SSRIs), with particular emphasis placed on clinically relevant distinctions. DATA SOURCES: A MEDLINE search was conducted to identify English language literature published within the last five years on the four SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine). Previous review articles were scrutinized for additional citations, and manufacturers provided a contemporary bibliography of more recent material. STUDY SELECTION/DATA EXTRACTION: Studies were selected for specific citation on the basis of comparative research merit and the contribution of this original literature to the pharmacologic profile(s) described. DATA SYNTHESIS: All SSRIs appear to be more efficacious than placebo for the acute treatment of major depressive disorder (MDD). Short-term (six-week) efficacy was comparable with that of tricyclic antidepressants for the amelioration of MDD regarded as moderate in severity. Further comparative trials are clearly indicated to demonstrate the therapeutic benefits of SSRIs in specific populations (e.g., geriatric, severely ill) and to demonstrate sustained benefit with long-term prophylaxis. Other potential indications for SSRIs include obsessive-compulsive disorder, panic disorder, bulimia, and chronic pain syndromes. Pharmacokinetic profiles of the four SSRIs reveal similar parametric values, and most quantitative differences are of limited clinical significance. Adverse effects are common but ordinarily mild and transient, primarily restricted to the gastrointestinal tract and central nervous system. Important differences in the prevalence or severity of these adverse effects await the accumulation of further clinical experience and the completion of additional comparative trials. Similarly, the relative propensity of SSRIs to inhibit the metabolism of other medications is currently under investigation. CONCLUSIONS: The four SSRIs studied appear to be more similar than they are different. Slowly, important distinctions are beginning to emerge with regard to adverse effect profiles and potential drug interactions. Given that the costs of these respective medications are comparable, such differences may ultimately serve to establish the preferential selection of individual agents in specific clinical situations.

Precipitation of benzodiazepine withdrawal following sudden discontinuation of midazolam.

Midazolam hydrochloride is an ultra-short acting benzodiazepine recently approved by the Food and Drug Administration for anesthesia induction and preoperative sedation. Frequently, midazolam is also used as an injection or infusion for the treatment of agitation in ventilator-dependent patients. A 53-year-old man underwent a gastrojejunostomy and was later intubated following the development of pseudomonal pneumonia. Midazolam was initiated in an effort to resolve his agitation and the patient continued to receive frequent bolus injections, averaging 22 mg/d over 21 days. Approximately eight hours after midazolam was abruptly discontinued, the patient became increasingly anxious and developed somatic complaints felt to be consistent with benzodiazepine withdrawal syndrome. Symptoms rapidly abated upon the reintroduction of midazolam and the drug was ultimately tapered over a period of four days and discontinued without further incident. Implications derived from the association of long-term midazolam therapy with benzodiazepine withdrawal syndrome are discussed.

Assay of cerebrospinal fluid protein: a rate biuret method evaluated.

We evaluated a rate colorimetric method (Beckman) for measuring total protein in cerebrospinal fluid. The automated instrument we used was Beckman's ASTRA TM. A 100-microL sample of spinal fluid is introduced into the biuret reagent in the reaction cell and the increase in absorbance at 545 nm is monitored for 20.5 s. Solid-state circuits determine the rate of alkaline biuret-protein chelate formation, which is directly proportional to the total protein concentration in the sample. The linear range of measurement is 120 to 7500 mg/L. Day-to-day precision (CV) over the range of 150 to 1200 mg/L ranged from 15.2 to 2.3%. The method was unaffected by radical alteration of the albumin/globulin ratio, but there is a positive interference in the presence of hemoglobin, a suppression in the presence of bilirubin, and no effect by xanthochromia. The method is precise, accurate, rapid, and convenient. The method was compared with the trichloroacetic acid method as performed on the Du Pont aca III, giving a correlation coefficient (r2) of 0.9693. The method is precise, accurate, rapid, and convenient.

Measurement of near-normal concentrations of erythrocyte protoporphyrin with the hematofluorometer: influence of plasma on "front-surface illumination" assay.

Zinc protoporphyrin in erythrocytes increases in iron depletion. Because the hematofluorometer directly measures zinc protoporphyrin in whole blood, it may therefore be a useful screening instrument for detecting iron deficiency. We evaluated its performance with normal to slightly above-normal zinc protoporphyrin concentrations (0.2 to 2.0 mg/L) in erythrocytes, because this is a critical range for differentiating normal and iron-deficient individuals. There was excellent correlation (r2 = 0.900) between erythrocyte protoporphyrin as measured by an extraction procedure and as measured directly with the hematofluorometer. However, at these concentrations, plasma caused hematofluorometer readings to be spuriously high, by 2.4 to 89.4%, an effect due to the instrument's optical design. The effect can be eliminated by washing the cells free of plasma or by allowing erythrocytes to displace plasma by settling to the illuminated surface before the measurement. The interference does not affect the hematofluorometer's sensitivity, but abnormal results obtained for whole blood should be confirmed with more-specific tests, and interlaboratory precision may be influenced if whole-blood samples are used. A 1-min delay from sample placement to measurement decreased zinc protoporphyrin values by 2.6 to 36.9%. We also describe the use of cryopreserved control erythrocytes, for which the CV is 2.3% for a concentration of 0.96 mg per liter of erythrocytes, which are not affected by time of measurement, and which are stable for three months.

Evaluation of homogeneous enzyme immunoassay of serum thyroxine with use of bichromatic analysis.

We evaluated the homogeneous enzyme immunoassay ("EMIT") of serum thyroxine with use of an ABA- 100 Bichromatic Analyzer, modified with an auxiliary dispenser syringe and a dual probe assembly. The modification allows two reagents to be dispensed at one time. The sera must be pre-treated with 0.1 mol/liter NaOH. The procedure thereafter is entirely automated. Twenty-four patients' samples may be analyzed in 15 min of instrument time. Precision and accuracy are excellent, and results correlate well with those by radioimmunoassay.

Methotrexate assay by enzymatic inhibition, with use of centrifugal analyzer.

We present a method for measuring methotrexate by enzymatic inhibition, with use of the centrifugal analyzer. In the presence of dihydrofolate reductase (EC 1.5.1.3), dihydrofolic acid is converted to tetrahydrofolate. NADPH acts as a coenzyme. Methotrexate inhibits the action of dihydrofolate reductase. Increasing concentrations of methotrexate depress the conversion of NADPH to NADP+, and the reaction may be followed at 340 nm. Precision, accuracy, and sensitivity are satisfactory. A comparison to the radioimmunoassay method (x) showed the following least-squares regression: y = 0.9813x + 5.6 microgram/liter; r = .9812; Sy = 6.3 microgram/liter. Some interference was noted from bilirubin, lipermia, and hemoglobin. Up to 60 patients' samples per hour may be estimated by this technique.