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Biomedical subjects

G Koren

Publications and source records attributed to G Koren.

At least 505 records · Page 28Linked to original sources
PubMed1990

Gating mechanism of a cloned potassium channel expressed in frog oocytes and mammalian cells.

We have cloned a cDNA coding for a delayed rectifier K+ channel from rat brain (RCK1) and rat muscle (RMK1) and expressed it in Xenopus oocytes and in a myoblast cell line (Sol-8). Stably transfected Sol-8 cells exhibited large outward K+ currents, which were indistinguishable from the K+ currents induced in Xenopus oocytes by injection of mRNA transcribed in vitro. RCK1 encodes a K+ channel with a unitary conductance of approximately 14 pS. The steep voltage dependence of channel opening resides in transitions between closed states, whereas the direct transitions into and out of the open state are very rapid and not markedly voltage-dependent. Channel inactivation is very slow, voltage-independent, and occurs from the open state only. We present a simple model that incorporates our findings and is consistent with the presumed structural symmetry of a functional K+ channel.

Animals↗
PubMed1990

Effect of endogenous digoxin-like substances on the interpretation of high concentrations of digoxin in children.

The objective of this study was to assess the effect of endogenous digoxin-like substances on the interpretation of excessive concentrations of digoxin in children. After the development of a high-pressure liquid chromatography (HPLC) method for digoxin in our laboratories, we analyzed sera of children in whom the fluorescence polarization immunoassay identified potentially toxic concentrations of the glycoside (greater than 3 nmol/L; 2.3 ng/ml). Sixteen of them were receiving long-term digoxin therapy, and one had an accidental overdose. The immunoassay yielded significantly higher concentrations (4.1 +/- 1.2 nmol/L; 3.2 +/- 0.9 ng/ml) than the HPLC method (3.3 +/- 1.6 nmol/L; 2.6 +/- 1.2 ng/ml; p less than 0.01). In five cases (30%) these differences were clinically significant because administration of digoxin had been discontinued in the presence of true digoxin concentrations within the therapeutic range and the lack of clinical toxic effects. These data suggest that therapeutic drug monitoring using immunoassays of digoxin may be too inaccurate to detect potential toxic effects, and that much more weight should be focused on clinical monitoring. The HPLC method for assay of digoxin is extremely meticulous and will not become clinically available; therefore the development of better immunoassays should be encouraged.

Adolescent↗
PubMed1990

Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia.

Because trimethoprim-sulfamethoxazole (TMP-SMX) causes neutropenia in children with leukemia, we investigated the possibility that pharmacokinetic interaction between methotrexate (MTX) and TMP-SMX causes accumulation of the antileukemia agent. We studied the pharmacokinetics of MTX given intravenously or orally to nine children with acute lymphoblastic leukemia, once with and once without TMP-SMX. There was an increase in free MTX fraction during TMP-SMX therapy in all patients, from (mean +/- SD) 37.4 +/- 11% without TMP-SMX to 52.2 +/- 6.4% with TMP-SMX (p less than 0.01). Plasma clearance of total MTX did not change significantly, whereas clearance of free MTX decreased significantly (from 12.5 +/- 4 to 7.6 +/- 1.5 ml/kg/min; p less than 0.05). There was a consistent decrease in the renal clearance of free MTX (from 12.1 +/- 6.8 to 5.6 +/- 2.4 ml/kg/min; p less than 0.05). Elimination half-life of MTX was not affected significantly by TMP-SMX. There was a significant correlation between serum concentrations of TMP-SMX and the percentage of decrease in the renal clearance of free MTX (r = 0.91; p less than 0.05). These changes in protein binding and tubular clearance of MTX, caused by competition with TMP-SMX, result in a mean 66% increase in systemic exposure to MTX and may explain the myelotoxicity often observed with the coadministration of the two drugs.

Bone Marrow↗
PubMed1990

Comparison of deferoxamine pharmacokinetics between asymptomatic thalassemic children and those exhibiting severe neurotoxicity.

The use of deferoxamine for iron chelation in transfusion-dependent thalassemia major is limited by serious neurotoxicity (hearing and vision loss). We assessed whether interpatient variability in handling deferoxamine and resultant accumulation of the drug may account for the neurotoxicity. We studied steady-state deferoxamine pharmacokinetics during intravenous infusion in two groups of patients--one group exhibited severe manifestations of auditory and visual loss and one group was asymptomatic. The groups were matched for age, sex distribution, weight, treatment period, ferritin levels, and hemoglobin levels. Similarly, doses of deferoxamine at the time of the study were not different. Clearance rates were not different between the symptomatic and asymptomatic patients (39.83 +/- 4.54 versus 30.66 +/- 4.39 ml/min.kg). However, patients who exhibited toxicity received significantly higher daily doses of subcutaneous deferoxamine at the time of diagnosis of neurotoxicity (9.03 +/- 0.96 and 5.58 +/- 0.61 mg/kg.hr, respectively; p less than 0.005). These data suggest that deferoxamine induced neurotoxicity is dose-dependent and cannot be attributed to accumulation of the drug caused by slower clearance rates.

Adolescent↗
PubMed1990

Respiratory response and pharmacokinetics of intravenous salbutamol in infants with bronchopulmonary dysplasia.

The effects of iv salbutamol on respiratory mechanics were studied in six infants with bronchopulmonary dysplasia. Salbutamol was infused at a dose of 30 micrograms/kg over 30 min in five infants; a sixth infant received 66.7 micrograms/kg over 4 min. Salbutamol caused improvement in total respiratory system compliance and in airflow resistance. There was no correlation between salbutamol serum concentration and pulmonary function. Elimination half-time appears to be dictated in these infants more by the distribution volume (Vd) than by clearance (Cl). The area under concentration-time curve of salbutamol correlated inversely to the change in heart rate (HR). There was a significant positive correlation between Vd and percent HR change. These data provide evidence that preterm infants have measurable activity of bronchiolar beta 2 receptor responsive to salbutamol.

Airway Resistance↗
PubMed1990

Calcium blocking agents in pediatric emergency care.

Blocking calcium ion entry into tissue cells appears to have therapeutic benefits in various diseases and symptoms. In the emergency department, as well as in the pediatric intensive care unit, the pediatrician often encounters life-threatening clinical episodes for which the safest, quickest, and most efficient treatment is required. Thus, being familiar with a large variety of emergency therapeutic options, including the use of CBAs, is important. In many medical centers, CBAs have already become the first line of drugs for converting PSVT into normal sinus rhythm (verapamil) and for ameliorating malignant hypertension (nifedipine). The increasing evidence that nimodipine effectively decreases the cerebral damage after head trauma and intracranial hemorrhage will also probably turn this compound into one of the drugs readily available in the emergency department. CBAs will continue to be thoroughly investigated, allowing more new therapeutic applications in pediatric emergency care.

Adolescent↗
PubMed1990

Simple measurement of captopril in plasma by high-performance liquid chromatography with ultraviolet detection.

Captopril is an orally active inhibitor of angiotensin-converting enzyme. A rapid, accurate, and sensitive high-performance chromatography (HPLC) method is described for measuring plasma concentrations of captopril. Captopril was stabilized by forming an adduct with p-bromophenacyl bromide. This adduct was measured by HPLC using a C-18 reverse-phase column and monitoring the column effluent by ultraviolet absorption at 260 nm. The method proved to be linear in the clinical range of 10-1,000 ng/ml. The plasma levels of captopril in a young patient given a small oral dose were determined by this method.

Acetophenones↗
PubMed1990

Drug-induced aplastic anemia: pathogenesis and clinical aspects.

Drug-induced aplastic anemia is one of the few life-threatening reactions to drugs. Although the majority of reported cases have been associated with chloramphenicol, many drugs have the potential to be toxic to the bone marrow. There are two distinct types of toxicity with differing pathogenic mechanisms--a dose-related reversible marrow aplasia and a dose-independent idiosyncratic aplasia with a high mortality. These two forms of marrow suppression may be difficult to distinguish. The pathogenesis of idiosyncratic marrow aplasia is not well understood. Various studies have demonstrated biochemical, immune, pharmacokinetic, and genetic defects that could affect hematopoietic stem cells. The clinical significance of the reported experimental findings is not established. The prognosis of drug-induced aplastic anemia is similar to that of idiopathic aplastic anemia. Patients with this condition respond to bone marrow transplantation or immunosuppressive therapy in a manner similar to patients with idiopathic marrow aplasia. Many questions regarding drug-induced aplastic anemia remain to be answered; little progress has been made in the last decade.

Anemia, Aplastic↗
PubMed1990

Pharmacokinetic analysis of cloxacillin loss in children undergoing major surgery with massive bleeding.

To determine the magnitude of cloxacillin loss during surgical procedures involving significant blood loss and high fluid replacement, we compared the pharmacokinetics of cloxacillin in children during craniomaxillofacial surgery with the disposition of the drug in healthy young adult volunteers with intact circulation. Blood loss during craniofacial operations may exceed blood volume, in some cases by as much as three times. Hemodynamic replacement with electrolyte solutions and blood products, which do not contain the drug, further dilute cloxacillin concentrations. In the patients that we studied, mean drug loss was estimated at 71%. Cloxacillin concentrations in serum fell below the lower range of the MIC for Staphylococcus aureus during significant portions of the surgical procedures. Thus, the traditional dosing of cloxacillin during prolonged operations with massive blood loss is inadequate. A more frequent dosing interval or priming of all replacement fluids with the drug may be required to maintain therapeutic levels. Our findings suggest that massive blood loss is likely to have a dramatic effect on the level of any drug with a small distribution volume. If such a drug is essential to the patient's well-being (e.g., antibiotics, antiarrhythmics, and anticonvulsants), it must be replaced promptly.

Adolescent↗
PubMed1990

Ethical boundaries of medical research in infants and children in the 80s: analysis of rejected protocols and a new solution for drug studies.

To assess the difficulties in conducting pediatric research, we reviewed the 351 protocols dealing with research in infants and children in our institute between July 1982 and August 1988. Of the 16 rejected protocols (4.5%), 12 were drug studies, 3 dealt with the nature of course of disease states and 1 was in the area of behavioral sciences. Drug studies were significantly more likely to be rejected than all other studies. The most common reason for rejection (n = 10) were major scientific flaws which, according to the committee, would result in inability of the study to answer the questions posed by the researchers. In 9 cases, the committee judged a study to be physically invasive without a direct benefit to the involved infant/child. In 3 cases, the committee rejected a study because patients with serious medical conditions might be randomized to receive placebo and not a drug which, based on current knowledge from adults, would possibly improve their condition. In 3 protocols current antimicrobial therapy covered all pathogens causing the infection and the proposed new therapy could not improve the prognosis further but only be equal or inferior. Researchers who had more than one protocol rejected had submitted significantly more protocols (7.17 +/- 1.35) than those who had only one rejection (1.86 +/- 0.36, p less than 0.0005) or than the 10 researchers with the highest number of studies without a single rejection (4.2 +/- 0.4, p less than 0.05). In trying to solve the problem of invasiveness in drug studies in neonates, we have conducted a pharmacokinetic analysis and have documented that 3 samples for drug concentration are all that is needed for pharmacokinetic analysis, as values achieved with these data are not different from those calculated from 8 concentration-time points. In a prospective study in neonates, the validity of these assumptions was proven for the use of the antibiotic vancomycin. This model may be applicable to other areas of pediatric research where careful analysis of existing data may reveal that accurate information can be derived from much fewer samples than previously believed.

Adolescent↗
PubMed1990

Medical research in infants and children in the eighties: analysis of rejected protocols.

We reviewed the 351 protocols dealing with research in infants and children in our institute between July 1982 and August 1988 to identify ethical issues that complicate the execution of pediatric research. Of the 16 rejected protocols (4.5%) 12 were drug studies, three dealt with the nature or course of disease states and one was in the area of behavioral sciences. Drug studies were significantly more likely to be rejected than all other studies. The most common reason for rejection (n = 10) were major scientific flaws that, according to the Committee, would result in inability of the study to answer the questions posed by the researchers. In nine cases the Committee judged a study to be physically invasive without a direct benefit to the involved infant/child. In three cases, the Committee rejected a study because patients with serious medical conditions might be randomized to receive placebo and not a drug that, based on current knowledge from adults, would possibly improve their condition. In three protocols, current antimicrobial therapy covered all pathogens causing the infection and the proposed new therapy could not improve the prognosis further but only be equal or inferior. Researchers who had more than one protocol rejected had significantly more protocols submitted (7.17 +/- 1.35) than those who had only one rejection (1.86 +/- 0.36, p less than 0.0005) or than the 10 researchers with the highest number of studies without a single rejection (4.2 +/- 0.4, p less than 0.05). These numbers suggest that scientists who perform more research are more likely to stand at the front line of unresolved ethical issues.

Adolescent↗
PubMed1990

Morphine excretion in breast milk and resultant exposure of a nursing infant.

We report the case of an infant who was breastfed while his mother was receiving low doses of morphine. Morphine concentration in his serum was in the analgesic range (4 ng/ml), while concentrations in the milk varied substantially in three samples collected within 2 hours (10, 100, 12 ng/ml). The calculated dose that the infant must have received to achieve the observed serum concentration had to be between 0.8 to 12% of maternal dose, based on reference literature values of clearance and bioavailability. The current perception that maternal morphine exposure is safe for the breastfed infant is based on a 50 year old data which were determined by an analytical method 1000 fold less sensitive than the present HPLC, thus leading to a likely erroneous conclusion.

Adult↗
PubMed1990

Clinical course and pharmacokinetics following a massive overdose of amphotericin B in a neonate.

Amphotericin is the drug of choice for the treatment of fungal infections in infants and children. When used in the recommended doses, amphotericin therapy is associated with high rates of adverse effects, including nephrotoxicity, hepatotoxicity, decrease in white blood cells, platelets and hemoglobin, chills, fever and even death (1). We report a case involving a neonate who was exposed to a 50 fold overdose of Amphotericin over a three day period.

Amphotericin B↗