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Biomedical subjects

A J Atkinson

Publications and source records attributed to A J Atkinson.

At least 19 recordsLinked to original sources
PubMed2001

Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies.

In the future, biomarkers will play an increasingly important role in all phases of drug development, including regulatory review. However, only a few of these biomarkers will become established well enough to serve in regulatory decision making as surrogate endpoints, thereby substituting for traditional clinical endpoints. Even generally accepted surrogate endpoints are unlikely to capture all the therapeutic benefits and potential adverse effects a drug will have in a diverse patient population. Accordingly, combinations of biomarkers probably will be needed to provide a more complete characterization of the spectrum of pharmacologic response. In the future, pharmacogenomic approaches, including those based on differential expression of gene arrays, will provide panels of relevant biomarkers that can be expected to transform the drug development process.

Animals↗
PubMed2000

Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates.

We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.

Administration, Oral↗
PubMed1994

Low-dose prazosin in patients with muscle cramps during hemodialysis.

Sympathetic nervous system response to volume stress is more marked in patients with frequent hemodialysis-associated skeletal muscle cramps than in most patients who cramp infrequently. Accordingly, we conducted a double-blind, randomized, and balanced trial in which five patients with frequent hemodialysis-associated cramps were given either placebo or a prazosin dose (ranging from 0.25 to 1.0 mg) at the start of 16 dialysis sessions. These low doses of prazosin appeared to reduce cramp frequency in four of the five patients, and patient-stratified multiple logistic regression analysis indicated an aggregate 58% reduction in cramp frequency (p = 0.030). On the other hand, prazosin therapy was associated with an increased incidence of hypotension that required therapeutic intervention both during (p = 0.033) and after (p = 0.010) hemodialysis. Our findings support the hypothesis that sympathetic activation plays a pathogenetic role in hemodialysis-associated skeletal muscle cramps and suggest that pharmacologic attenuation of this response may be of therapeutic benefit.

Adult↗
PubMed1994

A concurrent audit of high digoxin plasma levels.

A concurrent audit was made of 92 patients with plasma or serum digoxin levels of 3.0 ng/ml or more. Evidence of digoxin toxicity was present in 44 of these patients, and premature blood sampling accounted for the high levels in 30 nontoxic patients. Another 14 patients tolerated high digoxin levels without apparent adverse effects. Impaired renal function appeared to increase the risk of digoxin toxicity, even though digoxin levels were similar in patients with and without toxicity. Pharmacokinetic predictions based on patient weight and creatinine clearance often deviated considerably from measured digoxin levels even when these were drawn appropriately.

Aged↗
PubMed1994

Decreased intracellular compartmentalization of doxorubicin in cell lines expressing P-glycoprotein.

After initial rapid [14C]doxorubicin distribution into drug-sensitive HL-60 and SU-4 cells, slow uptake continues for more than 4 hr, accounting for up to 80% of the total intracellular drug. In contrast, in P-glycoprotein-expressing drug-resistant HL-60R and SU-4R cells, doxorubicin distribution rapidly approaches equilibrium. The simplest kinetic model of this behavior consists of rapid diffusion from extracellular fluid into the cell, followed by uptake into a nonexchangeable intracellular pool. At 3.4 microM doxorubicin, transmembrane diffusion clearance was similar for all cell lines (0.78-0.98 microliter sec-1). There was no decrease in the normalized apparent volume of distribution in the P-glycoprotein-expressing cell lines, as would be expected if an active, unidirectional efflux were present. However, in resistant cells, doxorubicin accumulation in the nonexchangeable pool was up to 15-fold slower than in sensitive cells (0.004 vs. 0.050 microliter sec-1 in HL-60R vs. HL-60; 0.004 vs. 0.058 microliter sec-1 in SU-4R vs. SU-4). No pool inflow could be detected in either SU-4 or SU-4R cells exposed to doxorubicin at 0 degrees C, indicating that the nonexchangeable accumulation requires energy. The process preventing accumulation began to saturate in SU-4R cells at 20 microM doxorubicin, whereas no evidence of saturation was seen with HL-60R, which is more highly resistant than SU4R. We propose that alteration in compartmentalization is primarily responsible for the doxorubicin resistance observed in these cell lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Pharmacokinetics of prednisolone transfer to breast milk.

Prednisolone transfer to breast milk was studied in three nursing women who required oral steroid therapy for asthma. Each patient received a 50 mg intravenous dose of prednisolone phosphate, and blood and breast milk were sampled for 6 hours. Concentrations of prednisolone in milk declined more rapidly than in serum but were similar to expected unbound serum concentrations, suggesting that exchange between unbound prednisolone in serum and breast milk is relatively rapid and bidirectional. Because an average of 0.025% (range, 0.010% to 0.049%) of the prednisolone dose was recovered in milk, prednisolone transfer to breast milk does not appear to pose a clinically significant risk to nursing infants.

Adult↗
PubMed1993

Simultaneous analysis of inulin and 15N2-urea kinetics in humans.

To elucidate the physiologic basis of multicompartmental systems used to model drug distribution, we studied inulin and 15N2-urea kinetics after simultaneous intravenous injection in five normal subjects. Distribution of both compounds was characterized by three-compartment models in which the central compartment corresponded to intravascular space. The mean distribution volumes of 0.164 +/- 0.009 L/kg (+/- SD) for inulin and of 0.670 +/- 0.143 L/kg for urea were similar to expected values for extracellular space and total body water, respectively. Distribution from intravascular space was kinetically heterogeneous, presumably reflecting differences in vascular beds supplied by either fenestrated and discontinuous capillaries or capillaries with a continuous basement membrane. Intercompartmental clearances of inulin and urea and the ratio of their free water diffusion coefficients were used to estimate blood flows and permeability coefficient-surface area products for the peripheral compartments. The sum of compartmental blood flows averaged 5.39 +/- 0.49 L/min and was similar to dual-beam Doppler measurements of cardiac output (5.47 +/- 0.40 L/min).

Adult↗
PubMed1992

Kinetic analysis of P-glycoprotein-mediated doxorubicin efflux.

P-glycoprotein lowers the intracellular concentration of a variety of unrelated compounds including doxorubicin by actively removing them from the cell. Mathematical modeling techniques have been applied to the transmembrane transport of doxorubicin in a nonresistant HL-60 cell line and in a P-glycoprotein-containing resistant subclone, HL-60R, to obtain clearances for inward and outward transport. Distribution of [14C]doxorubicin from extracellular fluid into the cell pellet was analyzed with a closed two-compartment system that fitted experimental measurements of drug concentrations in the extracellular fluid and in the cell pellet, represented by a third compartment that includes trapped extracellular doxorubicin along with the intact cells. Transmembrane diffusion clearance was similar for the two cell lines (1.00 vs. 1.06 microliters sec-1), yielding an apparent doxorubicin permeability coefficient of 7.4 x 10(-5) cm sec-1. However, the total efflux clearance averaged 0.99 +/- 0.05 microliters sec-1 in HL-60 and 2.29 +/- 0.62 microliters sec-1 in HL-60R. The estimated P-glycoprotein-mediated efflux clearance in HL-60R averaged 1.23 +/- 0.51 microliters sec-1. This experimental approach provides direct estimates of transport parameters in intact cells and should be useful in studying the mechanism of action and interactions of inhibitors of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Response to head-up tilt in cramping and noncramping hemodialysis patients.

Hemodialysis-associated skeletal muscle cramps are generally ascribed to a reduction in plasma volume, but during this procedure, it is not known how volume contraction results in cramps. To elucidate this mechanism, we compared responses to one hour of 60 degrees head-up tilt in 8 patients who cramped during no more than one-sixth of their dialyses and in 8 patients who cramped at least half the time. Age and recumbent blood pressure were similar in each group, but more patients with frequent cramps had diabetes underlying their renal failure (p = 0.013) and had been dialyzed for less than 3 years (p = 0.020). Baseline plasma renin activity and plasma norepinephrine and arginine vasopressin concentrations were similar in both groups, except plasma renin activity in one patient with frequent cramps, which was 15 times higher than in the other patients. After tilting, systolic blood pressure fell an average of 17% in patients who cramped infrequently (p = 0.0031) but only 10% in frequently cramping patients. The ratio of tilt/recumbent norepinephrine levels exceeded 1.5 in 7 patients with frequent cramps but was less than this in 6 patients who cramped infrequently (p = 0.020). One of the 2 infrequently cramping patients with a ratio above 1.5 was the only individual to have a normal renin response to tilt. We propose that cramps are prone to occur during hemodialysis in patients whose sympathetic nervous system response to volume stress is partially intact but is not modulated by concurrent activation of the renin-angiotensin system.

Adult↗
PubMed1991

Physiological basis of multicompartmental models of drug distribution.

Although most pharmacokinetic studies are conducted in normal subjects, their clinical utility depends on the reliability with which the results can be extrapolated to patients. This reliability can be improved by increased understanding of how drug absorption and disposition mechanisms are affected by physiological changes or by disease. In recent years, important insight has been gained regarding the effects of altered renal function on drug elimination by the kidneys. There has also been considerable progress in defining the interaction of hemodynamic and metabolic factors that affect the hepatic elimination of drugs. Although comparatively little progress has been made in elucidating the underlying basis of changes in the rate and extent of drug distribution, Arthur Atkinson and colleagues analyse methods of compartmental pharmacokinetic analysis that may provide physiological insight into the factors affecting drug distribution.

Animals↗
PubMed1991

Kinetics of D-xylose absorption in patients with human immunodeficiency virus enteropathy.

D-Xylose absorption was studied in 12 patients with acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex who had had diarrhea for more than 8 weeks, averaged an 11% (range, 3% to 21%) body weight loss during the previous 6 months, and had had negative stool examinations for enteric pathogens. Patients were evaluated by duodenal aspiration and biopsy and received both 25 gm oral and 10 gm intravenous doses of D-xylose. Kinetic analysis of D-xylose absorption was characterized by an absorption rate constant (ka) and a rate constant (ko) reflecting nonabsorptive loss. Extent of D-xylose absorption averaged 18.4% +/- 9.3% (+/- SD) in the 12 patients (normal greater than 60%). Percentage of weight loss during the previous 6 months was negatively correlated with ka (r = -0.69; p = 0.018) in the 11 patients in whom this parameter was reduced but was not correlated with either ko or extent of D-xylose absorption. In these patients with human immunodeficiency virus enteropathy, ka was reduced out of proportion to the minor histologic changes present in the duodenal biopsy specimens.

Acquired Immunodeficiency Syndrome↗