Eicosanoids in relation with LHRH secretion.
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Animals↗
Biomedical subjects
F A Levi
Publications and source records attributed to F A Levi.
Circadian changes in anticoagulant effect of heparin infused at a constant rate.
Six patients with venous thromboembolism were treated with heparin, administered intravenously by a constant infusion pump. The initial daily dose of heparin was adjusted to keep the activated partial thromboplastin time, sampled at 0800, between 1.5 and 2.5 times the control level. Once that level was obtained, this dose was kept constant. Anticoagulation was thereafter measured, every four hours for 48 hours, by activated partial thromboplastin time, thrombin time, and coagulation factor Xa inhibition assay. The results of all three coagulation tests showed a circadian variation in the six patients. Maximum values were achieved at night and minimum values in the morning. These circadian variations were reproduced for two consecutive days. Differences between night and morning values reached almost 50% for activated partial thromboplastin time, 60% for thrombin time, and 40% for factor Xa inhibition assay. This circadian variation resulted from two rhythms, a circadian rhythm lasting 24 hours and an ultradian rhythm lasting 12 hours, which were detected by cosinor analysis for each coagulation test (p less than 0.01). A circadian rhythm was detected individually in most of the patients for each coagulation test (p less than 0.05). All patients had a nocturnal peak in activated partial thromboplastin time on both days. In four patients this peak exceeded the upper desired limit of activated partial thromboplastin time. These rhythms should be taken into account when evaluating the dosage of heparin to be administered.
Aged↗
Circadian and/or circahemidian rhythms in nine lymphocyte-related variables from peripheral blood of healthy subjects.
Circadian variations were investigated for nine lymphocyte-related variables in the peripheral blood of healthy subjects. Monoclonal antibodies targeted at membrane immunoglobulins (anti-Ig, anti-kappa, anti-lambda) or differentiation antigens (anti-IA and OKT3) were used to characterize respectively mature B cells (SIg+, kappa +, lambda +), cells expressing HLA-DR antigen (IA+), and T cells (OKT3+). Blood (33 ml) was drawn every 4 hr for 24 hr starting at 8.30 hr, on seven occasions in five apparently healthy male volunteers, recumbent from 23.00 hr to 07.00 hr. Leukocyte and differential counts were measured. Mononuclear cells were isolated on Ficoll-Hypaque before being incubated with monoclonal antibodies. The proportion of fluorescent cells per 100 microscopically determined cells was multiplied by the number of circulating lymphocytes per milliliter of venous blood. Temporal variations were validated by both paired t-test and cosinor. Rhythms with a period (tau) identical to 24 hr were validated with statistical significance (p less than 0.05) for total lymphocytes, OKT3+ cells and OKT3+:SIg+ ratio, and suggested (0.05 less than or equal to p less than or equal to 0.10) for lambda + and (kappa + + lambda +) cells. Rhythms with tau identical to 12 hr were also found (p less than 0.05) for OKT3+, SIg+, kappa +, and IA+ cells as well as for the OKT3+:SIg+ and the kappa +:lambda + ratios. Validated rhythms exhibited a large amplitude, e.g., peak-through differences were 40% of the 24-hr mean. This circadian and circahemidian temporal structure of immunologic variables constitutes a time-qualified reference system for investigating immune regulations and a tool for optimizing both diagnostic criteria and effectiveness of immunotherapeutic attempts.
Adult↗
A four-day subrenal capsule assay for testing the effectiveness of anticancer drugs against human tumors.
The subrenal capsule assay may predict to which anticancer drug a given patient's tumor is sensitive and may also be used to screen new anticancer drugs. The present study documents that the use of this model requires a histological assessment of both the exploitability of a subrenal capsule assay and the extent of drug-induced antitumor lesions. Thirty-five tumors from 34 patients with solid tumor were submitted to a subrenal capsule assay in a total of 1130 male B6D2F1 mice. After being biopsied, each tumor was dissected by a pathologist and cut into 50 pieces (1.5 X 1.5 X 1.5 cu mm), and one piece was implanted under the renal capsule of 35 mice; the mean tumor diameter was measured on Day 0. Mice were randomized into groups of 6 to 10 animals each. On Days 1, 2, and 3, mice were treated either with placebo (control group) or with various anticancer agents. On Days 4 or 6, mice were sacrificed, the mean tumor diameter measured, and the tumor-bearing kidney fixed in Bouin's picroformol solution and processed for histological analysis after staining with hematein -eosin. Seven histological parameters were blindly rated in a semiquantitative fashion yielding a compound score ( PAPAN ) which estimated the overall quality of each xenograft between -3 and +11. On Day 4, as opposed to Day 6, mean lymphocytic infiltration was 3-fold lower (p less than 0.01), and the rate of xenografts containing well-preserved cancer cells was 2-fold larger (p less than 0.01) in three different tumor specimens. Twenty-two of 31 (71%) assays were evaluable, as defined by a histological quality control test. In those, drug effects were demonstrable by statistically significant differences among groups in 2 assays (9%) by using the relative variation in tumor size as an index of drug effectiveness and in 12 assays (54%) by PAPAN histological score. This suggests the higher sensitivity of histological scoring over tumor size measurements. Moreover, no correlation between relative variation in tumor size and PAPAN was demonstrable with statistical significance indicating the poor reliability of tumor size measurements as an index of the antitumor effectiveness of cytostatic drugs.
Adenocarcinoma↗
Lethal nephrotoxicity and hematologic toxicity of cis-diamminedichloroplatinum ameliorated by optimal circadian timing and hydration.
Three hundred and forty-one female F344 (Fischer) rats were kept in light for 8 hr alternating with darkness for 16 hr; some were observed for survival for 21 days, while others were killed for blood sampling 4.5 days after a single intraperitoneal (i.p.) injection of 11 mg/kg cis-diamminedichloroplatinum (cis-DDP). cis-DDP was administered with or without concomitant i.p. saline load at one of six equispaced circadian stages. This high dose of cis-DDP resulted in marked lethal and renal toxicity, but in a moderate bone marrow suppression. Blood urea nitrogen (BUN), circulating total white blood cell counts (WBC) and survival times revealed statistically significant circadian rhythms of drug toxicity (P less than 0.03). Optimal tolerance for cis-DDP gauged by these three variables resulted from drug administration in the second half of the dark span. Renal tolerance for cis-DDP guaged by BUN was improved two-fold by appropriate drug timing. This benefit from drug timing alone was further improved two-fold if hydration and cis-DDP were given at the optimal circadian stage. Hydration-induced ameloriation of cis-DDP nephrotoxicity requires time qualification of both hydration and cis-DDP.
Animals↗
Circadian stage dependence of cis-diamminedichloroplatinum lethal toxicity in rats.
Renal physiology is circadian rhythmic. The major toxicity of cis-diamminedichloroplatinum (cisplatin) is irreversible renal damage. A single dose of cisplatin (11 mg/kg) was given to groups of standardized female Fischer 344 rats at one of six equispaced circadian stages. A statistically significant effect of time of injection upon tolerance was found by chi 2 analysis. Differences of 3- to 8-fold in survival rate of 50% mortality and a nearly 3-fold difference in long-term survival depended on circadian timing of cisplatin administration. Cisplatin timing resulting in optimal tolerance was similar from study to study. Additional 0.9% NaCl solution was administered with cisplatin in three experiments and resulted in an increase in overall mean survival time. It also resulted in an amplification of the survival rhythm without changing its timing. The increase in survival resulting from 0.9% NaCl solution loading, when compared to controls receiving cisplatin alone, was also highly time dependent. A 52% improvement in mean survival time was achieved in those animals receiving cisplatin and 0.9% NaCl solution at the most favorable circadian stage, as compared to a 20% improvement when this regimen was administered at an inopportune circadian stage. The safest time for cisplatin administration is near the midactivity span, shortly after the maximum of the circadian rhythm in rectal temperature.
Animals↗
Reduction of cis-diamminedichloroplatinum nephrotoxicity in rats by optimal circadian drug timing.
A prominent circadian rhythm in the nephrotoxicity of a therapeutic dose of cis-diamminedichloroplatinum (cisplatin) is demonstrated in female Fischer rats. Rats were randomized to receive two doses of either cisplatin or 0.9% NaCl solution 14 days apart at the times of either high or low values in their circadian rhythm of urinary volume. Toxicity was assessed by measuring changes in body weight and changes in the 24-hr means of urinary volume, blood urea nitrogen, and urinary beta-N-acetylglucosaminidase (NAG) activity. Toxicity was least in rats which received the drug near the circadian maximum of urinary volume. Conversely, rats which received the same dose of drug near the circadian minimum of urinary volume lost more weight and exhibited a 2-fold increase in the 24-hr mean of urinary volume, a 3-fold rise in the 24-hr mean of blood urea nitrogen, and a 5-fold increase in the 24-hr mean of urinary NAG activity. A positive correlation between urinary NAG at the time of cisplatin administration and the extent of cisplatin nephrotoxicity was demonstrated (p less than 0.02). A correlation also was found between tissue NAG concentration and tissue uptake of cisplatin (p less than 0.001). A marked circadian rhythm of NAG activity in proximal tubular cells may contribute to the prominent circadian rhythm in murine renal tolerance for cisplatin.
Acetylglucosaminidase↗