Peripheral WBC Count Research Articles

The correlation between increased apoptosis and decreased peripheral blood WBC in patients receiving chemotherapy for ovarian cancer

Objective: The purpose of this study was to determine whether the decrease of WBC is correlated with the increase of apoptosis induced by cytotoxic drugs in patients who received neoadjuvant polychemotherapy for ovarian cancer and whether the reduction of peripheral blood WBC can be predicted by the detection of apoptosis. Methods: The study included 25 patients who received neoadjuvant polychemotherapy for ovarian cancer after operation. Total 2 ml of venous blood was collected from these subjects within 24 hours before chemotherapy and at the fifth day after the beginning of chemotherapy. Peripheral blood WBC count was performed and its apoptosis was analyzed using flow cytometry (FCM) and DNA electrophoresis. Results: 68% (17/25) of the patients had a decrease in WBC after chemotherapy. The average counts of WBC were 5.19±1.36×109/L and 4.36±1.56×109/L, the distributions were 4.10–8.60×109/L and 2.00–7.90×109/L before and after chemotherapy respectively. At the same time, 64%(16/25) of the patients had an increase in apoptotic cells. The proportions of apoptosis were 4.01±2.59% and 5.66±1.36%, the distributions were 1.05–11.02% and 0.8–14.08% before and after chemotherapy respectively. Both the decrease of WBC and the increase of apoptosis were statistical significant (P<0.05). The coefficient between the decrease of WBC and the increase of apoptosis is 0.646(P<0.05). The sensitivity of the quantitative analysis of apoptosis using FCM for clinical early diagnosis of the decrease of WBC is 82%, the speciality is 75% and the accuracy is 80%. Conclusion: The increased apoptosis induced by cytotoxic drugs contributed to the chemotherapy-associated reduction of WBC at some extend, there were somewhat correlation between them. The detection of peripheral apoptosis could be of some help to assess the decrease and scientific bases for the administration of G-CSF, GM-CSF to obtain the optimal cost-effectiveness of clinical chemotherapy.

Recommendations for optimized settings of the Amicus Crescendo cell separator for the collection of CD34+ progenitor cells.

CD34+ PBPCs for autologous transplantation purposes are collected by leukapheresis procedures on automated cell separators. In this study, the influence of different parameters on collection efficiency (CE) of the Amicus Crescendo cell separator (Baxter) was investigated. A total of 146 PBPC collections with Amicus cell separators were performed in 56 patients with either settings recommended by the manufacturer or modified settings to identify variables that have a significant and important impact on CE. By use of a standard setting with a cycle volume of 1400 mL, CE significantly decreases when patients' preapheresis peripheral blood WBC counts are between 25,000 and 35,000 per micro L. CE can be improved if cycle volume is reduced to 1000 mL. If WBC concentrations exceed 55,000 per micro L before apheresis, CE also significantly decreases despite of reduced cycle volume. Additionally, high flow rates greater than 60 mL per minute significantly reduce CE. Parameters influencing the outcome of CD34+ PBPC collections were identified, such as patients' WBC count, cycle volume, and whole blood flow rate. An optimized adjustment of these variables will further increase the CE of the device.

Identifying febrile young infants with bacteremia: Is the peripheral white blood cell count an accurate screen?

Study objective: We estimated the accuracy of the total peripheral WBC count as a screen for bacteremia in febrile young infants. Methods: We evaluated, retrospectively, the performance characteristics of linear and nonlinear (U-shaped) logistic models for predicting bacteremia that are based on the total peripheral WBC count. Research subjects were consecutive 0- to 89-day-old infants who had a temperature in triage of greater than or equal to 38°C (≥100.4°F) and were evaluated for infection at a pediatric emergency department (1993 to 1999). Infants with leukemia were excluded. Areas under the receiver operator characteristic curves (AUC), as well as sensitivity, specificity, interval likelihood ratios, and the corresponding odds of bacteremia predicted at various thresholds of the test, were calculated. Results: The rate of bacteremia was 1% (38/3,810). The U-shaped model was more accurate (AUC 0.69 versus 0.56); however, no threshold of the total peripheral WBC count had both good sensitivity and specificity. Sensitivity and specificity values were 79% and 5%, respectively, at a peripheral WBC count cutoff of 5,000 cells/mm3, and 45% and 78%, respectively, at a cutoff of 15,000 cells/mm3. The odds of bacteremia were not decreased substantially at any cutoff and were increased only modestly at values outside published norms of the test. Conclusion: The total peripheral WBC count is an inaccurate screen for bacteremia in febrile young infants; thus, decisions to obtain blood cultures should not rely on this test. [Ann Emerg Med. 2003;42:216-225.]

An evaluation of predictive factors for CD34+ cell harvest yields from patients mobilized with chemotherapy and growth factors.

Accurately predicting the outcomes of peripheral blood stem cell harvests is important because unproductive collections are expensive and subject the donor to unnecessary toxicity. Predictive factors for stem cell mobilization and collection by a retrospective review of 104 consecutive donors were evaluated. Of several previously suggested measures, the peripheral CD34+ cell concentration on the day of harvest (pCD34DH) correlated best with total numbers of CD34+ collected (r = 0.88). This was followed by the pCD34 on the day before harvest (pCD34Day -1) (r = 0.74). The peripheral WBC count on the day of harvest (pWBC) was inferior (r = 0.39). When ratios of potential predictive factors divided by the previous day's value were examined, pWBC ratio was found to be a significant independent predictive factor for cells collected (r = 0.45). Furthermore, the predictive value of both the pCD34Day -1 and the pWBC can be improved by combining with the pWBC ratio. To examine whether the chosen collection starting days were optimal, serial pCD34 obtained daily during the harvest procedures was examined. Poorly mobilizing donors, who required several days of collection, did not reach maximal harvest yields until the fourth collection day. pCD34DH is the optimal predictive factor for harvest yields. If pCD34DH is not available, pCD34Day -1 or pWBC combined with the pWBC ratio may offer the best prediction of harvest outcomes. The best harvest yields on poorly mobilizing donors occur 3 to 4 days after the usual collection starting times.

Utility of the peripheral blood white blood cell count for identifying sick young infants who need lumbar puncture

Study objective: We assess the utility of the peripheral blood WBC count as a screen for lumbar puncture among young infants evaluated for serious bacterial infections. Methods: We performed logistic regression modeling and receiver operating characteristic curve analysis of peripheral blood WBC count and cerebrospinal fluid WBC count for results obtained from 3- to 89-day-old infants undergoing a full sepsis evaluation. Results: Twenty-two of 5,353 (4.1 per 1,000) infants had acute bacterial meningitis. For diagnosing acute bacterial meningitis, the peripheral blood WBC count was poorly discriminating and significantly inferior to the cerebrospinal fluid WBC count. This was true both when the odds of meningitis were modeled to vary linearly and as a U-shaped function of the peripheral blood WBC count. When relying on single and interval-based high-risk thresholds of peripheral blood WBC counts alone, the majority of infants with acute bacterial meningitis would have been missed. Conclusion: Decisions to perform or withhold lumbar puncture should not be based on prevailing interpretations of the total peripheral blood WBC counts to maximize detection of bacterial meningitis in young infants. [Ann Emerg Med. 2003;41:206-214.]

BAL Induces an Increase in Peripheral Blood Neutrophils and Cytokine Levels in Healthy Volunteers and Patients With Pneumonia

To examine the peripheral effects of BAL on the neutrophil counts and cytokine levels in the circulation. WBC counts and plasma cytokines were measured before and 4 h after fiberoptic bronchoscopy (FOB) without further interventions (n = 6), or combined with BAL in normal volunteer subjects (n = 6), and in patients with bacterial pneumonia (n = 4). The bronchus of the right middle lobe was wedged, and three 50-mL aliquots of sterile saline solution was instilled. There was no endotoxin contamination in the saline solution or the fluid obtained through the working channel of bronchoscope. In volunteers, peripheral WBC counts and the number of nonsegmented and segmented neutrophils increased after the BAL procedure (p < 0.05) associated with the increase in plasma concentration (mean +/- SEM) of interleukin (IL)-6 (0.99 +/- 0.32 pg/mL before BAL and 20.38 +/- 13.42 pg/mL after BAL; p < 0.05) and granulocyte colony-stimulating factor (G-CSF; 14.1 +/- 1.7 pg/mL before BAL and 38.5 +/- 9.7 pg/mL after BAL; p < 0.05). The increase in WBC counts and neutrophil counts was positively correlated to the increase in IL-6 (p < 0.05) and the increase in G-CSF (p < 0.05). In patients with pneumonia, IL-6 and G-CSF levels were higher after BAL than in normal volunteer subjects (p < 0.05). There was no increase in plasma concentration of IL-1beta, tumor necrosis factor-alpha, or IL-8 after BAL in normal volunteer subjects or in patients with pneumonia. FOB without BAL did not increase the WBC count, neutrophil count, or plasma cytokine levels. The BAL procedure increases the number of WBCs, and segmented and nonsegmented neutrophils in the peripheral circulation as well as circulating IL-6 and G-CSF levels.

Feedback: Computed tomography for subarachnoid hemorrhage

Feedback: Computed tomography for subarachnoid hemorrhage

Serial granulocytapheresisunder daily administration of rHuG-CSF: effects on peripheral blood counts, collection efficiency, and yield.

An option for treatment of severe infections in neutropenic patients is the transfusion of granulocytes from donors stimulated with rHuG-CSF. The schedule of rHuG-CSF-stimulated granulocyte donations and the quality of the components remain controversial. This study was done with the intention of ensuring daily granulocyte support with therapeutic cell numbers, while keeping the patients' allogeneic exposure as low as possible. Granulocyte collection with multiple consecutive leukapheresis procedures under daily rHuG-CSF administration and with hydroxyethyl starch as sedimenting agent were prospectively studied. Complete blood counts of the donors, collection yield, and efficiency were analyzed. Products (n = 259) from 76 donors were examined. The median peripheral blood WBC and neutrophil counts were 28.1 g per L and 24.1 g per L, respectively, and they were significantly higher on Day 5 of collections than on Days 1 to 3. Platelet counts and Hb levels decreased steadily. Collection yields increased over time from 4.9 to 6.7 x 10(10) neutrophils. Side effects of cytokines and aphereses did not exceed World Health Organization grade II status. Repetitive daily rHuG-CSF administration-even under daily leukapheresis procedures-results in a continuing increase in WBC and neutrophil levels and thus leads to increased collection yields. Side effects are tolerable, although Hb and platelet levels should be monitored closely.

Time dependency of hematopoietic growth factor coupled to chronotoxicity of carboplatin.

A growing body of data suggests that cancer therapy may be improved and toxicity reduced by administration of antineoplastic agents and cytokines at carefully selected times of the day. The time-dependent effects of each of the drugs have been documented, but not their mutual time dependencies. In the present studies we sought to determine the best time for granulocyte colony-stimulating factor (G-CSF) administration after carboplatin treatment. Carboplatin was injected in different groups of ICR mice at four different circadian stages for 5 consecutive days. Mice were synchronized with an alternation of 12 h of light (from 6:00 a.m. to 6:00 p.m.) and 12 h of darkness. After the last injection, peripheral WBCs of three mice from each group were counted every 4 h over a 24-h period. Bone marrow toxicity was estimated with the mean 24-h WBC count. The most severe leukopenia occurred in the group injected at 3:00 p.m. - 9 h after light onset. The second set of experiments evaluated the time-dependent effect of G-CSF when singly injected or given after carboplatin injections for 5 days only at 3:00 p.m. G-CSF was injected into various groups on days 8 and 9 at the same four different circadian stages. On the 10th day after the first injection, peripheral WBCs of three mice from each group were counted every 4 h over a 24-h period. Time-dependent effects were observed when G-CSF was injected as a single agent. When G-CSF was given at various times to the group with the most severe carboplatin-induced leukopenia, peripheral WBC count recovery was monitored at all injection times; it reached its highest level (exceeding even that of the control) when G-CSF was injected at 3:00 a.m. Dosing times of both chemotherapy and growth factor are relevant for optimization of carboplatin's hematologic tolerability.

Alpha interferon administration paradoxically inhibits the development of diabetes in BB rats

Alpha-interferon (IFN-α) is thought to be important in the pathogenesis of insulin dependent diabetes mellitus (IDDM). However, since potent inducers of IFN-α, viruses, have been shown to modulate immune function and autoimmunity, we investigated whether administration of recombinant IFN-α (rIFN-α) would inhibit the diabetic process in BB rats. The development of diabetes was significantly inhibited by injections of either 10 5 units or 4 × 10 5 units rIFN-α. rIFN-α was more effective in preventing disease when injections were initiated at an earlier age (28–30 days vs 35–40 days). Histologic examination revealed a markedly lower degree of insulitis in rIFN-α treated rats. The mean total peripheral WBC and differential count, T-cell subsets, peripheral blood NK cell number, splenic NK cell activity, and serum cytotoxic beta cell surface antibody levels were unaltered by rIFN-α administration. In vitro incubation with rIFN-α inhibited the Con A proliferative response of mononuclear splenocytes of BB rats but not of Sprague Dawley rats. These results document that rIFN-α treatment potently prevents diabetes by inhibiting the development of insulitis. This paradoxical diabetes sparing effect may have significant implications for the treatment and prevention of IDDM and towards the understanding the autoimmune process.

Alterations of Circadian Rhythms in Mice Induced by Anti-Cancer Drugs

Carboplatinum was injected into four groups of mice for 5 successive days at one out of four daily equidistant hours. Upon the cessation of these injections, granulocyte colony stimulating factor was injected into half of these mice for 2 days at the same times. The stimulating factor was also injected into groups of untreated mice for 2 days at the same times. In each experiment the rhythms of four variables were monitored after the cessation of all injections: peripheral WBC count, bone marrow and sperm stem cells DNA synthesis, and sperm ribosomal RNA content. The results indicated that in the course of repeated drug administrations, variables' rhythm parameters (phases and periods) were altered. These changes have to be considered in chronotherapeutic schedules when variables which serve for toxicity diagnosis or as drug target are rhythmic in nature.

Bacterial or crystal-associated arthritis? Discriminating ability of serum inflammatory markers.

A retrospective study of patients with culture-verified septic arthritis (n = 54) and polarizing microscopy verified crystal-associated arthritis (n = 34) was conducted with the objective to identify discriminating laboratory parameters in serum. Serum CRP levels (p = 0.002) and ESR (p = 0.03) were significantly higher on admission in patients with septic arthritis than in those with crystal-associated arthritis. The peripheral WBC counts did not differ between the two groups, nor did the lactoferrin or procalcitonin (PCT) levels. Serum TNFalpha concentrations on admission were higher in patients with septic arthritis than in those with crystal-associated arthritis (p = 0.0008). Significant differences were also found for IL-8 (p = 0.01) and G-CSF (p = 0.002), but not for IL-6 (p = 0.5). However, extensive overlap between the groups was present, resulting in low sensitivity, specificity and predictive value for each test. Determining serum levels of acute phase reactants, including cytokines, does not replace careful synovial fluid examination, including direct microscopy and cultivation.

Philadelphia chromosome in relapsed childhood acute lymphoblastic leukemia: a matched-pair analysis. Berlin-Frankfurt-Münster Study Group.

The translocation t(9;22)(q34;q11), known as Philadelphia chromosome (Ph1) or its molecular equivalent the expression of BCR-ABL-mRNA, is one of the most striking and well-characterized cytogenetic abnormalities in leukemia. Although investigated for more than 30 years, it remains unclear whether the Ph1 is an independent risk factor for outcome of leukemia or not. A matched-pair analysis was performed within a homogeneous group of patients, which consisted of children who presented with a first relapse of acute lymphoblastic leukemia (ALL) who were treated according to ALL relapse trials (ALL-REZ BFM) protocols. A total of 307 patients were eligible for this analysis: 30 positive and 277 negative for Ph1. Positive patients were matched exactly for time point of relapse (on [during] or off [after cessation of] front-line therapy), site, and immunophenotype, and as close as possible for duration of first remission, peripheral blast-cell count, WBC count, and year of relapse diagnosis. The probability of event-free survival is 0.46 at 5 years for negative and 0.11 for positive patients, respectively (P = .0006). Multivariate analysis showed risk ratios of 4.229 for relapse on therapy, 3.561 for Ph1 and/or expression of BCR-ABL- mRNA, 1.691 for high peripheral blast-cell count, and 0.232 for bone marrow transplantation. It was shown that the Ph1 is indeed an independent risk factor in childhood relapsed ALL. There are striking similarities between these patients and children at initial diagnosis, as well as adult patients. Therefore, it is highly suggestive that the Ph1 is also an independent risk factor under all of these circumstances.

Effect of pentoxifylline on the course of systemic Candida albicans infection in mice.

Pentoxifylline can decrease the production of tumour necrosis factor alpha (TNF alpha) by endotoxin-stimulated macrophages and may improve survival in animals with overwhelming bacterial sepsis. In this study various doses of pentoxifylline were administered to mice with systemic Candida albicans infection to determine its effect on serum TNF alpha levels, organ fungal burden, and host survival. Intraperitoneal injections of pentoxifylline at 20 mg/kg every 8 h did not affect these endpoints. However, fungal counts were significantly higher in kidneys of animals that received 30 and 60 mg/kg of pentoxifylline every 8 h when compared to controls. Injection of 60 mg/kg of pentoxifylline at 8 h intervals also significantly shortened mean survival from 5.8 to 3.8 days (P = 0.01). Pentoxifylline did not affect peripheral WBC counts, serum TNF alpha and interleukin-6 levels, or the density of neutrophils in tissues. In vitro, pentoxifylline decreased the production of TNF alpha by C. albicans-stimulated macrophages in a dose-dependent manner, but only at concentrations greater than 100 mg/L. In contrast, pentoxifylline suppressed TNF alpha production by endotoxin-stimulated macrophages at concentrations as low as 10 mg/L. Thus, higher doses of pentoxifylline are detrimental in systemic C. albicans infection. However, the detrimental effect is not mediated by alterations in serum TNF alpha or interleukin-6 levels or the aggregation of neutrophils in tissues.

Measurements of Plasma Elastase α1-Proteinase Inhibitor Complexes in Patients Receiving Cancer Chemotherapy With Granulocyte Colony-Stimulating Factor

We monitored the plasma elastase alpha 1-proteinase inhibitor complex levels in 21 patients with primary lung cancer who received combination chemotherapy with or without recombinant human granulocyte colony-stimulating factor (rhG-CSF), and 15 normal nonsmokers as controls. Of the 21 patients, 14 received combination chemotherapy without rhG-CSF (among them, 6 developed pneumonia) and 7 received combination chemotherapy with rhG-CSF (among them, 1 developed pneumonia). We measured peripheral WBC counts, C-reactive protein (CRP) levels, plasma elastase alpha 1-proteinase inhibitor complex (complex) levels, and complex/WBC values during cancer chemotherapy. In patients who received cancer chemotherapy without rhG-CSF and had no complications (n = 8), WBC values decreased after chemotherapy, and then gradually increased. Complex levels also decreased slightly after chemotherapy and gradually recovered. The value obtained from dividing the complex concentration by WBC count (complex/WBC value) remained stable during cancer chemotherapy. In patients who received cancer chemotherapy with rhG-CSF and had no complications (n = 6), WBC values decreased after chemotherapy, and then rapidly increased to abnormally high values. Complex levels also decreased slightly after chemotherapy and rapidly increased to abnormally high values together with the WBC counts. The complex/WBC values remained stable during cancer chemotherapy. In patients who developed pneumonia during cancer chemotherapy with or without rhG-CSF (n = 7), their complex levels, complex/WBC values, and CRP levels were elevated at the onset of pneumonia. The maximum complex levels (the highest levels during chemotherapy) were significantly higher in patients who received cancer chemotherapy with rhG-CSF and did not develop pneumonia (583.1 +/- 114.5 ng/mL) and in patients who developed pneumonia during cancer chemotherapy (516.7 +/- 113.2 ng/mL), compared with normal nonsmokers (130.2 +/- 5.5, p < 0.01) and patients who received cancer chemotherapy without rhG-CSF and did not develop complications (211.5 +/- 23.3, p < 0.01). The maximum complex/WBC values were not increased in patients who received cancer chemotherapy with rhG-CSF (0.08 +/- 0.01) and patients who received cancer chemotherapy without rhG-CSF (0.092 +/- 0.01, p < 0.01). The maximum complex/WBC values were significantly higher in patients with pneumonia (0.56 +/- 0.12) compared with normal nonsmokers (0.026 +/- 0.002, p < 0.01) and patients without complications. These findings suggest that although rhG-CSF increases total plasma elastase burden, increased release of neutrophil elastase from individual neutrophils does not take place in vivo in the absence of pneumonia.

Site-specific conjugation of diethylenetriaminepentaacetic acid to recombinant human granulocyte-colony-stimulating factor: preservation of protein structure and function.

The chelating agent diethylenetriaminepentaacetic acid (DTPA) was conjugated site-specifically to the N-terminus of recombinant human granulocyte-colony-stimulating factor (rhG-CSF) by reaction of the protein with DTPA dianhydride at an initial pH of 6.0. The reaction was efficient in that 84% of the starting rhG-CSF was N-terminally modified and could be purified to homogeneity by cation-exchange chromatography. Chelation of 111In by the DTPA-rhG-CSF conjugate was demonstrated by cation-exchange HPLC and thin-layer chromatography. Metal contamination of conjugate preparations, as well as metal-loading onto the conjugate, could be monitored by either cation-exchange HPLC or isoelectric focusing. The 1:1 stoichiometric molar ratio of DTPA to protein for the DTPA-rhG-CSF conjugate was determined by thin-layer chromatography and mass spectrometry, and the localization of the conjugated DTPA moiety was resolved using a peptide mapping procedure. The secondary structure (i.e., alpha-helicity) of the protein was unmodified following conjugation as revealed by circular dichroism. Furthermore, the conjugate induced a similar induction of peripheral WBC counts as unmodified rhG-CSF when injected subcutaneously into hamsters, demonstrating preservation of protein bioactivity. These results reveal a simple and efficient method for conjugating DTPA to protein, via reaction with the dianhydride, to yield a homogeneous and well-defined product. The procedure may prove to be a useful method of labeling growth factors and related proteins while preserving structural and functional integrity.

Safety Of The Donor In Living-Related Liver Transplantation-An Analysis Of 100 Parental Donors

The safety and lack of undue operative stress on the donor are documented from an analysis of 100 parental donors, whose children (3 months to 17 years old), received LRLTx at our institution between June 1992 and May 1994. Survival rate of recipients was 86%. No primary nonfunctioning liver was observed. The donors were 56 mothers and 44 fathers. Their ages ranged from 19 to 51 years and their weight ranged from 44 to 80 kg. They received partial liver resections to harvest the grafts. With regard to the liver graft, the left lobe was used in 24 cases (group L) and the left lateral segment was used in 75 cases (group S). The right lobe was used in one case. In the two groups, blood losses were 242 +/- 5 (S) and 312 +/- 14 ml (L); operation times were 6.22 +/- 0.11 (S) and 7.15 +/- 0.21 hr (L), respectively; in both groups, the postoperative hospital stay was 11 days (S, L). No significant differences between the two groups were observed in peripheral RBC and WBC count or serum AST. An increase in total bilirubin was not observed. In the exceptional case using the right lobe, blood loss of 2300 ml necessitated a blood transfusion of 1000 ml, and the total bilirubin increased up to 4.0 mg/dl on the third postoperative day, which prolonged the postoperative hospital stay to 17 days. These results conclusively suggest that safety is guaranteed when the left lobe or the left lateral segment is used as the liver graft for LRLTx.

Modulation of peripheral leukocyte counts and bone marrow function in mice by oral administration of interleukin-2.

Interferons alpha, beta, and gamma have been shown to exert systemic effects following their oral administration to mice. It was of importance to determine whether oral administration of another biologic response modifier, interleukin-2 (IL-2), could also exert systemic effects in mice. Two systemic effects, peripheral WBC suppression and bone marrow suppression, were evaluated. Oral administration of IL-2 was found to suppress the peripheral WBC count in a dose-dependent manner. Oral administration of IL-2 was also found to suppress the bone marrow proliferative activity. The levels of suppression of both peripheral WBC and myelopoietic progenitor cell numbers observed with orally administered IL-2 were comparable to those seen with subcutaneously administered IL-2. The results demonstrate that orally administered IL-2 can exert systemic effects. Further, the results raise the possibility that oral administration of IL-2 may have therapeutic potential.

Complement Activation and Hemodynamic Changes Following Intravenous Administration of Phosphorothioate Oligonucleotides in the Monkey

Rapid intravenous infusion of GEM 91, a 25-mer phosphorothioate oligonucleotide complementary to the gag site of HIV, in the monkey produces transient decreases in peripheral total WBC and neutrophil counts, hemoconcentration, and a brief increase followed by a prolonged decrease in arterial blood pressure. These changes are preceded by and are likely mediated by activation of C5 complement. These effects are dose and infusion rate dependent and can be avoided by administering GEM 91 by slow intravenous infusion. Similar hemodynamic effects are produced with rapid intravenous infusion of other phosphorothioate oligonucleotides varying in length from 20- to 33-mer, and are, therefore, not sequence specific but a property of this chemical structure.

Circadian variation of 5-fluorouracil and cis-platinum toxicity in mice.

Circadian variations of organ specific and lethal toxicities were investigated in female C3H mice following intraperitoneal injection(s) of 5-fluorouracil (5-FU) and/or cis-platinum (CDDP) with different doses at one of the four equidistant time points, viz., 3, 9, 15 and 21 HALO (Hours After Light On). Lethality, peripheral WBC count, spleen size, femoral bone marrow cell population and changes in body weight were analyzed. A single injection of 5-FU (300 mg/kg) showed 45% mortality with 3 HALO and 15% with 9 HALO treatment (p < 0.05); that with CDDP (16 mg/kg) was 80% in 3 HALO and 10% in 9 HALO group (p < 0.01). Peripheral WBC count on the 4th post-treatment day showed that drug induced leukopenia was less severe with 15 HALO dosing compared to the other HALO points (p < 0.01). The reduction in spleen size following treatment was maximum in 3 HALO treated group with both drugs (p < 0.01). The combination therapy of these two drugs also showed circadian variation of toxicity. The results suggest that the toxic effects of chemotherapy are dosing time dependent.