scholarly journals Phenobarbital induction of cytochromes P-450. High-level long-term responsiveness of primary rat hepatocyte cultures to drug induction, and glucocorticoid dependence of the phenobarbital response

1990 ◽  
Vol 271 (1) ◽  
pp. 113-119 ◽  
Author(s):  
D J Waxman ◽  
J J Morrissey ◽  
S Naik ◽  
H O Jauregui
Keyword(s):  
Rat Hepatocytes ◽  
Fold Increase ◽  
Drug Induction ◽  
Fetal Bovine ◽  
Mechanistic Basis ◽  
High Level ◽  
Male Specific ◽  
Cytochrome P 450

The induction of hepatic cytochromes P-450 by phenobarbital (PB) was studied in rat hepatocytes cultured for up to 5 weeks on Vitrogen-coated plates in serum-free modified Chee's medium then exposed to PB (0.75 mM) for an additional 4 days. Immunoblotting analysis indicated that P-450 forms PB4 (IIB1) and PB5 (IIB2) were induced dramatically (greater than 50-fold increase), up to levels nearly as high as those achieved in PB-induced rat liver in vivo. The newly synthesized cytochrome P-450 was enzymically active, as shown by the major induction of the P-450 PB4-dependent steroid 16 β-hydroxylase and pentoxyresorufin O-dealkylase activities in the PB-induced hepatocyte microsomes (up to 90-fold increase). PB induction of these P-450s was markedly enhanced by the presence of dexamethasone (50 nM-1 microM), which alone was not an affective inducing agent, and was inhibited by greater than 90% by 10% fetal bovine serum. The PB response was also inhibited (greater than 85%) by growth hormone (250 ng/ml), indicating that this hormone probably acts directly on the hepatocyte when it antagonizes the induction of P-450 PB4 in intact rats. In untreated hepatocytes, P-450 RLM2 (IIA2), P-450 3 (IIA1) and NADPH P-450 reductase levels were substantially maintained in the cultures for 10-20 days. The latter two enzymes were also inducible by PB to an extent (3-4 fold elevation) that is comparable with that observed in the liver in vivo. Moreover, P-450c (IA1) and P-450 3 (IIA1) were highly inducible by 3-methylcholanthrene (5 microM; 48 h exposure) even after 3 weeks in culture. In contrast, the male-specific pituitary-regulated P-450 form 2c (IIC11) was rapidly lost upon culturing the hepatocytes, suggesting that supplementation of appropriate hormonal factors may be necessary for its expression. The present hepatocyte culture system exhibits a responsiveness to drug inducers that is qualitatively and quantitatively comparable with that observed in vivo, and should prove valuable for more detailed investigations of the molecular and mechanistic basis of the response to PB and its modulation by endogenous hormones.

scholarly journals Studies of the long-term regulation of hepatic pyruvate dehydrogenase kinase

1998 ◽  
Vol 329 (1) ◽  
pp. 89-94 ◽  
Author(s):  
C. Mary SUGDEN ◽  
G. D. Lee FRYER ◽  
A. Karen ORFALI ◽  
A. David PRIESTMAN ◽  
Elaine DONALD ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Pyruvate Dehydrogenase ◽  
Unsaturated Fatty Acids ◽  
Fold Increase ◽  
Membrane Lipid ◽  
Dietary Lipid ◽  
Pyruvate Dehydrogenase Kinase ◽  
Plasma Insulin Concentration

The administration of a low-carbohydrate/high-saturated-fat (LC/HF) diet for 28 days or starvation for 48 h both increased pyruvate dehydrogenase kinase (PDHK) activity in extracts of rat hepatic mitochondria, by approx. 2.1-fold and 3.5-fold respectively. ELISAs of extracts of hepatic mitochondria, conducted over a range of pyruvate dehydrogenase (PDH) activities, revealed that mitochondrial immunoreactive PDHKII (the major PDHK isoform in rat liver) was significantly increased by approx. 1.4-fold after 28 days of LC/HF feeding and by approx. 2-fold after 48 h of starvation. The effect of LC/HF feeding to increase hepatic PDHK activity was retained through hepatocyte preparation, but was decreased on 21 h culture with insulin (100μ-i.u./ml). A sustained (24 h) 2-4-fold elevation in plasma insulin concentration in vivo (achieved by insulin infusion via an osmotic pump) suppressed the effect of LC/HF feeding so that hepatic PDHK activities did not differ significantly from those of (insulin-infused) control rats. The increase in hepatic PDHK activity evoked by 28 days of LC/HF feeding was prevented and reversed (within 24 h) by the replacement of 7% of the dietary lipid with long-chain ω-3 fatty acids. Analysis of hepatic membrane lipid revealed a 1.9-fold increase in the ratio of total polyunsaturated ω-3 fatty acids to total mono-unsaturated fatty acids. The results indicate that the increased hepatic PDHK activities observed in livers of LC/HF-fed or 48 h-starved rats are associated with long-term actions to increase hepatic PDHKII concentrations. The long-term regulation of hepatic PDHK by LC/HF feeding might be achieved through an impaired action of insulin to suppress PDHK activity. In addition, the fatty acid composition of the diet, rather than the fat content, is a key influence.

Abstract TP379: “Build It and They Will Come”: How Comprehensive Stroke Certification Increases the Number of Transfers

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Betty Robertson
Keyword(s):  
Research Question ◽  
Heart Association ◽  
Fold Increase ◽  
Joint Commission ◽  
Level Of Care ◽  
Stroke Patients ◽  
Full Spectrum ◽  
Specialized Care ◽  
High Level

Introduction/Background: Stroke is the leading cause of long-term disability affecting 800,000 people in the U.S. each year. In September 2012 The Joint Commission, in collaboration with the American Heart Association/American Stroke Association’s Brain Attack Coalition, launched the Advanced Certification for Comprehensive Stroke Centers (CSCs). This new level of certification recognizes the significant resources in staff and training that comprehensive stroke centers must have to treat complex stroke. Certification is available only to comprehensive stroke centers in Joint Commission-accredited acute care hospitals. For CSC eligibility, there are numerous requirements and volumes that must be met. The most complicated stroke cases should be treated at the centers best equipped to provide specialized care that lead to better outcomes. Cedar-Sinai became the 4 th program in the nation to receive this prestigious certification. By providing expert care, numerous clinical trials, and high level treatment and procedures, we have become the center of choice for patients in need of a higher level of care. Research Question: Does comprehensive stroke certification lead to an increased number of transfers for higher level of care? Methods: Retrospective analysis of the number of acute strokes transferred to Cedars-Sinai between the first years of Comprehensive Stroke Certification in 2012 through 2015. Results: 2012 yielded a total transfer of 97 patients. In 2015 the volume had risen to 194, a 50% increase in 4 years. It is important to note that in 2014, 4 patients were transferred post TPA infusion (Drip and Ship), the gold standard for treatment of ischemic stroke. 2015 resulted in 25 such transfers, a six fold increase. Conclusion: The full spectrum and coordination of services that a CSC is equipped to provide contributes to increased access of specialized care for complex stroke patients. This in turn leads to better outcomes. This not only translates to delivery of timely optimal treatment for stroke patients, but also increases our expertise in delivery of this care.

scholarly journals Interactions of insulin, glucagon and dexamethasone in controlling the activity of glycerol phosphate acyltransferase and the activity and subcellular distribution of phosphatidate phosphohydrolase in cultured rat hepatocytes

1985 ◽  
Vol 230 (2) ◽  
pp. 525-534 ◽  
Author(s):  
R A Pittner ◽  
R Fears ◽  
D N Brindley
Keyword(s):  
Neutral Lipids ◽  
Relative Proportion ◽  
Rat Hepatocytes ◽  
Glycerol Phosphate ◽  
Acyltransferase Activity ◽  
Phosphatidate Phosphohydrolase ◽  
Cultured Rat Hepatocytes ◽  
Total Glycerol

Rat hepatocytes were incubated in monolayer culture for 8 h. Glucagon (10nM) increased the total phosphatidate phosphohydrolase activity by 1.7-fold. This effect was abolished by adding cycloheximide, actinomycin D or 500 pM-insulin to the incubations. The glucagon-induced increase was synergistic with that produced by an optimum concentration of 100 nM-dexamethasone. Theophylline (1mM) potentiated the effect of glucagon, but it did not affect the dexamethasone-induced increase in the phosphohydrolase activity. The relative proportion of the phosphohydrolase activity associated with membranes was decreased by glucagon when 0.15 mM-oleate was added 15 min before the end of the incubations to translocate the phosphohydrolase from the cytosol. This glucagon effect was not seen at 0.5 mM-oleate. Since glucagon also increased the total phosphohydrolase activity, the membrane-associated activity was maintained at 0.15 mM-oleate and was increased at 0.5 mM-oleate. This activity at both oleate concentrations was also increased in incubations that contained dexamethasone, particularly in the presence of glucagon. Insulin increased the relative proportion of phosphatidate phosphohydrolase that was associated with membranes at 0.15 mM-oleate, but not at 0.5 mM-oleate. It also decreased the absolute phosphohydrolase activity on the membranes at both oleate concentrations in incubations that also contained glucagon and dexamethasone. None of the hormonal combinations significantly altered the total glycerol phosphate acyltransferase activity. However, glucagon significantly increased the microsomal activities, and insulin had the opposite effect. Glucagon also decreased the mitochondrial acyltransferase activity. There was a highly significant correlation between the total phosphatidate phosphohydrolase activity and the synthesis of neutral lipids from glycerol phosphate and 0.5 mM-oleate in homogenates of cells from all of the hormonal combinations. Phosphatidate phosphohydrolase activity is increased in the long term by glucocorticoids and also by glucagon through cyclic AMP. In the short term, glucagon increases the concentration of fatty acid required to translocate the cytosolic reservoir of activity to the membranes on which phosphatidate is synthesized. Insulin opposes the combined actions of glucagon and glucocorticoids. The long-term events explain the large increases in the phosphohydrolase activity that occur in vivo in a variety of stress conditions. The expression of this activity depends on increases in the net availability of fatty acids and their CoA esters in the liver.

Hepatocytes are a rich source of novel aspirin-triggered 15-epi-lipoxin A4

1999 ◽  
Vol 277 (5) ◽  
pp. C870-C877 ◽  
Author(s):  
Esther Titos ◽  
Nan Chiang ◽  
Charles N. Serhan ◽  
Mario Romano ◽  
Joan Gaya ◽  
...  
Keyword(s):  
Rat Hepatocytes ◽  
Arachidonic Acid Metabolism ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Potent Inducer ◽  
Biologically Relevant ◽  
In Vivo Experiments ◽  
Cox 2 ◽  
Cytochrome P 450

Novel aspirin (ASA)-triggered 15-epi-lipoxins (ATL) comprise new potent bioactive eicosanoids that may contribute to the therapeutic effect of this drug. ATL biosynthesis is initiated by ASA acetylation of cyclooxygenase (COX)-2 and was originally identified during the interaction of leukocytes with either endothelial or epithelial cells. Here, we examined ATL biosynthesis in rat hepatocytes either alone or in coincubation with nonparenchymal liver cells (NPC) and in liver homogenates from ASA-treated rats. Rat hepatocytes and CC-1 cells, a rat hepatocyte cell line, displayed COX-1 but not COX-2 mRNA expression and predominantly produced thromboxane A2(TXA2) and 15-hydroxyeicosatetraenoic acid (15-HETE). In these cells, ASA shifted the arachidonic acid metabolism from TXA2 to 15-HETE in a concentration-dependent manner. In contrast, neither indomethacin, ibuprofen, valeryl salicylate, nor nimesulide was able to trigger 15-HETE biosynthesis. SKF-525A, a cytochrome P-450 inhibitor, significantly reduced the effect of ASA on 15-HETE biosynthesis. Furthermore, phenobarbital, a potent inducer of cytochrome P-450 activity, further increased ASA-induced 15-HETE production. ASA treatment of hepatocyte-NPC coincubations resulted in the generation of significant amounts of ATL. In addition, in vivo experiments demonstrated augmented hepatic levels of 15-epi-lipoxin A4 in ASA-treated rats. Taken together and considering that ASA is hydrolyzed on its first pass through the portal circulation, these data indicate that, during ASA's consumption, liver tissue generates biologically relevant amounts of ATL by COX-2-independent mechanisms.

Prolonged High-Level Detection of Retrovirally Marked Hematopoietic Cells in Nonhuman Primates after Transduction of CD34+ Progenitors Using Clinically Feasible Methods.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1137-1137
Author(s):  
Tong Wu ◽  
Hyeoung Joon Kim ◽  
Stephanie E. Sellers ◽  
Kristin E. Meade ◽  
Brian A. Agricola ◽  
...  
Keyword(s):  
Stem Cell ◽  
Gene Transfer ◽  
Nonhuman Primates ◽  
Ex Vivo ◽  
Hematopoietic Stem ◽  
Retroviral Transduction ◽  
Colony Pcr ◽  
High Level

Abstract Low-level retroviral transduction and engraftment of hematopoietic long-term repopulating cells in large animals and humans remain primary obstacles to the successful application of hematopoietic stem cell(HSC) gene transfer in humans. Recent studies have reported improved efficiency by including stromal cells(STR), or the fibronectin fragment CH-296(FN), and various cytokines such as flt3 ligand(FLT) during ex vivo culture and transduction in nonhuman primates. In this work, we extend our studies using the rhesus competitive repopulation model to further explore optimal and transduction in the presence of either preformed autologous STR or immobilized FN. Long-term clinically relevant gene marking levels in multiple hematopoietic lineages from both conditions were demonstrated in vivo by semiquantitative PCR, colony PCR, and genomic Southern blotting, suggesting that FN could replace STR in ex vivo transduction protocols. Second, we compared transduction on FN in the presence of IL-3, IL-6, stem cell factor(SCF), and FLT(our best cytokine combination in prior studies)with a combination of megakaryocyte growth and development factor(MGDF), SCF, and FLT. Gene marking levels were equivalent in these animals, with no significant effect on retroviral gene transfer efficiency assessed in vivo by the replacement of IL-3 and IL-6 with MGDF. Our results indicate that SCF/G-CSF-mobilized PB CD34+ cells are transduced with equivalent efficiency in the presence of either STR or FN, with stable long-term marking of multiple lineages at levels of 10–15% and transient marking as high as 54%. These results represent an advance in the field of HSC gene transfer using methods easily applied in the clinical setting.

Systemic Administration of Pleiotrophin Induces Hematopoietic Stem Cell Regeneration In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1498-1498
Author(s):  
Heather A Himburg ◽  
Pamela Daher ◽  
Sarah Kristen Meadows ◽  
J. Lauren Russell ◽  
Phuong Doan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Growth Factor ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Fold Increase ◽  
Cell Regeneration ◽  
Hematopoietic Stem ◽  
Hematopoietic Reconstitution

Abstract Abstract 1498 Poster Board I-521 Significant progress has been made toward delineating the intrinsic and extrinsic signaling pathways that regulate hematopoietic stem cell (HSC) self-renewal. However, much less is known regarding the process of HSC regeneration or the extrinsic signals that regulate hematopoietic reconstitution following stress or injury. Elucidation of the microenvironmental signals which promote HSC regeneration in vivo would have important implications for the treatment of patients undergoing radiation therapy, chemotherapy and stem cell transplantation. We recently reported that pleiotrophin, a soluble heparin-binding growth factor, induced a 10-fold expansion of murine long-term repopulating HSCs in short term culture (Himburg et al. Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: 78). Based on this observation, we hypothesized that PTN might also be a regenerative growth factor for HSCs. Here we tested the effect of systemic administration of PTN to non-irradiated and irradiated C57Bl6 mice to determine if PTN could promote HSC regeneration in vivo. C57Bl6 mice were irradiated with 700 cGy total body irradiation (TBI) followed by intraperitoneal administration of 2 μg PTN or saline x 7 days, followed by analysis of BM stem and progenitor cell content. Saline-treated mice demonstrated significant reductions in total BM cells, BM c-kit+sca-1+lin- (KSL) cells, colony forming cells (CFCs) and long term culture-initiating cells (LTC-ICs) compared to non-irradiated control mice. In contrast, PTN-treated mice demonstrated a 2.3-fold increase in total BM cells (p=0.03), a 5.6-fold increase in BM KSL stem/progenitor cells (p=0.04), a 2.9-fold increase in BM CFCs (p=0.004) and an 11-fold increase in LTC-ICs (p=0.03) compared to saline-treated mice. Moreover, competitive repopulating transplantation assays demonstrated that BM from PTN-treated, irradiated mice contained 5-fold increased competitive repopulating units (CRUs) compared to saline-treated, irradiated mice (p=0.04). Taken together, these data demonstrate that the administration of PTN induces BM HSC and progenitor cell regeneration in vivo following injury. Comparable increases in total BM cells, BM KSL cells and BM CFCs were also observed in PTN-treated mice compared to saline-treated controls following 300 cGy TBI, demonstrating that PTN is a potent growth factor for hematopoietic stem/progenitor cells in vivo at less than ablative doses of TBI. In order to determine whether PTN acted directly on BM HSCs to induce their proliferation and expansion in vivo, we exposed mice to BrDU in their drinking water x 7 days and compared the response to saline treatment versus PTN treatment. PTN-treated mice demonstrated a significant increase in BrDU+ BM KSL cells compared to saline-treated controls (p=0.04) and cell cycle analysis confirmed a significant increase in BM KSL cells in S phase in the PTN-treatment group compared to saline-treated controls (p=0.04). These data indicate that PTN serves as a soluble growth factor for BM HSCs and induces their proliferation and expansion in vivo while preserving their repopulating capacity. These results suggest that PTN has therapeutic potential as a novel growth factor to accelerate hematopoietic reconstitution in patients undergoing myelosuppressive radiotherapy or chemotherapy. Disclosures: No relevant conflicts of interest to declare.

Alemtuzumab Treatment Can Affect CD52 Positive As Well As CD52 Negative GPI-Deficient, Sezary Cells Allowing Long-Term Disease Control

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2491-2491
Author(s):  
C.J.M. Halkes ◽  
I Jedema ◽  
H.M. van Egmond ◽  
L van der Fits ◽  
J.H.F. Falkenburg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fold Increase ◽  
Cell Populations ◽  
Proliferative Potential ◽  
Small Populations ◽  
Collateral Damage ◽  
Sézary Cells

Abstract Abstract 2491 Alemtuzumab (ALT) is a monoclonal anti CD52 antibody used for the treatment of CD52 positive lymphoid malignancies and to deplete T cells in vivo and in vitro to prevent graft rejection or GVHD after allogeneic stem cell transplantation (alloSCT). Membrane CD52 expression depends on the presence of a glycosylphosphatidylinositol (GPI) anchor. GPI deficiency is frequently found in small populations of normal and malignant hematopoietic cells, including T and B cells (frequencies from <0.01 to 2%). These cells lack expression of GPI-linked proteins like CD52 as can be detected by absence of staining of FLAER, which is an aerolysin that specifically binds to mammalian GPI anchors. After alloSCT using ALT for T cell depletion, reconstitution of FLAER and CD52 double negative cells is seen, and outgrowth of CD52 negative malignant cell populations has been found after single agent treatment with ALT in malignant diseases. However, GPI deficient cells have been suggested to have a lower proliferative potential and a decreased survival due to their increased susceptibility to spontaneous complement mediated cell lysis, possibly explaining the infrequent dominant outgrowth of GPI deficient clones in healthy individuals. Sézary Syndrome (SS) is an aggressive cutaneous T cell lymphoma characterized by the presence of high numbers of neoplastic T cells expressing CD4 and CD52 in peripheral blood, lymph nodes and skin. Clinical responses in SS patients after single drug treatment with low dosed ALT have been described by several investigators. However, in 6 out of 6 patients analyzed, we found a small population of CD52 and FLAER negative Sézary cells, illustrating that a GPI negative subpopulation is frequently observed which may lead to outgrowth of CD52 negative Sézary cells. We treated 3 patients with successive courses of low dose ALT (10 mg subcutaneously once weekly until circulating malignant cells were < 1,000/mm3) and followed the kinetics of CD52- and CD52+ Sézary cells. Before ALT treatment, a CD4+CD52-FLAER- T cell population was found in all three patients (0.01–0.06% of all circulating CD4+ T cells). As expected, a rapid decrease in absolute numbers of CD4+CD52+FLAER+ cells was observed after ALT treatment (decrease 94 to 100%). Surprisingly, despite the absence of the CD52 target molecule, the absolute number of CD4+CD52-FLAER- T cells also decreased after the first and second treatment cycles in all three patients (decreases between 22 and 96%), indicating that the massive in vivo ALT mediated lysis of CD52+ Sézary cells coincided with collateral damage of CD52- Sézary cells. Between successive treatment courses in the absence of circulating ALT, the absolute numbers of CD4+CD52+FLAER+ T cells showed a more rapid increase compared to CD4+CD52-FLAER- T cells in all patients (median 193 fold increase (range 17–896) versus 9 fold increase (range 2–144) respectively), illustrating a decreased in vivo proliferative potential of these GPI negative cells. After repeated doses of ALT, one of the patients developed resistance to ALT treatment. Phenotype analysis revealed that 97% of the 23,000/mm3 circulating Sézary cells were CD4+CD52-FLAER-. Clonality analysis showed that CD4+CD52+FLAER+ and CD4+CD52-FLAER–Sézary cell populations expressed identical T cell receptor V-beta chains demonstrating that both cell populations are part of the same initial clone of Sézary cells. At present, one year after the start of ALT treatment, reponses are still observed in both other patients without overgrowth of a CD4+CD52-FLAER–Sézary cells. We conclude that despite presence of small populations of CD52 and GPI negative cells in patients with Sézary Syndrome, all patients respond to treatment with alemtuzumab. CD52 negative, GPI deficient Sézary cells showed high susceptibility to collateral damage during antibody treatment. During treatment intervals, CD52+ cells showed a faster recovery compared to CD52- cells, indicating a lower proliferative potential of the GPI deficient Sézary cells. Although, as shown in one patient, ultimate outgrowth of GPI deficient CD52- sezary cells can occur, the capacity to achieve long term control of both CD52+ and CD52- Sézary cells in several patients offers a rationale for treatment of SS with alemtuzumab, possibly in combination with a low dosed cytotoxic drug Disclosures: Off Label Use: Alemtuzumab for treatment of Sezary Syndrome.

scholarly journals Vesicular Stomatitis Virus Genomic RNA Persists In Vivo in the Absence of Viral Replication

2009 ◽  
Vol 84 (7) ◽  
pp. 3280-3286 ◽  
Author(s):  
Ian D. Simon ◽  
Nico van Rooijen ◽  
John K. Rose
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Viral Replication ◽  
Vesicular Stomatitis Virus ◽  
Genomic Rna ◽  
Intramuscular Inoculation ◽  
Vesicular Stomatitis ◽  
High Level

ABSTRACT Our previous studies using intranasal inoculation of mice with vesicular stomatitis virus (VSV) vaccine vectors showed persistence of vector genomic RNA (gRNA) for at least 60 days in lymph nodes in the absence of detectable infectious virus. Here we show high-level concentration of virus and gRNA in lymph nodes after intramuscular inoculation of mice with attenuated or single-cycle VSV vectors as well as long-term persistence of gRNA in the lymph nodes. To determine if the persistence of gRNA was due to ongoing viral replication, we developed a tagged-primer approach that was critical for detection of VSV mRNA specifically. Our results show that VSV gRNA persists long-term in the lymph nodes while VSV mRNA is present only transiently. Because VSV transcription is required for replication, our results indicate that persistence of gRNA does not result from continuing viral replication. We also performed macrophage depletion studies that are consistent with initial trapping of VSV gRNA largely in lymph node macrophages and subsequent persistence elsewhere in the lymph node.

Drug-induced dyslipoproteinemia: a report of two cases.

1980 ◽  
Vol 26 (1) ◽  
pp. 163-168
Author(s):  
H K Naito ◽  
M C McHenry ◽  
L A Lewis
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Serum Lipoproteins ◽  
Drug Induced ◽  
Drug Induction ◽  
Secondary Form ◽  
Species Specific

Abstract We describe two cases of atypical dyslipoproteinemia due to drug-induction. This secondary form of lipoprotein abnormality is unique because the newly available drug, miconazole, apparently directly delipidated the alpha-lipoproteins in the bloodstream. On closer study we found that the delipidation was caused by the vehicle rather than the fungicide--more specifically, only by the polyethoxylated castor oil in the vehicle. It affects serum lipoproteins both in vitro and in vivo, and the effect is species-specific. In vitro studies indicate that it preferentially delipidates high-density lipoprotein rather than low-density lipoprotein. Because its effects on the serum lipoproteins of rats resemble those on man, and because aortic lesions were produced in rats injected daily (90 mL/L) with this substance, caution is indicated in long-term use of drugs containing this chemical component in the vehicle.

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