Pharmacokinetics, tissue distribution and immunomodulatory effect of intralipid formulation of nystatin in mice.
ABSTRACT We developed a novel lipid formulation of nystatin suitable for parenteral administration, nystatin-intralipid (NYT-IL), with antifungal activity and reduced toxicity in mice. We investigated the pharmacokinetics, tissue distribution and immunomodulatory effect of NYT-IL in mice.
Nystatin levels in serum and organs were determined using HPLC after NYT-IL or nystatin administration in mice. The levels of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) and the anti-inflammatory cytokine interleukin 10 (IL-10) produced by splenocytes from mice injected with NYT-IL or nystatin were evaluated by an ELISA assay.
Injection of NYT-IL resulted in similar levels and similar kinetics of nystatin in serum, higher concentrations in the liver and lower concentrations in the kidneys, in comparison with nystatin injection. Injection of mice with NYT-IL yielded higher levels of IL-10 than that of nystatin, whereas the levels of TNF-α and IFN-γ induced by NYT-IL were lower than those elicited by nystatin.
Since polyene treatment is associated with nephrotoxicity, lower levels of nystatin in the kidneys following NYT-IL injection suggest the possibility of reduced toxicity. As the acute infusion-related adverse effects associated with polyene treatment are considered to be induced by pro-inflammatory cytokines, a higher level of anti-inflammatory and lower levels of pro-inflammatory cytokines elicited by NYT-IL administration suggest the possibility of amelioration of such effects. In summary, the altered pharmacokinetics, tissue distribution and immune response due to the use of this intralipid formulation of nystatin merit further research towards the development of a therapeutic agent against invasive mycoses.
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ABSTRACT: The purpose of this study was to analyze the usage of amphotericin B desoxycholate in a small community hospital, with special emphasis on its side effects and need for premedication. We performed a retrospective chart review for patients who received intravenous amphotericin B from January 1993 to May 1996. Temperature elevation, clinical symptoms during infusion, need for premedication, and fluctuations in serum potassium and creatinine values were especially noted. Statistical analysis showed that toxicity indicated by laboratory values (laboratory toxicity) increased with increasing amphotericin B dose, but clinical side-effects decreased with advancing age. Clinical side effects were not associated with total amphotericin B dosage; laboratory toxicity in our study was not more prevalent in elderly patients. The main finding of this study was that most patients tolerate amphotericin B well and only 23% of patients needed premedication. Our fungal cure rate was 83%. New, expensive preparations of amphotericin B should be reserved for the small subset of patients who either are intolerant of amphotericin B desoxycholate or need high doses for systemic fungal infections.Clinical Infectious Diseases 02/1998; 26(2):334-8. · 9.37 Impact Factor
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ABSTRACT: The aim of this study was to investigate whether apoptosis contributes to nephrotoxicity caused by amphotericin B (AmB). By detecting apoptosis-specific DNA fragmentation, it is demonstrated that proximal tubular cells (LLC-PK(1)) and medullary interstitial cells (RMIC) respond with programmed cell death when treated with therapeutic doses of AmB. Concomitant application of AmB and recombinant human insulin-like growth factor-1 (rhIGF-1), a known antiapoptotic agent, abrogated apoptosis in vitro. To validate that the observed apoptotic effects on renal tissue culture cells are applicable to an in vivo setting, an animal model was used for verification. Therefore, Sprague-Dawley rats were treated with AmB. The drug caused hypokalemia, decreased weight gain, loss of renal concentrating ability, and dehydration in a dose-dependent fashion. Microscopic examination of renal tissue sections revealed apoptotic alterations predominantly in proximal and distal tubular epithelial cells. To verify that the observed clinical side effects were linked to apoptosis, rhIGF-1 was applied concomitantly with AmB. In all animals, rhIGF-1 prevented the above-mentioned clinical side effects. Moreover, significantly reduced apoptosis was observed in renal tissue sections of these animals, indicating the relevance of apoptosis in nephrotoxicity. This is the first report to demonstrate that AmB induces apoptosis in the rat kidney in a dose-dependent fashion. The incidence of apoptosis correlates with renal toxicity and can be abrogated by concomitant treatment with rhIGF-1.Antimicrobial Agents and Chemotherapy 04/2001; 45(3):679-85. · 4.57 Impact Factor
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ABSTRACT: Amphotericin B (AMB) intralipid (IL) admixtures (AMB-IL) are composed of components approved for clinical use and are commercially available at low cost. They are stable and exhibit in-vitro and in-vivo efficacy against Candida infections, as well as resulting in significantly reduced toxicity in comparison with that of conventionally administered amphotericin B. We examined the production of cytokines in uninfected mice treated with AMB or AMB-IL, as evaluated by expression of mRNA corresponding to the cytokines. Expression was measured by intensity of bands in comparison to the intensity of beta-actin control bands, with the latter assigned an arbitrary standard value of 100% and other bands measured in relative percentages. We found that both in naive and compromised mice, AMB treatment caused significantly greater production of the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and interleukin 1 beta (IL-1beta) than was seen in animals treated with AMB-IL or with another lipid AMB formulation, AmBisome. We hypothesize that the superior tolerance for the AMB-IL admixtures, as compared with conventional AMB, might derive from the reduced expression of the pro-inflammatory cytokines. TNF-alpha and IL-1beta, which mediate many potentially adverse pathophysiological events similar to those seen as side-effects of AMB usage.Medical Mycology 05/2004; 42(2):123-8. · 1.98 Impact Factor
Intralipid and the Immune system
Joseph Eldor, MD
J Antimicrob Chemother. 2012 Jul;67(7):1716-21. Epub 2012 Apr 11.
Pharmacokinetics, tissue distribution and
immunomodulatory effect of intralipid formulation of
nystatin in mice.
Semis R, Nili SS, Munitz A, Zaslavsky Z, Polacheck I, Segal E.
Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel-Aviv University, Tel-
We developed a novel lipid formulation of nystatin suitable for parenteral administration,
nystatin-intralipid (NYT-IL), with antifungal activity and reduced toxicity in mice. We
investigated the pharmacokinetics, tissue distribution and immunomodulatory effect of NYT-IL
Nystatin levels in serum and organs were determined using HPLC after NYT-IL or nystatin
administration in mice. The levels of the pro-inflammatory cytokines tumour necrosis factor-α
(TNF-α) and interferon-γ (IFN-γ) and the anti-inflammatory cytokine interleukin 10 (IL-10)
produced by splenocytes from mice injected with NYT-IL or nystatin were evaluated by an
Injection of NYT-IL resulted in similar levels and similar kinetics of nystatin in serum, higher
concentrations in the liver and lower concentrations in the kidneys, in comparison with
nystatin injection. Injection of mice with NYT-IL yielded higher levels of IL-10 than that of
nystatin, whereas the levels of TNF-α and IFN-γ induced by NYT-IL were lower than those
elicited by nystatin.
Since polyene treatment is associated with nephrotoxicity, lower levels of nystatin in the
kidneys following NYT-IL injection suggest the possibility of reduced toxicity. As the acute
infusion-related adverse effects associated with polyene treatment are considered to be
induced by pro-inflammatory cytokines, a higher level of anti-inflammatory and lower levels of
pro-inflammatory cytokines elicited by NYT-IL administration suggest the possibility of
amelioration of such effects. In summary, the altered pharmacokinetics, tissue distribution
and immune response due to the use of this intralipid formulation of nystatin merit further
research towards the development of a therapeutic agent against invasive mycoses.
Crit Care Med. 2012 Jun;40(6):1792-8.
A double-blind, randomized clinical trial comparing
soybean oil-based versus olive oil-based lipid
emulsions in adult medical-surgical intensive care
unit patients requiring parenteral nutrition.
Umpierrez GE, Spiegelman R, Zhao V, Smiley DD, Pinzon I, Griffith DP, Peng L, Morris T, Luo
M, Garcia H, Thomas C, Newton CA, Ziegler TR.
Department of Medicine, Emory University, Atlanta, GA, USA. firstname.lastname@example.org
Parenteral nutrition has been associated with metabolic and infectious complications in
intensive care unit patients. The underlying mechanism for the high risk of complications is
not known but may relate to the proinflammatory effects of soybean oil-based lipid emulsions,
the only Food and Drug Administration-approved lipid formulation for clinical use.
Prospective, double-blind, randomized, controlled trial.
Medical-surgical intensive care units from a major urban teaching hospital and a tertiary
referral university hospital.
Adult medical-surgical intensive care unit patients.
Parenteral nutrition containing soybean oil-based (Intralipid) or olive oil-based (ClinOleic) lipid
Differences in hospital clinical outcomes (nosocomial infections and noninfectious
complications), hospital length of stay, glycemic control, inflammatory and oxidative stress
markers, and granulocyte and monocyte functions between study groups.
A total of 100 patients were randomized to either soybean oil-based parenteral nutrition or
olive oil-based parenteral nutrition for up to 28 days. A total of 49 patients received soybean
oil-based parenteral nutrition (age 51 ± 15 yrs, body mass index 27 ± 6 kg/m2, and Acute
Physiology and Chronic Health Evaluation II score 15.5 ± 7 [±SD]), and a total of 51 patients
received olive oil-based lipid emulsion in parenteral nutrition (age 46 ± 19 yrs, body mass
index 27 ± 8 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.1 ± 6
[±SD]) for a mean duration of 12.9 ± 8 days. The mean hospital blood glucose concentration
during parenteral nutrition was 129 ± 14 mg/dL, without differences between groups. Patients
treated with soybean oil-based and olive oil-based parenteral nutrition had a similar length of
stay (47 ± 47 days and 41 ± 36 days, p = .49), mortality (16.3% and 9.8%, p = .38),
nosocomial infections (43% vs. 57%, p = .16), and acute renal failure (26% vs. 18%, p = .34).
In addition, there were no differences in inflammatory and oxidative stress markers or in
granulocyte and monocyte functions between groups.
The administration of parenteral nutrition containing soybean oil-based and olive oil-based
lipid emulsion resulted in similar rates of infectious and noninfectious complications and no
differences in glycemic control, inflammatory and oxidative stress markers,
and immunefunction in critically ill adults.
Am J Physiol Gastrointest Liver Physiol. 2012 Jun 1;302(11):G1292-300. Epub 2012 Mar 29.
Activation of rat intestinal mucosal mast cells by fat
Ji Y, Sakata Y, Yang Q, Li X, Xu M, Yoder S, Langhans W, Tso P.
Dept. of Pathology and Laboratory Medicine, Univ. of Cincinnati College of Medicine, 2120 E. Galbraith Road,
Bldg. A, Cincinnati, Ohio 45237. email@example.com.
Previous studies have linked certain types of gut mucosal immune cells with fat intake. We
determined whether fat absorption activates intestinal mucosal mast cells (MMC), a key
component of the gut mucosal immune system. Conscious intestinal lymph fistula rats were
used. The mesenteric lymph ducts were cannulated, and the intraduodenal (i.d.) tubes were
installed for the infusion of Liposyn II 20% (an intralipid emulsion). Lymphatic concentrations
of histamine, rat MMC protease II (RMCPII), a specific marker of rat intestinal MMC
degranulation, and prostaglandin D(2) (PGD(2)) were measured by ELISA. Intestinal MMC
degranulation was visualized by immunofluorescent microscopy of jejunum sections taken at
1 h after Liposyn II gavage. Intraduodenal bolus infusion of Liposyn II 20% (4.4 kcal/3 ml)
induced approximately a onefold increase in lymphatic histamine and PGD(2), ?20-fold
increase in lymphatic RMCPII, but only onefold increase in peripheral serum RMCPII
concentrations. Release of RMCPII into lymph increased dose dependently with the amount
of lipid fed. In addition, i.d. infusion of long-chain triacylglycerol trilinolein (C18:2 n-6, the
major composite in Liposyn II) significantly increased the lymphatic RMCPII concentration,
whereas medium-chain triacylglycerol tricaprylin (C8:0) did not alter lymph RMCPII secretion.
Immunohistochemistry image revealed the degranulation of MMC into lamina propria after
lipid feeding. These novel findings indicate that intestinal MMC are activated and degranulate
to release MMC mediators to the circulation during fat absorption. This action of fatty acid is
dose and chain length dependent.
J Reprod Immunol. 2012 Jan;93(1):38-40. Epub 2011 Dec 21.
Intralipid therapy for recurrent implantation failure:
new hope or false dawn?
Shreeve N, Sadek K.
School of Biomedical Sciences, King's College London, Guy's Campus, London SE1 1UL, UK.
Recurrent embryo implantation failure (RIF) is a disorder with potentially devastating
physiological and psychological manifestations for those affected. Although its prevalence is
not uncommon, many of the mechanisms involved still require elucidation. Both organ-specific
and systemic autoimmunity are associated with an increased prevalence of recurrent
miscarriage and reproductive failure, rendering the role of the maternal immunological system
in fertility a key concept. It is believed by some that central to this theme is the maternal
cytokine profile, with particularly T-helper (Th) cells. Immune modulating therapies have
therefore been mooted as potential therapeutic strategies. Recent reports of high pregnancy
rates achievable in women with RIF have added fuel to the debate regarding the
effectiveness of intralipid in modulating the immunesystem. We would like to assess if there is
sufficient current evidence of acceptable quality to permit an assumption that intralipid therapy
is an effective treatment for women undergoing repeated assisted reproduction cycles. We
have concluded that appropriately controlled, large-scale, confirmatory studies are necessary
to prove the efficacy of intralipid before it can be recommended for routine use.
J Clin Endocrinol Metab. 2011 Oct;96(10):3207-16. Epub 2011 Aug 10.
Substitution of standard soybean oil with olive oil-
based lipid emulsion in parenteral nutrition:
comparison of vascular, metabolic, and
Siqueira J, Smiley D, Newton C, Le NA, Gosmanov AR, Spiegelman R, Peng L, Osteen SJ, Jones
DP,Quyyumi AA, Ziegler TR, Umpierrez GE.
Department of Medicine, Emory University, Atlanta, Georgia 30303, USA.
Soybean oil-based lipid emulsions are the only Food and Drug Administration-approved lipid
formulation for clinical use in parenteral nutrition (PN). Recently concerns with its use have
been raised due to the proinflammatory effects that may lead to increased complications
because they are rich in ω-6 polyunsaturated fatty acids.
This was a prospective, randomized, controlled, crossover study comparing the vascular,
metabolic, immune, and inflammatory effects of 24-h infusion of PN containing soybean oil-
based lipid emulsion (Intralipid), olive oil-based (ClinOleic), lipid free, and normal saline in 12
Soybean oil-PN increased systolic blood pressure compared with olive oil-PN (P < 0.05).
Soybean oil PN reduced brachial artery flow-mediated dilatation from baseline (-23% at 4 h
and -25% at 24 h, both P < 0.01); in contrast, olive oil PN, lipid free PN, and saline did not
change either systolic blood pressure or flow-mediated dilatation. Compared with saline,
soybean oil PN, olive oil PN, and lipid free PN similarly increased glucose and insulin
concentrations during infusion (P < 0.05). There were no significant changes in plasma free
fatty acids, lipid profile, inflammatory and oxidative stress markers, immune function
parameters, or sympathetic activity between soybean oil- and olive oil-based lipid emulsions.
The 24-h infusion of PN containing soybean oil-based lipid emulsion increased blood
pressure and impaired endothelial function compared with PN containing olive oil-based lipid
emulsion and lipid-free PN in healthy subjects. These vascular changes may have significant
implications in worsening outcome in subjects receiving nutrition support. Randomized
controlled trials with relevant clinical outcome measures are needed in patients receiving PN
with olive oil-based and soybean oil-based lipid emulsions.
J Orthop Trauma. 2011 Aug;25(8):511-5.
Androstenediol exerts salutary effects on
chemokine response after trauma-hemorrhage and
sepsis in mice.
Brunnemer U, Zeckey C, Hildebrand F, Frink M, Mommsen P, van Griensven M, Andruszkow
H, Krettek C,Barkhausen T.
Trauma Department, Hannover Medical School, Hannover, Germany.
The pathogenesis of multiple organ dysfunction syndrome and sepsis after polytrauma is
related to the posttraumatic immune response and the associated release of inflammatory
mediators. There exists a gender dimorphism in the posttraumatic host response. Sex
steroids are believed to beneficially modulate the posttraumatic immune response. The
specific effect of androstenediol on chemokines after trauma is unknown. We investigated
whether the application of androstenediol has an effect on plasma chemokine levels and the
associated remote organ damage in a two-hit mouse-model of trauma-hemorrhage, cecal
ligation, and cecal puncture.
MATERIALS AND METHODS:
Traumatic hemorrhage was induced followed by androstenediol application and volume
resuscitation. Thereafter, androstenediol was given once daily in combination with a vehicle
(Intralipid). The control group was injected with a solution containing only the vehicle at the
same time points as the treatment groups' androstenediol applications. Sepsis was induced
by cecal ligation and cecal puncture 48 hours afterward. Four hours after cecal ligation and
cecal puncture, plasma measurements of chemokines were performed. Pulmonary infiltration
by polymorphonuclear lymphocytes was measured by immunhistochemical staining and
myeloperoxidase measurements were taken.
Application of androstenediol led to significantly decreased monocyte chemoattractant
protein-1, monocyte chemoattractant protein-3, macrophage inflammatory protein-1α, and
macrophage inflammatory protein-1β levels compared with the control animals after trauma-
hemorrhage, cecal ligation, and cecal puncture (P < 0.05). Pulmonary infiltration and
myeloperoxidase activity were significantly decreased in androstenediol-treated animals (P <
Androstenediol modulates the immune response after trauma-hemorrhage, cecal ligation, and
cecal puncture by reducing systemic chemokine levels, which are known to
directimmune cells into the tissue possibly leading to organ damage. Androstenediol
represents a potential therapeutic agent after major trauma in high-risk patients.
Clin Exp Obstet Gynecol. 2010;37(2):81-3.
A practical approach to the prevention of
miscarriage: Part 3--Passive immunotherapy.
To evaluate the efficacy of passive immunotherapy in preventing miscarriage.