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PubMed1991

Transient expression of the CD2 cell surface antigen as a sortable marker to monitor high frequency transfection of human primary B cells.

We have used the T cell surface molecule CD2 gene, expressed from the human cytomegalovirus promoter as a reporter to optimize a transfection system for human primary B cells. The CD2-encoding DNA was transfected into cells by electroporation and transient expression was monitored by flow cytometric analysis. By using our optimal electroporation conditions on activated primary B cells, more than 30% of the resulting viable cells expressed CD2 on the cell surface. Moreover, unactivated primary B cells could also be transfected using this system but subsequent expression of CD2 required cellular activation. Magnetic beads or plastic culture bottles coated with anti-CD2 antibodies have been used to selectively purify transfected cells. The high transfection efficiency combined with the ability to specifically purify transfected cells may allow future studies on specific genes transiently expressed in human primary B cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1983

Crossbreeding channel catfish for improvement of body weight in earthen ponds.

Twelve experiments on intraspecific crossbreeding of channel catfish, Ictalurus punctatus, for improvement of body weight are compared and reviewed. Crossbred fingerlings resulting from matings of unrelated F1 crossbred populations did not show heterotic growth. Crossbreds resulting from pure strain P1 showed an average increase of 10.3 percent in growth above the fastest growing parent strain. Marion female X Kansas male, a crossbred from two rapidly growing domestic strains, was the fastest growing to fingerling size. Average increase in body weight (fingerling to harvest size) by crossbreds was 1.5 percent greater than the fastest growing parent strain. Marion X Kansas, Auburn X Kansas, and Auburn X Uvalde were the fastest growing crossbreds to harvest size (8-13 percent increase in growth rate). Six of nine crossbreds made from Pi generations expressed heterosis above both parent strains for body weight. Eight of nine crossbreds grew better than at least one of their parents. Reciprocal crossbreds did not grow at the same rate. Males and females of a specific strain had different combining abilities with other strains. There was a maternal effect for combining ability. All crossbreds made with Auburn females exhibited heterosis.

Animals↗
PubMed2000

Adoptive immunotherapy using specific cytotoxic T lymphocytes against human lung-cancer-engrafted severe combined immunodeficiency mice.

OBJECTIVE: We studied the ability of human lung-cancer-specific cytotoxic T lymphocytes to suppress the growth of human lung adenocarcinoma (PC-9) engrafted in severe combined immunodeficiency mice. METHODS: PC-9-specific cytotoxic T lymphocytes were generated by multiple stimulation with irradiated PC-9 cells of regional lymph node lymphocytes from lung cancer patients expressing the same human leukocyte antigen-A locus haplotype as PC-9 following expansion due to the administration of immobilized anti cluster of differentiation 3 mAb and interleukin-2. Cytotoxic T lymphocytes showed specific cytotoxicity against PC-9 cells in vitro. Severe combined immunodeficiency mice with a subcutaneous graft of PC-9 were treated with a PC-9-specific cytotoxic T lymphocyte by i.v. injection and/or with interleukin-2 by s.c. injection. RESULTS: Cytotoxic T lymphocyte treatment suppressed PC-9 graft growth significantly an effect, significantly enhanced when combined with interleukin-2 injection. To evaluate the in vivo specificity of anti-PC-9 cytotoxic T lymphocytes, each mouse was subcutaneously inoculated in the right flank with PC-9, and in the left flank with A549 or Sq-1. Cytotoxic T lymphocytes plus interleukin-2 treatment was found to suppress PC-9 growth selectively, but not A549 or Sq-1 growth. CONCLUSIONS: These results provide sufficient rationale for conducting further clinical trials on immunotherapy using cytotoxic T lymphocyte for lung cancer patients.

Adenocarcinoma↗
PubMed1981

Combined high performance liquid chromatography mass spectrometry.

Combined gas chromatography mass spectrometry, because of its ability to provide both high sensitivity and specificity, has become a vital technique for the identification and quantitation of natural and synthetic chemicals in a wide variety of areas. Unfortunately, a very large number of organic compounds are not directly amenable to gas chromatography since they are thermally labile and/or of low volatility. Chemical modification of compounds of interest can assist in some cases, but it is not universally applicable. High performance liquid chromatography has been increasingly utilized for studies of compounds of these types since heat is not usually involved in the analysis. Combined liquid chromatography mass spectrometry would lend a new dimension to these studies, enabling the separating ability of the liquid chromatograph to be combined with the sensitivity and specificity of the mass spectrometer. Approaches to liquid chromatography mass spectrometry are discussed. Using examples from our liquid chromatographic mass spectrometric studies of natural compounds, drugs and pesticides, the current abilities of such systems to identify and quantify natural and synthetic chemicals present in a complex matrix of other chemicals are described.

Carbohydrates↗
PubMed1991

[Work capacity evaluation in inorganic lead exposure].

When estimating the work ability of workers exposed to inorganic lead four zones should be differentiated: a zone of normal exposure (I), a zone of abnormal but acceptable exposure (II), a zone of abnormal but still acceptable exposure (III) and a zone of abnormal and unacceptable exposure (IV). In the zone of normal exposure specific work ability is preserved. In zones of abnormal but acceptable exposure specific work ability can, also, be preserved. However, in the zone of abnormal, unacceptable exposure specific work ability, temporarily or permanently, is lost. Combinations of three relevant laboratory tests are presented, which, while warning of the presence, i.e. the effect, of inorganic lead in the organism, directly dictate the estimation of specific work ability (blood lead, ALAD, EP, ZPP). Attention has been drawn to other contraindications, set by positive legislation, which also directly dictate the estimation of workers exposed to inorganic lead. It is emphasized that permanent disruption of relevant laboratory parameters (blood lead, ALAD, EP, ZPP) is a sufficient basis for recognizing occupational lead poisoning, within positive legislation.

Aminolevulinic Acid↗
PubMed2000

The detection and quantitation of inflammation in the central nervous system during experimental allergic encephalomyelitis using the radiopharmaceutical 99mTc-RP128.

RP128 is a novel agent which readily chelates 99mTc to form a radiopharmaceutical which binds in vivo to the tuftsin receptor located specifically on neutrophils and monocyte-macrophages, therefore removing the need for in vitro cell labelling prior to intravenous administration. We have assessed the ability of 99mTc-RP128 to detect central nervous system (CNS) inflammation in experimental allergic encephalomyelitis (EAE), an animal model of the human disease multiple sclerosis. The radiopharmaceutical was recorded at significantly increased levels in all EAE diseased CNS tissues, compared to normal and control samples, at 0.5, 1 and 3 h post-injection using a dual radioisotope technique to correct for non-extravasated tracer (P<0.05). Moreover, extravascular accumulation of the agent could be clearly demonstrated in inflammatory tissues with minimal loss of sensitivity when the secondary isotopic correction for blood volume was omitted. In addition, 99mTc-RP128 successfully monitored glucocorticoid suppression of inflammation (P<0.05), recording a typical dose-response to increasing steroid concentration. Clearly, 99mTc-RP128 can quantitatively detect CNS inflammation and assess responses to therapy indicating potential value as an imaging agent both clinically and as a research aid. Furthermore, the rapid in vivo labelling by 99mTc-RP128 of specific inflammatory cells combined with the ability to monitor the progress of anti-inflammatory therapeutics may recommend the agent for use in a variety of inflammatory conditions.

Animals↗
PubMed2002

Determination of nitrotyrosine and related compounds in biological specimens by competitive enzyme immunoassay.

A gas mediator, nitric oxide is converted to peroxynitrite in the presence of superoxide anion. Peroxynitrite is a potent oxidant, which injures various tissues and organs by nitration of the tyrosine residues of proteins, and it enhances the late response of inflammation. The determination of nitrated tyrosine, nitrotyrosine, which is a stable final metabolite of peroxynitrite, provides an important indicator of tissue disorders caused by peroxynitrite. This paper reports a competitive solid-phase immunoassay for measuring nitrotyrosine in various biological specimens. In this study, peroxidase-conjugated nitrotyrosine was prepared by reaction of nitrotyrosine with 1,4-benzoquinone treatment, and then it was allowed to compete with nitrotyrosine on an anti-nitrotyrosine antibody-coated 96-well multiplate. No amino acids or related compounds tested in the experiments interfered with the immune reaction of nitrotyrosine, except cysteine, which only slightly inhibited the immune reaction at the concentrations higher than 1000 times the concentration of nitrotyrosine. The limit of detection of free nitrotyrosine was approximately 500 pg/mL (2 nM) at a competition ratio (B/B(o)%) of 80%. The newly developed enzyme immunoassay (EIA) method was used for assay of nitrotyrosine in biological specimens, with the following results: (i) Lipopolysaccharide (LPS) activation of RAW264.7 cells induced a significant increase in nitrotyrosine production compared to that with nonactivated cells. N(omega)-nitro-L-arginine methyl ester decreased nitrotyrosine production with either LPS-activated or nonactivated RAW cells. There is a relationship between nitrotyrosine production and nitrite ion. (ii) The nitrotyrosine level detected in the plasma specimens from healthy volunteers was 35.21 +/- 4.87 ng/mL (135.4 +/- 18.7 nM). (iii) The concentration of nitrotyrosine in the nasal lavage fluid of allergic rhinitis patients was 41.40 +/- 20.96 ng/mL (159.02 +/- 80.6 nM). Thus, the EIA method combines sensitivity and specificity with the ability to process a large number of specimens to quantify nitrotyrosine produced with in vivo and in vitro sources.

Adolescent↗
PubMed2004

Regeneration along intact nerves using nerve growth factor and ciliary neurotrophic factor.

The purpose of this investigation was to evaluate the ability of a specific growth factor combination, nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF), to enhance peripheral nerve regeneration. Eight groups of eight Sprague-Dawley rats underwent repair of a nerve gap defect: Group A (immediate repair), Group B (intact nerve bridge), Group C (nerve autograft), Group D (gap in situ), Group E (NGF + CNTF), Group F (NGF), Group G (CNTF), and Group H (saline). Twelve weeks after surgery, analysis included the measurement of the isometric force of muscle contraction for the tibialis anterior muscle and tissue harvesting for both quantitative and qualitative analysis. When evaluating muscle contraction force, there was no statistically significant difference among the experimental groups receiving a growth factor injection and the normal saline control group. The hypothesis of this study was that peripheral nerve regeneration could be enhanced by the combination of NGF and CNTF. The evidence does not support this hypothesis.

Analysis of Variance↗
PubMed2005

Combinations of polyclonal or monoclonal antibodies to proteins of the outer membranes of the two infectious forms of vaccinia virus protect mice against a lethal respiratory challenge.

Previous studies demonstrated that antibodies to live vaccinia virus infection are needed for optimal protection against orthopoxvirus infection. The present report is the first to compare the protective abilities of individual and combinations of specific polyclonal and monoclonal antibodies that target proteins of the intracellular (IMV) and extracellular (EV) forms of vaccinia virus. The antibodies were directed to one IMV membrane protein, L1, and to two outer EV membrane proteins, A33 and B5. In vitro studies showed that the antibodies to L1 neutralized IMV and that the antibodies to A33 and B5 prevented the spread of EV in liquid medium. Prophylactic administration of individual antibodies to BALB/c mice partially protected them against disease following intranasal challenge with lethal doses of vaccinia virus. Combinations of antibodies, particularly anti-L1 and -A33 or -L1 and -B5, provided enhanced protection when administered 1 day before or 2 days after challenge. Furthermore, the protection was superior to that achieved with pooled immune gamma globulin from human volunteers inoculated with live vaccinia virus. In addition, single injections of anti-L1 plus anti-A33 antibodies greatly delayed the deaths of severe combined immunodeficiency mice challenged with vaccinia virus. These studies suggest that antibodies to two or three viral membrane proteins optimally derived from the outer membranes of IMV and EV, may be beneficial for prophylaxis or therapy of orthopoxvirus infections.

Animals↗
PubMed2005

Repeat-induced point mutation and the population structure of transposable elements in Microbotryum violaceum.

Repeat-induced point mutation (RIP) is a genome defense in fungi that hypermutates repetitive DNA and is suggested to limit the accumulation of transposable elements. The genome of Microbotryum violaceum has a high density of transposable elements compared to other fungi, but there is also evidence of RIP activity. This is the first report of RIP in a basidiomycete and was obtained by sequencing multiple copies of the integrase gene of a copia-type transposable element and the helicase gene of a Helitron-type element. In M. violaceum, the targets for RIP mutations are the cytosine residues of TCG trinucleotide combinations. Although RIP is a linkage-dependent process that tends to increase the variation among repetitive sequences, a chromosome-specific substructuring was observed in the transposable element population. The observed chromosome-specific patterns are not consistent with RIP, but rather suggest an effect of gene conversion, which is also a linkage-dependent process but results in a homogenization of repeated sequences. Particular sequences were found more widely distributed within the genome than expected by chance and may reflect the recently active variants. Therefore, sequence variation of transposable elements in M. violaceum appears to be driven by selection for transposition ability in combination with the context-specific forces of the RIP and gene conversion.

Analysis of Variance↗
PubMed1988

Specific D1 and D2 dopamine agonists have synergistic effects in the 6-hydroxydopamine circling model in the rat.

The effects of SK&F 38393, RU 24213 and quinpirole alone and the synergistic effects of a combination of both subtypes of dopamine agonist on circling behavior were studied in rats with a unilateral lesion of the nigro-striatal pathway. The ability of SCH 23390 and sulpiride to antagonize the synergistic effects induced by SK&F 38393 and RU 24213 in combination were also studied. Finally, the ability of these specific D1 and D2 dopamine antagonists to block the circling induced by two nonspecific dopamine agonists (apomorphine and amphetamine) was investigated. Some animals responded to only one of the selective dopamine agonists but all responded to apomorphine and to the combination of SK&F 38393 plus Ru 24213 or SK&F 38393 plus quinpirole. A powerful synergistic effect was able to antagonize these synergistic effects. The blocking capacity of SCH 23390 and sulpiride was highly diminished in the apomorphine-induced circling model, compared to the amphetamine-induced circling model where normosensitive dopamine receptors are involved. These data suggest an heterogeneous responsiveness to D1, D2D1 plus D2 and mixed D1/D2 dopamine agonists and a strong synergistic effect of the combination of SK&F 38393 plus RU 24213, or SK&F 38393 plus quinpirole. Denervation also induced some changes in the ability of specific dopamine antagonists to block the behavioral response after the administration of non-specific dopamine agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Diagnostic value of transient dilatation of the left ventricle in negative dipyridamole-thallium imaging.

To evaluate the diagnostic value of a transient dilatation of the left ventricle during dipyridamole-thallium imaging (DTI) for detecting significant coronary artery disease (CAD) in patients with negative DTI results, 81 consecutive patients were studied. Twenty one patients (26%) had CAD and 60 patients had normal coronary anatomy (NCA). The initial/delayed ratio of the left ventricular dimension, which was measured as the distance between the 2 peaks of a count profile curve on a 45 degrees left anterior oblique planar image, was defined as the dilatation ratio (DR) of the left ventricle. Patients with CAD had a higher incidence of chest pain after dipyridamole infusion (35 vs 13%; p < 0.05), and ST depression during exercise testing (50 vs 25%; p < 0.05) than those with NCA. DR was significantly greater in CAD patients than in NCA patients (1.08 +/- 0.10 vs 0.97 +/- 0.03; p < 0.0001). DR was considered abnormal (> 1.03) when it was greater than the mean +2 standard deviations of the DR in NCA patients. Seventy-six percent of CAD patients had an abnormal DR. A stepwise discriminant analysis revealed that an abnormal DR alone had the same ability to predict CAD (sensitivity 76%, specificity 98%, chi-square 80.9, p < 0.0001) as the best combination of abnormal DR, chest pain during exercise testing, age and gender (sensitivity 76%, specificity 98%, chi-square 98.5, p < 0.0001). When abnormal DR was excluded from this analysis, the best combination of the variables showed a reduced ability to predict CAD (sensitivity 81%, specificity 77%, Wilks' Lambda 0.71, chi-square 26.7, p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Multiple nuclear regulatory proteins bind a single cis-acting promoter element to control basal transcription of the human alpha 4 integrin gene in corneal epithelial cells.

Expression of the fibronectin-binding integrin alpha 4 beta 1 has been postulated to be an important event in the process of corneal epithelial wound healing. In a previous study, we identified upstream positive and negative cis-acting regulatory elements that are needed to modulate the transcriptional activity of the human alpha 4 integrin subunit gene promoter in primary cultures of rabbit corneal epithelial cells. We have shown that most of the basal activity directed by this promoter was dependent on the presence of a cis-acting DNA sequence designated the alpha 4.1 element, centered at position -45 relative to the human alpha 4 mRNA start site. Here, we demonstrate that five distinct nuclear regulatory proteins (designated Bp1 to Bp5) from rabbit corneal epithelial cells possess the ability to bind the alpha 4.1 element in a specific manner in vitro. However, when they are combined together, only two of them (Bp2 and Bp5) retained their ability to interact with their specific target sequence in in vitro assays. The apparent molecular masses of the Bp1 to Bp5 proteins were determined and found to be of 91, 74, 59, 45, and 39 kD, respectively. Electrophoretic mobility-shift assays (EMSAs) indicated that only Bp2 also possesses the ability to bind the alpha 4.2 element, a site homologous to alpha 4.1 which plays a minor role in alpha 4 gene expression. Despite the presence of three Ets binding sites in the immediate vicinity of alpha 4.1, competition experiments in EMSA clearly indicate that Bp1, Bp2, Bp4, and Bp5 do not belong to the Ets family of transcription factors. Insertion of both alpha 4.1 and alpha 4.2 upstream from the basal promoter of the mouse p12 gene provided evidence that both elements have the ability to modulate basal expression driven from a heterologous promoter. alpha 4.1 was shown to function as an activator, whereas alpha 4.2 acted as a repressor in a manner that is dependent on its orientation, further stressing the critical regulatory function played by these two elements on alpha 4 gene basal expression.

Animals↗
PubMed1998

Synergistic effect of type II phospholipase A2 and platelet-activating factor on Mac-1 surface expression and exocytosis of gelatinase granules in human neutrophils: evidence for the 5-lipoxygenase-dependent mechanism.

Stimulation of human neutrophils with inflammatory mediators such as TNF-alpha or platelet-activating factor (PAF) induces translocation of adhesion molecule Mac-1 (CD11b/CD18) from secretory vesicles to the plasma membrane. Type II phospholipase A2 (PLA2-II) also induces translocation of Mac-1 from secretory vesicles. However, there are more Mac-1 molecules in gelatinase granules and specific granules than in secretory vesicles. Therefore, different combinations of PLA2-II and other mediators were examined for their ability to induce gelatinase granules and specific granules to induce Mac-1 surface expression. The combination of PLA2-II and PAF synergistically increased Mac-1 surface expression, and the effect was greater than the combinations of PLA2-II with TNF-alpha, IL-8, or FMLP. Additionally, the combination of PLA2-II and PAF induced exocytosis of both secretory vesicles and gelatinase granules, which did not occur with either PLA2-II alone or PAF alone. The induction was accompanied by marked production of leukotriene B4. AA861, an inhibitor of 5-lipoxygenase, did not inhibit exocytosis of secretory vesicles but did inhibit exocytosis of gelatinase granules and decrease Mac-1 surface expression. It was also found that Ca2+ influx is essential for 5-lipoxygenase activation, because Ni2+, which blocks the influx of extracellular Ca2+, inhibited the production of leukotriene B4. These results suggest that stimulation by the combination of PLA2-II and PAF, unlike stimulation by each mediator alone, causes exocytosis of gelatinase granules via the 5-lipoxygenase pathway, resulting in a synergistic increase in neutrophil Mac-1 surface expression during inflammatory processes.

Arachidonate 5-Lipoxygenase↗
PubMed1999

Targeting cytokines to tumors to induce active antitumor immune responses by recombinant fusion proteins.

Cytokines such as interleukin-2(IL-2), gamma interferon (IFN-gamma) and alpha tumor necrosis factor (TNF-alpha) are important mediators in immune responses against tumors. However, their therapeutic efficacy and clinical utilities in treatment of human malignancies are in large part limited due to the low concentrations of cytokine in tumors and the severe toxic side-effects derived from high-dose administration of cytokines. One critical issue to improve therapeutic efficacy is how to increase the local concentration of cytokine in tumors without causing severe side-effects. A series of recent reports demonstrated that the introduction of cytokine genes into tumor cells and subsequent local secretion can circumvent the limitations associated with the systemic cytokine administration. An alternative means of cytokine delivery is to target cytokines to tumor cells with tumor specific antibodies. Thereby, effective local cytokine concentrations can be achieved at the tumor sites without resorting to patient-specific therapy. With the advance in biotechnology, two structurally disparate domains of immunoglobulin and cytokine can be brought together into one fusion protein molecule by protein engineering These engineered antibody-cytokine fusion proteins combine the unique targeting ability of tumor-specific antibodies with the multifunctional activity of cytokines. In general, there are two commonly engineered fusion proteins, the F(ab')2/cytokine expressed in mammalian cells and the single-chain FV/cytokine expressed in Escherichia coli. Both the tumor-binding reactivity and the functional cytokine activity are maintained in most of fusion proteins. Therefore, these fusion proteins may be useful in targeting cytokine to tumors to stimulate immune destruction of tumors, while limiting severe toxic side-effects by the high dose of cytokine administration. Recent preclinical studies have shown that these fusion proteins are able to target cytokines to tumors expressing the tumor-associated antigen in vivo, and to inhibit both the primary and metastatic tumors in an immune competent animal model. Therefore, these recombinant fusion proteins may represent a new generation of novel immunotherapeutic reagents for the treatment of human malignant diseases.

Animals↗
PubMed2003

Intracellular phospho-protein staining techniques for flow cytometry: monitoring single cell signaling events.

BACKGROUND: Recent advances in intracellular staining techniques, cytometer technology, fluorescent reagents, and antibody production have expanded the number of intracellular antigens that can be analyzed by flow cytometry. Measurement of protein phosphorylation with phospho-specific antibodies has given insight into kinase signaling cascades. However, available techniques for phospho-epitope staining can differ greatly, making it necessary to understand the differences between the outcomes when such techniques are applied and to develop robust and reproducible methods of application. METHODS: Ten different cellular fixation and permeabilization techniques were tested for their ability to provide phospho-specific staining. Combinations of formaldehyde, methanol, ethanol, acetone, Triton X-100, and saponin were used as fixation and permeabilization reagents. Phospho-specific antibodies were labeled with Alexa Fluor dyes to provide multicolor analysis of different signaling events simultaneously within individual cells. RESULTS: Fixing cells with 1.5% formaldehyde followed by permeabilization in methanol gave optimal results for pERK, pp38, pJNK, pStat1, pStat5, and pStat6 staining. Alteration of formaldehyde fixation and methanol permeabilization times affected measurements of phosphorylation induction. Phospho-specific flow cytometric analyses correlated well with Western blotting, providing cross platform validation of the technique. CONCLUSIONS: Measuring phosphorylation events by flow cytometry provides a rapid and efficient way to measure kinase cascades in individual cells. Stability of phospho-epitopes in methanol allows long-term storage of samples prior to analysis. Multiple signaling cascades can be monitored simultaneously through the use of different fluorophore labels to determine specificity of ligands or inhibitors. Application of optimized techniques to heterogeneous cell types such as peripheral blood or murine splenocytes may allow signaling to be analyzed simultaneously in immune cell subsets.

Antibodies, Monoclonal↗
PubMed2005

Cardiac myocyte differentiation: the Nkx2.5 and Cripto target genes in P19 clone 6 cells.

Genetic evidence has implicated several genes as being critical for the development of cardiomyocytes. Whereas a few of the targets of these genes and the pathways they constitute are known the majority of targets and the interrelationships of the pathways involved still remains largely unknown. The power of high-throughput analytical techniques like microarrays and real-time RT-PCR combined with the ability to selectively silence specific mRNA in model tissue culture systems can begin to fill in these gaps and increase our understanding of the molecular mechanisms of cell commitment and terminal differentiation. We have used microarray analysis and siRNA directed against the cardiac-specific transcription factor Nkx2.5 and one of its targets Cripto in P19 clone 6 (P19Cl6) cells to identify potential targets for these genes. We demonstrate Nkx2.5 affects genes that have been shown to be controlled by the canonical Wnt or TGFbeta/BMP signaling pathways. We also show that Cripto can regulate the critical stem cell gene Nanog and two Oct 4-regulated genes: Dppa2 and 4. Cripto also affects the formation of nitric oxide, a small signaling molecule that has been reported to be important for growth and development of cardiac and smooth muscle. It affects the nitric oxide system by regulating genes that control the levels of nitric oxide synthase mRNA concentration as well as the activation and bioavailability of the protein.

Animals↗
PubMed2004

Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs.

The oral delivery of hydrophobic drugs presents a major challenge because of the low aqueous solubility of such compounds. Self-emulsifying drug delivery systems (SEDDS), which are isotropic mixtures of oils, surfactants, solvents and co-solvents/surfactants, can be used for the design of formulations in order to improve the oral absorption of highly lipophilic drug compounds. SEDDS can be orally administered in soft or hard gelatin capsules and form fine relatively stable oil-in-water (o/w) emulsions upon aqueous dilution owing to the gentle agitation of the gastrointestinal fluids. The efficiency of oral absorption of the drug compound from the SEDDS depends on many formulation-related parameters, such as surfactant concentration, oil/surfactant ratio, polarity of the emulsion, droplet size and charge, all of which in essence determine the self-emulsification ability. Thus, only very specific pharmaceutical excipient combinations will lead to efficient self-emulsifying systems. Although many studies have been carried out, there are few drug products on the pharmaceutical market formulated as SEDDS confirming the difficulty of formulating hydrophobic drug compounds into such formulations. At present, there are four drug products, Sandimmune and Sandimmun Neoral (cyclosporin A), Norvir (ritonavir), and Fortovase (saquinavir) on the pharmaceutical market, the active compounds of which have been formulated into specific SEDDS. Significant improvement in the oral bioavailability of these drug compounds has been demonstrated for each case. The fact that almost 40% of the new drug compounds are hydrophobic in nature implies that studies with SEDDS will continue, and more drug compounds formulated as SEDDS will reach the pharmaceutical market in the future.

Administration, Oral↗