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PubMed2004

Transforming growth factor-beta 1 release from oligo(poly(ethylene glycol) fumarate) hydrogels in conditions that model the cartilage wound healing environment.

This research demonstrates that controlled material degradation and transforming growth factor-beta1 (TGF-beta1) release can be achieved by encapsulation of TGF-beta1-loaded gelatin microparticles within the biodegradable polymer oligo(poly(ethylene glycol) fumarate) (OPF), so that these microparticles function as both a digestible porogen and a delivery vehicle. Release studies performed with non-encapsulated microparticles confirmed that at normal physiological pH, TGF-beta1 complexes with acidic gelatin, resulting in slow release rates. At pH 4.0, this complexation no longer persists, and TGF-beta1 release is enhanced. However, by encapsulating TGF-beta1-loaded microparticles in a network of OPF, release at either pH can be diffusionally controlled. For instance, after 28 days of incubation at pH 4.0, final cumulative release from non-encapsulated microparticles crosslinked in 10 and 40 mM glutaraldehyde (GA) was 75.4+/-1.6% and 76.6+/-1.1%, respectively. However, when either microparticle formulation was encapsulated in an OPF hydrogel (noted as OPF-10 mM and OPF-40 mM, respectively), these values were reduced to 44.7+/-14.6% and 47.4+/-4.7%. More interestingly, release studies, in conditions that model the expected collagenase concentration of injured cartilage, demonstrated that by altering the microparticle crosslinking extent and loading within OPF hydrogels, TGF-beta1 release, composite swelling, and polymer loss could be systematically altered. Composites encapsulating less crosslinked microparticles (OPF-10 mM) exhibited 100% release after only 18 days and were completely degraded by day 24 in collagenase-containing phosphate-buffered saline (PBS). Hydrogels encapsulating 40 mM GA microparticles did not exhibit 100% release or polymer loss until day 28. Hydrogels with no microparticle component demonstrated only 79.3+/-9.2% release and 89.2+/-3.4% polymer loss after 28 days in enzyme-containing PBS. Accordingly, these studies confirm that the rate of TGF-beta1 release and material degradation can be controlled by altering key parameters of these novel, in situ crosslinkable biomaterials, so that TGF-beta1 release and scaffold degradation may be tailored to optimize cartilage repair.

Cartilage↗
PubMed2005

Dual growth factor delivery from degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds for cartilage tissue engineering.

This work describes the development of a non-invasive means of simultaneously delivering insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta1 (TGF-beta1) to injured cartilage tissue in a controlled manner. This novel delivery technology employs the water-soluble polymer, oligo(poly(ethylene glycol) fumarate) (OPF), in the fabrication of biodegradable hydrogels which encapsulate gelatin microparticles. Release studies first examined the effect of gelatin isoelectric point (IEP) and crosslinking extent on IGF-1 release from these microparticles. In the presence of collagenase, highly crosslinked, acidic gelatin (IEP=5.0) provided sustained release of IGF-1, 95.2+/-2.9% cumulative release at day 28, while less crosslinked microparticles and microparticles of alternate IEP exhibited similar release values after only 6 days. Encapsulation of these highly crosslinked microparticles in a network of OPF provided a means to further control release, reducing final cumulative release to 70.2+/-4.7% in collagenase-containing PBS. Final release values from OPF-gelatin microparticle composites could be altered by incorporating less crosslinked, non-loaded microparticles within these constructs. Finally, this technology was extended to the dual delivery of IGF-1 and TGF-beta1 by loading these growth factors into either the OPF hydrogel phase or gelatin microparticle phase of composites. Release profiles were successfully manipulated by altering the phase of growth factor loading and microparticle crosslinking extent. For instance, by loading TGF-beta1 into the gelatin microparticle phase, a burst release of 10.8+/-0.7% was achieved, while loading this growth factor into the OPF hydrogel phase resulted in a burst release of 25.2+/-1.5%. With either system, simultaneous, slow release of IGF-1 over a 4-week period was accomplished by selectively loading this protein into highly crosslinked, encapsulated microparticles. These results demonstrate the utility of these systems in future studies to assess the interplay and time course of multiple growth factors in cartilage repair.

Cartilage↗
PubMed2005

In vitro release of plasmid DNA from oligo(poly(ethylene glycol) fumarate) hydrogels.

This research investigates the release of plasmid DNA in vitro from novel, injectable hydrogels based on the polymer oligo(poly(ethylene glycol) fumarate) (OPF). These biodegradable hydrogels can be crosslinked under physiological conditions to physically entrap plasmid DNA. The DNA release kinetics were characterized fluorescently with the PicoGreen and OliGreen Reagents as well as through the use of radiolabeled plasmid. Further, the ability of the released DNA to be expressed was assessed through bacterial transformations. It was found that plasmid DNA can be released in a sustained, linear fashion over the course of 45-62 days, with the release kinetics depending upon the molecular weight of the poly(ethylene glycol) from which the OPF was synthesized. Two formulations of OPF were synthesized from poly(ethylene glycol) of a nominal molecular weight of either 3.35K (termed OPF 3K) or 10K (termed OPF 10K). By the time the gels had completely degraded, 97.8+/-0.3% of the initially loaded DNA was recovered from OPF 3K hydrogels, with 80.8+/-1.9% of the initial DNA retaining its double-stranded form. Likewise, for OPF 10K gels, 92.1+/-4.3% of the initially loaded DNA was recovered upon complete degradation of the gels, with 81.6+/-3.8% of the initial DNA retaining double-stranded form. Experiments suggest that the release of plasmid DNA from OPF hydrogels is dominated by the degradation of the gels. Bacterial transformation results indicated that the DNA retained bioactivity over the course of 42 days of release. Thus, these studies demonstrate the potential of OPF hydrogels in controlled gene delivery applications.

Biocompatible Materials↗
PubMed2005

In vivo release of plasmid DNA from composites of oligo(poly(ethylene glycol)fumarate) and cationized gelatin microspheres.

Composites of cationized gelatin microspheres (CGMS), crosslinked with either 3 mM or 6 mM glutaraldehyde solution, and a novel hydrogel material, oligo(poly(ethylene glycol)fumarate) (OPF) were fabricated and investigated toward prolonging the release of plasmid DNA in vivo relative to the constituent materials. The composites and constituent materials were investigated in a subcutaneous murine model to assess the release of 125I-labeled plasmid DNA and 125I-labeled cationized gelatin in vivo. The time profiles of the radioactivity remaining were employed to compare the profiles of DNA release and cationized gelatin degradation. Both composite formulations (incorporating either 3 mM or 6 mM CGMS) prolonged the bioavailability of plasmid DNA relative to both injected plasmid DNA solution and the respective non-embedded cationized gelatin microspheres. Injected plasmid DNA solution persisted in the subject for only 7-10 days, whereas the persistence of DNA from composites of OPF and either 3 mM or 6 mM CGMS extended to at least day 42. The 3 mM and 6 mM CGMS each increased the persistence of DNA slightly, relative to injection of DNA solution, to between 28 and 35 days. Interestingly, the release profile of plasmid DNA from composites was not significantly different from the release of DNA from OPF alone. The release of plasmid DNA from the composites was in accord with the degradation of the microspheres within the OPF. These results show that composites of OPF and cationized gelatin microspheres are able to prolong the availability of plasmid DNA in vivo relative to cationized gelatin microspheres alone and provide a promising candidate material for the sustained, controlled release of plasmid DNA.

Cations↗
PubMed2005

The fumarate sensor DcuS: progress in rapid protein fold elucidation by combining protein structure prediction methods with NMR spectroscopy.

We illustrate how moderate resolution protein structures can be rapidly obtained by interlinking computational prediction methodologies with un- or partially assigned NMR data. To facilitate the application of our recently described method of ranking and subsequent refining alternative structural models using unassigned NMR data [Proc. Natl. Acad. Sci. USA 100 (2003) 15404] for such "structural genomics"-type experiments it is combined with protein models from several prediction techniques, enhanced to utilize partial assignments, and applied on a protein with an unknown structure and fold. From the original NMR spectra obtained for the 140 residue fumarate sensor DcuS, 1100 1H, 13C, and 15N chemical shift signals, 3000 1H-1H NOESY cross peak intensities, and 209 backbone residual dipolar couplings were extracted and used to rank models produced by de novo structure prediction and comparative modeling methods. The ranking proceeds in two steps: first, an optimal assignment of the NMR peaks to atoms is found for each model independently, and second, the models are ranked based on the consistency between the NMR data and the model assuming these optimal assignments. The low-resolution model selected using this ranking procedure had the correct overall fold and a global backbone RMSD of 6.0 angstrom, and was subsequently refined to 3.7 angstrom RMSD. With the incorporation of a small number of NOE and residual dipolar coupling constraints available very early in the traditional spectral assignment process, a model with an RMSD of 2.8 angstrom could rapidly be built. The ability to generate moderate resolution models within days of NMR data collection should facilitate large scale NMR structure determination efforts.

Algorithms↗
PubMed2002

Succinate dehydrogenase and fumarate reductase from Escherichia coli.

Succinate-ubiquinone oxidoreductase (SQR) as part of the trichloroacetic acid cycle and menaquinol-fumarate oxidoreductase (QFR) used for anaerobic respiration by Escherichia coli are structurally and functionally related membrane-bound enzyme complexes. Each enzyme complex is composed of four distinct subunits. The recent solution of the X-ray structure of QFR has provided new insights into the function of these enzymes. Both enzyme complexes contain a catalytic domain composed of a subunit with a covalently bound flavin cofactor, the dicarboxylate binding site, and an iron-sulfur subunit which contains three distinct iron-sulfur clusters. The catalytic domain is bound to the cytoplasmic membrane by two hydrophobic membrane anchor subunits that also form the site(s) for interaction with quinones. The membrane domain of E. coli SQR is also the site where the heme b556 is located. The structure and function of SQR and QFR are briefly summarized in this communication and the similarities and differences in the membrane domain of the two enzymes are discussed.

Binding Sites↗
PubMed1991

The structure of the dihaem cytochrome b of fumarate reductase in Wolinella succinogenes: circular dichroism and sequence analysis studies.

The fumarate reductase from Wolinella succinogenes contains two haem groups with markedly different midpoint potentials (-20 mV and -200 mV). The enzyme is made up of three subunits, the lipophilic one of which (cytochrome b) ligates the haems. Circular dichroism (CD) spectroscopy has been applied to the reductase in order to obtain information on the structure of the haems and of their environment. This approach is integrated with amino acid sequence comparison of the cytochrome b with other quinone-reacting membrane haemoproteins for predicting the axial ligands of the haems as well as their location relative to the membrane. The following results have been obtained: (1) the CD spectra in the Soret region show exciton coupling indicating haem-haem interaction, which is particularly evident in the reduced state and disappears upon denaturation of the enzyme; (2) The apoprotein of cytochrome b is predicted to consist of five hydrophobic helices (helices A-D and cd), four of which should span the membrane. Helices A, B, C and cd contain a histidine residue each which possibly forms one of the ligands of the haems. It is proposed that haem b (-20 mV) is ligated by H44 and H93, and haem b (-200 mV) by H143 and H182.

Amino Acid Sequence↗
PubMed1998

Effect of 1,1-dimethyl-2-[2-morpholinophenyl]guanidine fumarate on pancreatic islet function.

The modality of the insulinotropic action of 1,1-dimethyl-2-[2-morpholinophenyl]guanidine fumarate (BTS 67 582), a new antidiabetic agent, was investigated in rat pancreatic islets. At a 0.1 mM concentration, which was sufficient to cause a close-to-maximal secretory response, BTS 67 582 failed to affect the utilization and oxidation of exogenous D-glucose, but slightly augmented 14CO2 production from islets prelabelled with either L-[U-14C]glutamine or [U-14C]palmitate. BTS 67 582 (0.1 mM) also failed to affect biosynthetic activity in islets incubated with L-[4-3H]phenylalanine. It augmented insulin release from islets incubated for 90 min in the absence or presence of D-glucose (2.8 to 16.7 mM), this coinciding with stimulation of 45Ca net uptake. In perifused islets deprived of extracellular D-glucose for 45 min, BTS 67 582 (0.1 mM) decreased 86Rb outflow from prelabelled islets, but failed to increase 45Ca efflux and insulin release. In the presence of D-glucose (7.0 mM), BTS 67 582, whilst failing to decrease 86Rb+ outflow, provoked rapid, sustained and rapidly reversible increases of both 45Ca2+ efflux and insulin output. The latter increases were attenuated, but not totally suppressed, in the absence of extracellular Ca2+. BTS 67 582 (0.1 mM) suppressed the inhibitory action of diazoxide (0.25 mM) upon glucose-stimulated insulin release, but nevertheless augmented insulin output from islets incubated in the presence of 90 mM K+. These findings support the view that the insulinotropic action of BTS 67 582 is mainly attributable to the inactivation of ATP-sensitive K+ channels. An intracellular redistribution of Ca2+ ions may also participate, however, to the islet functional response to BTS 67 582.

Animals↗
PubMed2003

Is a Q-cycle-like mechanism operative in dihaemic succinate:quinone and quinol:fumarate oxidoreductases?

Succinate:quinone (SQR) and quinol:fumarate oxidoreductases (QFR) are members of the same enzyme family. These are membrane bound enzymes anchored to the membrane by one or two subunits that may contain two, one or no haems. For the dihaemic enzymes the electron pathway from the flavin at the catalytic centre to the quinones remains to be established. Taking into account that the two haems are located on opposite sites of the membrane, and the possible presence of two quinone binding sites, also located on opposite sides of the membrane, we re-hypothesise the presence of a Q-cycle type mechanism in these enzymes. Such a mechanism can explain an active functional role for two haems and two quinone binding sites, allowing SQR to conserve energy. With this testable hypothesis we intend to challenge the discussion and drive further experimentation to unravel the functional mechanism of SQRs and QFRs.

Amino Acid Sequence↗
PubMed2003

Wolinella succinogenes quinol:fumarate reductase and its comparison to E. coli succinate:quinone reductase.

The three-dimensional structure of Wolinella succinogenes quinol:fumarate reductase (QFR), a dihaem-containing member of the superfamily of succinate:quinone oxidoreductases (SQOR), has been determined at 2.2 A resolution by X-ray crystallography [Lancaster et al., Nature 402 (1999) 377-385]. The structure and mechanism of W. succinogenes QFR and their relevance to the SQOR superfamily have recently been reviewed [Lancaster, Adv. Protein Chem. 63 (2003) 131-149]. Here, a comparison is presented of W. succinogenes QFR to the recently determined structure of the mono-haem containing succinate:quinone reductase from Escherichia coli [Yankovskaya et al., Science 299 (2003) 700-704]. In spite of differences in polypeptide and haem composition, the overall topology of the membrane anchors and their relative orientation to the conserved hydrophilic subunits is strikingly similar. A major difference is the lack of any evidence for a 'proximal' quinone site, close to the hydrophilic subunits, in W. succinogenes QFR.

Amino Acid Sequence↗
PubMed2002

Antiplatelet activity of semotiadil fumarate.

Calcium antagonists are known to exert antiplatelet activity. Semotiadil fumarate (SD-3211), a new benzothiazine, was therefore examined for its antiplatelet activity. The inhibitory activity on adenosine diphosphate (ADP)-, collagen-, arachidonic acid (AA)-, and platelet activating factor (PAF)-induced platelet aggregation after the 1-, 30-, 60- and 120-min incubation at concentrations ranging from 1 x 10(-3), 1 x 10(-4), 1 x 10(-5), 1 x 10(-6) and 1 x 10(-7) was examined. The data were compared with those using diltiazem, nifedipine and amlodipine under identical conditions in blood from eight healthy volunteers (four males, four females; aged 23-36 years) and eight hypertensive patients (four males, four females; aged 31-46 years). Semotiadil showed a dose-dependent inhibition of platelet aggregation in vitro with all the agents examined. Using the various aggregation-inducing agents, the dose-dependent inhibitory action was comparable for all the compounds tested. The antiaggregatory potency was in the order diltiazem, semotiadil, amlodipine and nifedipine. The incubation period did not significantly affect the antiaggregatory effect. No difference between platelets derived from healthy volunteers and hypertensive patients was noted. These findings indicate potent antiplatelet activity of the new calcium antagonist semotiadil.

Adenosine Diphosphate↗
PubMed2000

A comparison of the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival antigen challenge model.

OBJECTIVE: The purpose of this study was to compare the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival antigen challenge model. METHODS: This was a prospective, randomized, double-masked, contralaterally controlled, single-center, antigen challenge study. Of the 53 subjects screened, 32 were enrolled and completed the study. The study comprised 3 visits. Primary efficacy variables were ocular itching (assessed at visits 2 and 3) and subject satisfaction (assessed at visit 3). Tolerability variables were slit-lamp findings (all visits), visual acuity (all visits), ocular comfort after drug instillation (visit 3), and adverse events (visits 2 and 3). At visit 1, the antigen concentration that elicited a positive ocular allergic response was determined, and this concentration was confirmed at visit 2. Subjects graded itching on a 5-point scale at 3, 5, and 10 minutes postchallenge. The scores from this visit were used as baseline scores and compared with scores from visit 3 to determine drug efficacy. At visit 3, subjects were randomly assigned to 2 treatment groups. Group A received 1 drop of olopatadine in the right eye and I drop of ketotifen in the left eye. Group B received 1 drop of olopatadine in the left eye and 1 drop of ketotifen in the right eye. Following drug instillation, the subjects assessed the comfort level in each eye. Twelve hours after instillation, subjects were challenged with the antigen concentration that elicited a positive response at the previous visits. Itching was subjectively graded at 3, 5, and 10 minutes postchallenge. Subjects were asked to choose which therapy they were more satisfied with. RESULTS: Twelve hours after administration, efficacy scores for olopatadine were significantly higher than those for ketotifen at 3 and 5 minutes postchallenge (1.84 and 1.75 vs 1.25 and 1.34; P < 0.05). Olopatadine-treated eyes were rated significantly more comfortable than those treated with ketotifen immediately after drug instillation (1.25 vs 2.09; P < 0.05) and 12 hours later, as measured by patient ratings of ocular comfort. Of the 22 subjects who had a preference, 16 (73%) were more satisfied with olopatadine than with ketotifen. CONCLUSIONS: Olopatadine is more effective than ketotifen in reducing the itching associated with allergic conjunctivitis in the antigen challenge model. Olopatadine caused less ocular discomfort than ketotifen and was preferred by approximately 3 times as many patients as was ketotifen.

Allergens↗
PubMed2002

Randomized, double-masked, placebo-controlled comparison of the efficacy of emedastine difumarate 0.05% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the human conjunctival allergen challenge model.

BACKGROUND: Emedastine difumarate 0.05% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution are 2 topical antiallergic agents available in the United States and other countries. Emedastine is indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis. Ketotifen is indicated for the temporary relief of ocular itching caused by allergic conjunctivitis. OBJECTIVE: The purpose of this study was to compare the efficacy of these agents in the temporary relief of ocular itching due to allergic conjunctivitis. The 2 agents were compared with each other and with placebo (artificial tears) using the conjunctival allergen challenge (CAC) model. METHODS: This was a single-center, randomized, double-masked, placebo-controlled study. At visit 1, CAC was performed on eligible subjects to identify the dose required to elicit a positive allergic reaction. Subjects returned after 7 days for visit 2 to confirm the allergen dose. On day 14 (+/-3) of the study, enrolled subjects were randomized to 1 of 3 treatment groups: emedastine in I eye and placebo in the other, ketotifen in 1 eye and placebo in the other, or emedastine in 1 eye and ketotifen in the other. In 25 subjects, bilateral CAC was performed 5 minutes after study medication instillation. In a second group of 20 subjects, CAC was performed 15 minutes after medication instillation. Itching was graded according to a standardized 5-point scale (0 = none to 4 = severe itching) at 3, 5, and 10 minutes postchallenge. Differences in efficacy scores between treatments and versus placebo were compared using 2-sample t tests of equal variance. RESULTS: A total of 45 patients (mean age, 41.2 years) received treatment: 16 received emedastine in 1 eye and ketotifen in the other; 14 received emedastine in 1 eye and placebo in the other; and 15 received ketotifen in 1 eye and placebo in the other. Both emedastine and ketotifen significantly inhibited itching (P < 0.05) compared with placebo at all time points after the 5- and 15-minute CAC. Mean raw scores for the active treatments were not statistically different. The mean itching efficacy scores were also not statistically different between active treatments. No adverse events were reported in this study. CONCLUSION: The results of this study suggest that emedastine and ketotifen are not significantly different with respect to anti-itching efficacy in the CAC model of acute allergic conjunctivitis.

Allergens↗
PubMed2003

Comparison of ketotifen fumarate ophthalmic solution alone, desloratadine alone, and their combination for inhibition of the signs and symptoms of seasonal allergic rhinoconjunctivitis in the conjunctival allergen challenge model: a double-masked, placebo- and active-controlled trial.

BACKGROUND: Ketotifen fumarate is a topical antiallergic combination mast-cell stabilizer and antihistamine indicated for the temporary prevention of ocular itching due to allergic conjunctivitis. Desloratadine is a systemic antihistamine indicated for the treatment of seasonal and perennial allergic rhinitis. OBJECTIVE: The purpose of this study was to compare the efficacy of ketotifen 0.025% ophthalmic solution instilled in the eye, desloratadine 5-mg tablets taken orally, and their combination for prevention of the signs and symptoms of allergic rhinoconjunctivitis, as induced by the conjunctival allergen challenge (CAC) model. METHODS: This was a randomized, double-masked, placebo- and active-controlled, single-center clinical trial. At visit l, the dose of allergen necessary to elicit a qualifying allergic reaction was determined for subjects meeting the entry criteria. At visit 2, the allergen dose determined at visit 1 was confirmed, and all subjects who had a qualifying ocular and nasal allergic reaction were randomized to 1 of 3 treatment groups: ketotifen ophthalmic solution and placebo tablet, desloratadine tablet and placebo eyedrop, or ketotifen and desloratadine. Subjects were instructed to instill 1 drop into each eye twice daily and take 1 tablet with water once daily at the same time as the morning eyedrop for approximately 4 weeks. At visit 3, subjects brought in their medication and were given 1 drop of the eyedrop bilaterally and 1 tablet with water. Bilateral CAC was performed 2 hours after administration of medication. Using standardized scales, subjects rated ocular itching at 3, 5, and 7 minutes after CAC; ocular tearing and eyelid swelling at 10, 15, and 20 minutes after CAC; and nasal signs and symptoms (sneezing, rhinorrhea and postnasal drip, pruritus, and nasal congestion) at 10, 20, 30, 40, and 50 minutes after CAC. The investigator graded ocular redness and chemosis at 10, 15, and 20 minutes after CAC. At all visits, subjects were offered an anti-allergy eyedrop to relieve any immediate ocular discomfort caused by CAC. RESULTS: One hundred two subjects were screened-82 (55 women, 27 men; mean age, 42.8 years [range, 21-70 years]) were randomized to treatment, and 80 completed the study. Subjects in the group that received ketotifen (n = 27) and the group that received ketotifen with desloratadine (n = 26) had significantly lower mean itching scores compared with those in the group that received desloratadine alone (n = 27) at all time points (P </= 0.05). Total ocular redness, calculated by summing the mean redness scores for each of the 3 vessel beds, was significantly lower in the ketotifen group than in the other treatment groups at most time points (P </= 0.05). All treatments attenuated nasal symptoms; no statistically significant differences were noted between treatment groups, with the exception of the 50-minute time point, at which combination treatment was significantly more effective than ketotifen alone (P </= 0.05). The proportion of subjects who requested relief drops after CAC was significantly lower in both the ketotifen alone and combination treatment groups compared with the desloratadine alone group (P = 0.004). CONCLUSIONS: Ketotifen ophthalmic solution significantly decreased the signs and symptoms of ocular and nasal allergic rhinoconjunctivitis. The addition of ketotifen to the oral desloratadine regimen improved the overall antiallergic efficacy of both medications.

Adolescent↗
PubMed2000

Stage-specific isoforms of Ascaris suum complex. II: The fumarate reductase of the parasitic adult and the succinate dehydrogenase of free-living larvae share a common iron-sulfur subunit.

Complex II of adult Ascaris suum muscle exhibits high fumarate reductase (FRD) activity and plays a key role in anaerobic electron-transport during adaptation to their microaerobic habitat. In contrast, larval (L2) complex II shows a much lower FRD activity than the adult enzyme, and functions as succinate dehydrogenase (SDH) in aerobic respiration. We have reported the stage-specific isoforms of complex II in A. suum mitochondria, and showed that at least the flavoprotein subunit (Fp) and the small subunit of cytochrome b (cybS) of the larval complex II differ from those of adult. In the present study, complete cDNAs for the iron-sulfur subunit (Ip) of complex II, which with Fp forms the catalytic portion of complex II, have been cloned and sequenced from anaerobic adult A. suum, and the free-living nematode, Caenorhabditis elegans. The amino acid sequences of the Ip subunits of these two nematodes are similar, particularly around the three cysteine-rich regions that are thought to comprise the iron-sulfur clusters of the enzyme. The Ip from A. suum larvae was also characterized because Northern hybridization showed that the adult Ip is also expressed in L2. The Ip of larval complex II was recognized by the antibody against adult Ip, and was indistinguishable from the adult Ip by peptide mapping. The N-terminal 42 amino acid sequence of Ip in the larval complex II purified by DEAE-cellulofine column chromatography was identical to that of the mature form of the adult Ip. Furthermore, the amino acid composition of larval Ip determined by micro-analysis on a PVDF membrane is almost the same as that of adult Ip. These results, together with the fact, that homology probing by RT-PCR, using degenerated primers, failed to find a larval-specific Ip, suggest that the two different stage-specific forms of the A. suum complex II share a common Ip subunit, even though the adult enzyme functions as a FRD, while larval enzyme acts as an SDH.

Amino Acid Sequence↗
PubMed2002

Effect of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate, a novel acetylcholinesterase inhibitor, on spatial cognitive impairment induced by chronic cerebral hypoperfusion in rats.

It is of interest whether the acetylcholinesterase inhibitor, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone fumarate (TAK-147), can improve cognitive impairment caused by chronic cerebral ischemia in rats. Two weeks after four-vessel occlusion, apparent impairments of spatial retrieval memory were observed in the Morris water maze. Both TAK-147 at doses of 0.1, 0.3 and 1.0 mg/kg and donepezil at doses of 0.3 and 1.0 mg/kg significantly ameliorated ischemia-induced memory deficits dose-dependently, but tacrine had no appreciable effect. Furthermore, we demonstrate that the intensity of staining by 2,3,5-triphenyltetrazolium in the hippocampal and cortical slices was significantly decreased by ischemia (10 min anoxia/aglycemia), and that it was also significantly restored by treatment with TAK-147 and donepezil.

Animals↗
PubMed2001

Dry powder inhalation of liposomal Ketotifen fumarate: formulation and characterization.

The purpose of the experiment was to formulate and characterize the dry powder inhalation (DPI) formulation of liposomally entrapped anti-asthmatic drug, Ketotifen fumarate (KF). Liposomes composed of saturated egg phosphatidyl choline (EPC) and cholesterol (CHOL) were prepared by lipid film hydration and sonicated to have the desired size (<5 microm). Process variable such as vacuum, presonication hydration, postsonication hydration, purification and lamellae composition, were optimized for encapsulation efficiency of KF. Liposomal dispersion was blended with cryoprotectant (sugar) in varying bulk and mass ratios and assessed for its influence on retention of encapsulated drug on lyophilization. Characterization of liposomal dispersion was done for size, lamellarity, entrapped volume and oxidation index. DPI formulation was characterized for angle of repose, compressibility index, dispersibility and respirable fraction (British Pharmacopoeia, apparatus A). Process optimization revealed that a vacuum, 20 in.; presonication hydration, 60 min; postsonication hydration, 2 h and purification by dialysis gave maximum encapsulation efficiency. Sucrose was found to be the most suitable cryoprotectant at bulk strength of 500 mM and mass ratio of lipid/sugar, 1/12. Blending of sorbolac before lyophilization showed better retention of encapsulated KF (97.92+/-0.54%). In the preparation of sonicated MLVs, the presence of nitrogen atmosphere, alpha-tocopherol and EDTA could not totally eliminate EPC oxidation, expressed as the change in oxidation index from 0.427+/-0.01 to 1.510+/-0.01. The respirable fraction of the developed formulation (21.59+/-1.53%) is comparable with the control (26.49+/-1.52%). From studies, it may be concluded that an optimal bulk and mass ratio of sucrose, relative to the size of liposomes is necessary for effective cryoprotection. In this investigation, DPI of liposomal KF was successfully prepared and delivered to the required site in the lungs.

Administration, Inhalation↗