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PubMedDate not supplied

Synthesis, material properties, and biocompatibility of a novel self-cross-linkable poly(caprolactone fumarate) as an injectable tissue engineering scaffold.

A novel self-cross-linkable and biodegradable macromer, poly(caprolactone fumarate) (PCLF), has been developed for guided bone regeneration. This macromer is a copolymer of fumaryl chloride, which contains double bonds for in-situ cross-linking, and poly(epsilon-caprolactone), which has a flexible chain to facilitate self-cross-linkability. PCLF was characterized with Fourier transform infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopy, and gel permeation chromatography. Porous scaffolds were fabricated with sodium chloride particles as the porogen and a chemical initiation system. The PCLF scaffolds were characterized with scanning electron microscopy and micro-computed-tomography. The cytotoxicity and in vivo biocompatibility of PCLF were also assessed. Our results suggest that this novel copolymer, PCLF, is an injectable, self-cross-linkable, and biocompatible macromer that may be potentially used as a scaffold for tissue engineering applications.

Animals↗
PubMed2006

Bone-tissue-engineering material poly(propylene fumarate): correlation between molecular weight, chain dimensions, and physical properties.

Poly(propylene fumarate) (PPF) is an important biodegradable and cross-linkable polymer designed for bone-tissue-engineering applications. For the first time we report the extensive characterization of this biomaterial including molecular weight dependences of physical properties such as glass transition temperature Tg, thermal degradation temperature Td, density rho, melt viscosity eta0, hydrodynamic radius RH, and intrinsic viscosity [eta]. The temperature dependence of eta0 changes progressively with molecular weight, whereas it can be unified when the temperature is normalized to Tg. The plateau modulus and entanglement molecular weight Me have been obtained from the rheological master curves. A variety of chain microstructure parameters such as the Mark-Houwink-Sakurada constants K and alpha, characteristic ratio Cinfinity, unperturbed chain dimension r0(2)/M, packing lengthp, Kuhn length b, and tube diameter a have been deduced. Further correlation between the microstructure and macroscopic physical properties has been discussed in light of recent progress in polymer dynamics to supply a better understanding about this unsaturated polyester to advance its biomedical uses. The molecular weight dependence of Tg for six polymer species including PPF has been summarized to support that Me is irrelevant for the finite length effect on the glass transition, whereas surprisingly these polymers can be divided into two groups when their normalized Tg is plotted simply against Mw to indicate the deciding roles of inherent chain properties such as chain fragility, intermolecular cooperativity, and chain end mobility.

Bone Substitutes↗
PubMed2004

Chiral norbornadienes as efficient ligands for the rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to fumaric and maleic compounds.

[reaction: see text] A rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to fumaric and maleic compounds has been developed. While phosphorus-based chiral ligands fail to induce high stereoselectivity, chiral norbornadiene ligands have proved to be uniquely effective to achieve high enantioselectivity in these 1,4-addition reactions.

Boronic Acids↗
PubMed2003

Improving relative bioavailability of dicumarol by reducing particle size and adding the adhesive poly(fumaric-co-sebacic) anhydride.

PURPOSE: This study was carried out to show the effect of particle size reduction and bioadhesion on the dissolution and relative bioavailability of dicumarol. METHODS: Formulations were produced by a variety of methods including a novel technique to reduce particle size as well as phase inversion with poly(fumaric-co-sebacic)anhydride p(FA:SA) to create nanospheres. Drug was administered to groups of pigs and rats via oral gavage of a suspension, and dicumarol concentration in the blood was measured using a double extraction technique. RESULTS: In vitro results showed improved dissolution in both the micronized formulation and the encapsulated p(FA:SA) nanospheres. In vivo, relative bioavailability of a spray-dried formulation was increased by 17% in the rat and 72% in the pig by further reduction in particle size. The bioadhesive p(FA:SA) formulation also improved relative bioavailability over the spray-dried drug, increasing it by 55% in the rat and 96% in the pig. Additionally, the p(FA:SA) formulation prolonged Tmax and decreased Cmax in both species. CONCLUSION: This work demonstrates the importance of particle size and bioadhesion to improve oral bioavailability of ducumarol.

Adhesives↗
PubMed2006

Germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma.

Germline mutations in the fumarate hydratase (FH) gene were recently shown to predispose to the dominantly inherited syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is characterized by benign leiomyomas of the skin and the uterus, renal cell carcinoma, and uterine leiomyosarcoma. The aim of this study was to identify new families with FH mutations, and to further examine the tumor spectrum associated with FH mutations. FH germline mutations were screened from 89 patients with RCC, skin leiomyomas or ovarian tumors. Subsequently, 13 ovarian and 48 bladder carcinomas were analyzed for somatic FH mutations. Two patients diagnosed with ovarian mucinous cystadenoma (two out of 33, 6%) were found to be FH germline mutation carriers. One of the changes was a novel mutation (Ala231Thr) and the other one (435insAAA) was previously described in FH deficiency families. These results suggest that benign ovarian tumors may be associated with HLRCC.

Carcinoma, Renal Cell↗
PubMed2003

Germline mutations in fumarate hydratase (FH) do not predispose to prostate cancer.

Inherited susceptibility to prostate cancer has been linked to a number of chromosomal regions, however no genes have been unequivocally shown to underlie reported linkages. The putative gene localised to chromosome 1q42-q43, has been designated PCaP. We have recently shown that germline mutations in the fumarate hydratase (FH) gene located on 1q43 cause smooth muscle tumours and renal cell carcinoma. It is conceivable that germline FH mutations might confer an increased risk of prostate cancer and underlie linkage of prostate cancer to PCaP. To examine this proposition we have analysed the entire coding region of FH in 160 prostate cancer cases in 77 multiple case families. No pathogenic mutations in FH were identified in any of the cases. This data makes it highly unlikely that mutations in FH confer susceptibility to prostate cancer.

Aged↗
PubMed2003

Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis.

BACKGROUND: Therapy with fumaric acid esters (FAE) has been shown to be safe and effective in patients with severe psoriasis in several clinical studies with limited follow-up periods. In view of the chronic character of psoriasis, long-term safety aspects are of major importance in determining the suitability of a drug during prolonged periods of treatment. OBJECTIVES: To investigate adverse events of therapy with systemic FAE with follow-up periods of up to 14 years, in order to determine safety aspects of their long-term use in patients with severe psoriasis. METHODS: Current and/or past therapeutic use of FAE was reviewed in 66 patients with severe psoriasis. RESULTS: Forty-one of 66 patients had received FAE for at least 1 year, and 12 of these 41 patients had received FAE for between 10 and 14 years. Adverse events were reported in 73% of the patients. These were usually mild and mainly consisting of flushing (55%), diarrhoea (42%), nausea (14%), tiredness (14%) and stomach complaints (12%). A relative lymphocytopenia was observed in 76% of patients during therapy with FAE, resulting in a permanent discontinuation of therapy with FAE in four patients. A transient eosinophilia and moderate liver enzyme elevations were observed in 14% and 25% of patients, respectively. CONCLUSIONS: The present study indicates that FAE can be considered as a safe long-term treatment in patients with severe psoriasis.

Adult↗
PubMed1999

Fumaric acid esters: an alternative systemic treatment for psoriasis.

We report the successful clearance of severe chronic plaque psoriasis following treatment with fumaric acid esters (FAE) in two patients who had failed previous systemic therapy. FAE is gaining increasing acceptance for the treatment of psoriasis in countries such as Germany and the Netherlands, but at present remains unlicensed in Britain.

Fumarates↗
PubMed1990

[Acute kidney failure during psoriasis therapy with fumaric acid derivatives].

24 days after starting treatment of psoriasis with fumaric acid derivatives (0.8-1.0 g orally, plus unknown quantities locally) a 21-year-old woman developed acute oliguric renal failure with a rise of serum creatinine levels to 1094 mumol/l (12.4 mg/dl). Deterioration of renal function had been preceded by severe abdominal symptoms with nausea, vomiting and colicky pain. On admission to hospital she was dehydrated with hyponatraemia and hypokalaemia. There was glomerular microhaematuria, increased excretion of renal epithelia, and tubular proteinuria. Renal biopsy demonstrated acute tubular damage with vacuolization of proximal epithelia, dilated tubules and scattered necroses. After intermittent haemodialysis (13 courses over two weeks) renal function gradually recovered, as demonstrated at a follow-up examination four months after discharge.

Acute Kidney Injury↗
PubMed1990

[The nephrotoxic effect of therapy with fumaric acid esters in psoriasis].

Two sisters, aged 25 and 29 years, with generalized psoriasis guttata since childhood, developed nausea, upper-abdominal pain, loss of appetite, palpitations and flushes in the course of local and oral administration of fumaric acid esters. Because of these side effects the treatment was discontinued after about two weeks, and the symptoms disappeared. But proteinuria and haematuria were subsequently noted, creatinine concentration rose to 2.2 and 2.5 mg/dl, respectively, while creatinine clearance fell to 44 and 27 ml/min, respectively. Examination of urinary sediments and analysis of urinary proteins gave results compatible with tubular-interstitial renal damage. The abnormal renal functions and urinary findings proved reversible within three weeks.

Administration, Oral↗
PubMed2000

Quetiapine fumarate overdose: clinical and pharmacokinetic lessons from extreme conditions.

BACKGROUND: Although the new atypical antipsychotic, quetiapine fumarate, is growing in popularity over its progenitor, clozapine, clinical experience with overdose of this agent remains limited. Observation of an overdose situation provided a unique opportunity to define the safety, clinical effects, and pharmacokinetics of this medication more clearly. METHODS: A patient admitted immediately after ingesting an overdose of 30 tablets of 100 mg of quetiapine was observed carefully to document effects of the medication. These observations were compared with the only two other published cases of overdose, to the known pharmacology of the drug, and to serial measurements of serum drug concentrations obtained to document the time course of elimination of the drug. RESULTS: Consistent with the two previously published cases, the main clinical effects of overdose were hypotension, tachycardia, and somnolence as predicted by its known alpha-adrenergic receptor and histamine receptor blockade. These effects were managed with fluid resuscitation and supportive measures. No cardiac arrhythmias other than tachycardia have been reported, but the tachycardia was of an unexpectedly long duration in this case. Decline in serum quetiapine concentration followed a biexponential pattern with a terminal elimination half-life of 22 hours. Unexpectedly low peak serum concentrations in three patients with overdose suggest that absorption is highly reduced, either by the effects of the overdose or by the activated charcoal administered. CONCLUSIONS: Quetiapine appears to have greater safety in overdose than traditional antipsychotic agents. Its toxicity is consistent with its receptor pharmacology. Elevated serum concentrations associated with this overdose remained above the limit of detection long enough to document a terminal elimination half-life of 22 hours in this patient. This is much more consistent with previously noted duration of clinical effects and detectable serum concentrations after overdose than the published half-life of 6 hours. Physicians should be aware that any new drug that is active at low concentrations may have had its half-life underestimated during preclinical development because of the difficulty in detecting the drug after the distribution phase has ended.

Adrenergic alpha-Antagonists↗
PubMed2000

Prediction of the outcome of a phase 3 clinical trial of an antischizophrenic agent (quetiapine fumarate) by simulation with a population pharmacokinetic and pharmacodynamic model.

A completed phase 3 trial result was simulated 100 times on the basis of a simulation model of quetiapine fumarate (Seroquel), an antischizophrenic agent. The simulation was executed by analysts who were completely blinded from results of the actual trial until after the simulations were submitted to the holder of the trial results. Data from two clinical investigations of quetiapine in patients with schizophrenia were analyzed by use of nonlinear mixed effects modeling to derive a population pharmacokinetic- and pharmacodynamic-based simulation model. The time course of quetiapine concentrations was described by use of a one-compartment open linear pharmacokinetic model with first-order absorption and elimination. The combination of an inhibitory maximum effect pharmacodynamic model for the active treatment effect and a linear function of time for the placebo effect characterized the observed time course of change in the Brief Psychiatric Rating Scale. Simulation results were compared with those in the actual trial to evaluate how well the simulations predicted the outcome. The actual trial results for all doses except the placebo group fell within the predicted Brief Psychiatric Rating Scale scores +/- 1 SE. Unlike the phase 2 trial, from which the pharmacokinetic/pharmacodynamic model was developed, the placebo group in the actual phase 3 trial showed deterioration of Brief Psychiatric Rating Scale scores with time. We conclude that variable placebo responses observed in short-term studies of schizophrenia provide an inadequate basis for the modeling and simulation of placebo subjects in clinical trials. Knowledge of the range of placebo response observed in other studies may have provided an improved basis for the placebo effect model. The model for active drug produced adequate predictions of the actual trial outcomes.

Algorithms↗
PubMed2004

Release characteristics of a model plasmid DNA encapsulated in biodegradable poly(ethylene glycol fumarate)/acrylamide hydrogel microspheres.

Biodegradable hydrogel microspheres were synthesized by free radical suspension copolymerization of poly(ethylene glycol fumarate) macromer with bisacrylamide (PEGF/PAM). The acidic initiator ammonium persulphate in combination with the basic accelerator, N,N,N',N'-tetramethyethylenediamine, were used to form the PEGF/PAM hydrogel at a neutral pH. The equilibrium water content of the microspheres was greater than 90% w/w. A model double stranded plasmid DNA (dsDNA) coding for the enhanced green fluorescence protein (pEGFP) gene was encapsulated in the hydrogel and the effect of loading and water content before swelling on release kinetics was investigated. Fluorescent confocal microscopy demonstrated that the encapsulated dsDNA was in the biologically active double stranded configuration. The highest loading of 0.81 mg ml(-1) resulted in the best encapsulation efficiency of 95%. For that loading, 6% of the dsDNA was released in 25 days at a rate of 16 ng ml(-1). The highest water content of 70% resulted in the highest burst release of 27% and 14% of the dsDNA was released in 25 days at a rate of 30 ng ml(-1). For elucidating the release mechanism, the network mesh size was compared with the radius of gyration (Rg) of the dsDNA plasmid. The mesh size was 7 nm, which was less than Rg of the dsDNA (31 nm) but greater than the chain diameter of 1.1 nm. Since the mesh size was less than Rg, the release mechanism was by reptation of the segments of dsDNA within the tube formed by the network chains between crosslinks. These results indicate that the hydrogel mesh size and the size of the plasmid control the release mechanism.

Acrylamide↗
PubMed2003

The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase.

It is well documented that disturbances in mitochondrial function are associated with rare childhood disorders and possibly with many common diseases of ageing, such as Parkinson's disease and dementia. There has also been increasing evidence linking mitochondrial dysfunction with tumorigenesis. Recently, heterozygous germline mutations in two enzymes of the Krebs tricarboxylic acid cycle (TCA cycle) have been shown to predispose individuals to tumours. The two enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are ubiquitously expressed, playing a vital role in adenosine triphosphate (ATP) production through the mitochondrial respiratory chain. Germline mutations in FH are associated with leiomyomatosis and renal cell carcinoma, whilst SDH mutations are associated with predisposition to paraganglioma (PGL) and phaeochromocytoma (PCC). At present, there are few data to explain the pathway(s) involved in this predisposition to neoplasia through TCA cycle defects. We shall review the mechanisms by which mutations in FH and SDH might play a role in tumorigenesis. These include pseudo-hypoxia, mitochondrial dysfunction and impaired apoptosis, oxidative stress and anabolic drive. All of these mechanisms are currently poorly defined. To date, FH and SDH mutations have not been reported in non-familial leiomyomata, renal cancers, PCCs or PGLs. It remains entirely possible, however, that the underlying mechanisms of tumorigenesis in these sporadic tumours are the same as those in the Mendelian syndromes.

Citric Acid Cycle↗
PubMed2006

Maleic- and fumaric-diamides of (O,O-diacetyl)-L-Dopa-methylester as anti-Parkinson prodrugs in liposomal formulation.

The maleic and fumaric diamides preparation of (O,O-diacetyl)-L-Dopa-methylester [(+)-4, (+)-5] are reported; they were synthesized in order to attenuate marked fluctuations of L-DOPA (LD) plasma levels and to overcome the problem of low bioavailability of LD. The new compounds were characterized evaluating solubility, chemical stability, apparent partition coefficient (log P) and comparing neostriatum dopamine (DA) levels in freely moving rats after i.p. administration of prodrugs [(+)-4, (+)-5] with prodrugs in liposomal formulations [(+)-4Lip, (+)-5Lip]. All the new compounds showed chemical stability in aqueous buffer solutions (pH 1.3 and 7.4). A relatively slow release of LD in human plasma was observed. Among the studied products, prodrug was able to induce sustained delivery of DA in rat striatal dialysate with respect to equimolar i.p admistration of LD. Furthermore, neostriatum DA concentration after administration of the synthesized prodrugs vs. prodrugs in liposomal formulations was compared (+)-4Lip, (+)-5Lip). The results suggest that cis dimeric prodrug (+)-4 and (+)-4Lip can improve the release of DA in rat brain and demonstrate the potential of these formulations for controlled delivery of antiparkinson agents.

Amides↗
PubMed2003

Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age < or =30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC.

Carcinoma, Renal Cell↗
PubMed2002

Porous poly(propylene fumarate) foam coating of orthotopic cortical bone grafts for improved osteoconduction.

A porous biodegradable scaffold coating for perforated and demineralized cortical bone allografts could maintain immediate structural recovery and subsequently allow normal healing and remodeling by promoting bony ingrowth and avoiding accelerated graft resorption. This new type of osteoconductive surface modification should improve allograft incorporation by promoting new bone growth throughout the biodegradable scaffold, hence encasing the graft with the recipient's own bone. We investigated the feasibility of augmenting orthotopically transplanted cortical bone grafts with osteoconductive biodegradable polymeric scaffold coatings. Five types of bone grafts were prepared: type I, untreated fresh-frozen cortical bone grafts (negative control); type II, perforated and partially demineralized cortical bone grafts without additional coating (positive control); type III, perforated and partially demineralized cortical bone coated with a low-porosity poly(propylene fumarate) (PPF) foam; type IV, perforated and partially demineralized cortical bone coated with a medium-porosity PPF foam; and type V, perforated and partially demineralized cortical bone coated with a high-porosity PPF foam. Grafts were implanted into the rat tibial diaphysis. Fixation was achieved with an intramedullary threaded K-wire. Two sets of animals were operated on. Animals were killed in groups of eight with one set being killed 12 weeks, and the other 16 weeks, postoperatively. Radiographic, histologic, and histomorphometric analyses of grafts showed that the amount of new bone forming around the foam-coated grafts was significantly higher than that in the type I control group (uncoated) or that in type II group (perforated and partially demineralized cortical bone grafts). Although all foam formulations appeared initially equally osteoconductive, histologic evaluation of medium-porosity PPF foam-based coatings appeared to result in a sustained response 16 weeks postoperatively. Significant resorption was present in perforated and partially demineralized cortical bone graft allografts, with some accompanying new bone formation occurring primarily within the laser holes. Therefore, PPF foam-coated cortical bone grafts appeared to be better protected from excessive bone resorption, as frequently seen with invasion of fibrovascular tissue. Biomechanical analysis of the PPF foam-coated grafts corroborated findings of the morphometric analysis in that the failure strength at the allograft-host bone junction sites of all PPF-coated cortical bone grafts was higher than in the uncoated controls.

Animals↗
PubMed1999

Effect of a poly(propylene fumarate) foaming cement on the healing of bone defects.

Regeneration of skeletal tissues has been recognized as a new means for reconstruction of skeletal defects. We investigated the feasibility of an injectable and expandable porous implant system for in situ regeneration of bone. Therefore, a composite biodegradable foaming cement based on poly(propylene fumarate) was injected into a critical size defect made in the rat tibia. Animals were divided into two groups comparing the foam in the experimental group against sham-operated animals having a drill hole but no implant in the control group. Eight animals were included in each group. Animals were sacrificed at 1, 3, and 7 weeks postoperatively. Implantation sites were then evaluated with histologic and histomorphometric methods. Results of this study showed that defects did not heal in sham-operated animals. In the experimental group, metaphyseal and cortical defects healed within the first postoperative week by formation of immature woven bone. At the site of the cortical drill hole defect, healing was noted to progress to complete closure by formation of mature bone. Histomorphometry corroborated these findings and showed that metaphyseal bone remodeling peaked at 1 week postoperatively and then decreased as healing of the cortical defect progressed. This suggests that near-complete restoration of the original state of the tibial bone occurred in this animal model supporting the concept of in situ bone regeneration by application of engineered biodegradable porous scaffolds. () ()

Animals↗