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M Chasin

Publications and source records attributed to M Chasin.

At least 19 recordsLinked to original sources
PubMed1998

Correlations of PDE-4 inhibition between enzymes of smooth muscle and inflammatory cell sources.

The sensitivities of PDE-4 enzymes from smooth muscle and inflammatory cell sources from different species to a range of structurally diverse compounds were compared. All inflammatory cell PDE-4 sources displayed good crosscorrelations in their sensitivity to inhibition by these compounds. Similarly, PDE-4 enzymes from smooth muscle sources were well-correlated; however, there was no crosscorrelation between PDE-4 from smooth muscle sources and those of inflammatory cell sources, possibly reflecting differences in subcellular location of enzymes as well as subtype expression. The present study concludes that PDE-4 preparations from smooth muscle sources as well as those from inflammatory cell sources may be used to model the potential smooth muscle cell relaxing properties and anti-inflammatory properties of a compound in relation to human asthma.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

Differential effects of food on the bioavailability of controlled-release oxycodone tablets and immediate-release oxycodone solution.

The effects of a high-fat meal on the bioavailability of oxycodone hydrochloride, administered as a recently developed 40 mg controlled-release (CR) tablet or a 20 mg immediate-release (IR) solution, were evaluated in a randomized crossover study in 22 normal male and female subjects. Serial blood samples were collected for 36 h after dosing and analyzed for oxycodone by a validated method using gas chromatography/mass spectrometry. There was no significant food effect with CR oxycodone as judged by 90% confidence interval (CI) analysis of AUC0-infinity and Cmax values under fed and fasted conditions. For the IR solution, both oxycodone bioavailability and peak plasma oxycodone concentration were significantly altered by consumption of the high-fat meal, with the mean value for AUC0-infinity increasing to 120% (CI = 109-132%) and the mean value for Cmax decreasing to 82% (CI = 47-91%) of values observed in the fasted condition. Adverse events reported for both formulations were mostly mild to moderate in severity and typical of those observed with opioids.

Adult↗
PubMed1996

Prolonged regional nerve blockade. Injectable biodegradable bupivacaine/polyester microspheres.

BACKGROUND: Biodegradable microspheres are a useful method of drug delivery because they are both injectable and biodegradable, eliminating the need for surgical implantation or removal. Previous work has characterized implantable preparations of local anesthetics in polymer pellets for prolonged regional anesthesia. In this article, the authors characterize injectable suspensions of bupivacaine-polymer microspheres and examine whether they can produce prolonged blockade of the sciatic nerve in rats. METHODS: Microspheres were prepared using polylactic-co-glycolic acid polymers loaded with 75% w/w bupivacaine by a solvent evaporation method. Bupivacaine release from microspheres was determined in vitro by ultraviolet spectroscopy and scintillation counting. Sensory and motor blockade of the rat sciatic nerve were assessed in vivo after injection of microsphere suspensions. RESULTS: Depending on the type of microspheres, the dose, and the additive used, mean duration of sciatic nerve block ranged from 10 h to 5.5 days. Incorporation of 0.05% w/w dexamethasone into the microspheres resulted in significant prolongation of block (up to 13-fold), and only preparations that contained dexamethasone produced blocks lasting beyond 1 day. Bupivacaine was released in a controlled manner in vitro. Dexamethasone does not substantially slow bupivacaine release from microspheres in vitro. CONCLUSIONS: Prolonged percutaneous blockade of peripheral nerves is feasible. The recovery from blockade is complete, and plasma bupivacaine levels are far below the range associated with systemic toxicity. The mechanisms underlying the dexamethasone block-prolonging effect are under investigation.

Anesthetics, Local↗
PubMed1996

Glucocorticoids prolong rat sciatic nerve blockade in vivo from bupivacaine microspheres.

BACKGROUND: Previous work showed that incorporation of dexamethasone (0.05 weight/weight percentage) into bupivacaine microspheres prolonged blockade by eight to 13 times compared with that produced by bupivacaine microspheres alone. The determinants of dexamethasone's block-prolonging effect were examined and reported here. METHODS: Polylactic-co-glycolic acid polymer microspheres (65/35) with 75 weight/weight percentage bupivacaine were prepared. Microspheres were injected adjacent to the rat sciatic nerve, and sensory and motor blockade were assessed. A procedure was developed to test drugs for block-prolonging ability in vivo by placing test drugs in the injection fluid along with a suspension of bupivacaine microspheres. RESULTS: Dexamethasone alone in suspension did not produce blockade, nor did it prolong blockade induced by aqueous bupivacaine. Bupivacaine microspheres (150 mg drug/kg rat weight) produced blockade for 6 to 10 h. Dexamethasone in the suspending solution of microspheres prolonged block by up to five times. Glucocorticoids prolonged block in proportion to glucocorticoid/antiinflammatory potency. The corticosteroid antagonist cortexolone inhibited dexamethasone's blockade-prolonging action. Durations of blockade with or without dexamethasone were unaltered by hydroxyurea-induced neutrophil depletion. Microspheres were extracted from rats at time points ranging from 7 h to 7 days, and residual microsphere dry weight and bupivacaine content were similar in groups of rats injected with either bupivacaine microspheres or bupivacaine microspheres containing dexamethasone, respectively. CONCLUSIONS: Glucocorticoids prolong blockade from bupivacaine microspheres. The mechanism appears unrelated to the kinetics of bupivacaine release in vivo.

Anesthetics, Local↗
PubMed1993

Controlled release of polypeptides from polyanhydrides.

The effects of both polymer hydrophobicity and addition of stabilizers on the release and integrity of polymer-encapsulated proteins were studied. By using very hydrophobic poly[1,3-bis(p-carboxyhydroxy)hexane anhydride] with sucrose as an excipient, both recombinant bovine somatotropin and zinc insulin were released intact over 3 weeks. The released proteins appeared to maintain their integrity as judged by acidic reverse-phase HPLC, size-exclusion HPLC, radioimmunoassay, and conformation-sensitive immunoassays. Our results also suggest how polymer hydrophobicity can be used to enhance protein stability.

Animals↗
PubMed1993

Interstitial chemotherapy of the 9L gliosarcoma: controlled release polymers for drug delivery in the brain.

The administration of drugs directly into the central nervous system using polymers as drug carriers may improve the treatment of malignant brain tumors. In this study, the effect of the interstitial, localized delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) incorporated into controlled release polymers implanted adjacent to the 9L gliosarcoma was assessed in s.c. and intracranial (i.c.) models. In the s.c. experiment, the 9L gliosarcoma was implanted in the flank of rats and subsequently treated with BCNU either (a) delivered in controlled release polymers inserted adjacent to the tumor or (b) administered systemically by i.p. injections or by controlled release polymers inserted at a site distant from the tumor. The interstitial release of BCNU adjacent to the tumor in the flank resulted in a significant tumor growth delay of 16.3 days, as compared to a growth delay of 9.3 and 11.2 days obtained with the systemic administration of BCNU. In the i.c. experiment, the 9L gliosarcoma was implanted in the brain of Fischer 344 rats and treated either (a) with controlled release polymers containing BCNU inserted into the brain or (b) with the systemic i.p. administration of BCNU. The interstitial release of BCNU in the brain resulted in a significant 5.4- to 7.3-fold increased survival, compared with a 2.4-fold increased survival after the systemic administration of the same dose of BCNU. The two groups with i.c. tumors treated interstitially had 17 and 42% cures, but no long-term cures were obtained in the group treated with systemic therapy. The localized, controlled delivery of chemotherapeutic agents in the s.c. tissues and in the brain via polymeric carriers may be more effective than standard systemic chemotherapy. This approach could be used to deliver a wide variety of agents into the central nervous system to treat diverse neuropathological conditions which remain refractory to systemic therapy.

Animals↗
PubMed1992

Bone conduction implants: transcutaneous vs. percutaneous.

Clinical experience with transcutaneous bone conduction implants has demonstrated that they are most beneficial for patients with purely conductive hearing loss in at least one ear. Percutaneous bone conduction implants, however, have been reported to provide adequate benefit for patients with mixed hearing loss with bone conduction pure-tone averages up to 45 dB HL (Tjellstrom, 1989). The results of 24 Xomed Audiant osseointegrated bone conduction hearing devices (including a clinical trial on two patients using a new, larger magnet [Neodynium Iron Boron]), plus the results of eleven patients implanted and fitted with the percutaneous bone-anchored hearing aid are reported. Aided results with these devices will be presented. In addition, general comparisons of benefit obtained with the two devices will be made for patients who exhibit similar hearing losses. Finally, a direct comparison will be made on two patients who have undergone both implant procedures.

Adolescent↗
PubMed1992

The intracerebral distribution of BCNU delivered by surgically implanted biodegradable polymers.

The local concentration and distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) within normal brain tissue were studied following surgical implantation of biodegradable polymer containing BCNU in New Zealand White rabbits. Cylindrical discs of poly(bis(p-carboxyphenoxy)-propane:sebacic acid) copolymer in a 20:80 formulation were made containing [3H]-inulin or [3H]-BCNU labeled in the methylene hydrogens of the chloroethyl groups. These were implanted in the brains of 56 New Zealand White rabbits. The animals were sacrificed 3, 7, 14, or 21 days later and the brains were rapidly removed, frozen, and prepared for quantitative autoradiography. Autoradiographs from coronal sections bisecting the polymer were analyzed to determine both the proportion of the brain section exposed to the tracer and the local drug concentrations as a function of distance from the polymer. Tritiated BCNU was also injected directly into the brains of eight additional rabbits, and local brain concentrations were studied over time. The results of this study demonstrate that approximately 50% of the area of the brain sections was exposed to radiolabeled compound 3 days after BCNU-polymer implantation, 15% at 7 days, and less than 10% at 14 and 21 days. Polymer discs containing 600 micrograms BCNU generated 6 mM concentrations of BCNU in brain tissue 10 mm from the polymer at 3 and 7 days. Pharmacological studies demonstrated that approximately 25% of the tritium label was associated with intact BCNU 3 days following polymer implantation. Radiolabeled inulin delivered by polymer remained dispersed throughout the ipsilateral hemisphere for 14 days. Direct injection of [3H]-BCNU into brain parenchyma resulted in widely distributed tracer at 1 and 3 hours with rapid disappearance thereafter. It is concluded that local delivery of BCNU to brain tissue with this polymeric drug delivery system results in sustained high local concentrations of BCNU which may be of value in the treatment of patients with brain tumors.

Animals↗
PubMed1991

Drug delivery to the brain using polymers.

The delivery of drugs to the brain has been a major challenge to the scientist developing drugs designed for central nervous system (CNS) activity. One of the obstacles to the progress is the transport of drug through the blood brain barrier (BBB). The criteria for effective drug delivery to the CNS include the following: (a) the drug must have access to the brain, (b) the effect of the drug should be localized, (c) the drug must be stable, and (d) the effective dose should be sustained and controlled. To meet some of the above criteria, two approaches have been used: systemic administration of drugs, and direct delivery of drugs into the brain. The systemic administration of drugs relies on passive diffusion of drug through the BBB, formation of lipid soluble prodrugs and the use of monoclonal antibodies for targeting the drug to the CNS. The other approach includes the use of implantable polymer systems and infusion pumps. Both of the approaches have some advantages and disadvantages. Because of the enormous amount of literature on drug delivery to the brain, the following review focuses on the use of polymer-based implantable systems. The review includes nondegradable and biodegradable polymer implants from the conceptual phase to the clinic.

Animals↗
PubMed1990

Poly(anhydride) administration in high doses in vivo: studies of biocompatibility and toxicology.

Poly(anhydrides) proposed for use as vehicles for controlled drug delivery were administered subcutaneously in Sprague-Dawley rats at two dosage levels (800 mg/kg rat and 2400 mg/kg rat) for a period of eight weeks. Biocompatibility was assessed using a number of methods. Thirty-six clinical chemistry and hematology parameters were monitored throughout the study. Blood values were statistically analyzed for any possible effects due to the implanted polymer. After 8 weeks, rats were sacrificed and complete necropsies were performed. Histological evaluations of 33 organ sites including heart, lung, liver, kidney, and brain were performed. In addition, subcutaneous implant sites were excised and examined both grossly and microscopically. Results from evaluations of blood chemistry and hematology data, organ analyses and local implant site analyses overall demonstrated that the poly(anhydride) biomaterial possessed excellent in vivo biocompatibility.

Animals↗
PubMed1989

Brain biocompatibility of a biodegradable, controlled-release polymer in rats.

We report the biocompatibility in the rat brain of a controlled-release, biodegradable polymer, the polyanhydride poly-[bis(p-carboxyphenoxy)propane-sebacic acid] copolymer (PCPP-SA) in a 20:80 formulation. The biodegradable polyanhydride can be used for drug delivery directly into the brain, circumventing the difficulties posed by the blood-brain barrier and avoiding the consequences of having to administer toxic doses systematically to reach therapeutic doses in the central nervous system. The tissue reaction in the presence of PCPP-SA was compared to that seen with other standard neurosurgical implants. Fifty-six adult Sprague-Dawley rats were assigned to one of seven groups and underwent bilateral frontal lobe implantation of PCPP-SA (42 hemispheres), Surgicel (oxidized regenerated cellulose) (35 hemispheres), or Gelfoam (absorbable gelatin sponge) (35 hemispheres). None of the animals showed any behavioral changes or neurological deficits suggestive of either systemic or localized toxicity from the biodegradable polyanhydride, all surviving to the scheduled data of sacrifice. PCPP-SA evoked a well localized inflammatory reaction, comparable to that of Surgicel, which resolved as the PCPP-SA polymer degraded over five weeks. The biodegradable polyanhydride has been shown in this study to be nontoxic and biocompatible in the rat brain, when compared to standard neurosurgical implants.

Animals↗
PubMed1982

Heterogeneity of biochemical actions among vasodilators.

Thirty-four vasodilators were screened in several in vitro biochemical assays related to smooth muscle excitation-contraction coupling, binding to beta 1-,beta 2-, and alpha-adrenergic receptors, inhibition of phosphodiesterase activity, and antagonism of calcium accumulation. Isoproterenol and perhexiline only exhibited binding to beta-adrenergic sites. Ergocryptine, tolazoline, and amotriphene only bound to alpha-adrenergic receptors. Leniquinsin, papaverine, proquazone, dioxyline, hoquizil, quazodine, and theophylline were active only as phosphodiesterase inhibitors. Isoxsuprine, nylidrin, and bencyclane bound to alpha- and beta-receptors. Pentoxifylline bound to beta 1-sites and inhibited phosphodiesterase. Cyclandelate bound to beta 2-sites and blocked calcium accumulation. Cinnarizine and flunarizine antagonized calcium accumulation and bound to alpha-sites. Prazosin bound to alpha-sites and inhibited phosphodiesterase. Ethaverine and dipyridamole were inhibitors of phosphodiesterase and calcium accumulation. Nafronyl bound to beta 2- and alpha-sites and antagonized calcium accumulation. Mebeverine bound to beta 2- and alpha-receptors and inhibited phosphodiesterase activity and calcium accumulation. Verapamil bound to alpha-sites, and blocked phosphodiesterase and calcium accumulation. Quinazosin bound to beta 2- and alpha-receptors and antagonized both phosphodiesterase activity and calcium accumulation. Vasodilators that were inactive in all assays included niacin, nicotinyl alcohol, inositol nicotinate, amyl nitrite, sodium nitroprusside, diazoxide, hydralazine, and protoveratrine. Vasodilators should not be considered as a single drug class since they act on various mechanisms related to coupling of neuronal excitation to muscular contractility.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

Short in vitro half-life of thymopoietin32--36 pentapeptide in human plasma.

Thymopoietin32--36 (TP5) is a synthetic pentapeptide that has the biological activity of its parent molecule, the 49 amino acid thymic hormone thymopoietin. Tritiated thymopoietin32--36 (3 /-TP5) was prepared by reductive tritiation of dibromotyrosyl-TP5. The stability of 3 H-TP5 in human plasma was studied by analyzing samples by thin-layer chromatography at different time points and quantitating the radioactivity associated with TP5 (Arg-Lys-Asp-Val-Tyr) and its tyrosyl-containing breakdown products (Lys-Asp-Val-Tyr, Asp-Val-Tyr, Val-Tyr, Tyr). In plasma (but not in saline) the pentapeptide was rapidly degraded (apparent t1/2 approximately 30 seconds) with the corresponding appearance of radioactivity associated with the other tyrosyl-containing reference compounds. These data imply that the pentapeptide, which is active in vivo, may rapidly trigger changes in responsive cells; sustained circulating levels may not be required for activity.

Adult↗
PubMed1979

A new assay for the measurement of mediator release from rat peritoneal mast cells.

In this report, we describe a new in vitro experimental system for monitoring the release, and inhibition of release, of [3H]-serotonin from rat peritoneal mast cells, which can be used as a novel screen for evaluation of compounds effective in immediate hypersensitivity reactions. This assay is an improvement on existing assays since the cells are not required to be exposed to hormones at any time during the procedure. In this assay, 1 microgram/ml of compound 48/80 consistently produced a 6- to 8-fold-increase in release of serotonin with a low background release of 4-5%. Disodium chromoglycate (DSCG), a standard inhibitor of histamine release, effectively inhibited compound-48/80-stimulated serotonin release with an average I50 of 2.1 X 10(-4) M. Several other potential antiasthmatic agents were far more potent than DSCG.

5-Hydroxytryptophan↗