David W. Mason

Implantable microencapsulated dopamine (DA): a new approach for slow-release DA delivery into brain tissue.

Biodegradable controlled-release systems constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional and histochemical observations, indicating that implantation of DA microcapsules into striatal tissue assures a prolonged release of the transmitter in situ. This technology has considerable potential for basic and possibly also clinical research.

The fate of biodegradable microspheres injected into rat brain

Biodegradable microspheres made with poly-[D,L-lactide-co-glycolide] represent an evolving technology for drug delivery into the central nervous system. Even though these microspheres have been shown to be engulfed by astrocytes in vitro, the purpose of the present study was to track the fate of biodegradable microspheres in vivo. This was accomplished using microspheres containing the fluorescent dye coumarin-6 followed 1 day, 1 week and 1 month after intracerebral injections of this material were made into the rat brain. Using dual color immunohistochemistry and antisera against glial fibrillary acidic protein for astrocytes versus phosphotyrosine for microglia, results demonstrate that phagocytosis of small coumarin-containing microspheres <7.5 microm in diameter was primarily by microglia in vivo during the first week post-injection. In contrast, only a small minority of these microspheres appeared to be engulfed by astrocytes.

Catecholamine-containing biodegradable microsphere implants as a novel approach in the treatment of CNS neurodegenerative disease. A review of experimental studies in DA-lesioned rats.

Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly (dl-lactide-co-glycolide) constitute an exciting new technology for drug delivery to the central nervous system (CNS). Implantable controlled-release microspheres containing dopamine (DA) or norepinephrine (NE) provide a novel means to compare DA- or NE-induced restitution of function in unilateral 6-hydroxydopamine lesioned rats. A suspension of 3 μL of DA- or NE-containing microspheres or empty microspheres was implanted in 2 sites of the DA denervated striatum of rats previously unilaterally lesioned with 6-hydroxydopamine. Contralateral-rotational behavior induced by apomorphine was used as an index of lesion success and, following implantation of the microspheres, also as an index of functional recovery. Interestingly, both DA- and NE-microsphere-implanted rats displayed a 30–50% reduction in the number of apomorphine-induced rotations up to 8 wk postimplantation. Rats implanted with empty microspheres did not demonstrate significant changes in contralateral rotational behavior. Behavioral studies following implantation of a mixture of DA and NE microspheres revealed an 80% decrease in the number of apomorphine induced rotations up to 4 wk. On conclusion of the studies, immunocytochemical examination revealed growth of DA and tyrosine hydroxylase immunoreactive fibers in the striatum of DA and NE microsphere-implanted rats. Functional behavior appeared to correlate with the degree of fiber growth. Preliminary electron microscopic studies showed signs of axonal sprouting in the vicinity of the implanted microspheres. No growth was noted in rats implanted with empty microspheres. This report reviews the abilities of both microencapsulated NE and DA to assure functional recovery and to promote DA fiber (re)growth in parkinsonian rats. This novel means to deliver these substances to the central nervous system could be of therapeutic usefulness in Parkinsons disease.

Microencapsulated dopamine (DA)-induced restitution of function in 6-OHDA-denervated rat striatum in vivo: comparison between two microsphere excipients.

Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly [DL lactide-co-glycolide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microspheres encapsulated within two different polymer excipients into denervated- striatal tissue assures a prolonged release of the transmitter in vivo. Moreover, in this regard, the results show that there were clear cut temporal differences in the effect of the two DA microsphere formulations compared in this study, probably reflecting variations in the actual composition (i.e., lactide to glycolide ratio) of the two copolymer excipients examined. This technology has considerable potential for basic research with possible clinical application.

Dopamine fiber growth induction by implantation of synthetic dopamine-containing microspheres in rats with experimental hemi-parkinsonism.

Injectable local drug delivery formulations-so-called microspheres have recently been developed, in which drugs are microencapsulated within biocompatible and biodegradable copolymer excipients like poly[DL-lactide-co-glycolide]. In view of its potential therapeutical usefulness, we have studied the microsphere methodology as a means to substitute for experimentally induced subnormal levels of endogenous dopamine (DA). Administration of 6-hydroxydopamine (6-OH-DA) unilaterally in the medial forebrain bundle of rats results in an up-regulation of postsynaptic receptors in the denervated striatum, functionally manifested as contralateral rotational behavior after apomorphine. DA microspheres were implanted in the denervated striatum. The majority of the rats displayed an attenuation of the contralateral rotational behavior induced by apomorphine up to 8 wk postimplantation. Immunocytochemical observations unexpectedly demonstrated growth of DA and tyrosine hydroxylase immunoreactive fibers in the denervated striatum. Interestingly, there was an apparent correlation between functional recovery and the degree of growth of DA fibers. The present results suggest that implantation of DA microspheres may promote DA fiber growth and extended recovery of surviving DA neurons, and, therefore, could be of therapeutic usefulness in Parkinsons disease.

Implantable microencapsulated dopamine (DA): prolonged functional release of DA in denervated striatal tissue

Biodegradable controlled-release microcapsule systems made with the biocompatible biodegradable polyester excipient poly [DL-lactide-co-gly-colide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microcapsules encapsulated within two different polymer excipients into denervated striatal tissue assures a prolonged release of the transmitter in vivo. This technology has a considerable potential for basic and possibly clinical research.

Catecholamine-Containing Biodegradable Microsphere Implants: An Overview of Experimental Studies in Dopamine-Lesioned Rats

The main neurochemical characteristic of Parkinson’s disease (PD) is a marked lesion of the nigro-striatal dopamine pathway. In attempts to provide dopamine replacement therapy to Parkinson’s patients, the current medication is L-DOPA (Birkmayer and Hornykiewicz, 1961). Dopamine (DA) itself cannot be taken orally because it will not reach the brain. Unfortunately, L-DOPA can cause serious adverse reactions and its effectiveness decreases with time. For these reasons, there has been an increasing demand for and interest in novel techniques for site-directed delivery of substances into the central nervous system (CNS) (Stahl, 1984).

Sampling and Analytical Methods for the Determination of Monochloroacetic Acid in Air

A personal sampling and analytical method has been developed for the determination of monochloroacetic acid (MCA) vapor in air. The sampling procedure is the collection of MCA with a solid sorbent sampling tube packed with silica gel. The MCA is leached from the exposed sorbent into distilled, deionized water and quantitated by ion chromatographic analysis. The method has been validated in the concentration range of 0.35 to 29 mg/m3 in 3-L air samples. The capacity of the silica gel is in the range of 3 to 4 mg of MCA per 100 mg of sorbent, which allows for up to 8 hr of sampling at concentrations greater than 40 mg/m3. There are no significant interferences from glycolic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, fluoride and chloride compounds, or water vapor. The effects on the analytical data due to variations in the temperature and humidity of the test atmosphere, sample storage time and chromatographic parameters have been found to be minimal.