Properties controlling the diffusion and release of water-soluble solutes from poly(ethylene oxide) hydrogels: 3. Device geometry.

The diffusive release from hydrogels can be determined by both composition and geometry. This paper presents a theoretical and experimental comparison of the release characteristics of proxyphylline in water-swollen slabs, spheres, and cylinders of a urethane cross-linked poly(ethylene oxide). Contrary to general conventional wisdom it was found that practically cylinders and spheres, which have considerable potential advantages for oral delivery, can provide good 'anomalous' rates for which the 'exponent of release' into water from the dry xerogels is c. 0.8 compared with 1.0 for zero order. An exponent of 0.94 was found for release into water from 'larger' xerogel flat slabs thus confirming that these configurations can provide essentially constant delivery formulations from which the active agent cannot be 'dumped'. For up to 40% total drug release, the theoretical release profiles were essentially of identical form for all three geometries in the swollen state and, as expected in theory and practice, showed an exponent for release of close to 0.5. However, the experimental release of proxyphylline was found to be more sustained from swollen spheres of these polymers than theory would predict. The half life times for release were further extended by approximately two and a half times for the initially dry devices compared with the initially swollen ones.

Properties controlling the diffusion and release of water-soluble solutes from poly(ethylene oxide) hydrogels. 4. Extended constant rate release from partly-coated spheres.

Spheres of poly(ethylene oxide) xerogel from 4-17 mm diameter were impregnated with the drug, proxyphylline, or the herbicide, 2,4-DNa and then partly coated with a water-impermeable elastomer. When placed in water the active additive was released over periods ranging from hours to weeks at a nearly constant rate. The effect of the hydrogel sphere dimensions and the window size through the elastomer, on water uptake and consequent release of the active agent were examined. These devices superficially possess a configuration similar to some commercial osmotic devices though the active-agent release from the devices of this paper is, in fact, diffusive and not osmotically driven. They appear to provide a very versatile and simple design allowing relatively constant release of the active agent over periods of hours to months merely by changing the device geometry.

Porogens in the preparation of microporous hydrogels based on poly(ethylene oxides).

To enable the synthesis of hydrogels containing microporosity, a family of pore generating additives (porogens) were synthesized from poly(ethylene glycols) (PEGs) with different molecular weights using naphthyl acetic acid. The products formed were characterized by UV-vis, differential scanning calorimetry and solution nuclear magnetic resonance techniques. Subsequently, poly(ethylene oxide)-urethane hydrogels were synthesized incorporating the above mentioned PEG porogens to modify the structure of the hydrogel. These highly water soluble PEG porogens were inert and extracted out in water. The hydrogels obtained exhibited significant increase in the equilibrium water uptake. This was attributed to the formation of a microporous structure in the hydrogel. It was also evidenced by the observed increase in the diffusion coefficients of the drugs proxyphylline and vitamin B12 through this hydrogel. The proportional increase was greater for the higher molecular weight vitamin B12 than for the proxyphylline. These results may be useful in developing porous hydrogels for controlled release technology.

Properties controlling the diffusion and release of water-soluble solutes from poly(ethylene oxide) hydrogels. 2. Dispersion in an initially dry slab.

The mechanisms which control the release of dispersed water-soluble drugs from an initially dry hydrogel are complex. The release profile derives from a combination of several contributing factors which may change with time at different rates. It has been possible to isolate controlling factors and investigate their individual contributions to the release kinetics. The hydrogels presented in this paper owe their hydrophilicity to their poly(ethylene oxide) content. They swell and can absorb up to three times their dry weight in water. Having a glass transition temperature (Tg) below body temperature they are essentially different to those studied theoretically or experimentally, by other groups, which have Tg values above body temperature and are initially glassy. A range of diffusates was studied ranging from low water-soluble prostaglandin E2 to highly water-soluble lithium chloride. Device geometry was restricted to approximations to infinite slabs with more than 85% total surface area over the top and bottom surfaces so that release was predominantly one-dimensional and the controlling variable was thickness. The increase in surface area with time, drug-solubility in the water-swelling matrix and the presence of crystallinity were shown to be important factors governing the profile and level of release rate with time. It was observed that the release profile could be separated into three parts, the most important being the middle section from early in the release until at least the half-life time. This period could be characterized by the exponential time function, tn. The diffusional exponent, n, is an important indicator of the release mechanism and ranged from 0.79 to 1, i.e. good anomalous to zero order. This is a highly desirable range of values for controlled release devices. The value of n decreases at late-time. The very early-time release can also show a burst or lag effect depending on the diffusate solubility and its loading in the xerogel.

Properties controlling the diffusion and release of water-soluble solutes from poly(ethylene oxide) hydrogels. 1. Polymer composition.

This study examines the state of water-association with poly(ethylene oxide), as evidenced by diffusivity, in a series of crosslinked polyurethanes made from poly(ethylene glycols) of a range of molecular weights. As a subsidiary underpinning exercise the correlation of diffusivity with water content at relatively high levels of swelling (> 45%) using a variety of semi-empirical equations was analyzed. Three water-soluble compounds with similar molecular weights and which exhibit minimal interaction with the polymer, as shown by their partition coefficients, were chosen for this part of the research programme. These were proxyphylline, morphine hydrochloride and caffeine. The best statistical correlations of the data were obtained for plots of: (a) diffusivity against weight percent water; and (b) log diffusivity against the reciprocal of the weight percent of water in the hydrogels. Proxyphylline results for the high levels of swelling compositions were augmented with data from lower swelling compositions and a clear break in the slope of diffusivity against percentage of water in the swollen hydrogel was obtained. This indicated a change in the nature of the diffusion at this point. The probability of this transition point corresponding to a change for diffusion through water bound as trihydrate to diffusion in free water is discussed.

Effects of short-day photoperiods and of N-(2,4-dinitrophenyl)-5-methoxytryptamine, a putative melatonin antagonist, on melatonin synthesis in the Harderian gland of the Syrian hamster, Mesocricetus auratus.

The Harderian glands of Syrian hamsters contain melatonin and the enzymes N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) which synthesize melatonin from serotonin. Because the Harderian glands share this metabolic pathway with the pineal gland, we examined the effects of short-day photoperiods, which stimulate pineal-mediated gonadal regression, and N-(2,4-dinitrophenyl)-5-methoxytryptamine (ML-23), which has been described as a melatonin antagonist, on melatonin synthesis in the Harderian glands of the hamster. Harderian glands of male hamsters kept in short days had reduced NAT activity and melatonin concentration, but HIOMT activity was unchanged from that of long-day controls. In males kept in short days, ML-23 restored melatonin concentrations to levels seen in long days but did not affect the short-day induced reduction in NAT activity. ML-23 had no effect upon NAT or HIOMT activity or melatonin concentration in male hamsters kept on long days. Harderian glands of female hamsters kept on short days had reduced melatonin concentrations, but NAT and HIOMT activities similar to those of long-day controls. ML-23 had no effect on Harderian NAT or HIOMT activities or melatonin concentration in females kept in short days. However, in females kept in long days, ML-23 treatment led to increased NAT activity and decreased melatonin concentrations. We conclude from these results that short-day photoperiods alter some aspects of melatonin synthesis in hamster Harderian glands and that these effects differ in males and females. ML-23 does not usually prevent the effects of short days on Harderian melatonin synthesis, suggesting that it is not a melatonin antagonist in the Syrian hamster.

Multiple pregnancy-induced remissions of psoriatic arthritis: case report.

A patient experienced remission of the pain and inflammation of psoriatic arthritis during her first and second pregnancies. She achieved full remission during her third pregnancy and remained asymptomatic 15 months post partum. Patients with autoimmune arthritis who become pregnant provide an in vivo model in which the role of sex hormones on immune responses can be studied.

Mental imagery and its potential for physical therapy.

The purposes of this article are 1) to review the sports and motor-learning literature regarding the effects of mental imagery and mental practice on physical skills and 2) to explore the feasibility of using them as adjunctive techniques in physical therapy. In the area of sports, evidence exists that mental practice can improve motor skills. Research that supports a mind-body relationship is cited, in addition to research using mental imagery from the areas of medicine, biofeedback, psychoneuroimmunology, and physical therapy. Variables that influence the outcome of mental practice such as vividness, kinesthetic imagery, and combining physical and mental practice are examined, and two major variables associated with ineffective results are identified. The advantages and disadvantages of using mental imagery for physical therapy patients are discussed with the conclusion that mental imagery has the potential to be a viable technique for physical therapists.

Hydrogels for controlled drug delivery.

Physical properties such as number average molecular weight Mn, specific hydrates and changing diffusion coefficient of crystalline/rubbery hydrogels based on poly(ethylene glycol) Mn 3 000-8 000 which affect the diffusion of drugs through the water swollen matrix and across the polymer boundary are discussed. The advantage of starting with a dry, drug-impregnated polymer to obtain the desirable zero order release rate while the hydrogel absorbs water is illustrated. Drugs have been classified into five groups showing different release profiles. The effects of design and loading on the release profile, are described including the first clinical results of morphine loaded hydrogel suppositories.

Membranous structures in pinealocytes of the Chinese hamster (Cricetulus griseus); are they annulate lamellae?

Pinealocyte ultrastructure in the normal and spontaneously diabetic Chinese hamster has been studied. A literature comparison shows it to be similar to the pineal of the Syrian hamster; however, the incidence of membranous structures is more frequent in the Chinese as compared with the Syrian hamster. Stacks of membranous structures were present in pinealocytes of all animals in this study and, therefore, appear to be regularly occurring organelles in the pineal of this species. There are analogies between these membranes and annulate lamellae; however, like annulate lamellae, their functional significance is unknown.

Induction of labour with a sustained-release prostaglandin E2 vaginal pessary.

A new polymer vaginal pessary providing sustained constant release of prostaglandin E2 was administered to 66 patients before planned induction of labour. Effective ripening of the unfavourable cervix was achieved in each of 18 primigravidas, in eight of whom labour was initiated without further treatment. When the cervix was moderately favourable the need for orthodox induction of labour was obviated in 16 out of 23 primigravidas and 21 out of 23 multigravidas. This method of sustained release of prostaglandin E2 is simple and convenient and readily acceptable to the patient; it is an important step in the development of non-invasive methods of inducing labour.

The synaptic ribbons of the guinea pig pineal gland in sterile, pregnant and fertile but non-pregnant females and in reproductively active males.

Pinealocyte ultrastructure has been studied in four sterile, four pregnant and three fertile but non-pregnant females, and also in three reproductively active male pigmented Duncan Hartley guinea pigs. Synaptic ribbons are dense, rod-like structures with a linear arrangement of clear vesicles periodically spaced on both sides of the rodlet. Although these structures were observed in the pinealocytes of all of the animals studied, they were scarce and difficult to locate in tissue from the fertile, non-pregnant females and from the reproductively active males. They were numerous in the pineal glands of the pregnant and sterile females. Typically they lie perpendicular to the cell membrane of the pinealocyte polar process and in close proximity to a polar process of a neighboring cell. The increased incidence of synaptic ribbons in pinealocytes which appear to be in a heightened state of activity strongly suggests a function for this structure. Synaptic ribbons are also present in sensory systems such as rods and cones of the retina, hair cells of the organ of Corti and hair cells of the vestibular apparatus. This fact, plus the photoreceptor function of pinealocytes in lower vertebrates, lends credence to the possibility that this structure may serve a sensory or receptor function in the guinea pig gland.

Graphic representation of the distribution of acetylcholinesterase in cat dorsal root ganglion neurons.

Acetylcholinesterase (AChE) activity of primary sensory neurons of the cat has been quantitated and correlated with cell size. Dorsal root ganglia of the fourth and fifth thoracic spinal levels were studied. Frozen longitudinal and cross-sections were collected serially and stained with Cresyl Violet for total cell counts of the ganglia on the left; the average count was 3375 cells. Ganglia from the right were stained for AChE after the method of Karnovsky & Roots (1964) as modified by El Badawi & Schenk (1967), and counterstained with Haematoxylin. Cells were counted in every fourth section and the diameter of each was recorded. AChE-positive cells were classified as brown (B1, B2, B3) and AChE-negative ones as blue (BL). An inverse correlation exists between cell size and AChE activity. High activity was demonstrated in 29% of the cells (B1), moderate activity in 52% (B2), minimal activity in 15% (B3) and 4% were classified as AChE-negative (BL). Small cells with high activity were centrally located in the ganglia whereas large AChE-negative cells were peripherally distributed. Chi-Square analysis revealed that the size of the cell was not independent of the enzyme colour category.

Membranous structures in pinealocytes of the infertile diabetic mutant mouse (C 57 BL/Ks-db/db).

The fine structure of the pineal gland of the infertile, diabetic mutant mouse (C 57 BL/Ks-db/db) has been studied. Light and dark parenchymal cells were observed. The major population of pinealocytes in these animals is characterized by an abundance of highly organized membranes located in both the cell body and cell processes. Pinealocytes containing these membranous structures have low electron density (light pinealocytes) and large amounts of perinuclear cytoplasm containing granular vesicles and extensive Golgi. Dilated cisternae of the membranous structures may indicate secretory activity or selective aggregations or raw material. Changes in granule and vesicle content of the central core of cytoplasm of the concentric-shaped membranes and their apparent migration from the cell body to terminal process suggest a synthetic or secretory role. It is not known whether the membranous structures are related to the infertile condition or to the hyperglycemic syndrome; however, the presence of comparable membranes in subterranaen mammals lends support to the theory that the structures may be involved in the synthesis of pineal compounds.

Acetylcholinesterase activity of primary sensory neurons and dorsal root fibers in the cat.

Dorsal roots and spinal ganglion cells of adult cats were studied for acetylcholinesterase (AChE) content. An inverse correlation exists between cell size and AChE activity; large neurons are AChE-negative whereas small ones are intensely AChE-positive. A few AChE-positive fibers were demonstrated in the dorsal roots. A possible correlation between AChE activity and substance P content of primary sensory neurons is discussed.

An unusual organelle in the pineal gland of the rat.

An electron microscopic survey of pinealocytes from normal rats revealed a highly organized arrangement of cytoplasmic tubules. Such tubules had been previously observed in normal rats (Lin, 1967) and in rats after melatonin administration or two weeks exposure to darkness (Freire and Cardinali, 1975). In a later publication the presence of the tubules was attributed to experimental manipulation resulting in infertility (Gusek, 1976). The present study resolves the discrepancy in the literature by establishing that the tubular organelle does indeed occur in untreated male rats, but rather rarely.