Larry J. Caldwell

Enhancement of rectal absorption of insulin using salicylates in dogs

Sodium salicylate and 5‐methoxysalicylate both increased the rectal absorption of insulin in dogs when co‐administered with insulin in various formulations. Microenema formulations containing 4% gelatin showed the highest insulin biavailability of the formulations studied whereas microenemas (without gelatin) and suppository formulations were not as effective in enhancing the rectal absorption of insulin.

Controlled Gastric Emptying. 1. Effects of Physical Properties on Gastric Residence Times of Nondisintegrating Geometric Shapes in Beagle Dogs

The importance of three physical parameters (size, shape, and flexibility) on gastric retention in fasting dogs was examined to assess the feasibility of designing a dosage form to achieve a consistent and predictable residence in the stomach. Test shapes were molded from Silastic elastomer or made from extruded polyethylene or polyethylene blends and included 15% barium sulfate for X-ray visualization. Beagle dogs were dosed with test shapes administered in gelatin capsules. Gastric retention was monitored by X ray over a 24-hr period. Six shapes (ring, tetrahedron, cloverleaf, disk, string, and pellet) were screened in vivo for their gastric retention potential. The tetrahedrons (each leg 2 cm in length) exhibited 91–100% retention at 24 hr. The rings (3.6-cm diameter) provided 100% retention at 24 hr. Rings and tetrahedrons of varying flexural moduli were prepared by blending low-density polyethylene and ethylene: vinyl acetate copolymer. A positive correlation existed between flexural modulus and gastric retention. The results indicate that it is feasible to design a platform for a dosage form that can be administered to beagle dogs in capsule form and be retained for 24 hr.

Disposition of radiolabelled suppositories in humans

The disposition of Witepsol H 15 suppositories radiolabelled with [99m Tc] technetium hydroxymethyldiphosphonate was studied after rectal administration in volunteers. The migration of the radiolabel was monitored continuously by external scintigraphy. The resulting scintiphotos were superimposed on lower GI radiographs to determine the extent of spreading of the dosage form in the rectum. The dosage form migrated approximately 5−7 cm into the rectum in nearly all of the studies and was, in general, confined to the lower and middle regions of the rectum. Since the venous supply to the lower rectum leads primarily to the inferior vena cava, the data presented here indicate that the metabolism of drugs sensitive to the ‘first‐pass’ effect may be partially avoided by their rectal administration.

Lymphatic uptake of water-soluble drugs after rectal administration

Certain drugs appear to avoid first-pass liver metabolism following rectal administration (de Boer & Breimer 1980). This indicates that the hepatic portal system is not the only pathway by which rectally absorbed drugs enter the general circulation. Historically, first-pass avoidance after rectal administration was rationalized in terms of a partial direct shunt provided by certain haemorrhoidal veins connecting the rectal vasculature to the inferior vena cava. This study demonstrates the influence of lymphatic cannulation and diversion on bioavailability after rectal drug administration. A significant fraction of highly polar test compounds is shown to be absorbed into the lymphatic system after rectal administration in the presence of salicylate-type absorption adjuvants.

Systemic delivery of timolol after dermal application: Transdermal flux and skin irritation potential in the rat and dog.

Timolol, a beta-adrenergic antagonist, was evaluated for transdermal flux with rat skin in vitro and with the dog in vivo. Skin irritation after dermal application of timolol was assessed in the rat in vivo. Drug flux across rat skin in vitro ranged between 2 and 110 µg cm−2 hr−1, dependent on the formulation. The transdermal flux of timolol in the dog was greater than 10 µg cm−2 hr−1. This estimate was based on the degree of antagonism of isoproterenol challenge following transdermal administration of timolol relative to that obtained following intravenous administration of timolol. Irritation was observed in the rat after occluded dermal application of timolol free base but was not observed when the concentration of the drug in the formulation was decreased.

Enhancement of rectal absorption of water-soluble antibiotics in dogs

Abstract The effects of sodium 5-methoxysalicylate and sodium salicylate on the rectal absorption of sodium penicillin G, gentamicin sulfate, sodium cefoxitin and sodium cefmetazole are reported. It was found that both adjuvants improve the rectal absorption of these water-soluble antibiotics. However, sodium 5-methoxysalicylate was more effective. Rectal bioavailability of these antibiotics depends both on the concentration of the adjuvant used and on the dosage form. In these studies, a lipophilic suppository base seems to provide a satisfactory vehicle for delivery of the water-soluble drugs resulting in rectal bioavailabilities of ~85% for penicillin G, ~50% for cefoxitin, ~50% for cefmetazole and ~35% for gentamicin compared with intravenous administration over the time period of 0–120 min.

Inhibitory effect of salicylate on 2,4-dinitrophenol and diethyl maleate in isolated rat intestinal epithelial cells

Studies on the mechanism of chemically induced intestinal epithelial injury were carried out using isolated, rat small intestinal epithelial cells. Compounds such as 2,4-dinitrophenol (DNP) and diethyl maleate (DEM), caused NADH loss, an increase in cytosolic Ca2+ concentration and protein thiol loss. Further, these compounds accelerated cell aggregation and decreased cell viability. Calmodulin antagonists inhibited protein thiol loss induced by either of the compound, inhibited cell aggregation and prolonged cell viability, but did not influence NADH loss. It has been reported that the calmodulin-binding protein may regulate cytoskeletal activity. Therefore, the inhibition of protein thiol loss by calmodulin antagonist may be due to a dissociation of calmodulin-binding proteins from cytoskeletal elements. Salicylate also inhibited protein thiol loss induced by DNP and DEM, and inhibited cell aggregation. However, salicylate may have a direct effect in reducing the cytosolic free Ca2+ concentration by complexation and subsequent facilitated release of Ca2+ from cells. Further, in the present study, the induction of cell aggregation may be caused by the appearance of specific sites on the cell membrane surface to which arsenazo III could adsorb, since adsorption of arsenazo III to the isolated epithelial cells seemed to correlate with increased cell aggregation.

Drug Distribution and Biliary Excretion Pattern of a Cyclic Somatostatin Analog: A Comparison of 14C Labeled Drug and a 131I lodinated Drug Analog

A cyclic somatostatin analog was compared to an iodinated analog of the same compound with respect to organ distribution and biliary excretion in the rat. The cyclic hexapeptide was radiolabeled with either 14C or 131I (tyrosine). Organ distribution of the iodinated compound as a function of time was nearly identical to that observed for the non-iodinated compound. Results indicated a rapid uptake by the liver and subsequent rapid excretion of the intact peptide in bile. Activity in other organs examined tended to fall off in a manner similar to the activity in blood with sequential samples. Because of the similarity in the in vivo behavior of the two compounds, the iodinated analog was deemed a suitable model for less invasive distribution studies, and was further examined in the dog using external gamma scintigraphy. In the unanesthetized dog the iodine activity was rapidly taken up by liver and collected in the gallbladder, thus exhibiting a similar rapid excretion pattern to that observed in the rat.

Induction of microvillous fusion and pinching-off by Concanavalin A

Concanavalin A (Con A) caused dramatic changes in the structure and function of rat colonic epithelium. The morphological effect was a pronounced, permanent alteration of the microvilli, including fusion and blebbing. The functional change involved an increased permeability to passively transported hydrophilic marker compounds. The functional change was transient in nature. Since coadministration of glucose or mannose inhibited the effect of Con A, the mechanistic effect of Con A probably involves binding to saccharide components of the membrane surface.

Noninvasive Monitoring of the In Vivo Release Characteristics of Rectal Drug Delivery Devices

The rational design of controlled rectal delivery devices suggests that for a given drug there are preferred patterns of controlled release that may optimize the therapeutic value of a drug. The optimized temporal pattern designed within the dosage form should utilize, control or modify the physiological/biochemical environment in which the drug release is occurring.