George A. Elliott

The Propionic Acids. Gastrointestinal Toxicity in Various Species

The propionic acids represent the largest chemical class of nonsteroidal anti-inflammatory agents (NSAID). Several of them are widely used, both in the United States and internationally. This paper discusses observations made on fenoprofen, flurbiprofen, ibuprofen and naproxen. Of these compounds, three are racemates; the fourth, naproxen, is an enantiomer. As a group, the propionic acids, along with most members of the other classes of NSAID, produce gastrointestinal damage in most species. These lesions vary from erythema, hemorrhage and erosion to ulceration and peritonitis. As might be expected, the degree of gastrointestinal intolerance depends on many factors: the individual compound, the dose-level, the duration of the period of drug administration, and the pharmacokinetics and metabolism in a given species. For example, in our experience the rat is less tolerant of NSAID than is the monkey, and the dog is less tolerant than the rat. Gastrointestinal lesions have been seen following both parenteral and oral administration; these findings suggest that factors other than local irritation play a role in the development of lesions. Most NSAID inhibit prostaglandin cyclo-oxygenase activity, which results in a prostaglandin deficiency at the tissue level. The administration of relevant exogenous prostaglandins, such as 16,16-dimethyl PGE2, has been shown to inhibit the gastrointestinal toxicity accompanying the administration of several NSAID, including some of the propionic acids.

Herpes keratitis in rabbits: pathogenesis and effect of antiviral nucleosides.

Certain pyrimidine nucleosides have proved to be effective antiviral agents. The two that have received most attention are 5-iodo-2’-deoxyuridine (idoxuridine or IDU) and 1-/3-D-arabinofuranosylcytosine (cytarabine or CA) . IDU was first reported by Herrmann (1961) to show activity against herpes simplex virus in cell culture; subsequently, Kaufman (1962; see also Kaufman et al., 1962) found the compound to be markedly effective in treating herpetic keratitis in rabbits and in man. Shortly thereafter, CA, a nucleoside that contains a metabolically normal base but an abnormal sugar, was found in our laboratory to be similarly active against herpes virus in both cell cultures and rabbit eyes (Underwood, 1962; Buthala, 1964). CA also has demonstrated clinical efficacy in treatment of herpes keratitis (Kaufman & Maloney, 1963). Considerable interest has resulted from these reports describing successful therapy of established viral disease in man. Several publications have reported virus levels in the corneal epithelium of infected eyes treated with IDU (Jawetz et al., 1963; Ey et al., 1964; Engle & Stewart, 1964); however, these virus studies did not include other parts of the eye, nor was the effect of CA evaluated. There also are several papers describing the pathogenesis of experimental herpes keratitis (Wolter et al., 1956; Kimura, 1962; Hogan et al., 1964), but detailed studies on the pathology associated with virus infection in treated eyes are lacking. We undertook a comprehensive study of treated versus nontreated herpes eye infections in albino rabbits and will summarize the salient results in this report.

The clinical pharmacology of methylprednisolone sodium phosphate. I. Intramuscular route of administration.

Intramuscularly administered methylprednisolone sodium phosphate (Medrol Stabisol) in single doses of 40, 80, or 160 mg (methylprednisolone equivalents) had a similar effect as the same doses of methylprednisolone sodium succinate (Solu-Medrol) with regard to eosinophil suppression, elevation of glucose, white blood count differential shifts (lympholytic effect), urinary excretion of sodium and potassium, and localized (pain) and systemic side effects. The average plasma methylprednisolone concentration was approximately 20% higher after the intramuscular administration of methylprednisolone sodium phosphate than after methylprednisolone sodium succinate. The differences in plasma methylprednisolone levels produced by the two esters suggest that either hydrolysis of the succinate ester occurs more slowly or the succinate ester distributes more extensively. This difference in plasma level, however, is not reflected in any other pharmacologic evaluation of the two esters, e.g., both eosinophil depression and hyperglycemic response were identical. No clinically significant changes in the vital signs, standard hematology, and clinical chemistry parameters evaluated were noted after 21 successive doses (q.i.d. for five days with one dose in the morning of day 6) of 80 mg methylprednisolone sodium phosphate. An increase was noted in the systolic blood pressure from a pretreatment mean of 113 mm Hg to a posttreatment mean of 123 mm Hg and an increase in the body weight from a pretreatment mean of 177 pounds to a posttreatment mean of 183 pounds. No signs of adrenal suppression were found as judged by plasma cortisol and ACTH levels. Six (6/12) subjects of the methylprednisolone sodium phosphate group, one (1/12) subject of the vehicle group, and one (1/12) subject of the placebo (sterile saline) group reported the following systemic side effects: gas in stomach, headaches, anorectal itching, and dryness of itching of the skin. No trend was observed for any side effect reported. In these double-blind, randomized studies, single (40, 80, and 160 mg) and multiple (80 mg) intramuscular doses of methylprednisolone sodium phosphate were tolerated in healthy volunteers as well as the same doses of methylprednisolone sodium succinate and similar volumes of vehicle or placebo.

Preliminary animal toxicology and human tolerance of anti-herpes agent U-3243

This drug, 4′-[2-nitro-1-(p-tolythio)ethyl] acetanilide, has shown efficacy against herpes simplex infection in animal studies, In tolerance studies in animals, the LD50 was 234 mg/kg intraperitoneally in mice and >8000 mg/kg orally in rats. Given for 20–30 days, the drug was generally well tolerated by rats, dogs, and rabbits. In double-blind, placebo-controlled oral tolerance tests in healthy prison inmates, doses as high as 2 mg/kg—much higher than would be used topically in treating herpes simplex—appeared to be safe. Topical applications under double-blind conditions were well tolerated and caused no important side effects. No serious side effects were found in human tolerance testing with U-3243.

Morphologic effects of mildly irritating topical agents.

Abstract Subacute dermal applications of 5% U-3243, 4′-[2-nitro-1-( p -tolylthio)ethyl]acetanilide, in Veriderm base, 2 5% U-3243 in an 11.5% hexadecyl alcohol base 3 and U-19,718 (kalafungin, an antibiotic) in 5% N -methylpyrrolidone and 95% propylene glycol produced a similar repetitive, cyclic, exfoliative process in rabbits. Skin effects in the studies with U-3243 in Veriderm and in those with U-19,718 appeared to be associated primarily with the compounds themselves. However, in the studies with U-3243 in hexadecyl alcohol, applications of base alone produced effects that were indistinguishable from those produced by the base plus U-3243. Similar changes were seen in the keratinizing nonglandular forestomach of the rat dosed orally with U-19,718. The continuing need for a better animal model on which to base a prediction of human dermal toxicity is emphasized since human dermal tolerance studies with U-3243 in 11.5% hexadecyl alcohol have been free of skin changes.

INTRANASAL TOXICITY TESTING OF ANTIVIRAL AGENTS

The p r i n c i p a l f a c t o r s t o b e considered i n t h e i n t r a n a s a l t o x i c i t y t e s t i n g of a n t i v i r a l agen t s have much i n common wi th those considered i n t h e t e s t i n g of any o t h e r agent given by t h e same route . The goa l i n both in s t ances is t o approximate as nea r a s p o s s i b l e t h e test cond i t ions e s t a b l i s h e d f o r and encountered i n human c l i n i c a l s t u d i e s . I t e m s f o r cons ide ra t ion inc lude s e l e c t i o n of an i n s t i l l a t i o n technique, t h e spec ie s of t e s t animal and methods f o r eva lua t ing drug e f f e c t s .

The clinical pharmacology of methylprednisolone sodium phosphate. II. Intravenous route of administration.

Doses of 1, 3, 5, 10, 20 and 30 mg/kg of methylprednisolone sodium phosphate (MSP) or methylprednisolone sodium succinate (MSS) or similar volumes of vehicle or sterile saline administered intravenously at random in a double-blind fashion to healthy volunteers were well accepted, tolerated, and safe when given as a bolus over a 10-min period. MSP and MSS when administered in equal doses had a similar effect on eosinophil suppression, glucose elevation, WBC differential shifts (lympholytic effect), urinary excretion of sodium and potassium, and plasma cortisol concentrations (fasting or after ACTH challenge). No clinically significant drug-related changes were found in the vital signs, EKGs, EEGs, intraocular pressure, or standard clinical laboratory evaluations. With the 30-mg/kg dose, side effects were observed. In the multiple-dose iv study, no adverse drug reaction was noted after 80- or 40-mg single doses of MSP or MSS. Eosinopenia and hyperglycemia occurred within 2 hr postinjection. A tendency to return toward pretreatment values was noted within 24 hr after the last injection. Both forms of methylprednisolone when given in equivalent doses caused eosinopenia and hyperglycemia of a similar magnitude. No statistically significant differences were found among the four treatment groups in the EKGs PR, QRS, QT intervals, and PR rates. MSP when given in 40-mg iv doses was as well tolerated as MSS. However, 80-mg doses of MSP were not tolerated as well as 40-mg doses of MSP or 80-mg doses of MSS.