Ervin Novak

Effects of a single large intravenous dose of methylprednisolone sodium succinate.

A randomized double‐blind study with placebo control revealed that single large intravenous doses of methylprednisolone sodium succinate produced no serious systemic effects. The effects of a dose of 30 mg. per kilogram given over a 10 minute period were studied. A battery of tests given before, during, and after administration indicated that the physiologic changes are similar in kind and degree to those after oral administration. An ACTH stimulation test suggested that the ability of the adrenal gland to respond is preserved after the single large doses. On the basis of this study it was concluded that, when indicated, doses of up to 30 mg. per kilogram of methylprednisolone sodium succinate were safe for use.

The tolerance and safety of intravenously administered benzyl alcohol in methylprednisolone sodium succinate formulations in normal human subjects.

Abstract Two methylprednisolone sodium succinate formulations with different preservatives (benzyl alcohol and parabens) and a placebo were administered in single doses of 2.0 g to 24 subjects. Both formulations were well tolerated and no important drug-related side effects were encountered. No clinically significant changes in the vital signs, electrocardiograms, electroencephalograms, or laboratory parameters were noted. All expected corticosteroid-induced changes were reversible. The higher antibacterial activity of benzyl alcohol shown in the challenge tests plus comparable tolerance to parabens favor the use of benzyl alcohol as a preservative.

Inflammatory response to sodium lauryl sulfate in aqueous solutions applied to the skin of normal human volunteers.

In this double‐blind study, the intensity and duration of the inflammatory response induced by various concentrations of sodium lauryl sulfate (SLS) solution on the forearms of 36 normal male volunteers was dependent, upon the concentration and number of applications of SLS. One 24‐h application of the 4% or 5% aqueous SLS solution or two successive 24‐h applications of the 2% or 3% SLS solutions were sufficient to cause an inflammatory response in the epidermis. Such response makes the skin more permeable for the testing of topical formulations of compounds to document their propensity to irritate.

The Tolerance of High Dose Intravenous Spectinomycin Therapy in Man

SPECTINOMYCIN hydroehloride* is an aminocyclitol antibiotic1 that has yielded high cure rates (over 95% after a single injection2) in the treatment of gonorrhea.37 For gonorrhea, the antibiotic is given in a single intramuscular injection of 2 or 4 grams. Recent studies have delineated the activity of speetinomycin in vitro against certain Gram-negative aerobic or facultative organisms other than Neisseria gonorrhoeae.8’9 Investigations of clinical efficacy in infections due to other organisms would require multiple-dose administration of spectinomycin at higher dosage levels. This paper reports results of tolerance studies, including evaluation of ototoxicity, with intravenous dosages of up to 8 grams/day of spectinomycin hydrochloride in healthy volunteers.

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.

Antibiotic tolerance and serum levels after intravenous administration of multiple large doses of lincomycin

High doses of lincomycin ranging from 4,800 mg. to 8,400 mg. daily for 7 days were infused into 32 healthy volunteers on a 4 times a day basis in saline infusion volumes of 250 ml. given over a 120 minute period. Placebo groups given saline only in a similar manner were used as controls. No gross abnormalities in vital signs occurred at any time, and no statistically significant differences occurred between the drug and placebo groups. The laboratory tests were always within normal limits; there were no shifts or drug‐related findings. All electrocardiograms and audiometric tracings were normal, and there were no changes from prestudy readings. Side effects were minor and few. Serum levels averaged from approximately 24 to 37 flg per milliliter (peaks) and 10 to 12 μg per milliliter (nadir) for the low‐to high‐dose drug groups. The equilibrium state was reached early in the schedule with little or no drug accumulation after 26 doses. The elimination rate constant K averaged 0.0987 how‐1 with a corresponding average half‐life (T1/2) of 7.16 hours.

Chlorphenesin Carbamate Serum Levels During Subchronic Administration to Human (Normal) Volunteers

T lIE results of a subchronic tolerance study with chiorphenesin carbamate in healthy volunteers at a dose of 3200 mg daily for eight weeks was previously reported by Novak et al.’ As reported by these investigators, no clinically significant laboratory or vital sign changes from pretreatment values or between drug and placebo groups were noted. Concomitant with the above study, blood samples for the determination of serum levels of chlorphenesin carbamate were also collected. The results of these serum level determinations in ten subjects selected from the study group are presented here.

Drugs Affecting Hair Growth

The greatest impact on the study of hair was the discovery of the hair growth cycles1 and their characterisation.2 Hair follicles undergo periods of growth (anagen), quiescence (telogen) and transition (catagen). The cycle can be determined by examination of plucked hairs and by trichograms which give the percentage of growing versus quiescent follicles.3 Hair follicles in anagen and telogen phases differ in their response to X-ray irradiation, illustrating the importance of controlled hair growth studies.4 Cohens5 and Oliver6 showed that follicular growth depends on the interaction between the dermal papilla and the epidermal position of the follicle. Hamilton7 proved that the stimulating factor for common baldness is androgen and that hair follicles are active target organs of testosterone (incorporation and metabolism). Testosterone in the hair follicle is converted to two major metabolites: dihydrotestosterone and androstenedione. The enzyme 5-alpha-reductase converts testosterone to dihydrotestosterone. The activity of this enzyme is 3–8 times higher in anagen than in telogen follicles.8 The formation of dihydrotestosterone is also higher in hair follicles from the frontal scalp than from the occipital scalp.9 Price10 observed that in hair follicles predisposed to baldness increased dihydrotestosterone production played an important role in androgenic alopecia. Many theories have been offered trying to explain baldness: stress, lack of vascularity, lack of innervation, overinnervation, insufficiency of vitamins and hormones, mental disturbances and bad eating habits. However, hair transplantation demonstrated conclusively that the scalp which produces hairs abundantly in some areas but not in others can support hair growth when hairs are grafted onto the bald areas.11

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.