Edwin A. Peets

Interferon therapy for condylomata acuminata.

Current therapy for condylomata acuminata (genital warts) is not consistently effective. Therefore, we conducted a randomized, double-blind trial to compare interferon alpha-2b with placebo in the treatment of this disorder. Our rationale was that interferon has both antiproliferative and antiviral properties. The placebo or interferon (1 X 10(6) IU) was injected directly into one to three warts three times weekly for three weeks. The injections were well tolerated by both groups of patients. The side effects of fever, chills, myalgia, headache, fatigue, and leukopenia occurred more commonly in the interferon group than in the placebo group, but such effects rarely disrupted daily routines. Only 13 of 296 patients (4 percent) discontinued therapy because of side effects (11 in the interferon group and 2 in the placebo group). Twenty-six other patients were excluded from analysis because of a loss to follow-up or other deviations from protocol, thus leaving 257 patients in the final evaluation. At one week after the completion of therapy, interferon had produced a large and significantly greater reduction in mean wart area (a 62.4 percent decrease), as compared with placebo (a 1.2 percent increase in mean area) (P less than 0.001). At the conclusion of the study (13 weeks after the completion of therapy), the mean wart area was still decreased 39.9 percent below the initial size in the interferon group, whereas it had increased by 46 percent over base-line measurements in the placebo group (P less than 0.001). At the same time, all treated warts had completely cleared in 36 percent of the interferon recipients and in 17 percent of the placebo recipients (P less than 0.001), whereas treated warts progressed in 13 percent of the interferon recipients and in 50 percent of the placebo recipients (P less than 0.001). We conclude that injection of interferon alpha-2b directly into genital warts appears to be an effective and fairly well-tolerated form of therapy.

Treatment of basal cell carcinoma with intralesional interferon

Eight patients with basal cell carcinomas were treated with recombinant alpha-2 interferon. Each patient had a biopsy-proved basal cell carcinoma of the nodular or superficial type that was injected intralesionally three times a week for 3 weeks (9 total injections) with 1.5 X 10(6) IU (0.15 ml) of alpha-2 interferon per injection (total dose, 13.5 X 10(6) IU). Excisional biopsy 2 months after completion of therapy revealed no evidence of basal cell carcinoma in any patient. Minimal side effects were observed. In these eight patients alpha-2 interferon was therefore an effective and safe modality of treatment. The encouraging results of this pilot study suggest that additional evaluation of interferon in the treatment of basal cell carcinoma is warranted.

Intralesional interferon therapy for basal cell carcinoma

In a clinical trial of 172 patients at four medical centers, interferon alfa-2b (1.5 x 10(6) IU) or a placebo was injected directly into biopsy-proved noduloulcerative or superficial basal cell carcinomas three times weekly for 3 weeks, for a cumulative dose of 13.5 million IU. Efficacy of treatment was determined at 16 to 20 weeks by examination of biopsy specimens that demonstrated cure of lesions in 86% of interferon-treated patients and in only 29% of placebo-treated patients. During the treatment course and follow-up, an initial inflammatory response was observed at the treatment sites, followed by diminished erythema, improvement in overall appearance, and a decrease in size of lesions. Side effects of treatment, mainly flu-like symptoms, were usually mild and transient and occurred more commonly in the interferon-treated group. Only three patients, all in the interferon-treated group, discontinued therapy because of side effects. One year after initiation of therapy, 81% of interferon recipients and 20% of those given the placebo remained tumor free. Noduloulcerative and superficial lesions were equally responsive to treatment with interferon. For some patients with noduloulcerative or superficial basal cell carcinomas, intralesional interferon alfa-2b may be an alternative, effective treatment.

Plasma binding of betamethasone3H, dexamethasone-3H, and cortisol-14C— A comparative study

Abstract The binding of betamethasone (16β-methyl-9α-fluoroprednisolone) and dexamethasone (16α-methyl-9α-fluoroprednisolone) to the proteins of cow, dog, rat and human plasma has been studied in vitro by an equilibrium dialysis technique. These synthetic steroids were appreciably bound to the plasma proteins of all species, and the degree of binding did not change substantially over a wide range of concentration. Neither of the synthetic steroids was detectably bound to corticosteroid-binding globulin (CBG) in human plasma, nor did it compete with cortisol for its binding protein. In human and cow plasma, betamethasone was bound to protein to a lesser extent than was dexamethasone; while this condition held for dog plasma, the difference in binding was not as pronounced. In contrast to the other species, betamethasone was bound to a greater extent than was dexamethasone in the rat. The synthetic steroids were bound mainly to the albumin fraction of human plasma. Chromatography on Sephadex gel demonstrated that, although albumin has a high capacity for binding dexamethasone, the affinity constant of the steroid-protein complex is of a low order.

Mometasone furoate lotion once daily versus triamcinolone acetonide lotion twice daily in psoriasis

Given mometasones proven efficacy and safety, it was desirable to develop a lotion that would be cosmetically acceptable, particularly for treatment of the scalp. Such a lotion, 0.1%, has now been developed, and this clinical trial was designed to compare its effectiveness and safety when applied once daily (q.d.) in the treatment of scalp psoriasis to that of a widely used treatment of proven efficacy, triamcinolone acetonide lotion 0.1% twice daily (b.i.d.)

LIMITED APPLICATION OF MOMETASONE FUROATE ON THE FACE AND INTERTRIGINOUS AREAS: ANALYSIS OF SAFETY AND EFFICACY

Forty patients with moderate to severe psoriasis or atopic dermatitis were enrolled in a study to determine the safety and efficacy of mometasone furoate. Patients were instructed to apply mometasone furoate ointment 0.1% once daily for 2 weeks. Treatments were applied by the patients to an individual target area that was preselected for evaluation of change in disease signs and symptoms. Psoriatic lesions were graded by evaluating the extent of erythema, plaque thickness, scaling, and pruritus. In patients with atopic dermatitis, erythema, lichenification and pruritus were measured. Each of these parameters was assessed on a scale from 0 to 3: 0 = normal, 1 = mild, 2 = moderate, 3 = severe. Half values were permitted. Evaluations of treated areas were made upon entry into the study and at days 2, 3, 4, 8, and 15. Examinations for signs of skin atrophy and telangiectasia were also made at each visit.

Activity of Intralesional Interferon Alfa-2b in Viral and Malignant Skin Diseases

Interferon alfa-2b (Intron A®) is a highly purified single molecular species of alpha interferon and represents one of the more than twenty that exist naturally in man (1). It is produced using recombinant DNA techniques in the bacterium E. coli and is purified to a specific activity of approximately 2x100 IU/mg of protein. In common with the other alpha interferons, it has potent antiviral and antiproliferative properties when tested in vitro using human cell lines and viruses (2–4). Additionally, it causes the activation of natural killer cells (5), can restore cytotoxicity to functionally deficient monocytes (5), and like other alpha interferons would be expected to enhance antigen expression on cell surfaces (6). These properties suggested that interferon alfa-2b might have clinical utility in treating viral and malignant diseases in man. The ability to achieve high local concentrations in the skin by intralesional injection with comparatively little systemic exposure suggested further that malignant and premalignant skin diseases and those of a viral etiology might be especially amenable to treatment with interferon alfa-2b.

BIOLOGICAL ASPECTS OF ANTIANDROGENS

Flutamide (α,α,α-trifluoro-2-methyl-4′-nitro-m-propionotoluidide) at daily doses from 1–50 mg/kg reduced seminal vesicle and ventral prostate weights of intact male rats. A comparative study in castrated rats revealed that flutamide was equipotent to cyproterone acetate (CPA) as an antiandrogen. These potencies were substantiated by a newly developed assay measuring DNA synthesis rate (Sufrin and Coffey). No androgenic, estrogenic, anti-estrogenic, corticoid, progestational, anti-progestational, or antigonadotrophic activities were observed. Flutamide, given per os daily for either 6 weeks or 1 year to aged dogs with benign prostatic hyperplasia, reduced prostatic size in 6 weeks and the prostate remained reduced at 3, 6 and 12 months after the initiation of drug therapy. Flutamide, given im three times weekly for 4 weeks reduced the size of the baboon prostate (Muntzing et al.). In testosterone propionate-treated castrated rats CPA and flutamide inhibited 3H-testosterone uptake and retention by prostate and prostate nuclei. In a study in 18 patients with far-advanced carcinoma of the prostate, there were seven positive responders, 10 failures and one inconclusive report, following the daily administration of flutamide (Stoliar and Albert). In a similar study, 9 of 12 patients in stage D prostatic carcinoma responded favorably (Prout and Irwin).

Chapter 23. Drug Metabolism

Publisher Summary This chapter discusses results of some studies focusing on drug metabolism, which have revealed that dietary proteins are important factors in drug metabolism. In one study, it was shown that feeding rats a high protein diet led to an increase, and feeding a low or non-protein diet, to a decrease in metabolism of drugs by the liver microsomes. Drug toxicities were also affected by the content of the diet; high protein diets exhibited in most cases lower toxicities. The metabolism and the excretion of some drugs are pH dependent and this dependence (pH-sensitivity) for ephedrines in man varied with the methylation of the amine group. The role of the pituitary in drug metabolism was demonstrated by the decreased metabolism of hexobarbital, aminopyrine, and p-nitrobenzoic acid in rats bearing a pituitary mammotropic tumor. The anterior pituitary hormones secreted by the tumor were responsible for the observed decrease in hepatic microsomal metabolism. This finding was supported by the demonstration that somatotlopin, corticotropin, and prolactin decreased the metabolism of hexobarbital and aminopyrine in rats. The presence of another tumor, the Walker 256 carcinosarcoma, reduced the hydroxylation of amphetamine in rats.

Chapter 22. Drug Metabolism

Publisher Summary This chapter presents the basic concepts of drug metabolism. The metabolism of a drug is dependent on its physicochemical characteristics. Drugs with extremely low lipid solubility are generally not metabolized and are largely excreted in urine. Their excretion is dependent on the glomerular filtration rate, and they are not reabsorbed in the renal tubules. Many types of drugs are metabolized by the liver microsomes to more polar derivatives and however such metabolism is not limited to drugs alone. The analgesic phenyramidol, when given to subjects treated with diphenylhydantoin, increases the mean biological half-life of the latter drug from 25—55 hours. Such inhibition of drug metabolism may result in elevated levels of diphenylhydantoin in plasma and could account for the observed increases in anticonvulsant activity and in possible side effects. The therapeutic or pharmacological properties of noveril, metronidazole, ethionamide, 5-methylpyrazole-3-carboxylic acid are also examined.