The Incidence of Agranulocytosis During Treatment of Dermatitis Herpetiformis With Dapsone as Reported in Sweden, 1972 Through 1988

Hörnsten, Per; Keisu, Marianne; Wiholm, Bengt‐Erik

doi:10.1001/archderm.1990.01670310081011

Cited by 62 publications

(19 citation statements)

References 17 publications

(2 reference statements)

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“…Although we recently demonstrated that replacement of the nitro substituents with a cyano substituent has minimal to no effect on the in vivo clearance and half-life of the aryl propionamide SARMs in rats, because of the more rapid metabolism via other pathways in this species, this is unlikely to be the case in higher species (Gao et al, 2006a). As such, inclusion of a cyano substituent in the para-position of the A-ring of aryl propionamide SARMs is likely to be beneficial on the basis of pharmacokinetic and toxicologic considerations (Hornsten et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

Perera¹,

Yin²,

Wu³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Compound S-4 (S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide) is a novel nonsteroidal androgen agonist that mimics many of the beneficial pharmacologic effects of testosterone with lesser effects on the prostate. S-4 demonstrated high androgen receptor binding affinity as well as anabolic specificity during in vivo pharmacologic studies in rats, identifying it as the first member of a new class of selective androgen receptor modulators. The purpose of these studies was to determine the pharmacokinetics and metabolism of S-4 in dogs. S-4 showed linear pharmacokinetics after both intravenous (i.v.) and oral (p.o.) administrations at pharmacologically relevant doses, with a mean clearance of 4.6 ml/min/kg and a mean half-life of about 200 min. It is interesting that dose-dependent oral bioavailability was seen. However, at pharmacologically relevant doses, the oral bioavailability of S-4 was 91%. Species differences were observed in S-4 metabolism; the major metabolic pathway for S-4 in dogs was deacetylation of the B-ring acetamide group and reduction of the A-ring nitro group, whereas the major metabolic pathway for S-4 in rats was hydrolysis on the amide bond and reduction of the A-ring nitro group. In addition, oxidative metabolites and phase II metabolites were identified in both rats and dogs. These studies demonstrate that S-4 maintains its promising pharmacokinetic properties in dogs (i.e., high oral bioavailability and linear kinetics) and is largely eliminated via hepatic metabolism by both phase I and phase II enzymes.Testosterone, an endogenous ligand for the androgen receptor, plays important and diverse physiological roles in several different organ systems, including muscle and bone (George and Wilson, 1986;Hiort, 2002). Testosterone and related anabolic steroids are used clinically as replacement therapy for primary or hypogonadotropic hypogonadism, delayed puberty, anemia, or muscle wasting conditions (Mooradian et al., 1987;Bagatell and Bremner, 1996). However, there are many disadvantages associated with testosterone and anabolic steroid therapy (Basaria and Dobs, 1999). First, current testosterone preparations can only be administered via intramuscular injections (Snyder and Lawrence, 1980). Although 17␣-alkylated androgens were developed for oral administration, they are associated with hepatic toxicity and are less efficacious; hence, they are not recommended for long-term androgen therapy (Swerdloff and Wang, 2002). Second, testosterone injections produce large fluctuations in testosterone plasma concentrations, which may lead to adverse effects such as hepatoxicity, blood pressure effects, and gynecomastia (Heywood et al., 1977;Negro-Vilar, 1999). Third, current steroidal preparations demonstrate equal anabolic and androgenic activity (i.e., they are not tissue-selective). The nonselective nature of testosterone and its derivatives, poor pharmacokinetic properties, and toxicities have led to the search for androgens with improved pro...

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Section: Discussionmentioning

confidence: 99%

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

Perera¹,

Yin²,

Wu³

et al. 2006

Drug Metab Dispos

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“…Drugs containing a primary amine or aromatic nitro are usually associated with a high incidence of idiosyncratic drug reactions (Hornsten et al, 1990;Jorga et al, 1999). From Figs.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Metabolism of a Selective Androgen Receptor Modulator in Rats: Implication of Molecular Properties and Intensive Metabolic Profile to Investigate Ideal Pharmacokinetic Characteristics of a Propanamide in Preclinical Study

Wu¹,

Wu²,

Yang³

et al. 2005

Drug Metab Dispos

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Androgens play important roles in male phenotype development and maintenance of male and female physiology and reproduction (Mooradian et al., 1987). Testosterone and 5␣-dihydrotestosterone are the two main endogenous steroidal androgens involved in reproductive and nonreproductive tissue. Synthesized steroidal androgens have been used as therapeutic agents to treat a broad spectrum of disorders due to androgen deficiency. However, androgen preparations available in the market exhibit severe limitations. Testosterone shows low oral bioavailability, whereas testosterone esters are normally administered via intramuscular injection in oily vehicles, resulting in variable testosterone levels (Handelsman et al., 1990;Wilson, 1996). Although 17␣-alkylated testosterones are orally available, they exhibit a high incidence of hepatotoxicity and less efficacy (Ishak and Zimmerman, 1987). Thus, they are not recommended for long-term androgen therapy. In addition, cross-reactivity occurs between steroidal androgens and/or their in vivo metabolites with steroid receptors other than the androgen receptor, further limiting their clinical use (Wilson et al., 1980;Bhasin and Bremner, 1997). Therefore, there is an urgent need to develop an orally bioavailable drug for patients suffering from a variety of androgen disorders.Nonsteroidal selective androgen receptor modulators (SARMs) possess several advantages over synthesized steroidal androgens, including better receptor selectivity and greater flexibility in structural modification (Zhi and Martinborough, 2001; Yin et al., 2003b,c;Brown, 2004). Our laboratory recently reported the discovery of a series of novel SARMs, with propanamide as a template structure, having potent and tissue-selective in vivo pharmacologic activity (Dalton et al., 1998; Yin et al., 2003a,b,c;Gao et al., 2004;Marhefka et al., 2004;Chen et al., 2005). Among the SARMs discovered in our laboratory, 3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide (denoted hereafter as S-1; Fig. These studies were supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK59800-06).Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

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“…The most frequent adverse events are anemia, methemoglobulinemia, and increased liver enzymes [36]. Agranunlocytosis is rare but at least monthly blood counts are required and in case of fever, agranulocytosis needs to be excluded [46]. Other sulphonamides such as sulfapyridine can also be used [47].…”

Section: Linear Iga Diseasementioning

confidence: 99%

Current Treatment of Autoimmune Blistering Diseases

Kasperkiewicz

Schmidt

2009

CDDT

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Autoimmune bullous diseases are a heterogeneous group of disorders that can be subdivided according to the level of split formation in the intraepidermal blistering pemphigus diseases and subepidermal bullous disorders, latter including pemphigoid diseases, epidermolysis bullosa acquisita, and dermatitis herpetiformis. In the majority of autoimmune bullous disorders, disease activity can be sufficiently controlled by systemic corticosteroids in combination with further immunosuppressants/immunomodulants such as dapsone, doxycycline, methotrexate, azathioprine, or mycophenolate mofetil. In contrast, in pemphigus, mucous membrane pemphigoid, and epidermolysis bullosa acquisita, treatment is challenging and only in a minority of patients, conventional immunosuppressive therapy induces clinical remission. Since only a few years ago, only cyclophosphamide and high-dose intravenous immunoglobulin were available as potent second-line therapies. Meanwhile, immunoadsorption and the monoclonal anti-CD20 antibody rituximab have been established as further therapeutic options. Here, both conventional therapies and novel treatment regimens for autoimmune blistering diseases are discussed.

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The Incidence of Agranulocytosis During Treatment of Dermatitis Herpetiformis With Dapsone as Reported in Sweden, 1972 Through 1988

Cited by 62 publications

References 17 publications

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

Pharmacokinetics and Metabolism of a Selective Androgen Receptor Modulator in Rats: Implication of Molecular Properties and Intensive Metabolic Profile to Investigate Ideal Pharmacokinetic Characteristics of a Propanamide in Preclinical Study

Current Treatment of Autoimmune Blistering Diseases

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