Medical Literature - 2001

C1 esterase inhibitor: new preparation 6/2001 Prescrire International

(1) The reference prophylaxis of attacks of hereditary angioneurotic oedema is oral danazol, an androgenic steroid, which takes a few days to act. There was previously no curative treatment authorised in France. (2) C1 esterase inhibitor is now licensed in France as replacement therapy for patients with hereditary angioneurotic oedema due to a quantitative or qualitative deficiency in this protein. (3) The clinical evaluation file partly answers the practical questions that arise in this setting, but it does not include trials versus danazol. (4) In 36 patients with acute attacks of angioneurotic oedema, a double-blind trial showed that symptom relief was achieved in less than half an hour in 69% of attacks treated with C1 esterase inhibitor, compared to only 2% of attacks treated with placebo. (5) In the prophylactic setting, a crossover trial involving six patients refractory to conventional androgen therapy showed that injections of C1 esterase inhibitor every three days were more effective than a placebo in reducing the risk of attacks. (6) No major adverse effects have been attributed so far to C1 esterase inhibitor, but the fact that the drug is derived from human blood means that treatment carries a theoretical risk of infection by conventional infectious agents (especially nude viruses) and prions. (7) In practice, for life-threatening attacks of angioneurotic oedema, C1 esterase inhibitor is rapidly effective in two-thirds of patients and is now the reference treatment. In the absence of comparative trials, danazol remains the first-line prophylaxis when patients are scheduled for surgery a few days later, but C1 esterase inhibitor is useful when danazol is ineffective. C1 esterase inhibitor is the only available prophylaxis for patients undergoing emergency surgery (within a few hours).

Jun;10(53):67-70

Not available online.

Shahidi NT 9/2001 Clinical Therapeutics (Clin.Ther.)

BACKGROUND: Since its discovery in 1935, numerous derivatives of testosterone have been synthesized, with the goals of prolonging its biological activity in vivo, producing orally active androgens, and developing products, commonly referred to as anabolic-androgenic steroids (AAS), that are more anabolic and less androgenic than the parent molecule.

OBJECTIVE: This article reviews the structure, biotransformation, and mechanism of action of testosterone and some of the most commonly used AAS. Clinical applications of the AAS are discussed, and guidelines and therapeutic maneuvers for minimizing their side effects are outlined.

METHODS: Literature for inclusion in this review was identified using the libraries of the University of Wisconsin Medical School and School of Pharmacy, the author’s files, and searches of MEDLINE, Science Citation Index, Biological Abstracts, and Chemical Abstracts.

RESULTS: The myotrophic action of testosterone and its derivatives and their stimulatory effects on the brain have led to widespread use of AAS by athletes and “recreational” drug users. Consequently, all AAS were classified as class III controlled substances in 1991. Nonetheless, AAS have shown benefit in a variety of human disorders, including HIV-related muscle wasting and other catabolic conditions such as chronic obstructive pulmonary disease, severe burn injuries, and alcoholic hepatitis. Because of their diverse biological actions, AAS have been used to treat a variety of other conditions, including bone marrow failure syndromes, constitutional growth retardation in children, and hereditary angioedema. AAS therapy is associated with various side effects that are generally dose related; therefore, illicit use of megadoses of AAS for the purpose of bodybuilding and enhancement of athletic performance can lead to serious and irreversible organ damage. The most common side effects of AAS are some degree of masculinization in women and children, behavioral changes (eg, aggression), hepatotoxicity, and alteration of blood lipid levels and coagulation factors.

CONCLUSIONS: To minimize or avoid serious toxicities with AAS therapy, close medical supervision and periodic monitoring are important, with dose adjustment as appropriate to achieve the minimum effective dose. Given the biological effects and potential adverse effects of AAS, administration of these agents should be avoided in pregnant women, women with breast cancer or hypercalcemia, men with carcinoma of the prostate or breast, and patients with nephrotic syndromes or significant liver dysfunction. [References: 239].

Sep;23(9):1355-1390

Available online at: clinicaltherapeutics.com/article/S0149-2918%2801%2980114-4/abstract (small fee)

Kirschfink M, Mollnes TE 7/2001 Expert Opinion on Pharmacotherapy (Expert Opin.Pharmacother.)

Excessive activation of the protein cascade systems often leads to severe inflammatory tissue destruction with potential life-threatening outcome. These include clinical disorders, such as capillary leak syndrome, septic shock, myocardial infarction and other ischaemia/reperfusion injuries, trauma, burns, multiple organ failure, as well as graft rejection. A therapeutic substitution of appropriate regulators appears to be a reasonable approach to reduce undesirable inflammatory reactions. C1-inhibitor, a multifunctional regulator of the various kinin-generating cascade systems, is frequently reduced in patients suffering from severe inflammation. C1-inhibitor concentrate has been used for decades as a substitution therapy to treat acute attacks in patients with hereditary angioedema. Studies including pathophysiologically relevant animal models now provide sufficient evidence that C1-inhibitor may also serve as an effective means to protect against inflammatory tissue injury. Promising clinical results are emerging which support C1-inhibitor as a candidate for therapy in severe inflammatory disorders. Although treatment with C1-inhibitor is regarded as safe, recent reports on possible side effects in certain clinical situations emphasise the importance of controlled clinical studies. The following review will focus on the impact of C1-inhibitor treatment on diseases, where complement contributes to the pathogenesis. [References: 138].

Jul;2(7):1073-1083

Available online at: tandfonline.com/doi/abs/10.1517/14656566.2.7.1073 (small fee)

Lodi G, Sardella A, Bez C, Demarosi F, Cicardi M, Carrassi A /2001 Special Care in Dentistry

The purpose of this study was to investigate the self-perceived dental care needs and dental experiences of patients with angioedema. At the 1998 annual meeting of the Voluntary Association for the Fight, Study and Treatment of Hereditary Angioedema (“Associazione volontaria per la lotta, lo studio e la terapia dell’angioedema ereditario”), a self-administered questionnaire was distributed to participants affected by hereditary or acquired angioedema. Fifty-seven persons completed the questionnaire (37 females, 20 males; mean age, 39 +/- 17 yrs; range, 5-76). The vast majority (91%) had the hereditary form of the disease. One-third of the respondents had some problems in obtaining oral treatment, with one person having been refused care. About half of the group had experienced an acute attack following dental treatment. Preventive measures needed improvement in about two-thirds of respondents. More than half (58%) of the group perceived a need for dental care. We conclude that persons with angioedema may experience difficulty in obtaining dental treatment, a common cause of acute attacks.

21(1):27-31

Available online at: onlinelibrary.wiley.com/doi/10.1111/j.1754-4505.2001.tb00220.x/abstract (small fee)

Nzeako UC, Frigas E, Tremaine WJ 11/2001 Archives of Internal Medicine (Arch.Intern.Med.)

Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10,000 to 1 in 150,000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named “type 3” HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain. [References: 100].

Nov 12;161(20):2417-2429

Available online at: archinte.jamanetwork.com/article.aspx?articleid=649449

Duponchel C, Di Rocco C, Cicardi M, Tosi M /2001 Hum.Mutat

Hereditary angioedema (HAE) is due to a variety of defects in the C1 inhibitor gene (C1NH gene), including approximately 20% of partial deletions/duplications whose boundaries are usually within Alu repeats. To ensure complete molecular characterization of C1 inhibitor deficiencies a fluorescent multiplex assay was constructed to amplify simultaneously five exons of C1NH and an exon of the BRCA1 gene. PCR protocols were optimized for these amplicons (size range between 300 and 700 bp). Forward and reverse chimeric primers that carry strand-specific 5′ tags of 16 nucleotides were used to ensure similar levels of PCR products for each amplicon in the multiplex. Data were analyzed by superposing fluorescent profiles of test and control DNA and by visually comparing the normalized peak levels of corresponding amplicons, rather than by calculating the ratios of peak areas. Tests on a collection of known defects, including five different Alu-mediated deletions and a partial duplication have validated this approach. In a study of 19 sporadic cases of HAE, of which four had failed to reveal mutations upon screening all exons by fluorescent chemical cleavage, three de novo deletions were diagnosed by using this multiplex PCR approach: a deletion of exon 4, a deletion of exons 5 and 6, and an apparently complete gene deletion. Besides being suitable for the initial DNA screening of the C1NH gene in HAE patients prior to screening for point mutations, this method can be easily adapted to complex genes for the screening of rearrangements.Copyright 2001 Wiley-Liss, Inc.

17(1):61-70

Available online at: onlinelibrary.wiley.com/doi/10.1002/1098-1004%282001%2917:1%3C61::AID-HUMU7%3E3.0.CO;2-9/abstract;jsessionid=C1383B899400799A193ACFE43E278D79.f02t01 (small fee)

Pfefferkorn T, von Stuckrad-Barre S, Herzog J, Gasser T, Hamann GF, Dichgans M 1/2001 Stroke

Jan;32(1):17-21

Available online at: stroke.ahajournals.org/content/32/1/17.long