Effectiveness and safety of levocetirizine 10 mg versus a combination of levocetirizine 5 mg and montelukast 10 mg in chronic urticaria resistant to levocetirizine 5 mg: A double-blind, randomized, controlled trial.

BACKGROUND: Chronic urticaria is a vexing problem for patients and treating physicians alike. The EAACI/GA[2]LEN/EDF/WAO guidelines advocate an increased antihistamine dosage up to four times the standard, before adding leukotriene receptor antagonists. Patients are frequently intolerant of these higher dosages. We conducted this study to determine whether the addition of leukotriene receptor antagonists to the standard antihistamine dose was comparable to higher dosages of antihistamines alone, in terms of efficacy, safety and quality of life changes. We compared levocetirizine 10 mg (double dose of standard) versus a combination of levocetirizine 5 mg and montelukast 10 mg in cases of chronic urticaria not responding to single daily dose of 5 mg levocetirizine. METHODS: A single-center, double-blind, randomized, active-controlled, parallel group phase IV trial (CTRI/2014/12/005261) was conducted on 120 patients of chronic urticaria of either sex not responding to 5 mg levocetirizine. Patients were randomized into receiving either levocetirizine 10 mg or levocetirizine 5 mg + montelukast 10 mg for 4 weeks. Primary outcome measures were Urticaria Activity Score (UAS) and Urticaria Total Severity Score (TSS). Routine hematological and biochemical tests and treatment-emergent adverse events were monitored for safety. RESULTS: Fifty-two patients on levocetirizine 10 mg group and 51 patients on levocetirizine 5 mg + montelukast 10 mg group were analyzed. UAS and TSS reduced significantly in both treatment groups and reduction of score were comparable in between the groups (P = 0.628, P = 0.824, respectively). Among adverse effects, sedation was noted significantly more (P = 0.013) in levocetirizine 10 mg group. Quality of life was significantly improved in levocetirizine 5 mg + montelukast 10 mg group (P = 0.031). LIMITATIONS: The limitation of the study was that the follow-up period was 4 weeks. CONCLUSION: EAACI/GA[2]LEN/EDF/WAO guidelines need to be more flexible in allowing usage of montelukast before escalation of anti-histamine dosage.

"The legacy of thalidomide" - A multidisciplinary meeting held at the University of York, United Kingdom, on September 30, 2016.

BACKGROUND: Between 1957 and 1962 thalidomide was used as a nonaddictive, nonbarbiturate sedative that also was successful in relieving the symptoms of morning sickness in early pregnancy. Infamously, thousands of babies were subsequently born with severe birth defects. The drug is used again, today, to successfully treat leprosy, and tragically, there is a new generation of thalidomide damaged children in Brazil. While the outward damage in babies has been documented, the effects of the damage upon the survivors as they grow up, the lifestyle changes and adaptations required to be made, as well as studies into ageing in survivors, has received little attention and remains understudied. METHODS: A unique multidisciplinary meeting was organized at the University of York bringing together thalidomide survivors, clinicians, scientists, historians, and social scientists to discuss the past, the current and the future implications of thalidomide. RESULTS: There is still much to learn from thalidomide, from its complex history and ongoing impact on peoples' lives today, to understanding its mechanism/s to aid future drug safety, to help identify new drugs retaining clinical benefit without the risk of causing embryopathy. CONCLUSION: For thalidomide survivors, the original impairments caused by the drug are compounded by the consequences of a lifetime of living with a rare disability, and early onset age-related health problems. This has profound implications for their quality of life and need for health and social care services. It is vital that these issues are addressed in research, and in clinical practice if thalidomide survivors are to "age well". Birth Defects Research 109:296-299, 2017. © 2017 Wiley Periodicals, Inc.

O uso da talidomida em seres humanos e animais ­ passado, presente e futuro / The use of thalidomide in people and animals ­ past, present and future / El uso de talidomida en seres humanos y animales ­ pasado, presente y futuro

A talidomida foi desenvolvida na década de 50 do século XX, e foi amplamente utilizada como um sedativo-hipnótico e como fármaco contra enjoos durante a gestação. No final da década de 60 ela foi retirada do mercado devido ao seu catastrófico efeito colateral de teratogenicidade. Contudo, o próprio mecanismo que é basicamente responsável pela sua teratogenicidade é também responsável por uma de suas muitas propriedades farmacológicas potencialmente benéficas e desejáveis, a anti-angiogênese. Felizmente, as pesquisas dos efeitos terapêuticos da droga não se cessaram e em 1998 o fármaco foi aprovado pelo Food and Drug Administration (FDA) para tratamento do eritema nodoso leproso e em 2006 para tratamento de mieloma múltiplo. Hoje, quase 40 anos depois, a mesma temida talidomida ressurge como fármaco de propriedades imunomoduladoras e antiangiogênicas, com potencial para tratamento de doenças inflamatórias, infecciosas e neoplásicas. Na medicina veterinária ainda pouco se sabe sobre os efeitos terapêuticos do fármaco, entretanto, o sucesso terapêutico do fármaco já fora observado em diversas situações clínicas em pessoas e em testes com animais, podendo existir indicação nas doenças homólogas na medicina veterinária. Este artigo traz uma revisão de literatura sobre a talidomida e suas aplicações reais e potenciais em medicina veterinária.(AU)

Thalidomide was developed in the 1950's and was broadly used as a hypnotic-sedative drug and against nausea during pregnancy. At the end of the 1960's, the drug was withdrawn from the market due to its catastrophic side effect, teratogenicity. However, the anti-angiogenic action, which is the mechanism of action that is responsible for thalidomide´s teratogenicity is also responsible for one of the several potentially useful and desired pharmacologic properties. Fortunately, investigations on the therapeutic effects of thalidomide did not cease and in 1998, the drug was approved by the Food and Drug Administration (FDA) to treat erythema nodosum leprosum and, in 2006, for treating multiple myeloma. Nowadays, almost 40 years later, the same feared thalidomide is reborn as a pharmacologic agent with immunomodulatory and anti-angiogenic properties, with potential to treat inflammatory, infectious and neoplastic diseases. In veterinary medicine, very little is known about the useful healing effects of thalidomide. However, the drug therapeutic success has already been noted in several clinical situations in both animal tests and investigations with medical patients. This paper presents a literature review of thalidomide's real and potential applications in veterinary medicine.(AU)

La talidomida fue desarrollada en los años 50 del siglo XX, y fue ampliamente empleada como sedativo e hipnótico y como fármaco contra nauseas durante el embarazo. A finales de los años 60 ella fue retirada del mercado debido a su efecto secundario catastrófico de teratogenicidad. Sin embargo, el propio mecanismo que es básicamente responsable por su teratogenicidad es también responsable por una de las muchas propiedades farmacológicas potencialmente beneficiosas y deseables, la antiangiogénesis. Afortunadamente, las investigaciones de los efectos terapéuticos de la droga nunca se ha cesado y en 1998 el medicamento fue aprobado por Food and Drug Administration (FDA) para tratamiento del eritema nudoso leproso, y en 2006 para tratamiento del mieloma múltiple. Hoy, casi 40 años después, la misma y temida talidomida reaparece como medicamento con propiedades inmunomoduladoras y antiangiogénicas, con potencial para el tratamiento de enfermedades inflamatorias, infecciosas y neoplásicas. En medicina veterinaria, se sabe poco sobre los efectos terapéuticos del fármaco, sin embargo, el éxito terapéutico del medicamento se ha observado en varias situaciones clínicas en personas y en ensayos con animales, y puede ser indicado en las enfermedades homólogas en medicina veterinaria. Este artículo trae una revisión de literatura sobre la talidomida y sus aplicaciones reales y potenciales en medicina veterinaria.(AU)

Indicaciones terapéuticas actuales de la talidomida y la lenalidomida / Current therapeutic indications of thalidomide and lenalidomide

La talidomida es un derivado sintético del ácido glutámico, introducido por primera vez en Alemania en 1956 como un medicamento de venta sin receta. La aprobación fue como sedante seguro, incluso a pequeñas dosis, no adictivo y sin efectos secundarios tales como debilidad motora, pero fue retirada de la circulación por asociarse a graves malformaciones en recién nacidos. Más tarde, laFood and Drug Administration aprobó su uso en el tratamiento del eritema nudoso leproso y también demostró eficacia en otros procesos dermatológicos refractarios tales como el prurigo actínico, la histiocitosis de Langerhans del adulto, la estomatitis aftosa, el síndrome de Behçet, la enfermedad del injerto contra el huésped, la sarcoidosis cutánea, el eritema multiforme, la infiltración cutánea linfocitaria de Jessner-Kanof, el sarcoma de Kaposi, el liquen plano, el lupus eritematoso sistémico, el melanoma, el prurigo nodular, el pioderma gangrenoso y otros. En mayo de 2006 fue aprobada para el tratamiento del mieloma múltiple. Nuevos análogos de la talidomida, como la lenalidomida, han sido desarrollados, aunque con escasa experiencia clínica. Este trabajo es una revisión de la historia, farmacología, mecanismo de acción, usos clínicos y efectos adversos de la talidomida y sus análogos (AU)

Thalidomide is a synthetic glutamic acid derivative first introduced in 1956 in Germany as an over the counter medications. It was thought to be one of the safest sedatives ever produced as it was effective in small doses, was not addictive, and did not have acute side-effects such as motor impairment, but was quickly removed from market after it was linked to cases of severe birth defects. The Food and Drug Administration approved use in the treatment of erythema nodosum leprosum. Further, it was shown its effectiveness in unresponsive dermatological conditions such as actinic prurigo, adult Langerhans cell hystiocytosis, aphthous stomatitis, Behçet syndrome, graft-versus-host disease, cutaneous sarcoidosis, erythema multiforme, Jessner-Kanof lymphocytic infiltration of the skin, Kaposi sarcoma, lichen planus, lupus erythematosus, melanoma, prurigo nodularis, pyoderma gangrenosum and others. In May 2006, it was approved for the treating multiple myeloma. New thalidomide analogues have been developed but lack clinical experience. This paper is a review of the history, pharmacology, mechanism of action, clinical applications and side effects of thalidomide and its analogues (AU)

Recognition of the phenotype of thalidomide embryopathy in countries endemic for leprosy: new cases and review of the main dysmorphological findings.

Thalidomide is the best-known teratogen worldwide. It was first marketed as a sedative in the late 1950s, but the birth of ~10 000 children with birth defects resulted in the withdrawal of thalidomide from the market in 1962. Thalidomide embryopathy affects almost all organs but the main defects are concentrated in the limbs, eyes, ears, and heart. Shortly after the withdrawal of thalidomide from the market, its effectiveness in the treatment of erythema nodosum leprosum, an inflammatory condition resulting from leprosy, was reported and since the mid-1990s, the drug has been used widely in the treatment of cancers and autoimmune diseases, among other conditions. 40 000 new cases of leprosy are diagnosed every year in Brazil. Although there is a strict legislation for the prescription and use of thalidomide in Brazil, cases of thalidomide embryopathy have continued to be reported. Here, we present two new cases of thalidomide embryopathy identified in 2011 and review the major clinical findings in the literature that can aid the identification of the embryopathy.

Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction.

Systemic and oral clearances of alfentanil (ALF) are in vivo probes for hepatic and first-pass cytochrome P450 (CYP) 3A. Both ALF single-point plasma concentrations and miosis are surrogates for area under the concentration-time curve (AUC) and clearance and are minimal and noninvasive CYP3A probes. This investigation determined ALF sensitivity for detecting graded CYP3A induction and compared it with that of midazolam (MDZ). Twelve volunteers (sequential crossover) received 0, 5, 10, 25, or 75 mg oral rifampin for 5 days. MDZ and ALF were given intravenously and orally on sequential days. Dark-adapted pupil diameter was measured with blood sampling. Graded rifampin decreased plasma MDZ AUCs to 83, 76, 62, and 59% (intravenous (i.v.)) and 78, 66, 39, and 24% (oral) of control. Hepatic and first-pass CYP3A induction were detected comparably by plasma MDZ and ALF AUCs. Single ALF concentrations detected all CYP3A induction, whereas MDZ was less sensitive. ALF miosis detected induction of first-pass but not hepatic CYP3A.

Thalidomide: an old drug with new clinical applications.

Thalidomide has several targets and mechanisms of action: a hypnosedative effect, several immunomodulatory properties with an effect on the production of TNF-alpha and the balance between the different lymphocyte subsets and an antiangiogenic action. Thalidomide has been used in several cutaneous inflammatory disorders (e.g., erythema nodosum leprosum in lepromatous leprosy, cutaneous lupus erythematosus and severe aphtosis), cancers (e.g., relapsed/refractory multiple myeloma, malignant melanoma and systemic signs in cancer) and inflammatory conditions (e.g., Crohn's disease and rheumatoid arthritis). Several side effects are associated with thalidomide. Some are major, such as teratogenicity, peripheral neuropathy and deep vein thrombosis. Somnolence and rash are frequently reported when thalidomide is used at higher doses as an anticarcinogenic agent and can lead to dose reduction or treatment discontinuation depending on severity. Minor side effects include abdominal pain and endocrine disturbances. To prevent the teratogenicity, use of thalidomide is strictly controlled in western countries with close adherence to a birth control programme. Close monitoring for early development of peripheral neuropathy is also recommended.

[Thalidomide--a dreaded drug with new indications]. / Thalidomid--fryktet medikament med nye bruksområder.

BACKGROUND: Thalidomide was introduced as a non-toxic sleeping pill in 1957 and was prescribed in more than 20 countries. In 1961 the link between congenital limb defects and thalidomide use in pregnancy was proven, resulting in withdrawal of the drug. MATERIAL AND METHODS: On the basis of literature searches and personal experience we review the effects and use of thalidomide today. RESULTS: In vitro, thalidomide has immunoregulatory properties. This has lead to the administration of thalidomide in many immunological diseases. In 1964 it was discovered that thalidomide was effective against erythema nodosum leprosum. Thalidomide also has effect on aphthous stomatitis and Behçet's disease. The effect is more uncertain in graft-versus-host-disease, rheumatoid arthritis and Crohn's disease. Thalidomide reduces angiogenesis in experimental animals, and this has led to several studies of thalidomide as a possible anticancer drug. Advanced or resistant multiple myeloma may be a new target for thalidomide; at least 30% of these patients obtain response during treatment. Results indicate that patients with breast cancer and glioma do not benefit from treatment with thalidomide. INTERPRETATION: Thalidomide has proven to be effective in the treatment of erythema nodosum leprosum and aphthous stomatitis. It is also effective in advanced multiple myeloma, but not in other cancers.

Thalidomide: 40 years on.

Thalidomide was marketed in the late-1950s as a sedative and tranquilliser of exceptionally low general toxicity, but in 1961 it was implicated separately by Lenz and MacBride as the cause of the epidemic of congenital malformations that had been puzzling the world for some years. It is a very potent teratogen in humans, but in few other mammalian species; damage to the embryo is produced at specific stages of gestation, but the mechanism of embryopathic action is still not understood. Following the withdrawal of the drug worldwide, it was consigned to the history of medical tragedies. In 1965, however, Sheskin discovered that it was effective in treating erythema nodosum leprosum, a distressing complication of leprosy. As the drug is neither an antibiotic nor an analgesic, its action was assumed to be immunosuppressive. In Brazil the drug was used widely with few regulatory controls, since when more than 100 cases of congenital malformation have appeared. Sheskin's discovery led to the experimental use of thalidomide in many other indications thought to possess some immunological component. In some cases, e.g. Behçet's syndrome, graft-versus-host disease and aphthous ulceration in HIV-positive patients, the drug has been shown to possess some efficacy. And there is some evidence that it inhibits the replication of one of the immunodeficiency viruses. The AIDS community in the US has exerted much pressure on the FDA to allow the drug on to the market, although the use of a potent immunosuppressive drug of unknown mechanism in an immunodeficiency condition raises further questions. Thalidomide is not always beneficial; its use is associated with an increased mortality in epidermal necrolysis. In 1991, D'Amato confirmed it possessed antiangiogenic properties and this led to further trials in malignant conditions. Results were mixed, but those in multiple myeloma gave some grounds for optimism. In 1998, the FDA announced its extraordinary decision to grant marketing approval for thalidomide.

Thalidomide does not alter estrogen-progesterone hormone single dose pharmacokinetics.

OBJECTIVES: To determine the single- and multiple-dose pharmacokinetics of oral thalidomide (200 mg/day, administered for 21 days) and to assess the effects of steady-state plasma concentrations of thalidomide on the single-dose pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: A randomized, 2-period crossover study was performed in 10 healthy premenopausal female volunteers. The pharmacokinetic profiles of plasma concentrations of thalidomide were evaluated with both noncompartmental and compartmental methods, whereas those of ethinyl estradiol and norethindrone were calculated with noncompartmental methods. The effects of steady-state plasma thalidomide concentrations on the pharmacokinetics of ethinyl estradiol and norethindrone were determined with use of an ANOVA model that included treatment sequence, subject within sequence, period, and treatment as factors. RESULTS: Thalidomide plasma concentrations were best predicted by a 1-compartment model with first-order absorption and elimination and an absorption time-lag. There were no significant differences between pharmacokinetic parameters for thalidomide after 1 dose and those after 18 consecutive doses. Except for a minor decrease of the elimination rate constant (k(e)) for ethinyl estradiol, coadministration of thalidomide had no significant effects on the pharmacokinetic profiles for either ethinyl estradiol or norethindrone. The change in k(e) for ethinyl estradiol during thalidomide administration was not associated with any alteration in the clearance or elimination half-life for this hormone. CONCLUSIONS: Multiple-dose pharmacokinetics of thalidomide is similar to the single-dose profile. This study did not investigate the efficacy of the 21-day fixed ethinyl estradiol-norethindrone regimen, but the results suggest that thalidomide is unlikely to affect the pharmacokinetics of orally administered hormonal contraceptives.

Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity.

The sedative drug thalidomide ([+]-alpha-phthalimidoglutarimide), once abandoned for causing birth defects in humans, has found new therapeutic license in leprosy and other diseases, with renewed teratological consequences. Although the mechanism of teratogenesis and determinants of risk remain unclear, related teratogenic xenobiotics are bioactivated by embryonic prostaglandin H synthase (PHS) to a free-radical intermediates that produce reactive oxygen species (ROS), which cause oxidative damage to DNA and other cellular macromolecules. Similarly, thalidomide is bioactivated by horseradish peroxidase, and oxidizes DNA and glutathione, indicating free radical-mediated oxidative stress. Furthermore, thalidomide teratogenicity in rabbits is reduced by the PHS inhibitor acetylsalicylic acid, indicating PHS-catalyzed bioactivation. Here, we show in rabbits that thalidomide initiates embryonic DNA oxidation and teratogenicity, both of which are abolished by pre-treatment with the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). In contrast, in mice, a species resistant to thalidomide teratogenicity, thalidomide does not enhance DNA oxidation, even at a dose 300% higher than that used in rabbits, providing insight into an embryonic determinant of species-dependent susceptibility. In addition to their therapeutic implications, these results constitute direct evidence that the teratogenicity of thalidomide may involve free radical-mediated oxidative damage to embryonic cellular macromolecules.

Novel biological response modifiers derived from thalidomide.

Thalidomide (N-alpha-phthalimidoglutarimide) was used widely as a hypnotic/sedative agent in the late 1950s and the early 1960s, but had to be withdrawn from the market because of its severe teratogenicity. In spite of this, there has been a resurgence of interest in the drug in recent years due to its potential usefulness for the treatment of various diseases, including acquired immunodeficiency syndrome (AIDS) and graft-versus-host disease (GVHD). The effectiveness of the drug in these diseases has been attributed to its specific inhibitory activity on tumor necrosis factor-alpha (TNF-alpha) production. Because TNF-alpha, a cytokine mediating host defence and immune regulation, with a wide range of activities, has deleterious pathophysiological effects in various diseases, including AIDS, tumors, rheumatoid arthritis and diabetes, its production-regulators are attractive lead compounds for novel biological response modifiers. The regulatory effect of thalidomide on TNF-alpha production has been found to be bidirectional, depending on both the cell-type and the TNF-alpha production-inducer; i.e., thalidomide possesses both enhancing and inhibiting activities on TNF-alpha production. Structural modification of thalidomide aiming at the creation of superior TNF-alpha production-regulators has afforded a number of phenyl- and benzylphthalimide analogs possessing more potent activity than thalidomide itself. The structure-activity relationships of these analogs has been investigated. The bidirectional TNF-alpha production-regulating activity is electronic state- and enantio-dependent, and both pure inhibitors and pure enhancers of TNF-alpha production has been obtained. Further structural development of the phthalimide analogs has yielded potent non-steroidal androgen antagonists.

Immunomodulation by thalidomide: systematic review of the literature and of unpublished observations.

Three decades of immunological investigations using thalidomide are reviewed. Both in vitro and in vivo investigations are in accordance with the clinical finding that thalidomide does not impede T-cell competence in the control of infection by mycobacteriae. The term immunosuppressant does not apply. The immunomodulatory effects of thalidomide are evident in a myriad of phenomenological changes, and a molecularly defined common denominator of these activities is not known at present. Critical assessment with the objective to account for the clinical activity of thalidomide in specific human diseases leads to a focus on effects of thalidomide on phagocytic leukocytes and endothelia. The former are responsive to thalidomide by modulation of cytokine synthesis in vitro and in vivo; this activity can be shown using monocyte-specific stimuli in peripheral blood mononuclear cells but also in other phagocytic cells like microglia. For technical reasons, endothelial cells have until now been tested primarily in vitro. However, there is solid evidence now from intravital microscopy that the induction of adhesivity in postcapillary venules by LPS is modulated by thalidomide. Altered surface antigen expression has been described on leukocytes obtained from humans and experimental animals treated with thalidomide, but convincing evidence is lacking for in vitro modulation of surface antigen expression on leukocytes (as opposed to the modulation of adhesion antigens on endothelial cells stimulated by LPS or exogenous TNF alpha in the presence of thalidomide). Therefore, in vivo redistribution is likely to account for some, if not all, changes in circulating leukocyte phenotypes. The immunopathological conditions most clearly responsive to thalidomide are vasculitic alterations of post-capillary venules either in the context of mycobacterial infection (in the case of erythema nodosum leprosum) or mucocutaneous aphths. In both instances (as in the majority of focal inflammatory lesions), leukocyte infiltration and cytokine responses, in particular TNF alpha, are present. Thalidomide acts clinically not only by palliation of existing lesions but also by prevention of recurrence. The mechanism operates in skin, mucosa and parts of the nervous system and is most readily explained by synergism of TNF alpha modulation and a separate point of action on leukocyte migration patterns.