bluuebunny/crossref_metadata_2025 huggingface dataset:
Successive deep dives impair endothelial function and enhance oxidative stress in man
Authors: Obad Ante , Marinovic Jasna , Ljubkovic Marko , Breskovic Toni , Modun Darko , Boban Mladen , Dujic Zeljko
Published: August 2010

The aim of this study was to assess the effects of successive deep dives on endothelial function of large conduit arteries and plasma pro‐oxidant and antioxidant activity. Seven experienced divers performed six dives in six consecutive days using a compressed mixture of oxygen, helium and nitrogen (trimix) with diving depths ranging from 55 to 80 m. Before and after first, third and sixth dive, venous gas emboli formation and brachial artery function (flow‐mediated dilation, FMD) was assessed by ultrasound. In addition, plasma antioxidant capacity (AOC) was measured by ferric reducing antioxidant power, and the level of oxidative stress was assessed by thiobarbituric acid‐reactive substances (TBARS) method. Although the FMD was reduced to a similar extent after each dive, the comparison of predive FMD showed a reduction from 8·6% recorded before the first dive to 6·3% before the third (P = 0·03) and 5·7% before the sixth dive (P = 0·003). A gradual shift in baseline was also detected with TBARS assay, with malondialdehyde values increasing from 0·10 ± 0·02 μmol l−1 before the first dive to 0·16 ± 0·03 before the sixth (P = 0·005). Predive plasma AOC values also showed a decreasing trend from 0·67 ± 0·20 mmol l−1 trolox equivalents (first day) to 0·56 ± 0·12 (sixth day), although statistical significance was not reached (P = 0·08). This is the first documentation of acute endothelial dysfunction in the large conduit arteries occurring after successive deep trimix dives. Both endothelial function and plasma pro‐oxidant and antioxidant activity did not return to baseline during the course of repetitive dives, indicating possible cumulative and longer lasting detrimental effects.
Lymphoedema of the lower extremities – background, pathophysiology and diagnostic considerations
Authors: Jensen Mads R. , Simonsen Lene , Karlsmark Tonny , Bülow Jens
Published: August 2010

Lymphoedema of the lower extremities is a chronic debilitating disease that is often underdiagnosed. Early diagnosis and treatment is paramount in reducing the risk of progression and complications. Lymphoedema has traditionally been defined as interstitial oedema and protein accumulation because of a defect in the lymphatic drainage; however, some findings suggest that the interstitial protein concentration may be low in some types of lymphoedema. Primary lymphoedema is caused by an inherent defect in the lymphatic vessels or lymph nodes. Secondary lymphoedema is caused by damages to the lymphatic system most often caused by cancer or its treatment. Many of the underlying pathophysiological mechanisms have yet to be elucidated. Many methods have been developed for examination of the lymphatic system. Lymphoscintigraphy is presently the preferred diagnostic modality. Lack of consensus regarding protocol and qualitative interpretation criteria results in a too observer dependent outcome. Methods for objectifying the scintigraphy through quantification have been criticized. Depot clearance rates are an alternative method of quantification of lymphatic drainage capacity. This method however has mostly been applied on upper extremity lymphoedema. The aim of this review is to provide a literature‐based overview of the aetiology and pathophysiology of lower extremity lymphoedema and to summarize the current knowledge about lymphoscintigraphy and depot clearance techniques. The abundance of factors influencing the outcome of the examination stresses the need for consensus regarding examination protocols and interpretation. Further studies are needed to improve diagnostic performance and understanding of pathophysiological mechanisms.
Lymphedema as a Postulated Cause of Cutis Verticis Gyrata in Turner Syndrome
Authors: Larralde Margarita , Gardner Stephanie S. , Torrado Maria del V. , Fernhoff Paul M. , Muñoz Andrea E. Santos , Spraker Mary K. , Sybert Virginia P.
Published: August 2010

Abstract: Unusual skin lesions were present at birth in four infants with Turner syndrome. The skin changes in these patients appear to have resulted either from in utero entrapment or pinching of edematous skin or from redundant skin remaining after in utero resolution of lymphedema. Distention by lymphedema is thought to cause several of the phenotypic characteristics seen in patients with Turner syndrome, including nuchal webbing and nail changes. In three of these patients the clinical appearance of the skin changes was similar to cutis verticis gyrata, marked by fixed thickened plaques in folds.
Localized Dystrophic Periocular Calcification: A Complication of Intralesional Corticosteroid Therapy for Infantile Periocular Hemangiomas
Authors: Carruthers Jean , Jevon Gareth , Prendiville Julie
Published: August 2010

Abstract: Two female infants with eyelid hemangiomas developed prickly, rock‐hard, subcutaneous crystals following intralesional corticosteroid injections. In each case, the crystals were isocentered on the injection locus and partly eroded the skin, causing local discomfort and inflammation. This complication occurred after two treatment sessions and presented 8 to 9 months after the second injection. An MRI scan showed subcutaneous calcification in the location of the injected orbital hemangioma in one patient. Histopathologic examination confirmed calcification in areas of degenerate hemangioma. There was no recurrence of either hemangioma or calcium deposition following surgical excision. Localized dystrophic calcification may be a late complication of intralesional corticosteroid therapy of periocular hemangiomas.
Acute Hemorrhagic Edema of Childhood (AHE)
Authors: Gonggryp L. A. , Todd G.
Published: August 2010

Abstract: Four patients with acute hemorrhagic edema (AHE) of childhood are presented. Two patients had associated pulmonary tuberculosis. AHE of childhood is a benign condition, characterized by inflammatory edema and ecchymotic purpura in a target or cockade pattern. Histology of the skin lesions shows typical leucocytoclastic vasculitis and the condition has therefore been considered a variant of Henoch‐Schönlein purpura (HSP). However, because of its benign course, AHE should be considered as a separate entity.
Palmoplantar Eccrine Hidradenitis: Three New Cases and Review
Authors: Landau Marina , Metzker Aryeh , Gat Andrea , Ben‐Amitai Dani , Brenner Sarah
Published: August 2010

Abstract: Palmoplantar eccrine hidradenitis (PEH) is characterized by painful erythematous papules and nodules of abrupt onset on the soles of young individuals. The histologic hallmark is a predominant neutrophilic infiltrate surrounding the eccrine gland apparatus. A total of 28 cases have been published since 1988, with a broad variation in the age of patients, symptomatology, associated diseases, clinical course, and histologic features. These different histologic pictures have resulted in several names for this entity, including idiopathic plantar hidradenitis, neutrophilic eccrine hidradenitis, recurrent palmoplantar hidradenitis in children, and idiopathic palmoplantar hidradenitis. We present three cases of this disorder and review the literature on the varying symptomatology, clinical course, and histology that have led to the myriad of names for this disease.
Cutaneous Polyarteritis Nodosa in a Child
Authors: Ginarte Manuel , Pereiro Mercedes , Toribio Jaime
Published: August 2010

Abstract: Cutaneous polyarteritis nodosa (CPAN) is a benign form of vasculitis of small and medium‐size arteries with a recurrent but benign course without systemic involvement. This entity is very rare in children, with about 45 cases described in the literature we reviewed. Herein we report a 10‐year‐old girl with typical CPAN. Trigger factors such as streptococcal infection were not detected. Of four episodes over the last 2 years, only one required treatment with a moderate‐sized oral dose of prednisone. In diagnosing CPAN, it is necessary to rule out systemic polyarteritis nodosa, which is also rare in children, as well as other panniculitides and vasculitides.
An Intriguing Case of LEOPARD Syndrome
Authors: Schepis Carmelo , Greco Donatella , Siragusa Maddalena , Batolo Dario , Romano Corrado
Published: August 2010

Abstract: We report a 9‐year‐old boy affected by LEOPARD syndrome, who also had ichthyosis, axillary freckling, two caf#eA au lait spots, and one neurofibroma. The diagnosis of LEOPARD syndrome has been made on clinical grounds, whereas the ichthyosis and neurofibroma have been histologically confirmed. The analogies between LEOPARD syndrome and neurofibromatosis have been discussed. Finally, we maintain this case is an example of the multiple lentigines syndrome/LEOPARD syndrome spectrum.
Bullous Pemphigoid and Epidermolysis Bullosa Acquisita: Presentation, Prognosis, and Immunopathology in 11 Children
Authors: Edwards S. , Wakelin S. H. , Wojnarowska F. , Marsden R. A. , Kirtschig G. , Bhogal B. , Black M. M.
Published: August 2010

Abstract: The immunobullous diseases bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA) are very rare in childhood. Although case studies have been detailed, there are no reports of a large series of patients documenting the effectiveness of treatment and long‐term prognosis. We report the clinical presentation, immunopathologic features, disease course, and long‐term prognosis of BP and EBA in a series of 11 children. The initial diagnoses based on clinical features were BP (5), EBA (3), and chronic bullous disease of childhood (CBDC) (3). These were subsequently revised from BP to EBA (2), CBDC to BP (2), and CBDC to BP or EBA (1) following the results of direct and indirect immunofluorescence and immunoblotting. Analysis of IgG subclasses in eight cases showed that the predominant subclasses were lgG1 (8) and lgG4 (6). The clinical features appeared to be highly variable, and in patients presenting with inflammatory blistering, laboratory studies were required in order to differentiate between BP and EBA. All patients improved on treatment with corticosteroids and/or sulfones, although treatment regimens showed wide variation. Their diseases tended to remit within 2 years, and their long‐term prognosis was good.
Scleroatrophic Syndrome of Huriez in an Infant
Authors: Downs A. M. R. , Kennedy C. T. C.
Published: August 2010

Abstract: We present a 3‐year‐old boy with scleroatrophic syndrome of Huriez, a rare autosomal dominant condition with only seven affected families worldwide. Although assumed to occur from birth, an evolving case has not previously been documented. Infants do not possess the focal areas of keratoderma on the palms or soles; these develop in adult life. Of particular interest is the high incidence of squamous cell carcinomas that arise from the scleroatrophic skin.
Solitary Giant Molluscum Contagiosum of the Sole
Authors: Ha Seog‐Jun , Park Young‐Min , Cho Sang‐Hyun , Cho Baik‐Kee , Song Kye‐Yong
Published: August 2010

Abstract: Molluscum contagiosum of the sole is extremely rare and only three cases have been reported in the literature. We report a solitary giant molluscum contagiosum on the left sole of a 5‐year‐old boy, which should be clinically differentiated from plantar wart, eccrine poroma, epidermal cyst, foreign body granuloma, cryptococcal infection, and pyogenic granuloma.
Pili Annulati Coincident with Alopecia Areata
Authors: Moffitt D. L. , Lear J. T. , de Berker D. A. R. , Peachey R. D. G.
Published: August 2010

Abstract: Pili annulati is a rare hair shaft abnormality of unknown pathogenesis which gives a gross beading effect. An association with alopecia areata has been reported. We present a 13‐year‐old girl who had alopecia areata and coincidentally was found to have pili annulati. Her mother also had pili annulati which had become more noticeable as her hair had become paler with age. We discuss the possible pathogenesis of pili annulati and relate that to the microscopic banding appearance of the hair shaft. We note the relevance of the condition becoming more apparent with age. We also discuss the probable coincidental association with alopecia areata.
Lower and Upper Extremity Atrophy Associated with a Giant Congenital Melanocytic Nevus
Authors: Itin Peter H. , Lautenschlager Stephan
Published: August 2010

Abstract: Giant congenital melanocytic nevi (GCMN) may be associated with a variety of malformations. Recently, atrophy of the underlying extremity was reported for the first time. We observed two patients with GCMN on the extremities with marked atrophy of the underlying tissue without functional impairment. According to the definition of hamartoma, it seems possible that one component of tissue has decreased. Dermatologists treating patients with such nevi in the first weeks of life with dermabrasion, laser, or curettage need to know that the natural course of GCMN may lead to atrophy and that this does not necessarily result from the treatment regimen.
Generalized Nevus Spilus and Nevus Anemicus in a Patient with a Primary Lymphedema: A New Type of Phakomatosis Pigmentovascularis?
Authors: Bielsa Isabel , Paradelo Cristina , Ribera Miquel , Ferrándiz Carlos
Published: August 2010

Abstract: A patient with a generalized nevus spilus associated with a nevus anemicus and primary lymphedema is reported. We believe that this association does not reflect the merely coincidental coexistence of three kinds of anomalies but that it may represent a new type of phakomatosis pigmentovascularis.
Nevus Comedonicus Syndrome: A New Pediatric Case
Authors: Patrizi Annalisa , Neri Iria , Fiorentini Cristina , Marzaduri Sandro
Published: August 2010

Abstract: Nevus comedonicus (NC) is an uncommon developmental defect of the pilosebaceous apparatus. The individual lesions are large comedones often arranged in groups or in a linear pattern. Nevus comedonicus syndrome (NCS) is a well‐defined disorder within the large group of epidermal nevus syndromes. In patients suffering from NCS, the nevus is associated with noncutaneous abnormalities including skeletal defects, cerebral anomalies, and cataracts. We report a 9‐year‐old boy with open comedones in a linear pattern localized to the right cheek, clinodactyly and Polydactyly of the first right finger, bilateral syndactyly of the second and third toes, and some depigmented hairs since birth.
EMLA Cream Provides Rapid Pain Relief for the Curettage of Molluscum Contagiosum in Children with Atopic Dermatitis without Causing Serious Application‐Site Reactions
Authors: Rönnerfält Lena , Fransson Jessica , Wahlgren Carl‐Fredrik
Published: August 2010

Abstract: Twenty‐nine children with atopic dermatitis, 4 to 9 years of age, were included in an open study of the analgesic efficacy and the application‐site reactions produced by EMLA cream 5% at a maximum dose of 10 g applied for 30 minutes under occlusion prior to the curettage of molluscum contagiosum. Molluscum areas with and without eczema were treated. The overall magnitude of pain was assessed first by the child and then by the physician on a four‐step verbal rating scale immediately after completion of the curettage. Prior to the surgical treatment, the application site was examined for local skin reactions. Eighty‐three percent of the children rated the pain from the surgical procedure as none or mild, while the physicians rated the pain as none or mild in 86% of the children. The application‐site reactions were pallor, redness, and edema. These reactions were transient and required no clinical attention. Their incidence or severity did not differ significantly between areas with and without eczema. In conclusion, EMLA cream 5% applied for 30 minutes under an occlusive dressing provides effective local analgesia without serious application‐site reactions for the curettage of mollusca contagiosa in children with atopic dermatitis.
Cutaneous Manifestations of Childhood Systemic Lupus Erythematosus
Authors: Wananukul Siriwan , Watana Dhevy , Pongprasit Prapai
Published: August 2010

Abstract: We assessed the mucocutaneous signs in 57 children with classical systemic lupus erythematosus seen during a 6 year period. The female:male ratio was 4.2:1. Ages ranged from 4 to 15 years (mean 11.9 years) at the time of diagnosis. Cutaneous manifestations (77%) were the second most common finding, next to renal involvement (84%). The skin changes noted were malar rash (74%), oral ulcer (46%), vasculitis (42%), photosensitivity (40%), alopecia (32%), and discoid lupus erythematosus (LE) (19%). All 11 discoid LE patients were girls. Periungual erythema, Raynaud's phenomenon, periungual gangrene, nail involvement, and subacute LE were rare. Antinuclear antibody reaction was positive in 93% and anti‐dsDNA was positive in 46%. Eight patients died, six from severe infection and two from renal failure.
Perianal Cutaneous Larva Migrans in a Child
Authors: Grassi Alessandra , Angelo Corrado , Grosso Maria Gabriella , Paradisi Mauro
Published: August 2010

Abstract: Cutaneous larva migrans (CLM) is a dermatosis characterized by the presence of parasites which migrate into the skin, forming linear or serpiginous lesions. We report a child with cutaneous larva migrans of interest because of the involvement of an unusual site and the patient's age. We confirm the efficacy of therapy consisting of administration of albendazole by mouth.
Atopic Dermatitis Symptoms Decreased in Children Following Massage Therapy
Authors: Schachner Lawrence , Field Tiffany , Hernandez‐Reif Maria , Duarte Anna M. , Krasnegor Josh
Published: August 2010

Abstract: Young children with atopic dermatitis were treated with standard topical care and massaged by their parents for 20 minutes daily for a 1 month period. A control group received standard topical care only. The children's affect and activity level significantly improved, and their parent's anxiety decreased immediately after the massage therapy sessions. Over the 1 month period, parents of massaged children reported lower anxiety levels in their children, and the children improved significantly on all clinical measures including redness, scaling, lichenification, excoriation, and pruritus. The control group only improved significantly on the scaling measure. These data suggest that massage therapy may be a cost‐effective adjunct treatment for atopic dermatitis, since there is a one‐time expense of $30 for the child to receive the massage and the parent to learn the technique.
Measles Virus was Present in the Inner Cell of the Acrosyringium in the Skin Rash
Authors: Yanagihara Makoto , Fujii Toshiki , Mochizuki Takashi , Ishizaki Hiroshi , Sata Tetsutaro
Published: August 2010

Abstract: A case of measles in a 26‐year‐old Japanese man is reported. A skin specimen taken on the third eruptive day from a maculopapular eruption on his chest was immunohistopathologically and electron microscopically examined using a rabbit polyclonal antibody against the nucleocapsid protein of the measles virus. The measles virus antigen was found in the inner cells of the acrosyringium and hair follicles. The measles virus nucleocapsid was electron microscopically identified in the nuclei of the inner cells of the acrosyringium. The findings suggest that the sweat from skin lesions might contain the measles virus.
Van der Woude Syndrome. A Case Report
Authors: Vignale Raúl , Araujo Juan , Pascal Gerardo , Reissenweber Nelson , Abulafia Jorge , Quadrelli Roberto , Vaglio Alicia , Larrandaburo Mariela , Reyno Soraya
Published: August 2010

Abstract: We describe several members of a family with Van der Woude syndrome, a genetic and congenital malformation syndrome with autosomal dominant inheritance and 70% to 80% penetrance with variable expressivity. It is characterized by clinical signs localized to the face, such as bilateral or unilateral pits on conical elevations in babies or extensive depressions in adults, both in the vermilion border of the lower lip, with cleft lip, with or without cleft palate and uvula. Small accessory or heterotopic salivary glands empty into sinuses or fistulas in the lips. This eight member family had various clinical signs of the condition. All had cleft lip and palate. We studied the major characteristics of the eight patients and describe histopathologic and immunohistochemical features.
Benign Cutaneous Degos Disease in a 16‐Year‐Old Girl
Authors: Wilson Joshua , Walling Hobart W. , Stone Mary Seabury
Published: August 2010

Abstract:  Degos disease is a rare disorder, characterized by the development of typical atrophic porcelain‐white macules on the trunk and extremities. It most commonly occurs in middle‐aged Caucasian adults and eventuates in fatality in the majority of patients. A minority of reported patients have a more benign course and a favorable outcome. Degos disease is extremely rare in children. We report Degos disease in a teenager with an extended survival and the absence of internal involvement. We discuss the concept of benign cutaneous Degos and review the 34 patients (30 adults and four children) identified in the world literature with skin biopsy and at least 1 year of follow‐up; the average age was 37.6 years; 26 were female and eight were male. As opposed to the malignant form of Degos disease, benign cutaneous Degos is more commonly reported in women (3:1). No laboratory abnormalities have been predictive of a benign versus malignant course. We also discuss the 24 reported instances of Degos disease (malignant and benign) in the pediatric population, of which 14 (58%) were fatal, with death occurring on average 3.6 years after diagnosis.
Acquired Ichthyosis as a Manifestation of Acute Cutaneous Graft‐Versus‐Host Disease
Authors: Huang Jennifer , Pol‐Rodriguez Marlyanne , Silvers David , Garzon Maria C.
Published: August 2010

Abstract:  Acquired ichythosis has been described in adult hematopoietic stem cell transplant recipients. While some authors have suggested the association of acquired ichythosis with cutaneous graft‐versus‐host disease, the evidence to support this association is rare. We describe a patient who developed enteritis secondary to acute graft‐versus‐host disease and had concomitant ichthyosiform lesions. Several months later, he was diagnosed with cutaneous graft‐versus‐host disease. This patient is presented to suggest that acquired ichthyosis is an underrecognized manifestation of acute cutaneous graft‐versus‐host disease. Given the important prognostic implications of this diagnosis, we recommend a low threshold for performing a skin biopsy to rule out GVHD in the appropriate clinical setting.
Combined Omphalomesenteric and Urachal Remnants in an 18‐Month‐Old Girl
Authors: Helen Kranbuhl K. , Lucky Anne W. , Warner Brad W. , Miles Lili , Bove Kevin E.
Published: August 2010

Abstract:  A toddler with a persistent congenital umbilical papule is described. The papule was found to contain both omphalomesenteric and urachal remnants. This patient's findings illustrate the importance of further evaluation of umbilical lesions when conventional therapy with silver nitrate fails.
Role of β‐Adrenoceptor Desensitization in Heart Failure
Authors: Rapacciuolo Antonio , Rockman Howard A.
Published: August 2010

Abstract:Heart failure is characterized by left ventricular dysfunction associated with a complex of symptoms that relate to inadequate perfusion of tissues and pulmonary congestion. When the heart is damaged by an insult, compensatory mechanisms mediated through activation of the sympathetic nervous system are involved to stabilize myocardial performance. Although these mechanisms can sustain cardiac function for a short time, chronic activation of sympathetic activity has adverse biological effects.

This review will focus on the changes that occur in the β‐adrenergic receptor pathway in the failing heart and will discuss novel approaches to therapy through manipulation of this pathway.
Ridogrel: An Antiplatelet Agent with Antihypertensive Properties
Authors: Wilson Thomas W. , Quest Dale W.
Published: August 2010

Ridogrel is a member of the class of drugs known as thromboxane receptor antagonists/thromboxane synthase inhibitors or TRASIs. In vitro and in vivo studies have confirmed it selectively reduces thromboxane A2 (TXA2) synthesis in platelets and elsewhere, while leaving the synthesis of other eicosanoids unchanged or even increased. Theoretically, it should produce a greater overall antithrombotic effect than aspirin. Some animal and human studies support this concept. A large phase III study confirmed the safety and efficacy of ridogrel in patients following myocardial infarction. It may also be useful in other clinical situations. In spontaneously hypertensive‐stroke prone rats, ridogrel reduces blood pressure, but increases plasma renin activity. The antihypertensive effect is potentiated by losartan. an angiotensin‐type I receptor antagonist. Ridogrel may also have efficacy in pregnancy induced hypertension, inflammatory bowel disease, and asthma.
The Therapeutic Potential of Candoxatril, a Neutral Endopeptidase Inhibitor, in Humans
Authors: McDowell Garry , Nicholls D. Paul
Published: August 2010

Candoxatril (UK‐79,300) is the orally active prodrug of candoxatrilat (UK‐73,967), the active enantiomer of (±) candoxatrilat (UK‐69,578), a potent neutral endopeptidase inhibitor. This article describes the rationale behind the use of this drug in the treatment of hypertension and chronic heart failure in humans. It further describes the pharmacokinetic and pharmacodynamics of candoxatril in preclinical animal studies, normal healthy individuals, and in patients with hypertension and chronic cardiac failure. In addition, we have described the initial results of clinical trials in hypertension and chronic cardiac failure, together with the potential future clinical developments of combined neutral endopeptidase/angiotensin converting enzyme inhibitors.
Defibrotide and Endothelial Cell Activation
Authors: Pescador Rodolfo , Porta Roberto , Ferro Laura
Published: August 2010

Defibrotide has several activities [profibrinolytic, antithrombotic‐thrombolytic, anti‐ischemic (heart, liver, kidney, skin, brain), antishock, antiatherosclerotic, and antirejection]. This host of activities has puzzled several people accustomed to the concept: one drug — one activity. But, if you see defibrotide as an antiendothelial cell activation drug, each piece of the puzzle will neatly fit into its right place and the host of activities becomes an array of activities. In fact the polyhedric inflammatory process is the common background of seemingly different illnesses, both acute and chronic. So the old concept of one drug‐one activity proves true; one drug: defibrotide — one activity; antiendothelial cell activation activity.
ART‐123: Recombinant Human Soluble Thrombomodulin
Authors: Mohri Mitsunobu
Published: August 2010

ART‐123 is a soluble form of recombinant human thrombomodulin comprising all extracellular domains of thrombomodulin. Bound to thrombin, ART‐123 inhibits its procoagulant activity and promotes activation of protein C. ART‐123 inhibits thrombin generation by the activation of protein C and the subsequent inactivation of factor Va in the presence of protein S. ART‐123 attenuates the extension of the clot by inhibiting further thrombin generation on clots, while other anticoagulants inhibit the initiation of clot formation. A higher concentration of ART‐123 is needed to affect clotting time and platelet aggregation than thrombin generation. Intravenous administration of ART‐123 is effective in animal models of disseminated intravascular coagulation (DIC), AV‐shunt, and other models with a wider safety margin than conventional anticoagulants. The plasma half‐life of ART‐123 is long, especially on subcutaneous injection. Clinical studies have been performed or are planned to evaluate the efficacy of ART‐123 in DIC and deep venous thrombosis (DVT). In clinical trials against DIC ART‐123 was well tolerated and showed a good dose‐response effect. These findings suggested that ART‐123 is a promising drug for thrombotic diseases.
Xemilofiban/Orbofiban: Insight into Drug Development
Authors: Anders Robert , Kleiman Jay , Nicholson Nancy , Wazowicz Betty , Burns Dan
Published: August 2010

A number of studies have reported on the successful use of intravenous glycoprotein IIb/IIIa receptor antagonists in patients with unstable angina or undergoing percutaneous interventions. The promise of interrupting the aggregation of platelets in the setting of unstable plaques on a chronic basis had led to the evaluation of several oral agents for longer‐term administration. The development program of two of these agents, xemilofiban and orbofiban, will be reviewed and evaluated to understand the selection process of therapeutic targets for use based upon complex pharmacokinetic and pharmacodynamic responses. A review of the pivotal phase III trial results will also be provided along with insights into the potential reasons for the lack of significant benefit shown with these agents to date.
Carvedilol: Molecular and Cellular Basis for Its Multifaceted Therapeutic Potential
Authors: Cheng Jianhua , Kamiya Kaichiro , Kodama Itsuo
Published: August 2010

Carvedilol is a unique cardiovascular drug of multifaceted therapeutic potential. Its major molecular targets recognized to date are membrane adrenoceptors (β1,β2, and α1), reactive oxygen species, and ion channels (K+and Ca2+). Carvedilol provides prominent hemodynamic benefits mainly through a balanced adrenoceptor blockade, which causes a reduction in cardiac work in association with peripheral vasodilation. This drug assures remarkable cardiovascular protection through its antiproliferative/atherogenic, antiischemic, antihypertrophic, and antiarrhythmic actions. These actions are a consequence of its potent antioxidant effects, amelioration of glucose/lipid metabolism, modulation of neurohumoral factors, and modulation of cardiac electrophysiologic properties. The usefulness of carvedilol in the treatment of hypertension, ischemic heart disease, and congestive heart failure is based on a combination of hemodynamic benefits and cardiovascular protection.
An Overview of SR121463, a Selective Non‐Peptide Vasopressin V2Receptor Antagonist
Authors: Gal C. Serradeil‐Le
Published: August 2010

SR121463 is a selective, orally active, non‐peptide antagonist of vasopressin (AVP) V2receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free‐water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V2receptors and exhibits a remarkably selective V2receptor profile. SR121463 and [3H]SR121463 are used, therefore, as selective probes for characterization and labeling of V2receptors. In various functional studiesin vitro, SR121463 behaves as a potent antagonist. It inhibits AVP‐stimulated human renal adenylyl cyclase and dDAVP (1‐desamino, 8‐D arginine‐vasopressin)‐induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V2receptor mutant.In vitro, SR1 21463 rescued misfolded V2AVP receptor mutants by increasing cell surface expression and restoring V2function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose‐dependent aquaresis with no major changes in urinary Na+and K+excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10‐day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V2(or V2‐like) receptors involved in vascular relaxation or clotting factor releasein vitroandin vivo.In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V2receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V2receptors. Pure V2receptor antagonists are likely to be therapeutically useful in several water‐retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V2receptors (e.g., glaucoma).
Ibudilast: A Non‐selective PDE Inhibitor with Multiple Actions on Blood Cells and the Vascular Wall
Authors: Kishi Yukio , Ohta Seiko , Kasuya Natsuko , Sakita Shinya , Ashikaga Takashi , Isobe Mitsuaki
Published: August 2010

Ibudilast (3‐isobutyryl‐2‐isopropylpyrazolo[1,5‐a]pyridine) is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is widely used in Japan for improving prognosis and relieving symptoms in patients suffering from ischemic stroke or bronchial asthma. These clinical applications are based on the properties of ibudilast that inhibit platelet aggregation, improve cerebral blood flow and attenuate allergic reactions. The inhibition of platelet aggregation and vasodilatation by ibudilast may be due to synergistic elevation of intracellular cyclic nucleotides and release of nitric oxide (NO) or prostacyclin from endothelium, rather than direct inhibition of PDE5 or PDE3. Another important property of ibudilast is its antiinflammatory activity possibly associated with potent inhibition of PDE4. Combined with its relaxing effects on bronchial smooth muscle, antiinflammatory actvity of ibudilast could favorably influence pathophysiology of asthma by antagonizing chemical mediators triggering asthmatic attacks. Ibudilast was also reported to significantly attenuate inflammatory cell infiltration in the lumbar spinal cord in an animal model of encephalomyelitis. Future investigations should include effects of ibudilast on inflammatory reactions between endothelium and blood cells, which may initiate the development of atherosclerosis.
Gene Transfer Therapy in Vascular Diseases
Authors: McKay Mandi J. , Gaballa Mohamed A.
Published: August 2010

Somatic gene therapy of vascular diseases is a promising new field in modern medicine. Recent advancements in gene transfer technology have greatly evolved our understanding of the pathophysiologic role of candidate disease genes. With this knowledge, the expression of selective gene products provides the means to test the therapeutic use of gene therapy in a multitude of medical conditions. In addition, with the completion of genome sequencing programs, gene transfer can be used also to study the biologic function of novel genes in vivo.

Novel genes are delivered to targeted tissue via several different vehicles. These vectors include adenoviruses, retroviruses, plasmids, plasmid/liposomes, and oligonucleotides. However, each one of these vectors has inherent limitations. Further investigations into developing delivery systems that not only allow for efficient, targeted gene transfer, but also are stable and nonimmunogenic, will optimize the clinical application of gene therapy in vascular diseases. This review further discusses the available mode of gene delivery and examines six major areas in vascular gene therapy, namely prevention of restenosis, thrombosis, hypertension, atherosclerosis, peripheral vascular disease in congestive heart failure, and ischemia. Although we highlight some of the recent advances in the use of gene therapy in treating vascular disease discovered primarily during the past two years, many excellent studies published during that period are not included in this review due to space limitations.

The following is a selective review of practical uses of gene transfer therapy in vascular diseases. This review primarily covers work performed in the last 2 years. For earlier work, the reader may refer to several excellent review articles. For instance, Belalcazer et al. (6) reviewed general aspects of somatic gene therapy and the different vehicles used for the delivery of therapeutic genes. Gene therapy in restenosis and stimulation of angiogenesis in the cardiac muscle are discussed in reviews by several investigators (13,26,57, 74,83). In another review, Meyerson et al. (43) discuss advances in gene therapy for vascular proliferative disorders and chronic peripheral and cardiac ischemia.
AH‐1058: A Novel Cardioselective Ca2+Channel Blocker
Authors: Takahara Akira , Sugiyama Atsushi , Yoshimoto Ryota , Hashimoto Keitaro
Published: August 2010

The pharmacologic profile of a cyproheptadine‐related compound, 4‐(5H‐dibenzo[a,d]cyclohepten‐5‐ylidene)‐1‐[(E)‐3‐(3‐methoxy‐2‐nitro)phenyl‐2‐propenyl]piperidine hydrochloride (AH‐1058), was assessed in variousin vivoandin vitromodels. In guinea pig cardiomyocytes, AH‐1058 effectively suppressed L‐type Ca2+channel currents without affecting other ion channel or ion exchange currents. In rat cerebral cortical membranes AH‐1058 appears to bind preferentially to L‐type Ca2+channels at phenylalkylamine‐ and benzothiazepine‐binding sites. In canine isolated, blood‐perfused heart preparations, AH‐1058 exerted negative inotropic, dromotropic, and chronotropic and weak coronary vasodilator effects. In halothane‐anesthetized dogs, AH‐1058 suppressed ventricular contractility and decreased blood pressure and cardiac output. Total peripheral vascular resistance was hardly affected by the drug, suggesting thatin vivoAH‐1058 can selectively suppress cardiac, as compared to peripheral vascular, function. In conscious dogs, by intravenous administration AH‐1058 reduced systolic blood pressure and maximal upstroke velocity of the left ventricular pressure, while it increased heart rate in a dose‐dependent manner. The drug did not affect diastolic blood pressure, which is quite different from cardiovascular properties of well‐known Ca2+channel blockers, verapamil and diltiazem. This unique cardiovascular profile of AH‐1058 is expected to be useful in the treatment of certain pathological processes such as the obstructive hypertrophic cardiomyopathy, vasovagal syncope, dissecting aortic aneurysm, and ventricular arrhythmias, in which selective inhibition of the ventricular Ca2+channels is essential for drug therapy.
A Review of HNS‐32: A Novel Azulene‐l‐Carboxamidine Derivative with Multiple Cardiovascular Protective Actions
Authors: Tanaka Yoshio , Shigenobu Koki
Published: August 2010

HNS‐32 [N1,N1‐dimethyl‐N2‐(2‐pyridylmethyl)‐5‐isopropyl‐3,8‐dimethylazulene‐1‐carboxamidine] (CAS Registry Number: 186086‐10‐2) is a newly synthesized azulene derivative. Computer simulation showed that its three dimensional structure is similar to that of the class Ib antiarrhythmic drugs, e.g., lidocaine or mexiletine. HNS‐32 potently suppressed ventricular arrhythmias induced by ischemia due to coronary ligation and/or ischemia‐reperfusion in dogs and rats. In the isolated dog and guinea pig cardiac tissues, HNS‐32 had negative inotropic and chronotropic actions, prolonged atrial‐His and His‐ventricular conduction time and increased coronary blood flow. In the isolated guinea pig ventricular papillary muscle, HNS‐32 decreased maximal rate of action potential upstroke (V̇max) and shortened action potential duration (APD). These findings suggest that HNS‐32 inhibits inward Na+and Ca2+channel currents. In the isolated pig coronary and rabbit conduit arteries, HNS‐32 inhibited both Ca2+channel‐dependent and ‐independent contractions induced by a wide variety of chemical stimuli. HNS‐32 is a potent inhibitor of protein kinase C (PKC)‐mediated constriction of cerebral arteries. It is likely to block both, Na+and Ca2+channels expressed in cardiac and vascular smooth muscles. These multiple ion channel blocking effects are largely responsible for the antiarrhythmic and vasorelaxant actions of HNS‐32. This drug may represent a novel approach to the treatment of arrhythmias.
Cardiovascular Properties of Yangambin, a Lignan Isolated from Brazilian Plants
Authors: Tibiriçá Eduardo
Published: August 2010

Yangambin was initially selected from a number of lignans isolated from Brazilian plants for its ability to antagonize Platelet‐Activating Factor (PAF, 1‐O‐hexadecyl‐2‐acetyl‐sn‐glyceryl‐3‐phosphorylcholine)‐induced biological effects. Subsequently it was shown that, besides its antagonistic properties at PAF receptors, yangambin also prevents the cardiovascular collapse observed during anaphylactic and endotoxic/septic shocks, as well as the vascular and cardiac hyporesponsiveness to catecholamines in endotoxic shock. It is suggested that this naturally occurring compound could be of potential interest in the adjunctive management of the above mentioned pathologies. In the present article, we review the main studies investigating the pharmacological properties of yangambin related to the cardiovascular function.
Transforming Growth Factor‐β:A Promising Target for Anti‐Stenosis Therapy
Authors: Chamberlain J.
Published: August 2010

Transforming growth factor‐β (TGF‐β) is the general name for a family of cytokines which have widespread effects on many aspects of growth and development. The TGF‐β isoforms are produced by most cell types and exert a wide range of effects in a context‐dependent autocrine, paracrine or endocrine fashion via interactions with distinct receptors on the cell surface. TGF‐β is involved in the wound healing process and, thus plays a significant role in the formation of a restenotic lesion after percutaneous transluminal coronary angioplasty (PTCA) or stenting. Perhaps because of its wide‐ranging effects, TGF‐β is usually released from cells in a latent form, and its activation and signaling are complex. Manipulation of the TGF‐β1, TGF‐β2, and TGF‐β3 isoforms by inhibiting their expression, activation, or signaling reduces scarring and fibrosis in animal models. However, to date, few have reached clinical trial. This review summarizes current knowledge on the activation and signaling of TGF‐β, and focuses on the anti‐TGF‐β strategies which may lead to clinical applications in the prevention of restenosis following PTCA or stenting.
Bopindolol: Pharmacological Basis and Clinical Implications
Authors: Nagatomo Takafumi , Hosohata Yoshiaki , Ohnuki Toshio , Nakamura Takashi , Hattori Kaoru , Suzuki Jun , Ishiguro Masaji
Published: August 2010

Bopindolol, a non‐selective antagonist of β1‐ and β2‐adrenoceptors (ARs), has been found by pharmacological, molecular biological techniques and molecular modeling to have several unique properties. Bopindolol produces sustained blockade of β1‐ and β2‐ARs, has intrinsic sympathomimetic as well as membrane stabilizing actions, inhibits renin secretion, and interacts with 5‐HT receptors. Also, our recent molecular modeling studies identified possible interaction sites between bopindolol and beta‐AR subtypes. The reviewed studies support our findings that bopindolol is non‐selective for β1‐ and β2‐ARs, has low affinity for β3‐AR subtype and has pharmacological properties that are likely to be beneficial in the treatment of cardiovascular diseases.
UR‐3216: A Manageable Oral GPIIb/IIIa Antagonist
Authors: Baba Kosuke , Aga Yasuhiro , Nakanishi Takayuki , Motoyama Takahiro , Ueno Hitoshi
Published: August 2010

UR‐3216, a prodrug, is a novel, selective, and orally active platelet surface glycoprotein GPIIb/IIIa) receptor antagonist. The most important property of UR‐3216 is the very tight binding of its active metabolite to platelets (Kifor resting platelets is <1 nM). UR‐2992, the active form of UR‐3216, binds to platelets for a long period of time, while the unbound drug is rapidly cleared. Therefore, after an initial loading dose of 0.1 mg/kg, only once daily repeated low maintenance doses of UR‐3216 (<0.05 mg/kg p.o.) are required. This regimen maintains a high level of inhibition of platelet aggregation and, due to a small peak‐to‐trough ratio, severe bleeding is avoided. The therapy with UR‐3216 is easy to manage, because it has low peak‐to‐trough ratio and high efficacy (>80% inhibition of platelet aggregation). In addition, UR‐3216 does not produce excessive bleeding or thrombocytopenia and does not interact with abciximab. UR‐3216 is excreted mostly in bile, so that it will not accumulate in patients with chronic renal dysfunction. UR‐2316 has the following abciximab‐like features: (a) its half‐lives for residence on platelets, inhibition of platelets aggregation and bleeding time prolongation are 60 to 80 h, 24, and 2 h, respectively; (b) its receptor binding occupancy is similar to that of abciximab (Mab1 is inhibited and Mab2 is unaltered). In conclusion, UR‐3216 is a promising, orally active GPIIb/IIIa antagonist for the treatment of cardiovascular diseases.
Basic Experimental Studies and Clinical Aspects of Gadolinium Salts and Chelates
Authors: Adding L. Christofer , Bannenberg Gerard L. , Gustafsson Lars E.
Published: August 2010

Gadolinium is a lanthanide that has in recent years become more commonly present in our society. Organic chelates of gadolinium are increasingly used as contrast agents for the imaging of body fluids. Although adverse reactions to these agents are uncommon, it is known that gadolinium salts can bring about a wide variety of changes in physiology. Gadolinium chloride is widely used experimentally as an inhibitor of stretch‐activated ion channels and physiological responses of tissues to mechanical stimulation. It is also employed as a selective inhibitor of macrophagesin vivo. In this review, the known biochemical actions of gadolinium are brought together with itsin vivopharmacology and toxicology.
Angiotensin Receptor Blockers and the Kidney: Possible Advantages over ACE Inhibition?
Authors: Cooper Mark E. , Webb Randy L. , de Gasparo Marc
Published: August 2010

This review deals with similarities and differences between the effects of ACE inhibitors and AT1‐receptor blockers in the kidney. Specific receptor blockade has demonstrated that the beneficial effects of AT1blockers arise from two mechanisms: the reduction of the AT1receptor mediated response and the increase in plasma levels of Ang II through the AT1‐receptor blockade, which leads to increased stimulation of the AT2receptor (the so‐called yin‐yang effect). Both ACE inhibition and AT1‐receptor blockade provide significant renal protection in the majority of experimental animal models of kidney diseases. AT1receptor blockade may offer additional clinical benefits over ACE inhibitor treatment, particularly in the kidney, where AT1‐receptor blockade does not cause the fall in glomerular filtration rate seen with ACE inhibitor treatment. A number of long‐term clinical studies currently running should show the real value of this new class of compounds in the management of hypertension and associated cardiorenal diseases.
Endothelin Antagonism with Bosentan: Current Status and Future Perspectives
Authors: Ono Koh , Matsumori Akira
Published: August 2010

Endothelin receptor antagonist have been proposed for the treatment of a variety of disorders in which the endothelins may act as pathogenic mediators, such as hypertension, congestive heart failure, and cerebral vasospasm. Bosentan is a nonpeptide competitive antagonist, which can be a good tool for studying the endothelin system. It is specific for the endothelin system and blocks the actions of endothelin at both mammalian receptors (A and B). Bosentan has recently moved into Phase III clinical trial. This review will attempt to overview the experimental and clinical effects of bosentan.

ET receptor antagonists, such as bosentan, produce beneficial effects in various pathological conditions. Bosentan, as a mixed ETA/ETBreceptor antagonist, may be of particular benefit in heart failure and cerebral vasospasm where ETBreceptors are upregulated. For some clinical indications bosentan should be evaluated more vigorously in further controlled clinical trials.