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Here we report ramipril-induced cutaneous vasculitis in a patient who required steroid therapy to control it.
**********
Case Report
A 46-year-old gentleman developed a cutaneous vasculitic rash over his feet 3 days after starting ramipril and bisoprolol for left ventricular dysfunction. His medical history included Tetralogy of Fallot, corrected at the age of 14, ankylosing spondylitis, and Marfan’s syndrome. He had previously been on lisinopril for 5 years for reduced left ventricular function. A year ago, he had an aortic valve replacement for severe aortic regurgitation. A few months after his operation, he was admitted with pulmonary edema. He was treated with diuretics and prior to discharge, commenced on ramipril and bisoprolol in view of their documented prognostic benefits in left ventricular dysfunction. 3 days later, he developed a symmetrical palpable purpuric eruption over both feet (Figs. 1 & 2). Subsequently the rash spread to the calves, and both feet became swollen and painful. Given the close temporal relationship between the rash and recent change in medications, it was felt that the rash could have been caused by bisoprolol or ramipril. As he had tolerated lisinopril previously, bisoprolol was thought to be the most likely culprit. The bisoprolol was stopped and the dose of ramipril was increased. Over the next two weeks, however, the rash became more extensive and he developed areas of ulceration around the toes and pre-ulcerative areas around the ankles. Ramipril was discontinued and he was prescribed symptomatic treatment for the skin. A full vasculitis screen was performed which showed no evidence of systemic involvement. Investigations to determine the cause of the vasculitis were also negative. His skin biopsy was deferred in view of the fact that he was on warfarin and had a metallic aortic valve. 3 weeks later, he had a further flare of vasculitis with new lesions and progressive ulceration. He was treated with prednisolone 20 mg daily and the rash and ulcers slowly resolved.
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
Discussion
ACE inhibitors are commonly prescribed drugs and are standard therapy in the management of hypertension and heart failure. Recognized adverse cutaneous effects include angioedema, bullous eruptions, urticaria, erythema multiforme, and vasculitis. Psoriasiform maculopapular and lichenoid eruptions have also been described. The mechanisms for ACE inhibitor-induced adverse reactions in the skin are mostly based on non-immunological mechanisms. By contrast, proposed mechanisms for drug-induced vasculitis are mainly immunological and include autoantibodies directed against drug-related haptens, drug toxicity against vessel walls, autoantibodies reacting with endothelial cells and cell mediated cytotoxic reactions against vessels, in addition to non-immunological mechanisms (1). Researchers have demonstrated the expression of a complete renin-angiotensin system in human skin, including the precursor of angiotensin II, angiotensinogen, renin, angiotensin converting enzyme, and receptors of the AT1 and AT2 receptor subtype, but their function is unknow (2). This patient developed cutaneous vasculitis after starting ramipril although he had previously tolerated lisinopril. Both ramipril and lisinopril are structurally similar and are part of the group of ACE inhibitors that are related to enalapril, which contains a dicarboxyl group. Lisinopril is an active molecule and ramipril is a pro-drug which is converted to an active diacid metabolite (ramiprilat). Previous exposure to lisinopril may have been the primary sensitizing event and reexposure to a structurally similar molecule (ramipril) could have resulted in the secondary allergic manifestations. As reexposure to immunogenic substances often results in a more severe reaction, the reintroduction of lisinopril was avoided in this case. Angiotensin II antagonists, however, are chemically different from ACE inhibitors and remain a therapeutic alternative.
References
1. Steckelings UM. Artuc T, Wollschlager T, et al. Angiotensin-converting Enzyme Inhibitors as Inducers of Adverse Cutaneous Reactions. Acta Derm Venereol 2001; 81:321-325.
2. Husgow T, Artuc M, Henz BM, et al. Normal skin as a potential source of Angiotensin II. Arch Dermatol Res 1998; 290:49.

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Start of phase 2a clinical study of Angiotensin Therapeutic Vaccine
in hypertension

London, UK; Brentwood, TN, US; 24 June 2008 - Protherics PLC
(”Protherics” or the “Company”), the international biopharmaceutical
company focused on critical care and cancer, today announces that the
first patient has been enrolled in a phase 2a study of its Angiotensin
Therapeutic Vaccine (ATV) for the treatment of hypertension.

Hypertension is a major risk factor for serious and common
cardiovascular diseases such as heart attacks and strokes and the
global market for anti-hypertensive therapies is estimated to be worth
around USUSD30 billion*. The majority of existing therapies are tablets
which need to be taken on a daily basis, usually for the rest of a
patient’s life. However, many patients with high blood pressure fail
to take their medicines as prescribed, and it is estimated that
approximately 70% of patients with hypertension do not have their blood
pressure adequately controlled*. Therefore, a vaccine approach, which
may require only three injections and a booster after six months rather
than daily medication, should improve patient compliance with treatment.

The phase 2a, double-blind, placebo-controlled clinical study in
124 patients with mild to moderate hypertension has been initiated in
the UK. Patients will be given a course of injections over six weeks.
The study will assess the safety and tolerability of the vaccine,
incorporating Protherics’ promising novel vaccine adjuvant, CoVaccine
HT(TM). In addition both antibody response and effect on blood
pressure will be assessed. The blood pressure results are expected in
the first half of 2009.

Protherics has shown in a previous phase 2a study that a formulation of
ATV, incorporating the vaccine adjuvant Alhydrogel, modulated key
hormones involved in regulating blood pressure in hypertensive
patients. A new formulation of ATV has now been developed,
incorporating the CoVaccine HT(TM) adjuvant, which has demonstrated a
much stronger immune response in pre-clinical models.

CoVaccine HT(TM) and ATV are protected by extensive patents and
applications in the US, EU and the rest of the world. The first US
patent on ATV was granted in May 2008.

Andrew Heath, Chief Executive of Protherics, commented:”We are excited
about the prospects for ATV, a potential value driver
for the company. A vaccine approach to the treatment of high blood
pressure promises to address the issue of poor patient compliance with
daily medication and thus reduce the incidence of stroke and heart
attacks. With data expected within a year, this could be a major
outlicensing opportunity.”

*Company estimates

/ Ends /

For further information please contact:

Protherics

Nick Staples, Director of Corporate Affairs 44 (0) 7919 480510

Saul Komisar, President, Protherics Inc 1 615 327 1027

Financial Dynamics - press enquiries

London: Ben Atwell, Lara Mott 44 (0) 20 7831 3113

New York: John Capodanno 1 212 850 5600

Or visit www.protherics.com

Notes for Editors:

About Protherics

Protherics (LSE: PTI, NASDAQ: PTIL) is a leading international
biopharmaceutical company focused on specialist products for critical
care and cancer.

Protherics has produced two FDA approved biologics for critical care
use which are currently sold in the US: CroFabTM, a North American pit
viper antivenom and DigiFabTM, a digoxin antidote. Protherics reported
revenues of GBP26.1 million for its year ended 31 March 2008 and a
strong cash balance of GBP37.7 million. The Company’s strategy is to
use the revenues generated from its marketed and out-licensed products
to help fund the advancement of its broad, late stage pipeline.

Protherics has two major development opportunities in its portfolio.
CytoFab(TM) is being developed by AstraZeneca, for the treatment of
severe sepsis, following a major licensing deal announced in December
2005. AstraZeneca is conducting an additional phase 2 programme
following changes to the commercial manufacturing process. A new
formulation of Angiotensin Therapeutic Vaccine, for the treatment of
hypertension, has today commenced a phase 2a study. Protherics also
has four novel products being developed in a range of cancer
indications where it intends to undertake the sales and marketing in
the US and/or the EU.

With headquarters in London, the Company has approximately 300
employees across its operations in the UK, US and Australia.

For further information visit: www.protherics.com

About Angiotensin Therapeutic Vaccine

Angiotensin Therapeutic Vaccine (ATV) is a conjugate vaccine containing
a peptide analogue of the hormone angiotensin I cross linked to the
carrier protein keyhole limpet haemocyanin (KLH). ATV is designed to
treat hypertension by stimulating the immune system to neutralise
angiotensin I, a peptide hormone that plays a key role in the
regulation of blood pressure.

Protherics has previously shown in hypertensive patients that a first
generation formulation of ATV modulates key hormones involved in
regulating blood pressure. An improved formulation of ATV has now been
developed, incorporating a novel vaccine adjuvant, CoVaccine HT(TM),
which has shown evidence of stimulating a much stronger immune response
in pre-clinical models. CoVaccine HT(TM) was acquired by in June 2006
by Protherics from CoVaccine BV.

A vaccine approach to the management of hypertension is expected to
improve patient compliance with therapy, which is a major problem in
achieving control of high blood pressure with current therapy. Because
of its envisaged slow onset and sustained effect, ATV has the potential
to be used on its own, or in combination with existing high blood
pressure medications, to improve the control of hypertension. For more
information, visit

http://www.protherics.com/Products/other_products.aspx

About Hypertension

Hypertension is one of the most common medical conditions in developed
countries and is a risk factor associated with heart attacks, heart
failure, blood vessel problems and kidney damage. Current treatments
are tablet based, requiring daily doses, often for life, and patient
compliance is often poor. The pharmaceutical market for high blood
pressure treatment is the largest single therapeutic sector in the
world, with global sales exceeding USUSD30 billion per annum.

Disclaimer

This document contains forward-looking statements that involve risks
and uncertainties including with respect to products under development
and the progress and completion of clinical trials. Although we
believe that the expectations reflected in such forward-looking
statements are reasonable at this time, we can give no assurance that
such expectations will prove to be correct. Given these uncertainties,
readers are cautioned not to place undue reliance on such
forward-looking statements. Actual results could differ materially from
those anticipated in these forward-looking statements due to many
important factors discussed in Protherics’ Annual Report on Form 20-F
and other reports filed from time to time with the U.S. Securities and
Exchange Commission. We do not undertake to update any oral or written
forward-looking statements that may be made by, or on behalf of,
Protherics.

This information is provided by RNS
The company news service from the London Stock Exchange

END

Dilated cardiomyopathy is one of the cardiomyopathies, a group of diseases that primarily impact the myocardium. The disease is genetically heterogeneous, but the almost popular kind of its infection is an autosomal predominant form. For many affected individuals, dilated cardiomyopathy is a condition which will not limit the quality or duration of life. A minority, however, experience significant symptoms and there is sometimes a risk of sudden death. The virus infects and weakens the heart muscle. As in coronary artery disease, the weakened heart stretches in an attempt to compensate, resulting in dilated cardiomyopathy and often heart failure. Occasionally, dilated cardiomyopathy results from a bacterial infection. Rare causes of dilated cardiomyopathy include pregnancy and connective tissue disorders such as rheumatoid arthritis.

People with distinct stages of disease will get varying combinations of symptoms. When cardiomyopathy results from a transmission, the best symptoms may be an abrupt fever and flu-like symptoms. Vague chest pain may be present, but typical angina pectoris is unusual and suggests the presence of concomitant ischemic heart disease. Syncope due to arrhythmias, and systemic embolism may occur. Alcohol should be avoided. Leakage causes murmurs, which doctors can hear with a stethoscope. Damage to and stretching of the heart muscle may result in abnormal heart rhythms, which may cause awareness of heartbeats or death. Blood pools in the enlarged heart, increasing the risk of blood clots forming on heart chamber walls. The leakage of the valves and the abnormal heart rhythms may interfere further with the heart’s pumping action.

The diagnosis is based on the symptoms and the results of a physical examination. General treatment measures include avoiding stress, limiting salt in the diet, and having periods of rest, which help reduce strain on the heart, particularly when the cardiomyopathy is acute or severe. Anticoagulants may also be used. Drugs, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, spironolactone or eplerenone, and low-dose digoxin, improve the heart’s pumping function, prolong life, and decrease persistent symptoms. Artificial pacemakers may be used in patients with intraventricular conduction delay, and implantable cardioverter-defibrillators in those at risk of arrhythmia. In patients with advanced disease who are refractory to medical therapy, cardiac transplantation may be considered. If the heart function remains poor, a heart transplant may be considered.

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The prevalence of hyperkalemia in hospitalized patients is between 1 and 10 percent. (1) Although the exact prevalence of hyperkalemia in community-based medical practice is unknown, potassium elevation is a common, potentially life-threatening problem most often occuring in patients with chronic renal failure or other illnesses that reduce renal potassium excretion (Table 1 (2,3)). In these patients, acute hyperkalemia often is precipitated by stressors such as illness, dehydration, or initiation of medicines that alter potassium homeostasis (Table 24-10). (4-7)
Normal Potassium Physiology
Two mechanisms normally regulate potassium levels in response to variation of potassium intake. First, ingested potassium rapidly enters the portal circulation, stimulating the pancreas to release insulin. Elevated insulin levels induce rapid transport of potassium from the extracellular space into cells via cellular sodium-potassium adenosine triphosphatase. Second, increased potassium in the circulation causes the renal juxtaglomerular cells to release renin. This stimulates hepatic activation of angiotensin I that is then converted in the lungs to angiotensin II. Angiotensin II stimulates the adrenal zona glomerulosa to secrete aldosterone. Elevated serum aldosterone causes the renal cortical collecting ducts to excrete potassium and retain sodium, further lowering serum potassium.2
Causes of Hyperkalemia
The first step in the evaluation of a patient with elevated serum potassium is to exclude spurious potassium elevation (Table 3 (2,3)). If the elevation is shown to be real, the next step is to consider: (1) the effects of medications, including increased potassium intake (Table 2 (4-10)); (2) the impaired distribution of potassium between the intracellular and extracellular space; or (3) the impaired renal excretion of potassium. All three factors often are present (e.g., the stress of illness induces hyperkalemia in a patient rendered susceptible by impaired homeostatic mechanisms and the presence of a medication that impairs normal potassium regulation).
PSEUDOHYPERKALEMIA
Pseudohyperkalemia occurs when laboratory reports of potassium do not reflect actual values. The most common cause is lysis of red cells in a phlebotomy specimen. Other causes are listed in Table 3 (2,3). Potassium released from platelets can lead to spuriously high levels of potassium in a blood sample allowed to clot to collect serum. Pseudohyperkalemia can be excluded by repeating the sample collection as atraumatically as possible and obtaining serum and plasma potassium levels. In patients with pseudohyperkalemia, the plasma potassium will be normal in the face of an elevated serum potassium.
HYPERKALEMIA CAUSED BY DECREASED EXCRETION OF POTASSIUM
Effective excretion of potassium is dependent on aldosterone and sufficient distal delivery of sodium and water within the nephron. Hyperkalemia may occur when one of these mechanisms is impaired because of renal failure, renal hypoperfusion (e.g., volume depletion, congestive heart failure), or hypoaldosteronism. Hypoaldosteronism may be the cause of hyperkalemia in patients who do not have advanced renal failure or hypoperfusion. (11)
Hyporeninemic hypoaldosteronism, a syndrome associated with type IV renal tubular acidosis, may be part of the mechanism behind hyperkalemia in patients with mild renal failure, particularly diabetic nephropathy. Hyporeninemic hypoaldosteronism can cause patients who have diabetic nephropathy to develop acute elevations of potassium because of medications or stress (e.g., dehydration, acute illness). (12)
MEDICATION-INDUCED HYPERKALEMIA
The factors that decrease potassium excretion also increase the risk of medication-induced hyperkalemia. Because of the relative decline in renal function with age, family physicians should use caution when prescribing medications that alter potassium metabolism in older patients. Judicious monitoring of potassium levels is important in at-risk patients receiving these medicines.