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Recent Patents on Endocrine Metabolic
& Immune Drug Discovery
ISSN: 1872-2148
Recent Patents on Endocrine,
Metabolic & Immune Drug Discovery
Volume 2, Number 1, January 2008
Contents
Current Approaches for the Treatment with Thyroid
Hormone Analogs Pp. 1-8
Katharina Plikat and Christian E. Wrede
[Abstract]
Aberrant Activation of Arachidonic Acid and Eicosanoid
Pathways- Targets for Treating Prostate Cancer Pp.
9-15
Marzieh Niknami, Manish Patel, Paul Witting and Qihan
Dong
[Abstract]
Novel Plant Sterol and Stanol Derivatives with
Beneficial Properties: Efficacy and Safety Pp. 16-23
Amalia E. Yanni
[Abstract]
From Dual Peroxisome Proliferator Activated Receptor
Agonists to Selective Peroxisome Proliferator Activated Receptor
Modulators Pp. 24-28
Selcuk Dagdelen
[Abstract]
Anti-TSH Receptor Antibodies in the Congolese
with Hyperthyroidism Pp. 29-34
Joseph B. Mabika, Symphorien D. Mpandamadi and Jena René
M. Kabangu
[Abstract]
Periodontal Regenerative Materials and their
Applications: Goodness of Fit? Pp. 35-44
Mena Soory
[Abstract]
Evaluation of Two Recombinant Plasminogen Activators
in Massive Pulmonary Embolism Model and Potato Carboxypeptidase
Inhibitor (PCI) Role in Inhibition of Thrombin Activatable
Fibrinolysis Inhibitor TAFIa in Lungs Pp. 45-56
Filip Konecny
[Abstract]
Role of Thrombin Activatable Fibrinolysis Inhibitor
in Endocrine and Cardiovascular Disorders Pp. 57-61
Baris Akinci and Sena Yesil
[Abstract]
Patent Selections Pp. 62-71
Abstracts
[Back to top]
Current Approaches for the Treatment with Thyroid Hormone
Analogs
Katharina Plikat and Christian E. Wrede
Thyroid hormones affect the function of nearly every
organ of the body, including lipid homeostasis, regulation
of body weight and cardiovascular effects. Application of
thyroid hormones for the treatment of metabolic and cardiovascular
disorders is not possible due to their side effects, but the
discovery of drugs specifically affecting some of these functions
may overcome this limitation. In the current review, we outline
the physiology of thyroid receptors and summarize patterns
of new drugs that bind to different receptors, thereby providing
the base for a treatment of patients with metabolic and cardiovascular
disorders.
More recently, thyrotropin releasing hormone (TRH) has been
shown to improve thyroid function in patients with nonthyroidal
illness syndrome (NTIS), and may provide a future therapeutic
option for critically ill patients. In addition, there is
evidence that TRH is involved in central nervous regulation
of blood glucose and repair of brain damage. However, therapeutical
application of TRH is hampered by its rapid metabolization.
Specific long acting analogues may therefore allow better
treatment of these conditions. Recent patents on design and
therapeutical use of these drugs are summarized in this manuscript.
[Back to top]
Aberrant Activation of Arachidonic Acid and Eicosanoid
Pathways- Targets for Treating Prostate Cancer
Marzieh Niknami, Manish Patel, Paul Witting and Qihan
Dong
Eicosanoids have been the major therapeutic targets in
rheumatoid arthritis and other degenerative diseases where
inflammation is involved. In the past decade, the biological
significance of eicosanoids and their potential as therapeutic
targets in cancer have also been recognized and is now a focal
area of research in many laboratories. Recently, phospholipase
A2 (PLA2),
the enzyme responsible for arachidonic acid supply to eicosanoid-producing
enzymes has attracted attention. It has been proposed that
PLA2 inhibition can yield
a better therapeutic outcome than inhibition of individual
eicosanoid-producing enzymes. In this article, we focus on
the rationale for targeting arachidonic acid-eicosanoid pathways
as well as evaluate the recent patents that identify inhibitors
of the PLA2 family of enzymes.
[Back to top]
Novel Plant Sterol and Stanol Derivatives with Beneficial
Properties: Efficacy and Safety
Amalia E. Yanni
Plant sterols and stanols are substances with structural
homology to cholesterol, which exhibit hypo-cholesterolemic
properties. They compete cholesterol for intestinal absorption,
leading to inhibited entry of cholesterol into circulation
and consequently to its lower serum concentration. Since hypercholesterolemia
is closely linked with the development of cardiovascular disease
(CVD), the cholesterol lowering agents play key-role in preventing
CVD. A large body of evidence shows the cholesterol lowering
effect of plant sterol and stanol consumption. Due to this
significant property the induction of these substances in
appropriate amounts in the daily food pattern of mildly hyper-cholesterolemic
patients becomes an exigency since it is an alternative for
pharmaceutical treatment. A large number of novel plant sterol
and stanol derivatives have been developed with a purpose
to find applications in food and pharmaceutical industry.
The derivatives provide with two basic advantages: a) enhancement
of lipid solubility or acquisition of water solubility with
a purpose to extend the usefulness and b) additional beneficial
effects for cardiovascular system such as antioxidant, hypotriglyceridemic
and antiinflammatory.
The article discusses the role of plant sterol and stanol
consumption in lowering serum cholesterol concentration and
presents patented derivatives of these substances, which can
be incorporated into food and pharmaceutical products and
exhibit beneficial properties.
[Back to top]
From Dual Peroxisome Proliferator Activated Receptor Agonists
to Selective Peroxisome Proliferator Activated Receptor Modulators
Selcuk Dagdelen
Worldwide epidemic of type 2 diabetes mellitus, obesity,
dyslipidemia, hypertension and atherosclerosis (i.e. metabolic
syndrome) still requires further treatment strategies. Life
style change can be regarded as single evidenced option to
manage these co-morbid conditions, at the same time. Peroxisome
proliferator activated receptors (PPARs) are claimed to play
critical roles in metabolic adaptation to changing environmental
factors. PPAR alpha and gamma agonists are approved as hypolipidemic
and antidiabetic agents, respectively. Combination of PPAR
alpha and gamma agonistic effects in a single molecule (i.e.
dual PPAR agonists) has been tried to achieve a better multiple
cardiovascular risk management. Despite their efficacy, dual
PPAR agonists has been discontinued due to safety concerns.
New generation of PPAR ligands with a higher safety profile
is being actively investigated. Here, we review pursuits for
a new PPAR class, and discuss the potential role for selective
peroxisome proliferator activated receptor modulators (SPPARMs)
as new patented molecules. This article also includes recent
patents on this topic.
[Back to top]
Anti-TSH Receptor Antibodies in the Congolese with Hyperthyroidism
Joseph B. Mabika, Symphorien D. Mpandamadi and Jena-René
M. Kabangu
Hospital prevalence of hyperthyroidism is gradually increasing
in urban population of Kinshasa. However, the reasons of this
increase are not well known. Objective of this study to search
the presence of anti-TSH receptor antibodies in Kinshasa’s
inhabitants, to identify potential candidates to the Graves’
disease and to follow up hyperthyroid patients treated by
anti-thyroid drugs. For this, 53 hyperthyroid patients (cases)
and 44 euthyroid goiter patients (controls) were included
in this study; and 20 healthy free-goiter subjects serums
were measured to obtain local references. Thyrotropin-binding
inhibiting immunoglobulin assay (TBII) method was used to
measure the anti-TSH receptor activity in the serum. Multiple
logistic regression analysis was used to identify significant
risk factors and their prognostic values. A p. value of 0.05
was considered significative. It shows the prevalence of anti-TSH
receptor antibodies in hyperthyroid patients is 94.3%, whereas
it is 72.7% in controls; the presence of anti-TSH receptor
antibodies multiplies by 4 the risk to hyperthyroidism, especially
in the stressed females; and the concentrations of anti-TSH
receptor antibodies are higher in hyperthyroid subjects than
in controls (p = 0.025); 4) High sensitivity of the dosage
(VPN = 99.9%) allows to separate non hyperthyroid persons
or those with an non auto-immunological goiter, from the hyperthyroid
patients. The present study showed a likely autoimmune origin
of hyperthyroidism in urban population of Kinshasa; 2). The
presence of anti-TSH receptor antibodies would suggest that
the main cause of hyperthyroidism in hyperthyroid patients
is Graves’ disease, whereas their presence in patients
with euthyroid goiter should suggest that they could be potential
candidates to Graves’ disease. This article also discussed
some recent patent related to this field.
[Back to top]
Periodontal Regenerative Materials and their Applications:
Goodness of Fit?
Mena Soory
Substances that aid periodontal regeneration rely on
accurate dissemination of active agents to their targets comprising
connective tissue and bone. Healing is enhanced by incorporating
a carrier agent and a time-release microshape containing the
active agent for sustained release and improved uptake at
the site of delivery. Chemotherapeutic agents range from antimicrobial,
anti-inflammatory and tissue regenerative agents such as platelet
rich plasma, enamel matrix proteins, bioactive glass, soy
bean based bone fillers, calcium phosphate and brushite cements.
Cell recognition of tissue regenerative agents within a vehicular
microcapsule for local delivery aid capture of relevant cells
at the required site, enhancing its actions and sustenance.
Gene based therapies for tissue regeneration promote expression
of specific proteins which lead to a steady supply of targeted
stimulatory agents over stipulated periods. Techniques of
tissue engineering and gene therapy are combined to enhance
selective protein expression and expansion of specific cell
populations on biodegradable scaffolds acting as carriers
for dispensing the required agents. These concepts demonstrate
the relevance of optimal targeting and host response which
can enhance or detract from the outcome. Future work would
aim to provide more consistent results with greater accuracy
in targeting and optimal dosing of tissue-active agents. This
review also addresses recent patents related to the field.
[Back to top]
Evaluation of Two Recombinant Plasminogen Activators in Massive
Pulmonary Embolism Model and Potato Carboxypeptidase Inhibitor
(PCI) Role in Inhibition of Thrombin Activatable Fibrinolysis
Inhibitor TAFIa in Lungs
Filip Konecny
Massive pulmonary embolism (MPE) is characterized by
high mortality. Two thirds of patients die within the first
hour of MPE presentation. Significantly lower mortality could
be achieved by using the optimal therapeutic dose of plasminogen
activators (PAc’s). It was expected that Retavase, mutant
of wild type t-Pa, would be more efficient in thrombolysis
than Activase, due to its longer half-life and enhanced ability
to penetrate thrombus due to lack of fibrin attachments. Moreover,
the regulation of endogenous TAFIa activity was tested by
its inhibition by (PCI). The efficacy and safety in newly
developed treatment model of rabbit MPE was tested by PAc’s,
Activase and Retavase and PCI, direct TAFIa inhibitor. Net
clot radioactive thrombi, minced on specific size were injected
into left jugular vein simulating MPE. Autologous rabbit blood
clot was stabilized for one hour before mincing and injection
at room temperature. Treatment was instituted instantly with
doses of tested therapeutics divided equally into an immediate
bolus and infusion over 60 minutes. Control group was treated
with saline. No statistically significant lysis, compared
to saline control, was seen in Retavase doses of 0.25, 1mg,
2mg, but significant lysis was seen for the dose of Retavase
0.5mg (p < 0.05). Statisticaly significant lysis (p <
0.05) was seen for all doses of Activase. In dose of Activase
0.5mg was seen high statistical significance (p < 0.001)
compared to saline control. Both Activase and Retavase showed
a maximum lysis effect at the dose of 0.5mg/kg. The loss of
radioactivity in the saline group was considered as endogenous
clot lysis. The lytic ability of PCI was similar to Saline
innate lung thrombolysis. Statistical significant bleeding,
compared to the saline control, was seen for doses of Retavase
and Activase, except Activase 0.25 mg. Highly statistical
significant bleeding was observed using dose of 0.25 mg Retavase
(p = 0.0019) and dose of Activase 2mg (p=0.0041) compared
to the saline control.
Activase demonstrated distinct thrombolytic capacity over
Retavase in rabbit MPE study. PCI inhibitory potential has
to be further examined and later tested in higher doses or
in combination with lytics to reexamine its TAFIa regulatory
potential during MPE. This article also discussed recent patents
relevant to the field.
[Back to top]
Role of Thrombin Activatable Fibrinolysis Inhibitor in Endocrine
and Cardiovascular Disorders
Baris Akinci and Sena Yesil
Thrombin activatable fibrinolysis inhibitor (TAFI) is
a zymogene that potently inhibits fibrinolysis. It is synthesized
by the liver and has an inhibitor role in fibrinolysis through
the removal of the carboxy-terminal lysine and arginine residues
from partially degraded fibrin polymers. Besides, TAFI has
a suppressor effect on conversion of inactive plasminogen
to plasmin. Alterations in TAFI pathway have been reported
in many conditions. Few data are present in the literature
regarding the relationship between TAFI and endocrine disorders.
The results from few studies in patients with cardiovascular
disease are conflicting. Understanding the role of TAFI in
the pathogenesis of endocrine and cardiovascular disorders
may hold promise for improving management of these diseases.
This paper includes a review of the studies and patents concerned
with TAFI pathway and endocrine and cardiovascular problems.
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