8 research outputs found
Fatty transformation of angiomyolipoma in TSC patients after initiation of mTOR inhibitor therapy.
<p><b>A</b>: Example of a large AML at the central part of the right kidney in a 33 year-old female TSC patient. <b>A1</b>: At baseline a heterogeneous AML with a mixed-signal on the T2 fat saturated MR sequence (solid arrows) could be visualized. Slow flowing blood in a small vessel (dotted arrows) appears hyperintense on the fat saturated sequence. The unaffected “healthy” kidney tissue is also visualized with a hyperintense signal (*). <b>A2</b>: 2.5 months following the initiation of the mTOR inhibitor therapy a reduction in the overall signal of the AML on the T2 fat saturated sequence can be visualized. The vessel, which was visible at baseline (A1: dotted line) cannot be delineated anymore. Additionally, a reduction of size of the AML can be visualized. This case represents a good example of how difficult it can be to clearly quantify a size reduction in a heterogenous AML following the initiation of mTOR therapy. <b>B</b>: Example of a AML at the caudal part of the right kidney in a 45 year-old male TSC patient. <b>B1</b>: At baseline a heterogeneous relatively bright angiomyolipoma could be visualized on the T2 fat saturated sequence (arrows). The unaffected “healthy” kidney tissue is visualized with a homogenous hyperintense signal on the T2 fat saturated sequence (*). <b>B2</b>: 3 to 6 months following the initiation of the mTOR inhibitor therapy, a clear reduction in the signal on the T2 fat saturated sequence as well as in the size of the angiomyolipoma is visualized. The signal of the healthy kidney tissue does not change following the initiation of the therapy (*). MRI: Magnetic Resonance Imaging. Fatsat: Fat saturated. Scale bar: 1.5 cm.</p
Signal changes in magnetic resonance imaging with selective fat suppression in TSC patients following the initiation of mTOR inhibitor therapy.
<p>Patients were investigated at baseline and after 0–3 months, 3–6 months and 18–24 months of mTOR inhibitor therapy. Additionally, a control collective of TSC patients without mTOR inhibitor therapy was investigated. A pronounced and significant reduction of the mean contrast to noise ratio (CNR) was already observed in the early group within the first three months. In the control group, no reduction of the mean CNR value was observed. Error bars indicate the standard deviation. P-values generated from linear mixed model statistical analysis (* p<0.01, *** p<0.0001); CNR: Contrast to noise ratio.</p
Characteristics of the investigated TSC patient cohort.
<p>Characteristics of the investigated TSC patient cohort.</p
Size changes in magnetic resonance imaging in TSC patients following the initiation of mTOR inhibitor therapy.
<p>Patients were investigated at baseline and after 0–3 months, 3–6 months and 18–24 months of mTOR inhibitor therapy. Additionally, a control collective of TSC patients without mTOR inhibitor therapy was investigated. A significant (p ≤ 0.05) reduction of the size of angiomyolipomas (in mm<sup>2</sup>) was already observed in the early group within the first three months. In the control group, no reduction of the size was observed. Error bars indicate the standard deviation. P-values generated from linear mixed model statistical analysis (* p<0.01, ** p<0.001, *** p<0.0001).</p
Best percentage reduction of contrast to noise ratio as well as size of angiomyolipomas in each individual patient reported at any time point.
<p>In all analyzed patients a reduction in CNR could be observed whereas 2 patients did not show a size reduction of AML under everolimus treatment. AML size is given in mm<sup>2</sup>, results are sorted by value.</p
A Highly Selective Hydantoin Inhibitor of Aggrecanase‑1 and Aggrecanase‑2 with a Low Projected Human Dose
Aggrecanase-1 and -2 (ADAMTS-4 and
ADAMTS-5) are zinc metalloproteases
involved in the degradation of aggrecan in cartilage. Inhibitors could
provide a means of altering the progression of osteoarthritis. We
report the identification of <b>7</b> which had good oral pharmacokinetics
in rats and showed efficacy in a rat chemical model of osteoarthritis.
The projected human dose required to achieve sustained plasma levels
≥10 times the hADAMTS-5 IC<sub>50</sub> is 5 mg q.d
Identification of Potent and Selective Hydantoin Inhibitors of Aggrecanase‑1 and Aggrecanase‑2 That Are Efficacious in Both Chemical and Surgical Models of Osteoarthritis
A disintegrin and metalloproteinase
with thrombospondin motifs-4
(ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred
to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes
are involved in the degradation of aggrecan, a key component of cartilage.
Inhibitors of these enzymes could be potential osteoarthritis (OA)
therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5
were identified from a screening campaign and optimized through structure-based
drug design to give hydantoin <b>13</b>. Hydantoin <b>13</b> had excellent selectivity over other zinc metalloproteases such
as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced
efficacy in both a chemically induced and surgical model of OA in
rats