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Biotech / Medical : Ligand (LGND) Breakout! -- Ignore unavailable to you. Want to Upgrade?

To: Abuckatatime who wrote (28659)	4/6/1999 8:09:00 PM
From: Cacaito	Read Replies (1) \| Respond to of 32384

Hypthyroidism is a serious side effect, but in a patient with the burden of CTCL it will be easy to replace thyroid hormones if Targretin actually work. It was also related to high doses. How many patients will need this doses? Probably not many of them, Maybe this were patients in end stages of CTCL needing high doses?

To: Abuckatatime who wrote (28659)	4/6/1999 11:05:00 PM
From: Cacaito	Respond to of 32384

Targretin and hypothyroidism. What about hyperthyroidism? Caveat: pure speculation follows: If Targretin is so a good blocker of thyrotropin it could become a treatment for a group of patients with hyperthyroidism of central origin, not from the thyroid gland itself, but coming from the pitituary gland inside of the head. There is also a third variant coming from the neuroreceptor that stimulate the pitituary, and even other more subtle molecular variations. All of the central types result in an increase of thyrotopin production (not to be confused with thyroxin from the thyroid gland itself) and eventually increase in thyroxin. The treatment of many of the central types of hyperthyroidisms involve sometimes risky intracranial surgery, sometimes resulting in severe hypothyroidism. Just speculation.

To: Abuckatatime who wrote (28659)	4/14/1999 8:59:00 PM
From: Henry Niman	Read Replies (1) \| Respond to of 32384

Here's the abstract on the Targretin side effects, presented last Spring, indicating that only 1.6% of cancer patients with a maligancy other than CTCL develop hypothyrodism: [OR35-6] THYROID AXIS ALTERATIONS IN CTCL PATIENTS RECEIVING AN RXR-SELECTIVE LIGAND S I Sherman1, J Gopal1, A C Chiu1, K Whaley2, P Nowlakha2, J Truglia3, R Yocum3, M Duvic2, 1Sect. of Endocrine Neoplasia and Hormonal Disorders, Univ. of Texas M.D. Anderson Cancer Center, Houston, TX, 2Sect. of Dermatology, Univ. of Texas M.D. Anderson Cancer Center, Houston, TX, 3, Ligand Pharmaceuticals, San Diego, CA, In an interim analysis of multicenter phase 2-3 trials of oral Targretin (a synthetic RXR-selective retinoid analogue) in patients with cutaneous T-cell lymphoma (CTCL), 11% (8/76) of patients had mild baseline elevations of serum TSH. Thyroid testing in 24 of 31 patients enrolled at one study center revealed abnormally low TSH levels during treatment with Targretin, 300 mg/M2/d (lower doses in 3 patients). These 24 patients (12 men, 12 women; mean age 67 yrs; TNM stage IB-III) had a baseline log mean TSH of 2.27 mU/L that fell to a nadir of 0.05 (P<0.0001), whereas the free and/or total T4 declined below normal in 22 patients. Neither a baseline elevated TSH nor detectable antithyroid antibodies (found in 5 of 21 patients tested) was associated with subsequent hypothyrotropinemia. TRH stimulation performed in 2 patients on Targretin therapy increased the TSH level 7- and 11-fold, respectively. Following initiation of Targretin therapy, elicited hypothyroid symptoms included cold intolerance (11 patients), fatigue (10), impaired cognition, constipation, and depression (3 each) muscle cramps, hoarseness, and worsening hearing acuity (2 each), and resolution of palpitations associated with chronic atrial fibrillation (1). Physical findings included delayed deep tendon reflex relaxation (4), nonpitting edema (3), and decreased strength (1). In patients whose Targretin was interrupted, TSH and T4 levels recovered from suppression while off drug and were subsequently suppressed with restarting retinoid therapy. Some clinical improvement was noted following initiation of L-thyroxine therapy. In one patient treated with L-thyroxine, 0.175 mg, a doubling of her T4 level and further suppression of TSH was seen when she stopped Targretin. In summary, biochemical evidence of central hypothyroidism was frequently observed in CTCL patients treated with high-dose Targretin, though not all patients demonstrated clinical manifestations. Although the primary mechanism is likely reversible TSH suppression by the R-selective ligand, additional effects on thyroid hormone secretion and/or metabolism cannot be ruled out. These observations in CTCL patients contrast with the cumulative experience with oral Targretin therapy in 192 patients with other malignancies (of whom only 1.6% were reported to develop hypothyroidism during therapy), suggesting that the thyroid axis in CTCL patients may be particularly susceptible to the effects of an RXR-selective ligand.