Case report: clues to the diagnosis of an unsuspected massive levothyroxine overdose.

There is currently little literature pertaining to levothyroxine overdose apart from minor or accidental overdoses in the pediatric population. In particular, there is little information available on how to confidently differentiate levothyroxine overdose from endogenous causes of thyrotoxicosis when there is no history available at the time of assessment. We report a levothyroxine (15,800 mcg) and citalopram (2,460 mg) overdose in a 55-year-old woman presenting with seizure and tachycardia in which the diagnosis was not initially suspected. Clinical data, including a long history of treated hypothyroidism and lack of a goiter; and biochemical findings, such as an incompletely suppressed thyroid-stimulating hormone (TSH) level, despite a markedly elevated free thyroxine level (FT4), a normal sex hormone-binding globulin level at baseline, and an undetectable thyroglobulin, supported the diagnosis of thyrotoxicosis due to a massive exogenous thyroid hormone overdose. Treatment was given to decrease free triiodothyronine (FT3) conversion and increase thyroid hormone clearance with dexamethasone and cholestyramine. The patient made a full recovery. Levothyroxine overdose can result in subtle symptoms and signs clinically, even when in massive quantities. This can make diagnosis challenging. Biochemical features, such as the pattern of thyroid hormone elevation and thyroglobulin levels, help differentiate exogenous thyroid hormone overdose from endogenous causes of thyrotoxicosis.

Thirteen years' experience of pharmacokinetic monitoring and dosing of busulfan: can the strategy be improved?

BACKGROUND: A busulfan concentration monitoring and dosing service has been provided by Christchurch Hospital since 1998. This study aimed to see (1) the percentage of patients with an area under the concentration time curve (AUC) outside the target range and had dose adjustment, (2) how busulfan clearance (CL) relates to body weight, and (3) if fewer samples could be used to predict doses. METHODS: Blood samples were taken from patients after oral administration, usually at 0.5, 1, 1.5, and 6 hours, and after the start of a 2-hour intravenous (IV) infusion of busulfan, at 1, 2, 2.5, 3, 6, and 8 hours. Dose adjustment was made based on the AUC compared with the target range. The relationship of CL and body weight for the IV group was used to develop a revised IV dosing schedule. The bias and imprecision of AUCs estimated using fewer sampling points were examined to see if sampling could be economized. RESULTS: Data were available for 150 patients but for 6 patients, data were incomplete and excluded. Of the remaining 144 patients (256 sample sets, 209 oral, 47 IV, 62% with repeats), 38% (IV) and 35% (oral) of patients had AUCs within the target range after the first dose. Dose adjustment was made in 47% and 34% of patients dosed IV and orally, respectively, after which there was a trend to more patients achieving the target AUC. A nonlinear relationship was found between CL and body weight. The initial IV dosing schedule was revised to take this into account. Sampling for busulfan concentration measurement at 3 points (2.5, 4, 8 hours) or 2 points (2.5, 8 hours) after the start of the infusion enabled accurate and precise estimates of AUC0₋24. CONCLUSIONS: Around two thirds of patients treated with busulfan were outside the target AUC range after the first dose. Dose adjustment was made in 37% of patients. The relationship between CL and body weight was used to revise the initial IV dosing schedule. Sampling for AUC estimation could be reduced to 2 time points after IV dosing.

Raloxifene reduces triple-negative breast cancer tumor growth and decreases EGFR expression.

The poor prognosis of patients with triple-negative breast cancer (TNBC) and the lack of targeted treatments have raised the need for alternative therapies. Previous studies have suggested an effect of raloxifene, a selective estrogen receptor modulator that is independent of the estrogen receptor (ER). Therefore, we assessed the therapeutic value of raloxifene in TNBC mouse models. Mice received a daily oral treatment with different doses of raloxifene. Tumor progression was monitored weekly; in addition microvessel density, proliferation, migration and invasion, apoptosis and tumorigenicity were analyzed. This study demonstrates that raloxifene (0.85 mg/kg) prevents TNBC tumor growth and induces tumor regression. The treated tumors showed a 54% decreased microvascular density and proliferation and a 7-fold increase in apoptosis. The underlying therapeutic mechanism of raloxifene was associated with a 27-fold decrease in the expression of the epidermal growth factor receptor (EGFR). Moreover, raloxifene promoted the translocation of EGFR into endosomes associated with decreased cell migration, cell invasion and tumorigenicity in vitro. Together, these data showed that raloxifene acts independently of the ER and may be relevant for the treatment as well as control the progression of TNBC.