Immediate versus modified release hydrocortisone in mitotane-treated patients with adrenocortical cancer.

OBJECTIVE: Mitotane induces hepatic CYP3A4 activity, resulting in accelerated cortisol inactivation, and also increases cortisol binding globulin (CBG). Therefore, higher hydrocortisone doses are required in patients with adrenocortical cancer (ACC) on mitotane treatment. Modified release hydrocortisone has not been used in mitotane-treated ACC patients yet. AIM: Case series to compare serum cortisol, calculated free serum cortisol and ACTH levels in ACC patients on mitotane treatment with immediate and modified release hydrocortisone. DESIGN: Pharmacokinetics of immediate and modified release hydrocortisone, each administered at a dose of 40-20-0 mg, in nine patients with ACC and adjuvant mitotane treatment. For comparison, ten patients with secondary adrenal insufficiency (SAI) on three different hydrocortisone regimens and ten healthy males were included. METHODS: Serum cortisol and plasma ACTH were measured by chemiluminescent enzyme immunoassay, and CBG by RIA, followed by calculation of free cortisol. RESULTS: Calculated free serum cortisol levels after 40 mg immediate release hydrocortisone in ACC patients (46 ± 14 nmol/l) were similar to those after 10 mg immediate release hydrocortisone intake in men with SAI (64 ± 16 nmol/l) or to the physiological morning free cortisol levels in healthy subjects (31 ± 5 nmol/l). Compared to immediate release hydrocortisone, free cortisol levels after 40 mg modified release hydrocortisone in ACC patients were significantly lower (12 ± 3 nmol/l; P = 0·03) resulting in a generally lower AUC (98 ± 21 vs 149 ± 37 nmol h/l; P = 0·02). CONCLUSIONS: 40-20-0 mg immediate release, but not modified release hydrocortisone, resulted in sufficient glucocorticoid coverage in patients with ACC receiving mitotane treatment. The use of equivalent doses of modified release hydrocortisone preparation should be avoided in patients on mitotane treatment.

NMR analysis: potential and challenges as a homeopathic basic research tool

Homeopathic ultra-diluted solutions surpass the threshold of matter dispersion and, consequently, their chemical constitution is similar to inert solvent. Nevertheless, randomized clinical trials have shown that the clinical effects of these homeopathic medicines are superior to placebo1. Nuclear magnetic resonance (NMR) is one of the most promising techniques to detect physicochemical alterations induced by homeopathic procedures2,3. Aims: To investigate T2 NMR relaxation times of Zincum metallicumand lactose dynamized samples. Methodology: Zincum metallicumsamples were ground until 6dH using lactose as an excipient. Subsequently, these samples were dynamized with ultrapure water to produce 8dH, 9dH, 10dH,and 11dH. Lactose dynamized samples (6dH-11dH) were used as control. Aliquots of 540µl of each sample were diluted with 60µl of deuterated water (D2O) in 5mm tubes. The analyses were carried out in Bruker Ascend TM 500MHZ spectrometer at 288 K. Results and discussion: The Zincum metallicumand lactose T2 relaxation times were very similar, except for Zincum metallicum8dH, which presented a value of 1.226 in comparison to 1.036 of lactose 8dH. The following T2 values were registered: 1.287 -9dH; 1.413 -10dH; 1.467 -11dH, and 1.303 -9dH; 1.400 ­10dH; 1.350 -11dH, for Zincum metallicumand lactose, respectively. The differences detected in 8dH samples are probably due to the presence of lactose in the first dilution step, in which 1 part of the 6dH triturated mixture was diluted in 9 parts of water, to prepare 7dH. Following this homeopathic procedure, 8dH solutions remain around 1% of lactose which could be influenced by the T2 values registered.Conclusion: These preliminary results showed the possibility to apply the NMR technique to evaluate the influence of dynamization in the relaxation parameters. Further studies should be carried out with other potencies and/or other homeopathic substances, in addition to the evaluation of T1 and the T1/T2 parameters, as previously described by other groups.