Evaluation of Drug Supersaturation by Thermodynamic and Kinetic Approaches for the Prediction of Oral Absorbability in Amorphous Pharmaceuticals

Supersaturation behavior of model drugs, danazol, griseofulvin, itraconazole, vemurafenib, and ER-34122, was analyzed by both thermodynamic and kinetic approaches to better understand the absorption characteristics of amorphous pharmaceuticals. For each amorphous drug, the extent of supersaturation during in vitro dissolution was proved to be similar to that in vivo, which was estimated from relative bioavailability data. The theoretical limit of supersaturation was thermodynamically calculated from several thermal properties and water sorption isotherms of amorphous solids. in vitro and in vivo supersaturation of amorphous vemurafenib was thermodynamically controlled and was in good agreement with the theoretical limit. On the contrary, the supersaturation ratio of the other four drugs was highly overestimated by the thermodynamic calculation. However, it was satisfactorily explained by considering supersaturation stability, which indicated how long supersaturation can be maintained without crystal nucleation. Supersaturation stability was evaluated by measuring the induction time for crystal nucleation kinetically. Concomitant use of thermodynamic and kinetic approaches is, therefore, invaluable in evaluating supersaturation behavior of amorphous materials and assessing development potential of poorly water-soluble drugs. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4220–4230, 2012     

Inclusion of human intravenous study data in new drug applications-impact of the Japanese guidance

Human pharmacokinetic study after intravenous (i.v.) administration is inevitable in calculating basic pharmacokinetic parameters such as bioavailability, clearance, and distribution volume. However, i.v. data are not always included in the dossier, although the regulatory guidance recommends the inclusion of i.v. studies for Japanese new drug applications. We investigated the adherence to this guidance on the inclusion of i.v. data along with various factors. Logistic regression analyses were carried out on 117 new oral drugs approved in Japan between 1999 and 2009. Inclusion of i.v. data conspicuously increased after the issuance of the guidance for self-originated drugs developed by Japanese firms [odds ratio (OR) = 30-41). Moreover, drugs exhibiting large interindividual variations in pharmacokinetics showed a positive association (OR = 4.1-8.2), whereas solubility did not show notable association (OR = 1.0) with inclusion of i.v. data. Inclusion of i.v. data was not associated with physicochemical feasibility, but the developer's willingness to comply with the guidance seems to be involved.     

A crossover study of the acrylonitrile-co-methallyl sulfonate and polysulfone membranes for elderly hemodialysis patients: the effect on hemodynamic, nutritional, and inflammatory conditions

Many maintenance hemodialysis (MHD) patients have recently been treated with high flux (HF) dialysis membranes such as polysulfone (PSu) membranes. However, the appropriateness of HF for elderly MHD remains to be elucidated. In order to estimate hemodialysis (HD) efficiency, the hemodynamic condition during HD, and the nutritional status, 28 elderly MHD patients were treated with PSu for 3 months. After this, the patients were switched to acrylonitrile-co-methallyl sulfonate (AN69) membranes for the next 3 months and then returned to PSu for another 3 months. Reduction ratio of inflammatory cytokines (interleukin [IL]-6) by AN69 was significantly higher than the reduction ratio by PSu. After 3 months with AN69, the serum total protein, albumin, and cholesterol levels significantly increased, and after switching back to PSu, the levels returned to baseline. Furthermore, the frequency of saline used to treat episodes of hypotension during HD significantly decreased in the AN69 period. In elderly MHD patients, it was possible to achieve improvements in both malnutrition and chronic inflammatory conditions with AN69. This suggests that AN69 may be the preferred membrane for elderly MHD, because it stabilizes the hemodynamic condition and demonstrates a higher removal of inflammatory cytokines during HD.     

Minimal-change nephrotic syndrome associated with isoniazid in anti-tuberculosis chemoprophylaxis for a patient with rheumatoid arthritis

A 66-year-old woman with seropositive rheumatoid arthritis (RA) and latent tuberculosis infection developed minimal-change nephrotic syndrome following the initiation of anti-tuberculosis chemoprophylaxis with isoniazid. This is the first reported case of an isoniazid-induced nephrotic syndrome. Isoniazid as a single-drug intervention is widely accepted as a safe and effective means of anti-tuberculosis chemoprophylaxis, particularly for RA patients with latent tuberculosis infection; the present case, however, demonstrates that isoniazid has the potential to induce minimal-change nephrotic syndrome, even when used as a single-drug intervention.     

Acute myocardial infarction associated with small-size lung cancer in a young woman

A 34-year-old woman visited our hospital with chest pain and was diagnosed with acute myocardial infarction (AMI) on admission. Echocardiography imaging revealed the presence of complex masses in the aortic valve. As serum tumor marker CA19-9 was elevated, she was screened for malignant disease. A computed tomography (CT) scan revealed a solitary pulmonary nodule, but because the nodule was small and non-specific, CT follow-up was considered appropriate. However, she developed hemorrhagic stroke in the short term and was subsequently diagnosed with lung adenocarcinoma. Clinicians should be on alert for the occurrence of AMI in patients with small-size lung cancer.     

Feminizing adrenocortical carcinoma with selective suppression of follicle-stimulating hormone secretion and disorganized steroidogenesis: a case report and literature review

We report a 61-year-old male with gynecomastia, poor libido and erectile dysfunction. Endocrinological studies showed high levels of estradiol and dehydroepiandrosterone sulfate. Although luteinizing hormone (LH) level was within the normal limit, the concentration of follicle-stimulating hormone (FSH) was under the normal limit. Delayed response of LH and poor response of FSH to gonadotropin-releasing hormone administration were detected. Magnetic resonance imaging of the abdomen revealed a left adrenal tumor. Although the surgically-resected tumor was diagnosed as a high grade ACC based on Weiss's criteria of adrenocortical malignancy, no metastasis was detected. Since estrogen levels normalized after resection, feminizing ACC was confirmed. While LH concentration increased slightly after operation, FSH level became transiently elevated over the normal limit, and finally reached the normal range. These data may suggest that FSH was suppressed selectively by hormone produced by ACC different from estrogen.