Nonclinical Safety Profile of Tolvaptan

Purpose

In the present study, the nonclinical safety profile of tolvaptan was evaluated.

Methods

A series of safety pharmacology and toxicology studies were performed in vitro and in mice, rats, dogs, rabbits and guinea pigs.

Results

In safety pharmacological studies, tolvaptan had no adverse effects on the central nervous, somatic nervous, autonomic nervous, smooth muscle, respiratory and cardiovascular, or digestive systems. In general toxicity studies, a single dose of tolvaptan up to 2,000 mg/kg was not lethal in rats and dogs. Tolvaptan did not cause any target organ toxicity in rats after treatment for 26 weeks or in dogs after treatment for 52 weeks at oral doses of up to 1,000 mg/kg/day. The toxicities observed in the present studies were generally attributable to the exaggerated pharmacological action of tolvaptan. In reproductive and developmental toxicity studies in rats, fertility was not affected. Suppressed viability or growth observed in the prenatal and postnatal progeny occurred at the maternally toxic dose of 1,000 mg/kg/day. In rabbits, tolvaptan showed teratogenicity at 1,000 mg/kg/day, a dose that was maternally toxic causing abortion. Tolvaptan was not genotoxic or carcinogenic, and did not induce phototoxicity, antigenicity or immunotoxicity.

Conclusion

Nonclinical toxicity that precludes the safe administration of tolvaptan to humans was not observed. However, appropriate cautions should be taken in women of childbearing potential.

     

Treatment of patients with hypothalamic-pituitary lesions as adult-onset Langerhans cell histiocytosis

We report four cases of adult-onset Langerhans cell histiocytosis (LCH) with central nervous system (CNS) lesions in the hypothalamic-pituitary region. The first clinical symptoms were diabetes insipidus (two patients), hypothyroidism (one patient), and decreased libido/erectile dysfunction (one patient). Diagnosis was delayed as the CNS lesion was not initially suspected to be secondary to LCH, with a median time from symptom onset to treatment of 3.0 (range <1–5.3) years. In three patients, the tumor mass was effectively reduced by chemotherapy; however, all patients continue to exhibit hypopituitarism. Early diagnosis and initiation of treatment are required to improve the outcome of CNS-LCH in adult patients.     

Efficacy of magnifying endoscopy with flexible spectral imaging color enhancement in the diagnosis of colorectal tumors

Background

Magnifying endoscopy with flexible spectral imaging color enhancement (FICE) is an image-enhanced endoscopy that captures the surface and vascular patterns of colorectal tumors. We evaluated and compared FICE magnification to narrow-band imaging (NBI) magnification.

Methods

Flexible spectral imaging color enhancement or NBI magnification was performed to the visualize surface and vascular patterns of colorectal tumors, classified into 4 types: Type A, Type B, Type C1/C2, and Type C3, as previously reported. A total of 235 colorectal tumors were examined. The correlations between classifications found by FICE or NBI magnification and histopathological diagnoses were examined. Image evaluation was validated by assessing inter-observer and intra-observer agreements on examinations.

Results

Twenty-eight hyperplastic polyps (HPs), 115 tubular adenomas (TAs), 72 mucosal and slightly invaded submucosal cancers (M-sSM), and 20 massively invaded submucosal cancers (mSM) were diagnosed. By FICE magnification, HP and TA were observed in 93.3 and 6.7% of Type A (15 lesions), respectively. TA, M-sSM, and HP were observed in 82.6, 15.4, and 2.0% of Type B (52 lesions), respectively. M-sSM, TA, and mSM were observed in 50.0, 46.0, and 4.0% of Type C1/2 (50 lesions), respectively. mSMs were observed in all 7 Type C3 lesions. In diagnosing mSM in Type C3, the sensitivity and specificity of FICE magnification were 77.7 and 100%, respectively, compared to those of NBI, at 63.6 and 99.0%, respectively. Imaging evaluation was validated accurately by intra- and intra-observer measurements showing consistent results.

Conclusions

The classification of colorectal tumors by FICE magnification correlated well with the histopathological diagnoses, similar to findings for NBI magnification. FICE magnification can be evaluated accurately with the same diagnostic classifications as those used for NBI magnification.     

Evaluation of risk factors for the development of cirrhosis in autoimmune hepatitis: Japanese NHO-AIH prospective study

Autoimmune hepatitis (AIH) is a chronic and progressive liver disease characterized by histological interface hepatitis and circulating autoantibodies. Our aims were to evaluate risk factors that contribute to the outcome and, particularly, the development of liver cirrhosis in a prospective multicenter cohort study of AIH. One hundred and seventy-four patients were enrolled. Histologically 21 (12.1%) had cirrhosis at the initial observation and the remaining 153 showed chronic or acute hepatitis at presentation. Among the latter 153 patients, 14 developed cirrhosis during the follow-up period (mean 8.0 years). Demographic, clinical, and laboratory indices associated with the development of cirrhosis were identified. Patients who developed cirrhosis differed in mean levels of alanine aminotransferase (ALT; 158 ± 182 vs. 441 ± 423 IU/ml) and platelet counts (14.7 ± 5.5 vs. 19.4 ± 6.9 × 10(4)/μl) at presentation and received lower doses of corticosteroid (13.9 ± 15.8 vs. 31.8 ± 85.5 mg/day). In a multivariate analysis, an independent predictor for progression to cirrhosis was an older age of onset (≥ 60 years). AIH patients with cirrhosis, or those who developed cirrhosis, had a worse survival. AIH patients with an older age of onset were likely to develop cirrhosis, and careful observation and aggressive treatments are necessary for such patients.     

Primary aldosteronism

Primary aldosteronism (PA) is the most common cause of secondary hypertension, accounting for 10% of all hypertension. Far from being benign, hypertension due to PA is associated with high cardiovascular morbidity and mortality. However, PA is still underdiagnosed in general practice. Recent reports strongly recommend that identifying patients with PA is cost-beneficial based on improved cardiovascular outcomes afforded by specific surgical and medical treatment. This review provides an update of PA including controversial aspects of diagnosis and treatment.