Safety profile and metabolic effects of 14 days of treatment with DIO-902: results of a phase IIa multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in patients with type 2 diabetes mellitus

BACKGROUND: Elevated levels of cortisol have been implicated in the development of type 2 diabetes mellitus and the metabolic syndrome. Modulation of cortisol levels and activity may be useful in the treatment of type 2 diabetes and its comorbidities. OBJECTIVE: The purpose of this study was to evaluate the safety profile and pharmacodynamic effects of DIO-902 (2S,4R-ketoconazole), an inhibitor of cortisol synthesis. METHODS: Subjects with type 2 diabetes who were between the ages of 18 and 70 years and were drug naive or receiving metformin at a stable dose were randomized to receive one of the following once daily at bedtime for 14 days: ketoconazole 400 mg; DIO-902 200, 400, or 600 mg; or placebo. Tolerability was assessed based on adverse events reported by subjects and the results of physical examinations and standard hematology, chemistry, and urinalysis tests performed on days 8 and 15. Glycosylated hemoglobin (HbA1c) and levels of fructosamine, fasting glucose, lipoproteins, and C-reactive protein were measured at baseline and the end of treatment. The Jonckheere-Terpstra test was used to test for an ordinal dose-response trend between the DIO-902 doses and placebo. Morning (7:30 am) salivary cortisol levels were measured and overnight plasma cortisol levels were analyzed as a 12-hour AUC at baseline and the end of treatment. Adrenocorticotropic hormone (ACTH) levels were measured and an ACTH stimulation test was used to assess adrenal reserve at baseline and the end of treatment. RESULTS: The study enrolled 21 women (58.3%) and 15 (41.7%) men. Their mean (SD) age was 55.4 (8.5) years; mean HbA1c, 8.1% (1.3%); and mean duration of diabetes, 4.8 (3.7) years. White subjects were in the majority (86.1%), with black subjects constituting 11.1% of the population and those of other racial backgrounds constituting 2.8%; 47.2% of subjects were of Hispanic ethnicity. The proportions of subjects experiencing any adverse event were 62.5% in the ketoconazole group; 60.0%, 83.3%, and 100% in the DIO-902 200-, 400-, and 600-mg groups, respectively; and 50.0% in the placebo group. Gastrointestinal disorders were the most common adverse event, reported in 12.5% of the ketoconazole group, 35.0% of the combined DIO-902 treatment group, and 16.7% of the placebo group. Headache, the second most commonly reported adverse event, was reported in 12.5% of the ketoconazole group, 30.0% of the overall DIO-902 group, and none of the placebo group. DIO-902 treatment was not associated with any significant differences in measures of glycemic control relative to placebo or any significant decreases in mean morning salivary cortisol levels or mean overnight cortisol exposure. Dose-dependent reductions from baseline were seen in mean levels of low-density lipoprotein cholesterol (mean percent reductions: -11.39, -23.38, and -42.10 with DIO-902 200, 400, and 600 mg, respectively; P<0.001), as well as in total cholesterol (P<0.001) and high-density lipoprotein cholesterol (P=0.034). Mean levels of C-reactive protein were significantly reduced relative to placebo at all doses of DIO-902 (P=0.027); no reductions in either of these parameters were seen in the placebo group. CONCLUSION: In this small, short-term study in subjects with type 2 diabetes, DIO-902 was generally well tolerated, although it was associated with an increased incidence of gastrointestinal disorders and headache. Levels of low-density lipoprotein cholesterol were significantly decreased in subjects treated with DIO-902.     

Co-occurrence of radiological features of progressive supranuclear palsy and corticobasal degeneration

We report an interesting case demonstrating co-occurrence of radiological features of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The clinical features were typical of PSP but magnetic resonance imaging (MRI) showed both typical brainstem changes of PSP and an atypical pattern of cortical atrophy. While the MRI had markers of CBD, the clinical features were not classical of CBD.     

Molecular analysis of anoikis resistance in oral cavity squamous cell carcinoma

Oral cavity squamous cell carcinoma (OSCC) is one of the leading causes of cancer deaths worldwide and most of these deaths result from local-regional recurrence and metastases. Evasion of apoptosis is an important hallmark of cancer development and progression, and previous studies have shown that evasion of anoikis, or detachment-induced apoptosis, correlates with a more aggressive phenotype of carcinoma cells in OSCC. To elucidate the cytogenetic and molecular characteristics of anoikis resistance, we generated several cell lines and clones that displayed this cellular phenotype. To test the hypothesis that chromosomal alterations may underlie this phenotypic transformation, we used karyotype analysis to observe changes in the chromosomal structure of anoikis-sensitive and anoikis-resistant cell lines. We further hypothesized that a unique pattern of gene expression was induced by cell-detachment of anoikis-resistant cell lines, and cDNA microarray analysis was performed using a panel of anoikis-resistant oral cancer cell lines grown under attached and detached growth conditions. We identified S100P, KLK6 and CTNNAL1 as genes whose expression levels were differentially regulated in the anoikis-resistant cell lines compared to the anoikis-sensitive cells under detached conditions. These results were verified using real-time RT-PCR. The anoikis-resistant phenotype of squamous cell carcinoma has a distinct genetic expression pattern that is marked by chromosomal alterations that may contribute to differential expression of genes involved in diverse cellular functions. Therapies targeting these potential mediators of anoikis resistance may prove to be beneficial in the treatment of metastatic squamous cell carcinoma.     

Synthesis and in vitro evaluation of some isatin-thiazolidinone hybrid analogues as anti-proliferative agents

A range of isatin-thiazolidinone hybrid analogues were synthesized and their cytotoxicity was evaluated against several cancer cell lines in vitro. The acute toxicity studies in mice models revealed that these analogues possess low systemic toxicity and are safe up to 1600mg/Kg. Among the compounds synthesized, 5-(2-nitrobenzylidene)-2-(isatin-3-azino)-thiazolidin-4-one (CI) has been shown to be the most active, highly promising compound which induced S phase arrest in cell cycle in a time dependent manner. Our initial analysis indicate that incorporation of electron withdrawing group at ortho position of the ring favors over the meta and para positions for eliciting its cytostatic effect. Overall, the in vitro biological evaluation suggests that the growth inhibitory effect of CI is promising and can be studied further.     

Perceptions of genetic counseling services in direct‐to‐consumer personal genomic testing

To describe consumers' perceptions of genetic counseling services in the context of direct‐to‐consumer personal genomic testing is the purpose of this research. Utilizing data from the Scripps Genomic Health Initiative, we assessed direct‐to‐consumer genomic test consumers' utilization and perceptions of genetic counseling services. At long‐term follow‐up, approximately 14 months post‐testing, participants were asked to respond to several items gauging their interactions, if any, with a Navigenics genetic counselor, and their perceptions of those interactions. Out of 1325 individuals who completed long‐term follow‐up, 187 (14.1%) indicated that they had spoken with a genetic counselor. The most commonly given reason for not utilizing the counseling service was a lack of need due to the perception of already understanding one's results (55.6%). The most common reasons for utilizing the service included wanting to take advantage of a free service (43.9%) and wanting more information on risk calculations (42.2%). Among those who utilized the service, a large fraction reported that counseling improved their understanding of their results (54.5%) and genetics in general (43.9%). A relatively small proportion of participants utilized genetic counseling after direct‐to‐consumer personal genomic testing. Among those individuals who did utilize the service, however, a large fraction perceived it to be informative, and thus presumably beneficial.     

Medicinal Plants and Formulations Used by the Soren Clan of the Santal Tribe in Rajshahi District,Bangladesh for Treatment of Various Ailments

The Santals form the largest tribal community in northern Bangladesh reside primarily in Rajshahi and Rangpur Divisions, where they live in the districts of Rajshahi, Rangpur, Thakurgaon, Dinajpur, and Panchagarh. Although they are fast losing their traditional medicinal practices, they still have their own medicinal practitioners who rely mostly on medicinal plants for treatment of a variety of ailments. The traditional medicinal practices vary quite extensively between the twelve clans of the Santals. The objective of the present study was to conduct an ethnomedicinal survey amongst the Soren clan of the Santal community residing in two villages of Tanor Santal Para in Rajshahi district to collect information on their use of medicinal plants. Interviews were conducted of the two existing Santal traditional medicinal practitioners of the Soren clan with the help of a semi-structured questionnaire and using the guided field-walk method. Plant specimens as pointed out by the practitioners were collected and pressed on the field and identification completed at the Bangladesh National Herbarium. Information on 53 medicinal plants distributed into 32 families was obtained in this survey. Ailments treated by these plants included skin disorders, respiratory tract disorders, gastro-intestinal disorders, sexual dysfunctions, sexually transmitted diseases, diabetes, helminthiasis, pain, urinary problems, filariasis, leprosy, tuberculosis, epilepsy, snake bite, enlarged heart, and paralysis. The medicinal plants used by the Santals merit further scientific studies for some of their formulations are used to treat diseases like diabetes, paralysis, enlarged heart, tuberculosis, and filariasis for which modern medicine has no known cure or medicines have developed resistant vectors.