Development and in-vitro evaluation of an optimized carvedilol transdermal therapeutic system using experimental design approach

AbstractThe effect of formulation variables on in-vitro release and permeation properties of carvedilol from transdermal patch was studied by varying one factor at a time as preliminary study. Based on these results, design of experiments technique was applied followed by regression analysis and response surface methodology to optimize formulation variables. Central Composite IV model design was used with four formulation variables: drug loading, matrix thickness, adhesive layer thickness, and propylene glycol concentration. Nineteen formulations were prepared according to the design; and the effect of formulation variables was studied on in-vitro release and permeation profiles of these formulations. In all cases, the permeation profiles paralleled in-vitro release profiles. The drug released at 7 h and 24 h was used as release response parameters while permeation flux obtained was employed as permeation response parameter. All four formulation variables were found to be significant for release properties and three of these exhibited significant effect on permeation profile of carvedilol across artificial membrane. Constrained optimization, using 47.9% of cumulative carvedilol released at 7 h and 99.8% at 24 h as well as 25.7 μg/cm2/h of permeation flux, was applied to obtain desired release and permeation profiles. Experimentally, carvedilol was observed to release from the optimized formulation with 51.4% drug release at 7 h and 98.5% at 24 h with an observed flux value of 27.4 μg/cm2/h across artificial membrane, which showed an excellent agreement with the predicted values. The results of this investigation show that the quadratic mathematical model developed could be used to further predict formulations with desirable release and permeation properties

True polyploid meiosis in the human male

Genetics of disease, diagnosis and treatmen

<em>TP53</em> intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome.

Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified &quot;TP53 wild-type&quot; LFS

Phase I Study of TAK-659, an Investigational, Dual SYK/FLT3 Inhibitor, in Patients with B-Cell Lymphoma

PURPOSE: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. PATIENTS AND METHODS: Patients received continuous, once-daily oral TAK-659, 60-120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. RESULTS: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (Tmax 3c2 hours) with a long terminal half-life ( 3c37 hours). Exposure generally increased with dose (60-120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). CONCLUSIONS: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted