Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5.

Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC50 value (1.5 nM) against PDE5 than parent sildenafil (5.6 nM) in in vitro enzyme assay. The isoform selectivity of the compound-4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, cLogP along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold.

Development of a validated UPLC-qTOF-MS Method for the determination of curcuminoids and their pharmacokinetic study in mice.

BACKGROUND: A specific and sensitive UPLC-qTOF-MS/MS method has been developed for the simultaneous determination of curcuminoids. These Curcuminoids comprises of curcumin, a principal curcuminoid and other two namely, demethoxycurcumin, and bisdemethoxycurcumin obtained from rhizomes of Curcuma longa an ancient Indian curry spice turmeric, family (Zingiberaceae). METHODS: These analytes were separated on a reverse phase C18 column by using a mobile phase of acetonitrile: 5% acetonitrile in water with 0.07% acetic acid (75:25 v/v), flow rate of 100 µL/min was maintained. The qTOF-MS was operated under multiple reaction monitoring (MRM) mode using electro-spray ionization (ESI) technique with positive ion polarity. The major product ions in the positive mode for curcuminoids were at m/z 369.1066, 339.1023 and 309.0214 respectively. The recovery of the analytes from mouse plasma was optimized using solid phase extraction technique. RESULTS: The total run time was 5 min and the peaks of the compounds, bisdemethoxycurcumin, demethoxycurcumin and curcumin occurred at 2.06, 2.23 and 2.40 min respectively. The calibration curves of bisdemethoxycurcumin, demethoxycurcumin and curcumin were linear over the concentration range of 2-1000 ng/mL (r2, 0.9951), 2-1000 ng/mL (r2, 0.9970) and 2-1000 ng/mL (r2, 0.9906) respectively.Intra-assay and inter-assay accuracy in terms of % bias for curcumin was in between -7.95to +6.21, and -7.03 to + 6.34; for demethoxycurcumin was -6.72 to +6.34, and -7.86 to +6.74 and for bisdesmetoxycurcumin was -8.23 to +6.37 and -8.47 to +7.81. The lower limit of quantitation for curcumin, demethoxycurcumin and bisdemethoxycurcumin was 2.0 ng/mL. Analytes were stable under various conditions (in autosampler, during freeze-thaw, at room temperature, and under deep-freeze conditions). This validated method was used during pharmacokinetic studies of curcumin in the mouse plasma. CONCLUSIONS: A specific, accurate and precise UPLC-qTOF-MS/MS method for the determination of curcumin, demethoxycurcumin and bisdemethoxycurcumin both individually and simultaneously was optimized.

Embolia Cutis Medicamentosa (Nicolau Syndrome) Secondary to Intramuscular Fulvestrant Injection: A Case Report.

PURPOSE: A case of embolia cutis medicamentosa (Nicolau syndrome) in a patient receiving monthly intramuscular fulvestrant injections is presented. SUMMARY: An 85-year-old woman receiving monthly fulvestrant injections in the outpatient setting developed a necrotic lesion at the fulvestrant injection site on her right buttock. Her medical history is notable for metastatic breast cancer with bone metastases. Prior to developing the necrotic lesion, the patient was receiving monthly fulvestrant injections for 6 years. Other potential causes such as infection and pressure necrosis were ruled out clinically. After 185 days of wound care involving multiple surgical debridements, topical therapy, and frequent follow-up appointments, the patient's wound resolved with 100% epithelialization. Nicolau syndrome has been reported with other non-vesicant, injectable medications such as antibiotics and corticosteroids; however, it has not been previously reported with fulvestrant. CONCLUSION: Nicolau syndrome developed in the right buttock of a patient with metastatic breast cancer following an intramuscular fulvestrant injection. Healthcare practitioners need to be cognizant of this adverse effect with intramuscular injections in order to recognize and refer patients for wound care evaluation early in the evolution of this syndrome. Proper injection technique is recommended to reduce the risk of this idiopathic adverse effect.

Clinical implications of adopting Monte Carlo treatment planning for CyberKnife.

It is documented that well-modeled Monte Carlo dose calculation algorithms are more accurate than traditional correction-based algorithms or convolution algorithms at predicting dose distributions delivered to heterogeneous volumes. This increased accuracy has clinical implications for CyberKnife, particularly when comparing dose distributions between the ray-tracing and Monte Carlo algorithms. Differences between ray-tracing and Monte Carlo calculations are exacerbated for highly heterogeneous volumes and small field sizes. In this study, the anthropomorphic thorax phantom from the Radiological Physics Center was used to validate the accuracy of the CyberKnife Monte Carlo dose calculation algorithm. Retrospective comparisons of dose distributions calculated by ray-tracing and Monte Carlo were made for a selection of CyberKnife treatment plans; comparisons were based on target coverage and conformality. For highly heterogeneous cases, such as those involving the lungs, the ray-tracing algorithm consistently overestimated the target dose and coverage. In our sample of lung treatment plans, the average target coverage for ray-tracing calculations was 97.7%, while for Monte Carlo, the average coverage dropped to 69.2%. In each plan comparison, the same beam orientations and monitor units were used for both calculations. Significant changes in conformality were also observed. Isodose prescription lines and subsequent target coverage selected for treatment plans calculated with the ray-tracing algorithm may be different from comparable treatment plans calculated with Monte Carlo, and as such, may have clinical implications for dose prescriptions.

Commissioning and acceptance testing of a CyberKnife linear accelerator.

Acceptance testing and commissioning of a CyberKnife robotic stereotactic radiosurgery system was performed in April 2006. The CyberKnife linear accelerator produces a photon beam of 6 MV nominal energy, without the use of a flattening filter. Clinically measured tissue-phantom ratios, off-center ratios, and output factors are presented and compared with similar data from other CyberKnife sites throughout the United States. In general, these values agreed to within 2%.

Practical considerations for electron beam small field size dosimetry.

Special care of superficial lesions surrounding critical structures, such as an eye, may require tight margins. When this is the case, small megavoltage electron treatment fields and nonstandard treatment distances become necessary. When the field size is found to be less than the practical range of the electron beam, dosimetric measurements should be performed. This research includes data proving that very small electron fields can be employed for treatment with appropriate beam flatness and penumbra. This is accomplished by first coming down the incident beam to a small field size, then secondly by adding a single lead sheet to the patient's skin surface. The aperture of the sheet is required to be greater than 2 x 2 cm2 in size, and must be cut properly to adequately confine the treatment area.

Total skin high-dose-rate electron therapy dosimetry using TG-51.

An approach to dosimetry for total skin electron therapy (TSET) is discussed using the currently accepted TG-51 high-energy calibration protocol. The methodology incorporates water phantom data for absolute calibration and plastic phantom data for efficient reference dosimetry. The scheme is simplified to include the high-dose-rate mode conversion and provides support for its use, as it becomes more available on newer linear accelerators. Using a 6-field, modified Stanford technique, one may follow the process for accurate determination of absorbed dose.

A novel phantom model for mouse tumor dose assessment under MV beams.

In order to determine a mouse's dose accurately and prior to engaging in live mouse radiobiological research, a tissue-equivalent tumor-bearing phantom mouse was constructed and bored to accommodate detectors. Comparisons were made among four different types of radiation detectors, each inserted into the mouse phantom for radiation measurement under a 6 MV linear accelerator beam. Dose detection response from a diode, thermoluminescent dosimeters, and metal-oxide semiconductor field-effect transistors were used and compared to that of a reference pinpoint ionization chamber. A computerized treatment planning system was also directly compared to the chamber. Each detector system demonstrated results similar to the dose computed by the treatment planning system, although some differences were noted. The average disagreement from an accelerator calibrated output dose prescription in the range of 200-400 cGy was -0.4% ± 0.5 σ for the diode, -2.4% ± 2.6 σ for the TLD, -2.9% ± 5.0 σ for the MOSFET, and +1.3% ± 1.4 σ for the treatment planning system. This phantom mouse design is unique, simple, reproducible, and therefore recommended as a standard approach to dosimetry for radiobiological mouse studies by means of any of the detectors used in this study. The authors fully advocate for treatment planning modeling when possible prior to linac-based dose delivery.

Analytical correction of an extension of the "MU Fraction Approximation" for Varian enhanced dynamic wedges.

The most common method to determine enhanced dynamic wedge factors begins with the use of segmented treatment tables. These segmental dose delivery values set as a function of upper jaw position are the backbone of a calculation process coined the "MU Fraction Approximation." Analytical and theoretical attempts have been made to extend and alter the mathematics for this approximation for greater accuracy. A set of linear equations in the form of a matrix are introduced here which correct one published extension of the MU Fraction Approximation as it applies to both symmetric and asymmetric photon fields. The matrix results are compared to data collected from a commissioned Varian Eclipse Treatment Planning System and previously published research for Varian linear accelerators. A total enhanced dynamic wedge factor with excellent accuracy was achieved in comparison to the most accurate previous research found. The deviation seen here is only 0.4% and 1.0% for symmetric and asymmetric fields respectively, for both 6MV and 18MV photon beams.

Generalized anxiety disorder and personality traits.

UNLABELLED: There are an increasing number of studies which show that certain personality traits predispose an individual to develop psychiatric disorders. The current study tried to examine whether neuroticism is more associated to generalized anxiety disorder. METHODOLOGY: A sample of 28 cases of Generalized Anxiety Disorder (GAD) was selected in the study and the degree of neuroticism was measured using Eysenck's Personality Questionnaire (EPQ). RESULT: It was found that neuroticism correlated significantly with GAD than other parameters of EPQ. CONCLUSION: Neuroticism and its inherent traits were more prevalent in patients suffering from GAD.