Preclinical and clinical activity of the topoisomerase I inhibitor, karenitecin, in melanoma

INTRODUCTION: This review covers the preclinical and clinical activity of the novel camptothecin analog, karenitecin, in melanoma. AREAS COVERED: While the camptothecins are widely used antitumor agents that inhibit topoisomerase I, their utility is limited by instability, high interpatient variability and the development of drug resistance. Karenitecin was rationally designed to overcome these limitations. The authors review the data on karenitecin in preclinical models and in clinical trials in melanoma using studies published in Medline and reports presented at AACR and ASCO. EXPERT OPINION: Karenitecin shows activity in melanoma, both as a single agent and in combination. In adverse prognostic factor melanoma, karenitecin showed prolonged disease stabilization in 34% of patients. Because preclinical studies suggested a synergistic interaction between karenitecin and HDAC inhibitors, a schedule-specific combination Phase I-II trial of valproic acid and karenitecin was carried out in heavily pretreated melanoma patients which showed a benefit rate in 47% patients with acceptable toxicity. The treatment for melanoma is in rapid transition and genomic profiling is now an integral part, and hence the optimal use of karenitecin in melanoma should be re-evaluated with regard to specific mutational status.     

Treatment of Non-infectious Uveitic Macular Edema with the Intravitreal Dexamethasone Implant

Purpose: To describe the clinical outcome of phakic eyes with macular edema (ME) due to non-infectious uveitis treated with a dexamethasone intravitreal implant.

Methods: A retrospective analysis of 41 eyes treated with a total of 58 dexamethasone intravitreal implants was conducted. Best corrected visual acuity (BCVA), central retinal thickness (CRT) and complications data were collected.

Results: One month after the first implant, even as CRT improved significantly in most eyes (p<0.001), 31.7% showed no improvement in BCVA. At 6 months post-implantation, CRT and BCVA had deteriorated in up to 70% of patients. Thirteen eyes were re-implanted, with a similar effect to that of the first implant. Ocular hypertension developed in 36.2% of eyes, and three eyes had cataract surgery, all in eyes with repeated implants.

Conclusions: The dexamethasone intravitreal implant can be safely used to treat ME due to non-infectious uveitis, but with a limited and short effect on BCVA.     

Possible participation of nitric oxide/cyclic guanosine monophosphate/protein kinase C/ATP-sensitive K(+) channels pathway in the systemic antinociception of flavokawin B

The possible mechanisms of action in the antinociceptive activity induced by systemic administration (intraperitoneal, i.p.) of flavokawin B (FKB) were analysed using chemical models of nociception in mice. It was demonstrated that i.p. administration of FKB to the mice at 0.3, 1.0, 3.0 and 10 mg/kg produced significant dose-related reduction in the number of abdominal constrictions. The antinociception induced by FKB in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with L-arginine, the substrate for nitric oxide synthase or glibenclamide, the ATP-sensitive K(+) channel inhibitor, but was enhanced by methylene blue, the non-specific guanylyl cyclase inhibitor. FKB also produced dose-dependent inhibition of licking response caused by intraplantar injection of phorbol 12-myristate 13-acetate, a protein kinase C activator (PKC). Together, these data indicate that the NO/cyclic guanosine monophosphate/PKC/ATP-sensitive K(+) channel pathway possibly participated in the antinociceptive action induced by FKB.     

Zerumbone-induced antinociception: involvement of the L-arginine-nitric oxide-cGMP -PKC-K+ ATP channel pathways

This study investigated the antinociceptive effects of zerumbone in chemical behavioural models of nociception in mice. Zerumbone given through intraperitoneal route (i.p.) produced dose-related antinociception when assessed on acetic acid-induced abdominal writhing test in mice. In addition, the i.p. administration of zerumbone exhibited significant inhibition of the neurogenic pain induced by intraplantar (i.pl.) injection of capsaicin and bradykinin. Likewise, zerumbone given by i.p. route reduced the nociception produced by i.pl. injection of glutamate and phorbol myristate acetate (PMA). The antinociception caused by zerumbone in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with l-arginine (nitric oxide precursor) and glibenclamide (ATP-sensitive K(+) channel inhibitor). However, the antinociception of zerumbone was enhanced by methylene blue (non-specific gyanylyl cyclase inhibitor). Together, these results indicate that zerumbone produces pronounced antinociception against chemical models of nociception in mice. It also strongly suggests that the l-arginine-nitric oxide-cGMP-PKC-K(+) ATP channel pathways, the TRPV1 and kinin B2 receptors play an important role in the zerumbone-induced antinociception.     

Update of tests of colon and rectal structure and function

This review deals with the indications, methods, strengths, and limitations of anorectal testing in clinical practice. In chronic constipation, anal manometry and a rectal balloon expulsion test, occasionally supplemented by defecography, are useful to identify a functional defecatory disorder, because symptoms may respond to pelvic floor retraining. In patients with fecal incontinence, diagnostic testing complements the clinical assessment for evaluating the pathophysiology and guiding management. Manometry measures anal resting and squeeze pressures, which predominantly reflect internal and external anal sphincter function, respectively. Defecation may be indirectly assessed by measuring the recto-anal pressure gradient during straining and by the rectal balloon expulsion test. Endoanal ultrasound and magnetic resonance imaging (MRI) can identify anal sphincter structural pathology, which may be clinically occult, and/or amenable to surgical repair. Only MRI can identify external sphincter atrophy, whereas ultrasound is more sensitive for internal sphincter imaging. By characterizing rectal evacuation and puborectalis contraction, barium defecography may demonstrate an evacuation disorder, excessive perineal descent or a rectocele. Dynamic MRI can provide similar information and also image the bladder and genital organs without radiation exposure. Because the measurement of pudendal nerve latencies suffers from several limitations, anal sphincter electromyography is recommended when neurogenic sphincter weakness is suspected.     

Time-based elution of TEGDMA and BisGMA from resin composite cured with LED, QTH and high-intensity QTH lights

This study measured the elution of TEGDMA and BisGMA monomers from hybrid, micro-filled resin composites over 72 hours at different time intervals after polymerization with standard quartz-tungsten-halogen (QTH), high-intensity fast-curing QTH and standard blue light emitting diode (LED) light units. Samples were polymerized from the top and bottom surfaces, then immersed in methanol. High performance liquid chromatography (HPLC) was used to measure the amount of monomers released from the samples at various time intervals, ranging from 0 to 72 hours (0, 3, 6, 9, 12, 24, 48 and 72 hours). Data was analyzed using two-way ANOVA and Duncan tests with a significance level of 0.05. No significant differences were observed among curing groups in the elution of TEGDMA monomers at 0, 9, 12, 24, 48 and 72 hours; whereas, significant differences were observed among curing groups at 3 and 6 hours. BisGMA elution in samples immersed for longer periods (9-72 hours) were significantly higher than samples immersed for shorter time periods (0-6 hours); however, 72 hours appeared to be too short a period for the total elution of BisGMA into methanol.