Aprepitant

Aprepitant (also known as MK-0869) is a novel and highly selective Neurokinin-1 (NK-1) receptors that inhibits the activity of substance P (SP), an undecapeptide belonging to the tachykinin family of peptides, on the NK-1 receptor with the dissociation constant Kd of 86 pM for human NK-1 receptor and the half maximal inhibition concentration IC50 of 0.1 nM, 4 nM and 0.7 nM for human, rat and ferret NK-1 receptors respectively [1,2].

Since SP has been demonstrated to induce cell proliferation in several human cancer cell lines with overexpressed NK-1 receptors, aprepitant has also been found to concentration-dependently induce growth inhibition in a variety of tumor cell lines, including glioma (GAMG), neuroblastoma (SKN-BE2, IMR-32 and KELLY), retinoblastoma (Y-79 and WERI-Rb-1), pancreas carcinoma (PA-TU-8902 and CAPAN-1), larynx carcinoma (HEp-2), gastric carcinoma (23132-87) and colon carcinoma (SW-403), with IC50 of 33.1 μΜ, 24.6 μΜ, 19.6 μΜ, 27.7 μΜ, 30.4 μΜ, 23 μΜ, 31.2 μΜ, 27.4 μΜ, 22.7 μΜ, 24.2 μΜ and 30.5 μΜ respectively [2].

References:
[1] Tattersall FD1, Rycroft W, Cumberbatch M, Mason G, Tye S, Williamson DJ, Hale JJ, Mills SG, Finke PE, MacCoss M, Sadowski S, Ber E, Cascieri M, Hill RG, MacIntyre DE, Hargreaves RJ. The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets. Neuropharmacology. 2000 Feb 14;39(4):652-63.
[2] Muñoz M1, Rosso M. The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. Invest New Drugs. 2010 Apr;28(2):187-93. doi: 10.1007/s10637-009-9218-8. Epub 2009 Jan 17.

Production of aprepitant nanocrystals by wet media milling and subsequent solidification.[Pubmed:28257885]

Int J Pharm. 2017 Nov 30;533(2):324-334.

The present study investigates the effects of formulation and process parameters on the production of Aprepitant nanosuspensions applying wet media milling and subsequent solidification. Six stabilizers were used: two brands of hydroxylpropylmethyl cellulose (HPMC E-15LV and Pharmacoat 603), hydroxypropyl cellulose (HPC-SSL), polyvinylpyrollidone (PVP), D-alpha-Tocopherol polyethylene glycol 1000 succinate (TPGS 1000), Poloxamer P188 and sodium dodecyl sulfate (SDS), while two diluents (mannitol and sucrose) were incorporated prior to solidification by two methods (spray- and freeze-drying). The polymorphic purity of the raw material, the particle size of nanocrystals, and the physicochemical properties of the final dried powders were assessed. Focus was placed on the energetic aspects of the crystal structure of Aprepitant in order to rationalize particle breakage during wet milling. It was found that a combination of cellulosic polymers with SDS are suitable stabilizers for the production of Aprepitant nanocrystals ( approximately 300nm or smaller) by wet media milling. Regarding the solidification of the nanosuspensions, spray-drying is advantageous compared to freeze-drying, as it leads to the production of almost spherical individual micron-sized agglomerates of nanocrystals and few secondary agglomerates of them which are expected to exhibit improved handling behavior. Spray-dried nanocrystal agglomerates containing Pharmacoat 603 and mannitol exhibit reduced hygroscopity compared to those prepared with sucrose and HPC-SSL, making them the excipients of choice.

Aprepitant for refractory cutaneous T-cell lymphoma-associated pruritus: 4 cases and a review of the literature.[Pubmed:28302100]

BMC Cancer. 2017 Mar 16;17(1):200.

BACKGROUND: Aprepitant is an FDA-approved medication for chemotherapy-induced nausea and vomiting. It blocks substance P binding to neurokinin-1; substance P has been implicated in itch pathways both as a local and global mediator. CASE PRESENTATIONS: We report a series of four patients, diagnosed with cutaneous T-cell lymphoma, who experienced full body pruritus recalcitrant to standard therapies. All patients experienced rapid symptom improvement (within days) following Aprepitant treatment. CONCLUSION: Aprepitant has been shown in small studies to be efficacious for treating chronic and malignancy-associated pruritus. Prior studies have shown no change in clinical efficacy of chemotherapeutics with concurrent Aprepitant administration. These cases further demonstrate that Aprepitant can be considered as a therapeutic option in malignancy-associated pruritus and further support the need for larger clinical trials.

Combination of Aprepitant, Azasetron, and Dexamethasone as Antiemetic Prophylaxis in Women with Gynecologic Cancers Receiving Paclitaxel/Carboplatin Therapy.[Pubmed:28198358]

Med Sci Monit. 2017 Feb 15;23:826-833.

BACKGROUND The aim of this study was to evaluate the antiemetic effect of Aprepitant and to determine how to provide triple combination therapy (Aprepitant/azasetron/dexamethasone) to women receiving paclitaxel/carboplatin moderately emetogenic chemotherapy (MEC). MATERIAL AND METHODS The current study was a prospective study of 163 women with gynecologic cancers. We compared the digestive symptoms scores (nausea, vomiting, appetite loss, and dietary intake) of 37 women with ovarian cancers before and after Aprepitant administration. We also compared these symptoms in women who underwent 193 cycles of triple combination therapy with symptoms of women who underwent 226 cycles of double combination therapy. For triple combination therapy, azasetron, dexamethasone (reduced dose: 40% of 20 mg), and Aprepitant (125 mg) were administered on Day 1, followed by only Aprepitant (80 mg) administration on Days 2 and Day 3. RESULTS In 37 women with ovarian cancer, three symptoms, nausea, appetite loss, and dietary intake, were significantly improved by primarily adding Aprepitant to double combination therapy in the delayed phase of MEC. Upon comparing their digestive symptoms in all cycles, however, these three symptoms were not significantly different in the delayed phase. Furthermore, all four symptoms in all cycles were worse following triple combination therapy than following double combination therapy in the acute phase (p<0.02). The control of digestive symptoms was generally insufficient without the administration of dexamethasone. CONCLUSIONS Primary Aprepitant as an addition to MEC demonstrated efficacy in improving digestive symptoms in the delayed phase. However, its effect may decrease with repeated use. To improve the antiemetic effect, the dose reduction of dexamethasone should be restricted on Day 1 and dexamethasone should be used throughout the delayed phase as well.

Aprepitant limits in vivo neuroinflammatory responses in a rhesus model of Lyme neuroborreliosis.[Pubmed:28202084]

J Neuroinflammation. 2017 Feb 15;14(1):37.

BACKGROUND: Substance P (SP) is produced at high levels in the central nervous system (CNS), and its target receptor, neurokinin 1 receptor (NK-1R), is expressed by glia and leukocytes. This tachykinin functions to exacerbate inflammatory responses at peripheral sites. Moreover, SP/NK-1R interactions have recently been associated with severe neuroinflammation and neuronal damage. We have previously demonstrated that NK-1R antagonists can limit neuroinflammatory damage in a mouse model of bacterial meningitis. Furthermore, we have since shown that these agents can attenuate Borrelia burgdorferi-induced neuronal and glial inflammatory mediator production in non-human primate brain explants and isolated neuronal cells. METHODS: In the present study, we have assessed the role played by endogenous SP/NK-1R interactions in damaging CNS inflammation in an established rhesus macaque model that faithfully reproduces the key clinical features of Lyme neuroborreliosis, using the specific NK-1R antagonist, Aprepitant. We have utilized multiplex ELISA to quantify immune mediator levels in cerebrospinal fluid, and RT-PCR and immunoblot analyses to quantify cytokine and NK-1R expression, respectively, in brain cortex, dorsal root ganglia, and spinal cord tissues. In addition, we have assessed astrocyte number/activation status in brain cortical tissue by immunofluorescence staining and confocal microscopy. RESULTS: We demonstrate that Aprepitant treatment attenuates B. burgdorferi-induced elevations in CCL2, CXCL13, IL-17A, and IL-6 gene expression in dorsal root ganglia, spinal cord, and/or cerebrospinal fluid of rhesus macaques at 2 to 4 weeks following intrathecal infection. In addition, we demonstrate that this selective NK-1R antagonist also prevents increases in total cortical brain NK-1R expression and decreases in the expression of the astrocyte marker, glial fibrillary acidic protein, associated with B. burgdorferi infection. CONCLUSIONS: The ability of a centrally acting NK-1R inhibitor to attenuate B. burgdorferi-associated neuroinflammatory responses and sequelae raises the intriguing possibility that such FDA-approved agents could be repurposed for use as an adjunctive therapy for the treatment of bacterial CNS infections.