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Transplantation and Cellular Therapy May 2022Therapy for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) involves intensive immunosuppression, which is associated with significant risk of infection....
Therapy for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) involves intensive immunosuppression, which is associated with significant risk of infection. Extracorporeal photopheresis (ECP) is used to treat SR-aGVHD and is considered more immunomodulatory than immunosuppressive. However, pediatric data are mostly retrospective and often involve multistep ECP that includes apheresis followed by separate photosensitizing/reinfusion on another device. This study aimed to prospectively evaluate the efficacy and safety of a single-device ECP system in children with SR-aGVHD. In this open-label multicenter phase 3 study of the Therakos CellEx Photopheresis System in children/young adults age 1 to 21 years with SR-aGVHD. Patients were treated 3 times per week for 4 weeks, then twice weekly through week 12 while maintaining standard aGVHD prophylaxis. The primary efficacy endpoint was the proportion of patients achieving an overall response (OR) at day +28 without the addition of next-line systemic treatment. Secondary endpoints included the proportion of patients achieving OR at weeks 8 and 12; the mean weekly steroid dose at weeks 4, 8, and 12; and treatment-emergent adverse events (TEAEs). Twenty-nine children (median age, 8 years) were enrolled. OR was 55% by day 28, 74% by week 8, and 79% by week 12. Progressive improvements were observed in the skin and the gastrointestinal tract. The mean steroid dose was decreased from 1.54 mg/kg/day at baseline to 0.90 mg/kg/day at week 4; 35% of patients achieved a >50% steroid dose reduction by week 4, and 75% achieved a >50% steroid dose reduction by week 12. Of the 168 TEAEs reported among 25 patients (86%), 28 events (17%) were infections and 14 events (8%) were considered likely treatment related (all nonserious). Of 627 ECP treatments administered in children and young adults, 68% required blood priming. TEAEs related to Uvadex or ECP were rare, hypocalcemia was the most common (3 events total). Three deaths occurred and were deemed unrelated to ECP by the investigators. Use of the Therakos CellEx Photopheresis System was effective in children with SR-aGVHD, with more than one-half experiencing improvement by day 28 and further responses observed over 12 weeks. Very few TEAEs were attributable to ECP, and no new safety signals were observed.
Topics: Adolescent; Adult; Child; Child, Preschool; Graft vs Host Disease; Humans; Infant; Photopheresis; Prospective Studies; Retrospective Studies; Steroids; Young Adult
PubMed: 35124293
DOI: 10.1016/j.jtct.2022.01.025 -
Investigational New Drugs Apr 2021Background Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, non-metastatic prostate cancer (BRPC) but is not curative...
Background Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, non-metastatic prostate cancer (BRPC) but is not curative and associated with toxicity. Racemetyrosine (SM-88) is an amino-acid analogue used with methoxsalen, phenytoin, and sirolimus (MPS) to enhance SM-88 activity. Method A phase 1b/2, open-label trial in BRPC and rising PSA. Patients were given daily SM-88 (230 mg BID), methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg)). Outcome measures included changes in PSA, circulating tumor cells (CTCs) and imaging. Results 34 subjects were screened, 23 treated and 21 remained on study for ≥12 weeks. The median PSA was 6.4 ng/ml (range 1.7-80.1); doubling-time 6.2 months (range 1.4-36.6) and baseline testosterone 319.1 ng/ml (range 2.5-913.7). Median duration of therapy was 6.5 months (2.6-14.0). CTCs (median 48.5 cells/4 ml (range 15-268) at baseline) decreased a median of 65.3% in 18 of 19 patients. For patients who achieved an absolute CTC nadir count of <10 cells/4 ml (n = 10), disease control was 100% i.e. no metastases or PSA progression, while on trial (p = 0.005). PSA fell by ≥50% in 4.3% (1 subject). No patients developed metastatic disease while on treatment (metastases free survival =100%). There were no treatment-related adverse events (AEs) and quality of life was unchanged from baseline on the EORTC QLQ-C30 and QLQ-PR25. Testosterone levels rose slightly on SM-88 and were unrelated to efficacy or toxicity. Conclusions Use of SM-88 was associated with disease control while maintaining QOL. SM-88 may delay the need for ADT and the associated hormonal side effects. Larger trials are planned.Trial registration number, date of registration - NCT02796898, June 13, 2016.
Topics: Aged; Aged, 80 and over; Androgen Antagonists; Humans; Kaplan-Meier Estimate; Male; Methoxsalen; Middle Aged; Neoplasm Recurrence, Local; Phenytoin; Prostate-Specific Antigen; Prostatic Neoplasms; Quality of Life; Sirolimus; Tyrosine
PubMed: 32924093
DOI: 10.1007/s10637-020-00993-4 -
International Journal of Molecular... Jan 2021(1) Cisplatin (CDDP) is used in melanoma chemotherapy, but it has many side effects. Hence, the search for natural substances that can reduce the dose of CDDP, and...
(1) Cisplatin (CDDP) is used in melanoma chemotherapy, but it has many side effects. Hence, the search for natural substances that can reduce the dose of CDDP, and CDDP-related toxicity, is highly desired. Coumarins have many biological properties, including anticancer and antiproliferative effects. (2) An in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay on two human melanoma cell lines (FM55P and FM55M2) examined the antitumor properties of CDDP and five naturally occurring coumarins (osthole, xanthotoxin, xanthotoxol, isopimpinellin, and imperatorin). The antiproliferative effects produced by combinations of CDDP with the coumarins were assessed using type I isobolographic analysis. (3) The most potent anticancer properties of coumarins were presented by osthole and xanthotoxol. These compounds were characterized by the lowest median inhibitory concentration (IC) values relative to the FM55P and FM55M2 melanoma cells. Isobolographic analysis showed that for both melanoma cell lines, the combination of CDDP and osthole exerted synergistic and additive interactions, while the combination of CDDP and xanthotoxol exerted additive interactions. Combinations of CDDP with xanthotoxin, isopimpinellin, and imperatorin showed antagonistic and additive interactions in two melanoma cell lines. (4) The combination of CDDP and osthole was characterized by the most desirable synergistic interaction. Isobolographic analysis allows the selection of potential candidates for cancer drugs among natural substances.
Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Coumarins; Drug Synergism; Furocoumarins; Humans; Melanoma; Methoxsalen
PubMed: 33430369
DOI: 10.3390/ijms22020537 -
Biochemical and Biophysical Research... Dec 2023Epidemiological studies have found that high citrus fruit consumption was associated with higher risk of skin cancer. Citrus fruits and some vegetables contain...
Epidemiological studies have found that high citrus fruit consumption was associated with higher risk of skin cancer. Citrus fruits and some vegetables contain furocoumarins, which may interact with ultraviolet radiation to induce skin cancer. We aimed to determine the effects of two furocoumarins, including 8-methoxypsoralen (8-MOP) and 6',7'-dihydroxybergamottin (DHB), on UVA-induced DNA damage in human epidermal melanocytes, the origin of melanoma. Our hypothesis was that these dietary furocoumarins increase UVA-induced DNA damage in melanocytes, compared to cells exposed to UV alone. We incubated melanocytes with 8-MOP or DHB, followed by exposure to physiological doses of UVA radiation. We used Western blots to quantify the UVA-induced DNA damage measured by the fraction of phosphorylated histone variant H2AX (γH2AX), which is a marker of DNA damage, relative to total H2AX (γH2AX/H2AX) in the presence or absence of furocoumarins. To quantify the UVA-induced change in γH2AX/H2AX, we calculated the UVA:Control ratio as the ratio of γH2AX/H2AX in UVA-exposed cells to that in cells without UVA (control). The mean UVA:Control ratios were borderline significantly higher for cells treated with 8-MOP and significantly higher for cells treated with DHB, compared to that of untreated cells. This study suggests that furocoumarins (particularly 8-MOP and DHB) enhance UVA-induced DNA damage in melanocytes, which is a potential novel mechanism for citrus and furocoumarins to elevate the risk of skin cancer.
Topics: Humans; Furocoumarins; Methoxsalen; Ultraviolet Rays; Melanocytes; DNA Damage; Skin Neoplasms; Citrus
PubMed: 37866241
DOI: 10.1016/j.bbrc.2023.09.094 -
Archives of Biochemistry and Biophysics Jun 2023This study aimed to investigate the effect and mechanism of 8-methoxypsoralen (8-MOP) on acetaminophen (APAP)-induced hepatotoxicity in mice. The study found that 1 h...
This study aimed to investigate the effect and mechanism of 8-methoxypsoralen (8-MOP) on acetaminophen (APAP)-induced hepatotoxicity in mice. The study found that 1 h after intraperitoneal injection of 300 mg/kg APAP, treatment with 40 mg/kg, 80 mg/kg and 120 mg/kg 8-MOP could reduce serum transaminase level and histopathological liver necrosis area. Elevated mRNA expression of liver inflammatory mediators caused by excessive APAP was also reversed. 8-MOP significantly reduced APAP-induced hepatotoxicity dose-dependently, and the highest therapeutic dose of 8-MOP (120 mg/kg) had no harmful effects on the liver. Cocktail probe assay revealed that 8-MOP can inhibit Cyp2e1 enzymatic activities of mice, thereby reducing the production of acetaminophen-cysteine (APAP-CYS), a toxic metabolite of APAP. 8-MOP had no significant effect on the protein and gene expression of Cyp2e1. The three-dimensional structures of mouse Cyp2e1 were constructed by homologous modeling. Molecular docking showed that 8-MOP had a good binding effect on the enzyme activity site of Cyp2e1. In summary, 8-MOP dose-dependently attenuated APAP-induced hepatotoxicity by binding to Cyp2e1 and occupying the active center of the enzyme, thus competitively inhibiting the oxidative metabolism of APAP, and reducing the generation of toxic product APAP-CYS.
Topics: Animals; Mice; Acetaminophen; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2E1; Liver; Methoxsalen; Molecular Docking Simulation
PubMed: 37121295
DOI: 10.1016/j.abb.2023.109617 -
Chemico-biological Interactions Dec 2017Methoxsalen (MTS) is a natural bioactive compound found in a variety of plants that has many known biofunctions; however, its effects on osteoporosis and related...
Methoxsalen (MTS) is a natural bioactive compound found in a variety of plants that has many known biofunctions; however, its effects on osteoporosis and related mechanisms are not clear. This study examined whether MTS exhibited preventive effects against postmenopausal osteoporosis. Female C3H/HeN mice were divided into four groups: Sham, ovariectomy (OVX), OVX with MTS (0.02% in diet), and OVX with estradiol (0.03 μg/day, s.c). After 6 weeks, MTS supplementation significantly increased femur bone mineral density and bone surface along with bone surface/total volume. MTS significantly elevated the levels of serum formation markers (estradiol, osteocalcin and bone-alkaline phosphatase) such as estradiol in OVX mice. Tartrate resistant acid phosphatase staining revealed that MTS suppressed osteoclast numbers and formation in femur tissues compared with the OVX group. Supplementation of MTS slightly up-regulated osteoblastogenesis-related genes (Runx-2, osterix, osteocalcin, and Alp) expression, whereas it significantly down-regulated inflammatory genes (Nfκb and Il6) expression in femur tissue compared with the OVX group. These results indicate that MTS supplementation effectively prevented OVX-induced osteoporosis via enhancement of bone formation and suppression of inflammatory response in OVX mice. Our study provides valid scientific information regarding the development and application of MTS as a food ingredient, a food supplement or an alternative agent for preventing postmenopausal osteoporosis.
Topics: Animals; Biomarkers; Body Weight; Bone Density; Bone and Bones; Core Binding Factor Alpha 1 Subunit; Down-Regulation; Estradiol; Female; Femur; Interleukin-6; Methoxsalen; Mice; Mice, Inbred C3H; NF-kappa B; Osteoporosis; Ovariectomy; Sp7 Transcription Factor; Up-Regulation
PubMed: 29074052
DOI: 10.1016/j.cbi.2017.10.014 -
Food Chemistry Feb 2017The dietary phenol tyrosol has been reported to be endogenously transformed into hydroxytyrosol, a potent antioxidant with multiple health benefits. In this work, we...
The dietary phenol tyrosol has been reported to be endogenously transformed into hydroxytyrosol, a potent antioxidant with multiple health benefits. In this work, we evaluated whether tyrosine hydroxylase (TH) and cytochrome P450s (CYPs) catalyzed this process. To assess TH involvement, Wistar rats were treated with α-methyl-L-tyrosine and tyrosol. Tyrosol was converted into hydroxytyrosol whilst α-methyl-L-tyrosine did not inhibit the biotransformation. The role of CYP was assessed in human liver microsomes (HLM) and tyrosol-to-hydroxytyrosol conversion was observed. Screening with selective enzymatic CYP inhibitors identified CYP2A6 as the major isoform involved in this process. Studies with baculosomes further demonstrated that CYP2D6 and CYP3A4 could transform tyrosol into hydroxytyrosol. Experiments using human genotyped livers showed an interindividual variability in hydroxytyrosol formation and supported findings that CYP2D6 and CYP2A6 mediated this reaction. The dietary health benefits of tyrosol-containing foods remain to be evaluated in light of CYP pharmacogenetics.
Topics: Animals; Antioxidants; Biotransformation; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2D6; Humans; Male; Microsomes, Liver; Phenylethyl Alcohol; Rats; Rats, Wistar; Tyrosine
PubMed: 27664690
DOI: 10.1016/j.foodchem.2016.09.026 -
The Chinese Journal of Physiology Jun 2017Methoxsalen is a natural compound found in many seed plants. The effect of methoxsalen on Ca²⁺- related physiology in human osteosarcoma is unclear. This study...
Methoxsalen is a natural compound found in many seed plants. The effect of methoxsalen on Ca²⁺- related physiology in human osteosarcoma is unclear. This study investigated the effect of methoxsalen on cytosolic free Ca²⁺ concentrations ([Ca²⁺]i) in MG63 human osteosarcoma cells. Methoxsalen induced [Ca²⁺]i rises concentration-dependently. Methoxsalen-induced Ca²⁺ entry was confirmed by Mn²⁺-induced quench of fura-2 fluorescence. This Ca²⁺ entry was suppressed by nifedipine, econazole, and SKF96365. In Ca²⁺-free medium, incubation with the endoplasmic reticulum Ca²⁺ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) inhibited methoxsalen-evoked [Ca²⁺]i rises by 96%. In contrast, incubation with methoxsalen abolished BHQ-evoked [Ca²⁺]i rises. Inhibition of phospholipase C (PLC) with U73122 abolished methoxsalen-induced [Ca²⁺]i rises. Methoxsalen was cytotoxic at 300-700 μM in a concentration-dependent fashion. Chelating cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid/acetoxymethyl ester (BAPTA/AM) did not prevent methoxsalen-induced cytotoxicity. Collectively, our data suggest that in MG63 cells, methoxsalen induced [Ca²⁺]i rises by evoking PLC-dependent Ca²⁺ release from the endoplasmic reticulum, and Ca²⁺ entry via store-operated Ca²⁺ entry. Methoxsalen also induced Ca²⁺- disassociated cell death.
Topics: Apoptosis; Calcium; Calcium Signaling; Cell Line, Tumor; Cell Survival; Endoplasmic Reticulum; Fura-2; Homeostasis; Humans; Methoxsalen; Osteosarcoma; Type C Phospholipases
PubMed: 28629211
DOI: 10.4077/CJP.2017.BAF482 -
Iranian Journal of Reproductive Medicine Aug 2015Different investigation showed that 5-methoxypsoralen and 8- methoxypsoralen reduce birth rates in the rats.
BACKGROUND
Different investigation showed that 5-methoxypsoralen and 8- methoxypsoralen reduce birth rates in the rats.
OBJECTIVE
In this study we worked out the effect of methoxsalen together with ultraviolent A (UVA) radiation on mature Balb/C mice spermatogenesis.
MATERIALS AND METHODS
The LD50 standard was determined 160 mg/kg and the UVA dose which causes erythema was calculated 0.046 J/cm2. A sub-lethal dose of 80 mg/kg of methoxsalen solution was injected intrapritoneally to mature mice and after one hour they were exposed to UVA radiation for 20 minutes. Experiments applied included methoxsalen alone, methoxsalen with UVA, UVA alone, sham group (a group received Tween 80), and control group (N=6). In all experimental groups except UVA alone group, injections were carried out, during two consecutive weeks. Serial cross sections (5 µm thickness) were prepared for morphological and histological studies. Tunica albuginea diameter, and number of type A and type B spermatogonia and histological investigation of the testes were measured.
RESULTS
Microscopical and statistical analyses showed significant anomalies among the experimental groups compared to control and sham group. These anomalies included decrease the body weight; increase the relative testis weight; and decrease the number of spermapogonia (type A and B), primary spermatocytes, spermatids and sperms in experimental groups I and II compared to control group. Our results showed the number of spermatozoa in experimental group I was 22.6±2.12, in experimental group II was 33.6±2.05 and in control group was 44.3±2.77 (p<0.05). Moreover in some experimental groups (I and II) shrinkage of seminiferous tubules and release of primary spermatocyte and spermatids were observed to the lumen of them.
CONCLUSION
It is concluded from the results of this work that treatment with methoxsalen with UVA can damage and disorganize seminiferous tubules and decrease spermatogenic cells.
PubMed: 26568751
DOI: No ID Found -
Journal of Molecular Modeling May 2022In this work, the pharmaceutical cocrystals xanthotoxin-para-aminobenzoic acid (XT-PABA) and xanthotoxin-oxalic acid (XT-OA) were systematically investigated in the gas...
In this work, the pharmaceutical cocrystals xanthotoxin-para-aminobenzoic acid (XT-PABA) and xanthotoxin-oxalic acid (XT-OA) were systematically investigated in the gas and water phases by using the quantum chemical approach. The weak intermolecular interactions have been estimated and the O1…H4 (O1…H5) intermolecular hydrogen bond (IHB) with moderate intensity and partial covalent natures was confirmed based on the computed structural parameters, topology analysis, and reduced density gradient (RDG) isosurfaces. The electrophilic and nucleophilic reactivities of different positions associated with intermolecular interactions in XT, PABA, and OA were predicted by plotting the molecular electrostatic potential (MESP) diagrams. The calculated natural bond orbital (NBO) population analysis has quantitatively unveiled the intrinsic reason for the variations in weak intermolecular interactions within XT-PABA and XT-OA cocrystals, from the gas phase to the water phase. Besides, the frontier molecular orbitals (FMOs), Fukui function, and various global reactivity descriptors were computed to measure the chemical reactivity of all the investigated molecular systems. The XT-PABA and XT-OA cocrystals explored in this work could be regarded as valuable exemplar systems to design and synthesize the high-efficiency pharmaceutical cocrystals in the experiment.
Topics: 4-Aminobenzoic Acid; Methoxsalen; Pharmaceutical Preparations; Structure-Activity Relationship; Water
PubMed: 35579707
DOI: 10.1007/s00894-022-05152-5