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Microbiology Spectrum Jun 2022Despite a remarkable improvement in health care and continued drug discovery efforts, malaria control efforts are continuously challenged by the emergence of...
Despite a remarkable improvement in health care and continued drug discovery efforts, malaria control efforts are continuously challenged by the emergence of drug-resistant parasite strains. Given a long and risky development path of new drugs, repurposing existing drugs for the treatment of malaria is an attractive and shorter path. Tamoxifen, a selective estrogen receptor modulator (SERM) for the treatment and prevention of estrogen receptor-positive breast cancer, possesses antibacterial, antifungal, and antiparasitic activities. Hence, we assessed tamoxifen, raloxifene, and bazedoxifene, which represent the first-, second-, and third-generation SERMs, respectively, for antimalarial activity. Raloxifene and bazedoxifene inhibited the erythrocytic development of Plasmodium falciparum with submicromolar 50% inhibitory concentration (IC) values. Among the three, bazedoxifene was the most potent and also decreased P. berghei infection in female mice but not in male mice. However, bazedoxifene similarly inhibited P. falciparum growth in erythrocytes of male and female origin, which highlights the importance of sex-specific host physiology in drug efficacy. Bazedoxifene was most potent on early ring-stage parasites, and about 35% of the treated parasites did not contain hemozoin in the food vacuole. Bazedoxifene-treated parasites had almost 34% less hemozoin content than the control parasites. However, both control and bazedoxifene-treated parasites had similar hemoglobin levels, suggesting that bazedoxifene inhibits hemozoin formation and that toxicity due to accumulation of free heme could be a mechanism of its antimalarial activity. Because bazedoxifene is in clinical use and bazedoxifene-chloroquine combination shows an additive antiparasitic effect, bazedoxifene could be an adjunctive partner of currently used antimalarial regimens. The emergence and spread of drug-resistant strains of the human malaria parasite Plasmodium falciparum has necessitated new drugs. Selective estrogen receptor modulators are in clinical use for the prevention and treatment of breast cancer and postmenopausal osteoporosis. We demonstrate that bazedoxifene, a third-generation selective estrogen receptor modulator, has potent inhibitory activity against both susceptible and drug-resistant strains of Plasmodium falciparum. It also blocked the development of Plasmodium berghei in mice. The inhibitory effect was strongest on the ring stage and resulted in the inhibition of hemozoin formation, which could be the major mechanism of bazedoxifene action. Hemozoin is a nontoxic polymer of heme, which is a by-product of hemoglobin degradation by the malaria parasite during its development within the erythrocyte. Because bazedoxifene is already in clinical use for the treatment of postmenopausal osteoporosis, our findings support repurposing of bazedoxifene as an antimalarial.
Topics: Animals; Antimalarials; Female; Heme; Hemeproteins; Hemoglobins; Humans; Indoles; Malaria; Malaria, Falciparum; Male; Mice; Neoplasms; Osteoporosis, Postmenopausal; Plasmodium falciparum; Postmenopause; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen
PubMed: 35616371
DOI: 10.1128/spectrum.02781-21 -
JAMA Jul 2020
Review
Topics: Anticarcinogenic Agents; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Primary Prevention; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Uterine Neoplasms; Venous Thromboembolism
PubMed: 32692377
DOI: 10.1001/jama.2020.9246 -
The American Journal of Pathology Apr 2018The third most common form of limb-girdle muscular dystrophies is caused by mutations of the Fukutin-related protein (FKRP) gene, with no effective therapy available....
The third most common form of limb-girdle muscular dystrophies is caused by mutations of the Fukutin-related protein (FKRP) gene, with no effective therapy available. Selective estrogen receptor modulators, tamoxifen and raloxifene, have been widely used for human conditions for their anti-inflammatory, antifibrosis, prevention of bone loss, and muscle building effects (essential features for muscular dystrophy therapies). We evaluated therapeutic values of tamoxifen and raloxifene in FKRPP448L mutant mouse with severe dystrophic phenotype. The mice were treated with the drugs for 1 year through daily gavage. We demonstrate that tamoxifen and raloxifene significantly ameliorated the disease progression. The improvement includes increase in grip force production, extended running time and distance in treadmill test, and enhancement in cardiac and respiratory functions. Significant reduction in muscle pathology includes diminished fibrosis and fiber degeneration. Tamoxifen and raloxifene also significantly mitigated bone loss. Tamoxifen, but not raloxifene, caused severe adverse effects on male reproductive organs. The results demonstrate that tamoxifen and raloxifene hold significant potential for treating FKRP-related muscular dystrophy and probably other muscular dystrophies. Sex-related differential effects of the drugs call for a careful consideration for the drug and dosage selection in male and female patient populations.
Topics: Animals; Body Weight; Bone Density; Dystroglycans; Female; Glycosylation; Heart; Male; Mice, Inbred C57BL; Muscles; Muscular Dystrophy, Animal; Organ Specificity; Pentosyltransferases; Phenotype; Proteins; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Time Factors; Transferases
PubMed: 29571322
DOI: 10.1016/j.ajpath.2017.12.011 -
Clinical Therapeutics Apr 2021In patients with primary hyperparathyroidism (PHPT) and severe hypercalcemia, parathyroidectomy remains the only curative therapy. During the coronavirus disease 2019... (Review)
Review
PURPOSE
In patients with primary hyperparathyroidism (PHPT) and severe hypercalcemia, parathyroidectomy remains the only curative therapy. During the coronavirus disease 2019 (COVID-19) pandemic, when many hospital visits are suspended and surgeries cannot be performed, the management of these patients represents a challenging clinical situation. This article presents a literature review and discussion of the pharmacologic management of PHPT and severe hypercalcemia, which can be used as a temporary measure during the COVID-19 pandemic until parathyroidectomy can be performed safely.
METHODS
This narrative review was conducted by searching literature on the PubMed, Medline, and Google Scholar databases using the terms primary hyperparathyroidism, hypercalcemia, cinacalcet, bisphosphonates, denosumab, vitamin D, raloxifene, hormone replacement therapy, coronavirus, and COVID-19.
FINDINGS
Appropriate monitoring and remote medical follow-up of these patients are essential until the resolution of the pandemic. Cinacalcet is the drug of choice for controlling hypercalcemia, whereas bisphosphonate or denosumab is the drug for improving bone mineral density. Combined therapy with cinacalcet and bisphosphonates or cinacalcet and denosumab should be considered when the effects on serum calcium and bone mineral density are simultaneously desired.
IMPLICATIONS
Medical management of PHPT and severe hypercalcemia presents a reasonable alternative for parathyroid surgery during the COVID-19 outbreak and should be instituted until the pandemic ends and surgery can be performed safely.
Topics: Bone Density; COVID-19; Calcium; Cinacalcet; Diphosphonates; Humans; Hypercalcemia; Hyperparathyroidism, Primary; Middle Aged; Parathyroidectomy; Raloxifene Hydrochloride; Vitamin D
PubMed: 33752899
DOI: 10.1016/j.clinthera.2021.02.003 -
Zhongguo Ying Yong Sheng Li Xue Za Zhi... Jun 2024Raloxifene hydrochloride (RLX) is used extensively in the treatment of osteoporosis, only 2% of RLX's bioavailability remains after a significant first pass metabolism....
OBJECTIVE
Raloxifene hydrochloride (RLX) is used extensively in the treatment of osteoporosis, only 2% of RLX's bioavailability remains after a significant first pass metabolism. Besides coming from BCS class II, RLX is not very soluble in water. Thus, the goal of the current study was to improve RLX solubility by creating an inclusion complex using β cyclodextrin (β-CD) as a carrier and solid dispersion with Poloxamer 407.
METHODS
Inclusion complex and solid dispersion were made using a variety of techniques, including kneading, co-precipitation, and physical mixing and solid dispersion using different drug to carrier ratios (1:1, 1:2 and 1:3).
RESULTS
Inclusion complex made using the co-precipitation method had shown 9-fold improvements in water solubility when compared with plain RLX. In order to assess the optimized complex's compatibility, thermal analysis, and crystallinity, X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy were used. The XRD and DSC study's results indicated that RLX changed from a crystalline to an amorphous state. IC-6 exhibits effective water solubility based on the outcome. However, upon comparison of the two techniques, the β-CD complexation method shown an impressive rise in drug solubility when compared to solid dispersion.
Topics: Raloxifene Hydrochloride; Biological Availability; Solubility; beta-Cyclodextrins; Animals; Poloxamer; Drug Carriers
PubMed: 38862271
DOI: 10.62958/j.cjap.2024.002 -
Medicina (Kaunas, Lithuania) Aug 2023The study aimed to assess the efficacy of using Raloxifene with ultrasonic processing to enhance Bio-Oss, a bone graft substitute, for maxillary sinus bone height...
The study aimed to assess the efficacy of using Raloxifene with ultrasonic processing to enhance Bio-Oss, a bone graft substitute, for maxillary sinus bone height reconstruction. A total of 24 rabbit maxillary sinuses were distributed into three groups, each receiving different treatments: Bio-Oss only, sonicated Bio-Oss, and sonicated Bio-Oss with Raloxifene. Surgical procedures and subsequent histomorphometric and immunohistochemistry analyses were conducted to evaluate the bone formation, connective tissue, and remaining biomaterial, as well as the osteoblastic differentiation and maturation of collagen fibers. Results indicated that the sonicated Bio-Oss and Bio-Oss groups showed similar histological behavior and bone formation, but the Raloxifene group displayed inflammatory infiltrate, low bone formation, and disorganized connective tissue. The statistical analysis confirmed significant differences between the groups in terms of bone formation, connective tissue, and remaining biomaterial. In conclusion, the study found that while sonicated Bio-Oss performed comparably to Bio-Oss alone, the addition of Raloxifene led to an unexpected delay in bone repair. The findings stress the importance of histological evaluation for accurate bone repair assessment and the necessity for further investigation into the local application of Raloxifene. Future research may focus on optimizing bone substitutes with growth factors to improve bone repair.
Topics: Animals; Rabbits; Maxillary Sinus; Raloxifene Hydrochloride; Bone Regeneration; Bone Substitutes; Minerals; Biocompatible Materials
PubMed: 37763640
DOI: 10.3390/medicina59091521 -
Integrative Cancer Therapies Sep 2016
Topics: Breast Neoplasms; Estrogen Antagonists; Female; Humans; Raloxifene Hydrochloride; Substance Withdrawal Syndrome; Translational Research, Biomedical
PubMed: 27271771
DOI: 10.1177/1534735416651329 -
Cancer Medicine Feb 2023The aim of this cross-sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated...
The aim of this cross-sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or magnetic resonance imaging (MRI) markers of neurodegeneration associated with Alzheimer's disease. We included women with prior history of breast cancer or no prior history of any cancer at enrollment in the Mayo Clinic Study of Aging (MCSA). This information was abstracted using the Rochester Epidemiology Project medical-linkage system. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive z-scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), and MRI markers. Among 2840 women aged 50 and older in the MCSA, 151 had a history of breast cancer, and 42 (28%) of these had a history of tamoxifen treatment. A total of 2235 women had no prior history of any cancer, and 76 (3%) of these had a history of raloxifene use. No significant associations between tamoxifen use and cognition, or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders. Similarly, raloxifene use was not significantly associated with cognition, or odds of MCI in women without a history of cancer after adjusting for confounders. We did not find significant associations between the use of either SERM and MRI markers. Use of tamoxifen or raloxifene was not significantly associated with cognition in postmenopausal women.
Topics: Female; Humans; Middle Aged; Aged; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Cross-Sectional Studies; Tamoxifen; Breast Neoplasms; Cognition; Cognitive Dysfunction; Receptors, Estrogen; Brain
PubMed: 36040183
DOI: 10.1002/cam4.5175 -
The Oncologist 2002Epidemiological, experimental, and clinical data strongly support the possibility that breast cancer will be prevented by using anti-estrogenic interventions in healthy...
Epidemiological, experimental, and clinical data strongly support the possibility that breast cancer will be prevented by using anti-estrogenic interventions in healthy women. Three trials involving over 20,000 women have so far been reported using tamoxifen 20 mg/day or placebo in healthy women to chemoprevent breast cancer. The American National Surgical Adjuvant Breast and Bowel P-1 Project randomized over 13,000 women to take tamoxifen or placebo and showed a 49% reduction in the early incidence of breast cancer. This was associated with a reduction in osteoporotic fractures but increases in the risks of endometrial cancer, cataract, and thromboembolism. The Royal Marsden tamoxifen trial randomized 2,500 women, and the Italian national trial randomized 5,000 women. Interim analyses from these two trials showed no effect on the early incidence of breast cancer. These results, therefore, have not been able to clearly show an overall clinical benefit of giving tamoxifen to healthy women, nor have they shown which women are likely to benefit. Another selective anti-estrogen (SERM), raloxifene, has been used in a clinical trial to prevent osteoporotic fractures in women with low bone mineral density. Annual mammography in this trial has shown an approximate 80% reduction in the early incidence of breast cancer, and further follow-up of this trial continues. New trials in chemoprevention of breast cancer being started or being proposed use luteinizing-hormone-releasing hormone analogues, aromatase inhibitors, and other SERMs.
Topics: Adult; Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Estrogen Antagonists; Female; Humans; Middle Aged; Multicenter Studies as Topic; Raloxifene Hydrochloride; Tamoxifen
PubMed: 11854547
DOI: 10.1634/theoncologist.7-1-60 -
Molecules (Basel, Switzerland) Nov 2010Raloxifene is a selective estrogen receptor modulator which is structurally similar to tamoxifen. As flavonoids can interact with raloxifene in vitro, we evaluated the...
PURPOSE
Raloxifene is a selective estrogen receptor modulator which is structurally similar to tamoxifen. As flavonoids can interact with raloxifene in vitro, we evaluated the in vivo pharmacokinetics of raloxifene in rats when co-administered with apigenin.
METHODS
The pharmacokinetics of raloxifene in the absence or presence of apigenin was investigated in rats after different dosage regimens. The plasma concentrations before and after enzymatic hydrolysis were analyzed by HPLC, and the pharmacokinetic profiles of raloxifene administered alone and in combination with apigenin were compared.
RESULTS
Co-administration of apigenin with raloxifene in a 1:2 ratio by weight resulted in a 55% and 37% increase in the C(max) and AUC of intact raloxifene, respectively. When equal proportions of raloxifene and apigenin (1:1) were administered, the C(max) and AUC of intact raloxifene were increased by 173% and 97% respectively. This increase in intact raloxifene was not associated with an increase in total raloxifene (intact plus conjugated raloxifene) because AUC and C(max) of total raloxifene when administered alone or in combination with apigenin were found to be similar. The results indicated that apigenin inhibited the glucuronidation and sulfation of raloxifene in the intestine bringing about an increased bioavailability of the drug.
CONCLUSIONS
The results showed that apigenin decreased the first-pass metabolism of raloxifene but did not increase its absorption from the gastrointestinal tract.
Topics: Animals; Apigenin; Drug Interactions; Female; Male; Raloxifene Hydrochloride; Random Allocation; Rats; Rats, Wistar
PubMed: 21088662
DOI: 10.3390/molecules15118478