Patients with advanced Parkinson&... more Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including postural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) of a highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, the underlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hampering optimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre(+) transgenic rats were sham-lesioned or rendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomal system inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD), to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of the human PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including a partial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients. In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in the lactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO), dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait, sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordings revealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fos expression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased by CNO administration, consistent with upregulated neuronal activation in this defined neuronal population. Overall, these findings provide evidence that functional modulation of PPN cholinergic neurons alleviates parkinsonian motor symptoms.
Introduction: Osteoporosis is a skeletal disorder characterized by compromised bone strength and ... more Introduction: Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is a common disorder in elderly subjects and represents a major public health problem, affecting up to 40% postmenopausal women and 15% of men. Among the several therapeutical interventions, hormone replacement therapy (HRT) was traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women, as well as for the management of menopausal symptoms. However HRT, especially if administered long-term, may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter was considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remain uncertain. Aims: The purpose of this arti...
Bazedoxifene acetate is a novel, chemically distinct selective estrogen receptor modulator (SERM)... more Bazedoxifene acetate is a novel, chemically distinct selective estrogen receptor modulator (SERM) that has been specifically developed after a stringent preclinical screening in order to obtain favorable effects on the skeleton and lipid metabolism with the additional improvement of a neutral effect on hot flushes and without stimulating the uterus or the breast. In both preclinical and clinical studies this SERM was shown to maintain BMD, prevent fractures, and reduce total cholesterol. Moreover, bazedoxifene also showed an improved uterine profile and demonstrated estrogen antagonistic activity on the endometrium. Importantly, this latter capacity has led to the development of a novel class of menopausal therapy called tissue selective estrogen complex (TSEC), in which bazedoxifene is combined with conjugated estrogen. The rationale for selecting bazedoxifene as the SERM in this TSEC combination is that it may offset estrogen stimulation of endometrial and breast tissue, without t...
Osteoporosi e malattie metaboliche dell’osso, 2009
Malattia di Paget Luigi Gennari, Daniela Merlotti, Vincenzo De Paola, Anna Calabrò, Giuseppe Mart... more Malattia di Paget Luigi Gennari, Daniela Merlotti, Vincenzo De Paola, Anna Calabrò, Giuseppe Martini, Annalisa Avanzati, Ranuccio Nuti 23 Indice 23.1 Epidemiologia 23.2 Eziopatogenesi 23.3 Fisiopatologia e istologia 23.4 Clinica 23.5 Diagnosi 23.6 Diagnosi differenziale L. ...
Vitamin D and calcium are essential for normal skeletal growth and for maintaining the mechanical... more Vitamin D and calcium are essential for normal skeletal growth and for maintaining the mechanical and structural integrity of the skeleton. Reduced intake of calcium and vitamin D may be associated with reduced bone mass and osteoporosis while a chronic and severe vitamin D deficiency may lead to osteomalacia. Given the importance of vitamin D in bone homeostasis, common polymorphisms in the vitamin D receptor gene were the first to be investigated as possible determinants of bone mass and fracture risk. Even though results are still conflicting and the molecular mechanisms by which these polymorphisms influence receptor activity remain in part to be investigated, an additional important issue is represented by their potential pharmacogenomic and pharmacogenetic implications. This review analyzes major pharmacogenetic studies of polymorphisms in the vitamin D receptor gene and osteoporosis.
Paget&amp... more Paget's disease of bone is a focal skeletal disorder characterized by the formation of structurally abnormal bone, deformity and other complications leading to significant disability and bone pain. Recently, the availability of newer, more potent nitrogen-containing bisphosphonates has improved treatment outcomes, allowing a more effective and convenient management of this disorder.
Osteoporosis is a common skeletal disorder with a strong genetic component. In recent years, sign... more Osteoporosis is a common skeletal disorder with a strong genetic component. In recent years, significant progress has been made in understanding the genetic basis of osteoporosis. Given the biological significance of signalling through steroid hormone receptors, bone biology and calcium homeostasis, alleles of steroid hormone receptor genes have been postulated to contribute to the well-documented genetic predisposition to osteoporosis; and in different studies, these alleles have been associated with variation in bone mass and fracture risk. Even though results are still conflicting and the molecular mechanisms by which these polymorphisms influence receptor activity remain, in part, to be investigated, an additional important issue is represented by potential pharmacogenomic (the investigation of variations of DNA or RNA characteristics as related to drug response) or pharmacogenetic (the influence of variations of DNA sequence on drug response) implications. In fact, steroid hormone receptors actually mediate the action of several compounds known to positively or negatively affect bone homeostasis, such as vitamin D, estrogen and glucocorticoids. This review analyses major pharmacogenetic studies of polymorphisms in steroid hormone receptor genes.
Raloxifene is a benzothiophene, selective estrogen receptor modulator with estrogen-agonist effec... more Raloxifene is a benzothiophene, selective estrogen receptor modulator with estrogen-agonist effects in the skeleton and the cardiovascular system but estrogen-antagonist effects in the uterus and the mammary gland. This compound was first approved in different countries for the prevention and treatment of osteoporosis. We performed a literature search to review available preclinical and clinical data that has led to the recent FDA approval of raloxifene as a chemopreventive agent for breast cancer in postmenopausal women. Different placebo-controlled trials indicated that raloxifene is effective in reducing invasive breast cancer risk in postmenopausal women. In a recent comparative study, a similar efficacy between raloxifene and tamoxifen for breast cancer prevention was demonstrated, but raloxifene showed a more favorable safety profile.
Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk... more Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is a common disorder in elderly subjects and represents a major public health problem, affecting up to 40% postmenopausal women and 15% of men. Among the several therapeutical interventions, hormone replacement therapy (HRT) was traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women, as well as for the management of menopausal symptoms. However HRT, especially if administered long-term, may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter was considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remain uncertain. The purpose of this article is to review the clinical trials of lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis. The medical literature was reviewed for appropriate articles containing the terms "lasofoxifene" and SERMs". There are three (phase II or phase III) clinical trials that clearly demonstrate efficacy and safety of this new SERM in the suppression of bone loss and the prevention of vertebral and nonvertebral fractures. Moreover, lasofoxifene treatment also reduced breast cancer risk and the occurrence of vaginal atrophy. With its increased potency and efficacy on the prevention of nonvertebral fractures lasofoxifene may be an alternative and cost-effective therapy for osteoporosis in postmenopausal women.
Patients with advanced Parkinson&... more Patients with advanced Parkinson's disease (PD) often present with axial symptoms, including postural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) of a highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, the underlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hampering optimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre(+) transgenic rats were sham-lesioned or rendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomal system inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD), to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of the human PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including a partial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients. In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in the lactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO), dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait, sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordings revealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fos expression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased by CNO administration, consistent with upregulated neuronal activation in this defined neuronal population. Overall, these findings provide evidence that functional modulation of PPN cholinergic neurons alleviates parkinsonian motor symptoms.
Introduction: Osteoporosis is a skeletal disorder characterized by compromised bone strength and ... more Introduction: Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is a common disorder in elderly subjects and represents a major public health problem, affecting up to 40% postmenopausal women and 15% of men. Among the several therapeutical interventions, hormone replacement therapy (HRT) was traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women, as well as for the management of menopausal symptoms. However HRT, especially if administered long-term, may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter was considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remain uncertain. Aims: The purpose of this arti...
Bazedoxifene acetate is a novel, chemically distinct selective estrogen receptor modulator (SERM)... more Bazedoxifene acetate is a novel, chemically distinct selective estrogen receptor modulator (SERM) that has been specifically developed after a stringent preclinical screening in order to obtain favorable effects on the skeleton and lipid metabolism with the additional improvement of a neutral effect on hot flushes and without stimulating the uterus or the breast. In both preclinical and clinical studies this SERM was shown to maintain BMD, prevent fractures, and reduce total cholesterol. Moreover, bazedoxifene also showed an improved uterine profile and demonstrated estrogen antagonistic activity on the endometrium. Importantly, this latter capacity has led to the development of a novel class of menopausal therapy called tissue selective estrogen complex (TSEC), in which bazedoxifene is combined with conjugated estrogen. The rationale for selecting bazedoxifene as the SERM in this TSEC combination is that it may offset estrogen stimulation of endometrial and breast tissue, without t...
Osteoporosi e malattie metaboliche dell’osso, 2009
Malattia di Paget Luigi Gennari, Daniela Merlotti, Vincenzo De Paola, Anna Calabrò, Giuseppe Mart... more Malattia di Paget Luigi Gennari, Daniela Merlotti, Vincenzo De Paola, Anna Calabrò, Giuseppe Martini, Annalisa Avanzati, Ranuccio Nuti 23 Indice 23.1 Epidemiologia 23.2 Eziopatogenesi 23.3 Fisiopatologia e istologia 23.4 Clinica 23.5 Diagnosi 23.6 Diagnosi differenziale L. ...
Vitamin D and calcium are essential for normal skeletal growth and for maintaining the mechanical... more Vitamin D and calcium are essential for normal skeletal growth and for maintaining the mechanical and structural integrity of the skeleton. Reduced intake of calcium and vitamin D may be associated with reduced bone mass and osteoporosis while a chronic and severe vitamin D deficiency may lead to osteomalacia. Given the importance of vitamin D in bone homeostasis, common polymorphisms in the vitamin D receptor gene were the first to be investigated as possible determinants of bone mass and fracture risk. Even though results are still conflicting and the molecular mechanisms by which these polymorphisms influence receptor activity remain in part to be investigated, an additional important issue is represented by their potential pharmacogenomic and pharmacogenetic implications. This review analyzes major pharmacogenetic studies of polymorphisms in the vitamin D receptor gene and osteoporosis.
Paget&amp... more Paget's disease of bone is a focal skeletal disorder characterized by the formation of structurally abnormal bone, deformity and other complications leading to significant disability and bone pain. Recently, the availability of newer, more potent nitrogen-containing bisphosphonates has improved treatment outcomes, allowing a more effective and convenient management of this disorder.
Osteoporosis is a common skeletal disorder with a strong genetic component. In recent years, sign... more Osteoporosis is a common skeletal disorder with a strong genetic component. In recent years, significant progress has been made in understanding the genetic basis of osteoporosis. Given the biological significance of signalling through steroid hormone receptors, bone biology and calcium homeostasis, alleles of steroid hormone receptor genes have been postulated to contribute to the well-documented genetic predisposition to osteoporosis; and in different studies, these alleles have been associated with variation in bone mass and fracture risk. Even though results are still conflicting and the molecular mechanisms by which these polymorphisms influence receptor activity remain, in part, to be investigated, an additional important issue is represented by potential pharmacogenomic (the investigation of variations of DNA or RNA characteristics as related to drug response) or pharmacogenetic (the influence of variations of DNA sequence on drug response) implications. In fact, steroid hormone receptors actually mediate the action of several compounds known to positively or negatively affect bone homeostasis, such as vitamin D, estrogen and glucocorticoids. This review analyses major pharmacogenetic studies of polymorphisms in steroid hormone receptor genes.
Raloxifene is a benzothiophene, selective estrogen receptor modulator with estrogen-agonist effec... more Raloxifene is a benzothiophene, selective estrogen receptor modulator with estrogen-agonist effects in the skeleton and the cardiovascular system but estrogen-antagonist effects in the uterus and the mammary gland. This compound was first approved in different countries for the prevention and treatment of osteoporosis. We performed a literature search to review available preclinical and clinical data that has led to the recent FDA approval of raloxifene as a chemopreventive agent for breast cancer in postmenopausal women. Different placebo-controlled trials indicated that raloxifene is effective in reducing invasive breast cancer risk in postmenopausal women. In a recent comparative study, a similar efficacy between raloxifene and tamoxifen for breast cancer prevention was demonstrated, but raloxifene showed a more favorable safety profile.
Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk... more Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is a common disorder in elderly subjects and represents a major public health problem, affecting up to 40% postmenopausal women and 15% of men. Among the several therapeutical interventions, hormone replacement therapy (HRT) was traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women, as well as for the management of menopausal symptoms. However HRT, especially if administered long-term, may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter was considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remain uncertain. The purpose of this article is to review the clinical trials of lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis. The medical literature was reviewed for appropriate articles containing the terms "lasofoxifene" and SERMs". There are three (phase II or phase III) clinical trials that clearly demonstrate efficacy and safety of this new SERM in the suppression of bone loss and the prevention of vertebral and nonvertebral fractures. Moreover, lasofoxifene treatment also reduced breast cancer risk and the occurrence of vaginal atrophy. With its increased potency and efficacy on the prevention of nonvertebral fractures lasofoxifene may be an alternative and cost-effective therapy for osteoporosis in postmenopausal women.
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