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1.
J ASEAN Fed Endocr Soc ; 39(1): 95-105, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38863918

RESUMO

Introduction: There has been an increasing awareness of the effects of combining bromocriptine-QR with other medications for diabetes mellitus type 2. This study aimed to assess the efficacy and safety of bromocriptine-QR as an adjunctive therapy for patients with uncontrolled type 2 diabetes mellitus. Methodology: This systematic review is registered at the International Prospective Register of Systematic Reviews (CRD42022360326). Literature search was done via MEDLINE, NCBI, Google Scholar, Science Direct, Europe PMC and Cochrane Library databases. We included randomized controlled trials with participants 18 years old and above with uncontrolled type 2 diabetes mellitus. The primary outcome of interest is the efficacy and safety of bromocriptine-QR as an adjunctive therapy for glycemic control. Case reports, case series, reviews and animal studies were excluded. The risk of bias was reviewed using the Cochrane Risk of Bias tool. Meta-analysis was performed using Review Manager 5.4 and presented as a weighted mean difference and 95% confidence interval for changes from the baseline level. Results: Nine studies were included in the systematic review with a total of 2709 participants. The baseline HbA1c in the bromocriptine-QR group was 7.42% and 7.51% in the control group. The bromocriptine-QR group was favoured, outperforming the control group in terms of reducing hemoglobin A1c(HbA1c), with a statistically significant difference (weighted mean difference -0.6%; 95% CI [-0.83,-0.36]; p<0.00001). The most common side effects were nausea (33.75% vs 6.92%), fatigue (13.11% vs 5.94%), and headache (11.17% vs 6.87%). Conclusion: Administration of bromocriptine-QR at a dose range of 1.6 to 4.8 mg/day as an adjunctive therapy reduced HbA1c and FBG in patients with uncontrolled type 2 diabetes mellitus (T2DM). However, there were also statistically greater odds of the occurrence of adverse events such as nausea, vomiting, and headache compared to controls.


Assuntos
Bromocriptina , Diabetes Mellitus Tipo 2 , Controle Glicêmico , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Bromocriptina/uso terapêutico , Bromocriptina/administração & dosagem , Bromocriptina/efeitos adversos , Controle Glicêmico/métodos , Controle Glicêmico/efeitos adversos , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Glicemia/análise , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/metabolismo , Resultado do Tratamento , Quimioterapia Combinada , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/administração & dosagem
2.
Int J Mol Sci ; 25(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731862

RESUMO

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.


Assuntos
Agonistas de Dopamina , Doença de Parkinson , Tirosina 3-Mono-Oxigenase , Animais , Humanos , Dopamina/metabolismo , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Quimioterapia Combinada , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/metabolismo
3.
Sci Rep ; 14(1): 11561, 2024 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773300

RESUMO

Mitochondrial diseases are mainly caused by dysfunction of mitochondrial respiratory chain complexes and have a variety of genetic variants or phenotypes. There are only a few approved treatments, and fundamental therapies are yet to be developed. Leigh syndrome (LS) is the most severe type of progressive encephalopathy. We previously reported that apomorphine, an anti- "off" agent for Parkinson's disease, has cell-protective activity in patient-derived skin fibroblasts in addition to strong dopamine agonist effect. We obtained 26 apomorphine analogs, synthesized 20 apomorphine derivatives, and determined their anti-cell death effect, dopamine agonist activity, and effects on the mitochondrial function. We found three novel apomorphine derivatives with an active hydroxy group at position 11 of the aporphine framework, with a high anti-cell death effect without emetic dopamine agonist activity. These synthetic aporphine alkaloids are potent therapeutics for mitochondrial diseases without emetic side effects and have the potential to overcome the low bioavailability of apomorphine. Moreover, they have high anti-ferroptotic activity and therefore have potential as a therapeutic agent for diseases related to ferroptosis.


Assuntos
Aporfinas , Doença de Leigh , Mitocôndrias , Doença de Leigh/tratamento farmacológico , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Aporfinas/farmacologia , Aporfinas/química , Aporfinas/síntese química , Aporfinas/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Apomorfina/farmacologia , Apomorfina/uso terapêutico , Apomorfina/análogos & derivados , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/química , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/uso terapêutico
4.
J Psychiatr Pract ; 30(3): 200-211, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38819244

RESUMO

OBJECTIVE: Prolactinomas-pituitary tumors that overproduce prolactin-can cause various troublesome symptoms. Dopamine agonists (DAs) reduce prolactin production in the prolactin pathway, making them the first-line treatment for prolactinomas. However, the main side effect of DA treatment, hyperdopaminergia, is an explicit etiology for psychiatric side effects. Psychiatric conditions are often treated with dopamine antagonists, which can induce hyperprolactinemia. This presents a challenge for patients with both a prolactinoma and a preexisting psychiatric condition, as treatment of one condition could worsen the other. This review seeks to identify an adequate therapeutic regimen for patients with coexisting prolactinomas and psychiatric symptoms. METHODS: This review examined PubMed citations from 1960 to 2023 published in English and involving human subjects. Case reports, case series, and cohort studies involving patients with concomitant prolactinomas and psychiatric symptoms, as validated by brain imaging, serologic prolactin levels, and medical history or chart reports of psychiatric symptoms, were included. RESULTS: Thematic analysis included 23 reports involving 42 participants; 27 of the 42 patients experienced a significant reduction in prolactin levels and psychiatric symptoms (64%). Treatment of those 42 patients included discontinuing or altering antipsychotic/dopamine antagonist therapy or discontinuing DA therapy to reduce psychiatric symptoms, with surgery or radiation postpharmacotherapy as a last-line strategy. However, in some cases (reported in Tables 2 to 4), either psychiatric or prolactin-related symptoms recurred despite adjustment. CONCLUSIONS: Clinicians may find it beneficial to prioritize specific antipsychotics (aripiprazole, olanzapine, ziprasidone, or clozapine) over others (risperidone, thioridazine, thiothixene, and remoxipride). Discontinuing DA medication at least periodically until the patient's condition improves may also be advisable. If these 2 initial approaches do not yield a significant improvement in symptom management, surgery or radiation therapy may be considered. As patients may respond differently to these therapies, our study still recommends a patient-centered approach.


Assuntos
Agonistas de Dopamina , Transtornos Mentais , Neoplasias Hipofisárias , Prolactinoma , Humanos , Prolactinoma/tratamento farmacológico , Prolactinoma/terapia , Neoplasias Hipofisárias/complicações , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/terapia , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/farmacologia , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Antagonistas de Dopamina/farmacologia
5.
Eur J Endocrinol ; 190(6): 421-433, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38701338

RESUMO

INTRODUCTION: Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management. OBJECTIVES: The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression. METHODS: Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables. RESULTS: Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P < .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator's penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs). CONCLUSIONS: A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas.


Assuntos
Acromegalia , Adenoma , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Invasividade Neoplásica , Humanos , Masculino , Feminino , Acromegalia/metabolismo , Pessoa de Meia-Idade , Adulto , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma/metabolismo , Adenoma/patologia , Idoso , Agonistas de Dopamina/uso terapêutico , Biomarcadores Tumorais/metabolismo , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Hormônio do Crescimento Humano/metabolismo
6.
Neurobiol Learn Mem ; 212: 107937, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38735637

RESUMO

Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABAA/GABAB receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed.


Assuntos
Corpo Estriado , Extinção Psicológica , Medo , Receptores de Dopamina D1 , Animais , Medo/fisiologia , Medo/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Masculino , Ratos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiologia , Corpo Estriado/metabolismo , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Agonistas de Dopamina/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Substância Negra/efeitos dos fármacos , Substância Negra/fisiologia , Ratos Long-Evans , Dopamina/metabolismo , Dopamina/fisiologia
7.
Arch Endocrinol Metab ; 68: e230504, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578473

RESUMO

Dopamine agonists are the first line of treatment for patients with symptomatic hyperprolactinemia due to prolactinomas and in those with idiopathic hyperprolactinemia. Treatment with these agents is effective in 80%-90% of the cases. Infertility treatment of patients with hyperprolactinemia is also carried out with dopamine agonists, aiming for the normalization of prolactin levels. The risk of symptomatic growth of prolactinomas during pregnancy is dependent on the tumor's size, duration of previous treatments, and prolactin levels. Notably, the corresponding risk is relatively low in cases of microprolactinomas (<5%). Remission of hyperprolactinemia occurs in about 30% of the patients after drug treatment and may also occur after pregnancy and menopause. The use of some drugs, such as antidepressants and antipsychotics, is a frequent cause of hyperprolactinemia, and managing this occurrence involves unique considerations. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Society of Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and drug-induced hyperprolactinemia in women.


Assuntos
Hiperprolactinemia , Neoplasias Hipofisárias , Prolactinoma , Gravidez , Humanos , Feminino , Hiperprolactinemia/tratamento farmacológico , Prolactinoma/terapia , Agonistas de Dopamina/efeitos adversos , Prolactina , Neoplasias Hipofisárias/terapia , Brasil
8.
Mol Pharm ; 21(5): 2512-2533, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38602861

RESUMO

Parkinson's disease (PD) is a debilitating neurodegenerative disease primarily impacting neurons responsible for dopamine production within the brain. Pramipexole (PRA) is a dopamine agonist that is currently available in tablet form. However, individuals with PD commonly encounter difficulties with swallowing and gastrointestinal motility, making oral formulations less preferable. Microneedle (MN) patches represent innovative transdermal drug delivery devices capable of enhancing skin permeability through the creation of microconduits on the surface of the skin. MNs effectively reduce the barrier function of skin and facilitate the permeation of drugs. The work described here focuses on the development of polymeric MN systems designed to enhance the transdermal delivery of PRA. PRA was formulated into both dissolving MNs (DMNs) and directly compressed tablets (DCTs) to be used in conjunction with hydrogel-forming MNs (HFMNs). In vivo investigations using a Sprague-Dawley rat model examined, for the first time, if it was beneficial to prolong the application of DMNs and HFMNs beyond 24 h. Half of the patches in the MN cohorts were left in place for 24 h, whereas the other half remained in place for 5 days. Throughout the entire 5 day study, PRA plasma levels were monitored for all cohorts. This study confirmed the successful delivery of PRA from DMNs (Cmax = 511.00 ± 277.24 ng/mL, Tmax = 4 h) and HFMNs (Cmax = 328.30 ± 98.04 ng/mL, Tmax = 24 h). Notably, both types of MNs achieved sustained PRA plasma levels over a 5 day period. In contrast, following oral administration, PRA remained detectable in plasma for only 48 h, achieving a Cmax of 159.32 ± 113.43 ng/mL at 2 h. The HFMN that remained in place for 5 days demonstrated the most promising performance among all investigated formulations. Although in the early stages of development, the findings reported here offer a hopeful alternative to orally administered PRA. The sustained plasma profile observed here has the potential to reduce the frequency of PRA administration, potentially enhancing patient compliance and ultimately improving their quality of life. This work provides substantial evidence advocating the development of polymeric MN-mediated drug delivery systems to include sustained plasma levels of hydrophilic pharmaceuticals.


Assuntos
Administração Cutânea , Sistemas de Liberação de Medicamentos , Agulhas , Doença de Parkinson , Pramipexol , Ratos Sprague-Dawley , Pramipexol/administração & dosagem , Pramipexol/farmacocinética , Animais , Ratos , Doença de Parkinson/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Masculino , Absorção Cutânea/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos dos fármacos , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacocinética , Hidrogéis/química
9.
Artigo em Russo | MEDLINE | ID: mdl-38676674

RESUMO

The article is of a review nature and is devoted to tremor, one of the maladaptive and difficult-to-treat symptoms of Parkinson's disease (PD). Along with the classic rest tremor, patients with PD may experience tremor of other modalities: postural tremor, kinetic tremor, which reflects a multimodal mechanism of tremor formation involving multiple neurotransmitter systems. The unpredictable response to therapeutic options, the ambiguous response to levodopa, also reflects the role of multiple underlying pathophysiological processes. Among the drug methods of tremor correction, preference is given to dopamine receptor agonists - due to the spectrum of their pharmaceutical action, high efficiency in relation to all leading motor and a number of non-motor manifestations. The evidence for advanced neurosurgical, non-invasive modalities is mixed, and there are insufficient comparative studies to assess their efficacy in patients with tremor-dominant forms of PD.


Assuntos
Levodopa , Doença de Parkinson , Tremor , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Tremor/tratamento farmacológico , Tremor/etiologia , Tremor/fisiopatologia , Levodopa/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Antiparkinsonianos/uso terapêutico
10.
Behav Neurosci ; 138(2): 85-93, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38661668

RESUMO

Rodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing representation in behavioral neuroscience. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Assuntos
Percepção do Tempo , Feminino , Masculino , Animais , Percepção do Tempo/fisiologia , Percepção do Tempo/efeitos dos fármacos , Humanos , Caracteres Sexuais , Dopamina/metabolismo , Ratos , Receptores de Dopamina D2/metabolismo , Sulpirida/farmacologia , Quimpirol/farmacologia , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/administração & dosagem , Adulto , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Benzazepinas/farmacologia , Adulto Jovem , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Memória de Curto Prazo/fisiologia , Memória de Curto Prazo/efeitos dos fármacos
11.
CNS Drugs ; 38(6): 443-457, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38613665

RESUMO

Impulse control disorders in Parkinson's disease are relatively common drug-induced addictive behaviours that are usually triggered by the dopamine agonists pramipexole, ropinirole and rotigotine. This narrative review aimed to provide a comprehensive overview of the current knowledge of impulse control disorders in Parkinson's disease. We summarised the prevalence, clinical features, risk factors and potential underlying mechanisms of impulse control disorders in Parkinson's disease. Moreover, recent advances in behavioural and imaging characteristics and management strategies are discussed. Early detection as well as a tailored multidisciplinary approach, which typically includes careful adjustment of the dopaminergic therapy and the treatment of associated neuropsychiatric symptoms, are necessary. In some cases, a continuous delivery of levodopa via a pump or the dopamine D1 receptor agonist, apomorphine, can be considered. In selected patients without cognitive or speech impairment, deep brain stimulation of the subthalamic nucleus can also improve addictions. Finding the right balance of tapering dopaminergic dose (usually dopamine agonists) without worsening motor symptoms is essential for a beneficial long-term outcome.


Assuntos
Transtornos Disruptivos, de Controle do Impulso e da Conduta , Agonistas de Dopamina , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/induzido quimicamente , Transtornos Disruptivos, de Controle do Impulso e da Conduta/tratamento farmacológico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/etiologia , Fatores de Risco , Agonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Estimulação Encefálica Profunda
12.
Behav Pharmacol ; 35(4): 193-200, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38567425

RESUMO

Prepulse inhibition (PPI) is a crucial indicator of sensorimotor gating that is often impaired in neuropsychiatric diseases. Although dopamine D1 receptor agonists have been found to disrupt PPI in mice, the underlying mechanisms are not fully understood. In this study, we aimed to identify the brain regions responsible for the PPI-disruptive effect of the D1 agonist in mice. Results demonstrated that intraperitoneal administration of the selective dopamine D1 receptor agonist SKF82958 dramatically inhibited PPI, while the dopamine D1 receptor antagonist SCH23390 enhanced PPI. Additionally, local infusion of SKF82958 into the nucleus accumbens and medial prefrontal cortex disrupted PPI, but not in the ventral hippocampus. Infusion of SCH23390 into these brain regions also failed to enhance PPI. Overall, the study suggests that the nucleus accumbens and medial prefrontal cortex are responsible for the PPI-disruptive effect of dopamine D1 receptor agonists. These findings provide essential insights into the cellular and neural circuit mechanisms underlying the disruptive effects of dopamine D1 receptor agonists on PPI and may contribute to the development of novel treatments for neuropsychiatric diseases.


Assuntos
Benzazepinas , Agonistas de Dopamina , Núcleo Accumbens , Córtex Pré-Frontal , Inibição Pré-Pulso , Receptores de Dopamina D1 , Animais , Masculino , Camundongos , Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Inibição Pré-Pulso/efeitos dos fármacos , Inibição Pré-Pulso/fisiologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo
13.
J Affect Disord ; 356: 586-596, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38657764

RESUMO

BACKGROUND: Diabetes mellitus (DM) is frequently associated with the occurrence and development of depression, and the co-occurrence of diabetes mellitus with depression (DD) may further reduce patients' quality of life. Recent research indicates that dopamine receptors (DRs) play a crucial role in immune and metabolic regulation. Pramipexole (PPX), a D2/3R agonist, has demonstrated promising neuroprotective and immunomodulatory effects. Nevertheless, the therapeutic effects and mechanisms of action of PPX on DM-induced depression are not clear at present. METHODS: Depression, DM, and DD were induced in a rat model through a combination of a high-fat diet (HFD) supplemented with streptozotocin (STZ) and chronic unpredictable mild stress (CUMS) combined with solitary cage rearing. The pathogenesis of DD and the neuroprotective effects of DRs agonists were investigated using behavioral assays, enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (HE) staining, Nissl staining, Western blotting (WB) and immunofluorescence (IF). RESULTS: DD rats exhibited more severe dopaminergic, neuroinflammatory, and neuroplastic impairments and more pronounced depressive behaviors than rats with depression alone or DM. Our findings suggest that DRs agonists have significant therapeutic effects on DD rats and that PPX improved neuroplasticity and decreased neuroinflammation in the hippocampus of DD rats while also promoting DG cell growth and differentiation, ultimately mitigating depression-like behaviors. LIMITATION: Our study is based on a rat model. Further evidence is needed to determine whether the therapeutic effects of PPX apply to patients suffering from DD. CONCLUSIONS: Neuroinflammation mediated by damage to the dopaminergic system is one of the key pathogenic mechanisms of DD. We provide evidence that PPX has a neuroprotective effect on the hippocampus in DD rats and the mechanism may involve the inhibition of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation by DRs to attenuate the neuroinflammatory response and neuroplasticity damage.


Assuntos
Depressão , Diabetes Mellitus Experimental , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Plasticidade Neuronal , Pramipexol , Animais , Pramipexol/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Plasticidade Neuronal/efeitos dos fármacos , Masculino , Inflamassomos/efeitos dos fármacos , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Ratos Sprague-Dawley , Doenças Neuroinflamatórias/tratamento farmacológico , Agonistas de Dopamina/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças
14.
Pituitary ; 27(3): 239-247, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38656635

RESUMO

BACKGROUND: Prolactinomas are common tumours that significantly reduce quality-of-life (QOL) due to sellar mass effect, secondary hypogonadism, and the peripheral effects of prolactin. Understanding the factors that influence QOL would provide insights into therapeutic targets to optimise patient outcomes and improve wellbeing in prolactinoma. METHODS: A systematic review was performed in accordance with the PRISMA statement. Studies that reported patient QoL using validated metrics were included. Bias and methodological rigour were assessed using the MINORS criteria. RESULTS: A total of 18 studies were identified studies were available for review, comprising 877 patients. Most were small cross-sectional studies at high risk of bias. Prolactinoma exhibit worse QOL than healthy controls, particularly mental and psychosocial wellbeing. QOL is also worse than patients with non-functional adenomas, but better than those with Cushing's disease and acromegaly. QOL correlates with prolactin levels, and approaches population baseline with prolonged biochemical control. Dopamine agonists and surgery both improve overall QOL, however improvements are more rapid with surgery. CONCLUSION: Poor quality of life in prolactinoma is multifactorial, related to biochemical control, side effects of therapy, and sellar mass effect. Targeting persistent symptoms, reducing healthcare costs, and reducing side-effects of therapy are avenues to improving QOL in patients with prolactinoma.


Assuntos
Neoplasias Hipofisárias , Prolactinoma , Qualidade de Vida , Prolactinoma/tratamento farmacológico , Humanos , Neoplasias Hipofisárias/psicologia , Agonistas de Dopamina/uso terapêutico
15.
Pharmacol Res Perspect ; 12(2): e1190, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38597598

RESUMO

Analysis was conducted to compare levodopa/carbidopa pharmacokinetics and drug-related material in plasma of healthy participants after receiving a continuous infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) to a continuous subcutaneous infusion of foslevodopa/foscarbidopa. Study samples were from a randomized, open-label, 2-period crossover study in 20 healthy participants. Participants received either 24-h foslevodopa/foscarbidopa SC infusion to the abdomen or LCIG delivered for 24 h to the jejunum through a nasogastric tube with jejunal extension. Serial blood samples were collected for PK. Comparability of the LD PK parameters between the two treatment regimens was determined. Selected plasma samples were pooled per treatment group and per time point for metabolite profiling. LC-MSn was performed using high-resolution mass spectrometry to identify drug-related material across the dosing regimens and time points. The LD PK parameter central values and 90% confidence intervals following the foslevodopa/foscarbidopa subcutaneous infusion were between 0.8 and 1.25 relative to the LCIG infusion. With LCIG administration, LD, CD, 3-OMD, DHPA, DOPAC, and vanillacetic acid were identified in plasma at early and late time points (0.75 and 24 h); the metabolic profile after administration of foslevodopa/foscarbidopa demonstrated the same drug-related compounds with the exception of the administered foslevodopa. 3-OMD and vanillacetic acid levels increased over time in both treatment regimens. Relative quantification of LC-MS peak areas showed no major differences in the metabolite profiles. These results indicate that neither the addition of monophosphate prodrug moieties nor SC administration affects the circulating metabolite profile of foslevodopa/foscarbidopa compared to LCIG.


Assuntos
Carbidopa , Doença de Parkinson , Humanos , Carbidopa/farmacocinética , Levodopa/farmacocinética , Antiparkinsonianos/farmacocinética , Estudos Cross-Over , Voluntários Saudáveis , Doença de Parkinson/tratamento farmacológico , Géis/uso terapêutico , Agonistas de Dopamina
16.
Sci Rep ; 14(1): 8424, 2024 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600209

RESUMO

Using deep learning has demonstrated significant potential in making informed decisions based on clinical evidence. In this study, we deal with optimizing medication and quantitatively present the role of deep learning in predicting the medication dosage for patients with Parkinson's disease (PD). The proposed method is based on recurrent neural networks (RNNs) and tries to predict the dosage of five critical medication types for PD, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, catechol-O-methyltransferase inhibitors, and amantadine. Recurrent neural networks have memory blocks that retain crucial information from previous patient visits. This feature is helpful for patients with PD, as the neurologist can refer to the patient's previous state and the prescribed medication to make informed decisions. We employed data from the Parkinson's Progression Markers Initiative. The dataset included information on the Unified Parkinson's Disease Rating Scale, Activities of Daily Living, Hoehn and Yahr scale, demographic details, and medication use logs for each patient. We evaluated several models, such as multi-layer perceptron (MLP), Simple-RNN, long short-term memory (LSTM), and gated recurrent units (GRU). Our analysis found that recurrent neural networks (LSTM and GRU) performed the best. More specifically, when using LSTM, we were able to predict levodopa and dopamine agonist dosage with a mean squared error of 0.009 and 0.003, mean absolute error of 0.062 and 0.030, root mean square error of 0.099 and 0.053, and R-squared of 0.514 and 0.711, respectively.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Levodopa/uso terapêutico , Catecol O-Metiltransferase , Atividades Cotidianas , Agonistas de Dopamina/uso terapêutico , Redes Neurais de Computação
17.
Brain Inj ; 38(8): 652-658, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38555516

RESUMO

INTRODUCTION: Bromocriptine is a dopamine receptor agonist used for central hyperthermia with limited data. We describe our single-center experience utilizing bromocriptine for central hyperthermia, including the population treated, most common dosing regimens, adverse events, and discontinuation reasons. METHODS: A retrospective study was conducted screening patients who were admitted to intensive care units for acute neurological insults and administered bromocriptine for central hyperthermia between April 2016 and September 2022. Baseline characteristics, disease severity markers, and bromocriptine doses were collected. Body temperatures prior to the first dose of bromocriptine, at the time of dose, and after each dose were recorded. Co-administration of additional hyperthermia management therapies was noted. RESULTS: Thirty patients were included. The most common diagnosis was traumatic brain injury (TBI) (N = 14). The most common reason for discontinuation was resolution of indication (N = 14). Discontinuation due to mild adverse effects occurred in four patients; hepatotoxicity was the most common. There was a paired mean difference of -0.37°C (p = 0.005) between temperatures before and after bromocriptine initiation. CONCLUSION: Bromocriptine is a potential therapy for the management of central hyperthermia in patients with severe acute neurologic insults who have failed other therapies. Bromocriptine was well tolerated and associated with a low incidence of adverse events.


Assuntos
Bromocriptina , Agonistas de Dopamina , Humanos , Bromocriptina/uso terapêutico , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Adulto , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/administração & dosagem , Idoso , Lesões Encefálicas , Hipertermia/tratamento farmacológico , Lesões Encefálicas Traumáticas/complicações , Resultado do Tratamento , Adulto Jovem
18.
J Gynecol Obstet Hum Reprod ; 53(6): 102783, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38554942

RESUMO

This systematic review aims to evaluate the efficacy and safety of Pyridoxine compared to Dopaminergic agonists (cabergoline and bromocriptine) in post-partum lactation inhibition. Cochrane Central, PubMed/MEDLINE, Cochrane Central, ScienceDirect, ClinicalTrials.gov, Web of Science, CINAHL and Google Scholar, covering the period from inception to November 2023. Additionally, the bibliographies of included articles and previous meta-analyses were screened for any relevant articles. The systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. The outcomes of interest encompassed inhibition of lactation, breast pain/tenderness, breast engorgement, milk secretion, fever, mastitis, prolactin level and adverse events related to pyridoxine, cabergoline and bromocriptine. Methodological quality assessment was conducted using the Cochrane risk of bias assessment tool for rigorous evaluation. Three clinical trials assessed the effectiveness of pyridoxine and dopaminergic agents (cabergoline and bromocriptine) for lactation inhibition. It was assessed by using different assessment methods such as a scale for milk secretion, serum prolactin levels, and questionnaires for assessing breast engorgement, breast pain, and milk leakage. On the global assessment of the therapeutic efficacy of dopaminergic agents, it was found that there was significant inhibition of lactation as compared to pyridoxine (p < 0.001). In conclusion, this systematic review contributes significant insights into lactation inhibition interventions. Dopaminergic agonists, specifically cabergoline and bromocriptine, stand out as more effective and tolerable choices compared to Pyridoxine. These findings provide a foundation for informed clinical decisions and underscore the need for careful consideration of lactation inhibition strategies in diverse clinical contexts.


Assuntos
Bromocriptina , Cabergolina , Agonistas de Dopamina , Lactação , Piridoxina , Humanos , Bromocriptina/uso terapêutico , Bromocriptina/farmacologia , Feminino , Piridoxina/uso terapêutico , Piridoxina/farmacologia , Cabergolina/uso terapêutico , Cabergolina/farmacologia , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/farmacologia , Lactação/efeitos dos fármacos , Transtornos da Lactação/tratamento farmacológico , Ensaios Clínicos como Assunto
19.
Pharmacol Biochem Behav ; 239: 173754, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38537873

RESUMO

BACKGROUND: Pituitary lactotrophs are under tonic dopaminergic inhibitory control and bromocriptine treatment blocks prolactin secretion. METHODS: Sleep and local field potential were addressed for 72 h after bromocriptine treatments applied during the different stages of the estrus cycle and for 24 h in the early- and middle postpartum period characterized by spontaneously different dynamics of prolactin release in female rats. RESULTS: Sleep changes showed strong dependency on the estrus cycle phase of the drug application. Strongest increase of wakefulness and reduction of slow wave sleep- and rapid eye movements sleep appeared during diestrus-proestrus and middle postpartum treatments. Stronger sleep-wake effects appeared in the dark phase in case of the estrus cycle treatments, but in the light phase in postpartum treatments. Slow wave sleep and REM sleep loss in case of estrus cycle treatments was not compensated at all and sleep loss seen in the first day post-injection was gained further later. In opposition, slow wave sleep loss in the light phase after bromocriptine injections showed compensation in the postpartum period treatments. Bromocriptine treatments resulted in a depression of local field potential delta power during slow wave sleep while an enhancement in beta and gamma power during wakefulness regardless of the treatment timing. CONCLUSIONS: These results can be explained by the interplay of dopamine D2 receptor agonism, lack of prolactin release and the spontaneous homeostatic sleep drive being altered in the different stages of the estrus cycle and the postpartum period.


Assuntos
Bromocriptina , Agonistas de Dopamina , Ciclo Estral , Período Pós-Parto , Ratos Wistar , Receptores de Dopamina D2 , Sono , Animais , Bromocriptina/farmacologia , Feminino , Período Pós-Parto/efeitos dos fármacos , Ratos , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Agonistas de Dopamina/farmacologia , Ciclo Estral/efeitos dos fármacos , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Prolactina
20.
Pituitary ; 27(3): 269-276, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38499816

RESUMO

PURPOSE: Prolactin (PRL)-secreting tumours are associated with infertility and can be reverted by dopamine agonist (DA) therapy. The suspension of DA is recommended once pregnancy is established, as all DAs cross the placenta. The aim of the study was to evaluate the rate of maternal-foetal complications in women treated with cabergoline (CAB) or bromocriptine (BRM) for prolactinoma during gestation and the effect of pregnancy on prolactinoma progression. METHODS: This was a retrospective observational study involving 43 women affected by prolactinoma who became pregnant during therapy with CAB or BRM for a total of 58 pregnancies. For each patient, medical records were analysed by integrating the data with outpatient or telephone interview. RESULTS: At the time of conception, 18 women were in the BRM group, while 40 were in CAB group. No differences were found in obstetric or neonatal outcomes between the two groups. There was a significant difference (p = 0.046) in child complications reported in maternal interview found exclusively in the CAB group. No further confounding factors were detected. Disease remission rate after the first pregnancy was 42.9% and the main predictor was a lower PRL nadir before pregnancy (p = 0.023). No difference was detected between the two groups in terms of tumor remission. Breastfeeding did not modify the outcome. CONCLUSION: Foetal exposure to DAs during the first weeks of embryogenesis is not associated with a greater risk of complications. The transient and mild developmental disorders recorded resolved spontaneously and the prevalence was substantially overlapping with that observed in the general population.


Assuntos
Bromocriptina , Cabergolina , Agonistas de Dopamina , Prolactinoma , Humanos , Feminino , Gravidez , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/efeitos adversos , Adulto , Estudos Retrospectivos , Prolactinoma/tratamento farmacológico , Cabergolina/uso terapêutico , Bromocriptina/uso terapêutico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/metabolismo , Ergolinas/uso terapêutico , Ergolinas/efeitos adversos , Estudos Longitudinais , Prolactina/sangue , Prolactina/metabolismo , Adulto Jovem
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