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Journal of Medicinal Chemistry Jun 2024Development of more efficacious medications with improved safety profiles to manage and treat multiple forms of pain is a critical element of healthcare. To this end, we...
Development of more efficacious medications with improved safety profiles to manage and treat multiple forms of pain is a critical element of healthcare. To this end, we have designed and synthesized a novel class of tetracyclic pyridopyrroloquinoxalinone derivatives with analgesic properties. The receptor binding profiles and analgesic properties of these tetracyclic compounds were studied. Systematic optimizations of this novel scaffold culminated in the discovery of the clinical candidate, (6,10)-8-[3-(4-fluorophenoxy)propyl]-6,7,8,9,10,10-hexahydro-1-pyrido[3',4':4,5]pyrrolo[1,2,3-]quinoxalin-2(3)-one (compound , ITI-333), which exhibited potent binding affinity to serotonin 5-HT ( = 8.3 nM) and μ-opioid receptors (MOR, = 11 nM) and moderate affinity to adrenergic α ( = 28 nM) and dopamine D ( = 50 nM) receptors. ITI-333 acts as a 5-HT receptor antagonist, a MOR partial agonist, and an adrenergic α receptor antagonist. ITI-333 exhibited dose-dependent analgesic effects in rodent models of acute pain. Currently, this investigational new drug is in phase I clinical development.
Topics: Animals; Humans; Analgesics; Structure-Activity Relationship; Administration, Oral; Pain; Mice; Male; Rats; Drug Discovery; Rats, Sprague-Dawley; Biological Availability; Receptors, Opioid, mu; Pyridines; Pyrroles
PubMed: 38805667
DOI: 10.1021/acs.jmedchem.4c00480 -
The Lancet. Psychiatry May 2024In recent history, the world has witnessed a trend towards liberalization of abortion laws driven by an increasing understanding of the negative personal and public... (Review)
Review
In recent history, the world has witnessed a trend towards liberalization of abortion laws driven by an increasing understanding of the negative personal and public health consequences of criminalizing abortion. By contrast, several countries have recently implemented restrictive reproductive laws, joining the 112 countries where access to abortion care is banned completely or with narrow exceptions. On June 24, 2022, the US Supreme Court ruling in Dobbs v Jackson Women's Health Organization overturned its landmark decisions in Roe v Wade that established abortion until the point of viability of the fetus as a constitutional right. After Roe v Wade having been overturned, it is projected that many women in the USA will be prevented from accessing safe abortion care. Importantly, abortion bans not only impose constraints on patient autonomy, they also restrict physicians' ability to practice evidence-based medicine, which will negatively impact psychiatric care. It is therefore crucial for the practicing psychiatrist to be familiar with this new legal landscape. In this Personal View, we aim to provide a topical overview to help clinicians gain a clear understanding of legal, clinical, and ethical responsibilities, focusing on the USA. We also discuss the reality that psychiatrists might be called upon to determine medical necessity for an abortion on psychiatric grounds, which is new for most US psychiatrists. We predict that psychiatrists will be confronted with very difficult situations in which lawful and ethical conduct might be incongruent, and that abortion bans will result in greater numbers of patients needing psychiatric care from a system that is ill-prepared for additional demands.
PubMed: 38795722
DOI: 10.1016/S2215-0366(24)00096-8 -
Pharmaceuticals (Basel, Switzerland) May 2024The relapse rate of substance abusers is high, and addiction rehabilitation adjunct drugs need to be developed urgently. There have been numerous reports on blocking the... (Review)
Review
The relapse rate of substance abusers is high, and addiction rehabilitation adjunct drugs need to be developed urgently. There have been numerous reports on blocking the formation of substance addiction, but studies on drugs that can alleviate withdrawal symptoms are very limited. Both the dopamine transporter (DAT) hypothesis and D3 dopamine receptor (D3R) hypothesis are proposed. DAT activators reduce the extracellular dopamine level, and D3R antagonists reduce the neuron's sensitivity to dopamine, both of which may exacerbate the withdrawal symptoms subsequently. The D3R partial agonist SK608 has biased signaling properties via the G-protein-dependent pathway but did not induce D3R desensitization and, thus, may be a promising drug for the withdrawal symptoms. Drugs for serotoninergic neurons or GABAergic neurons and anti-inflammatory drugs may have auxiliary effects to addiction treatments. Drugs that promote structural synaptic plasticity are also discussed.
PubMed: 38794185
DOI: 10.3390/ph17050615 -
Medicina (Kaunas, Lithuania) Apr 2024This study delves into the multifaceted approaches to treating Parkinson's disease (PD), a neurodegenerative disorder primarily affecting motor function but also... (Review)
Review
This study delves into the multifaceted approaches to treating Parkinson's disease (PD), a neurodegenerative disorder primarily affecting motor function but also manifesting in a variety of symptoms that vary greatly among individuals. The complexity of PD symptoms necessitates a comprehensive treatment strategy that integrates surgical interventions, pharmacotherapy, and physical therapy to tailor to the unique needs of each patient. Surgical options, such as deep brain stimulation (DBS), have been pivotal for patients not responding adequately to medication, offering significant symptom relief. Pharmacotherapy remains a cornerstone of PD management, utilizing drugs like levodopa, dopamine agonists, and others to manage symptoms and, in some cases, slow down disease progression. However, these treatments often lead to complications over time, such as motor fluctuations and dyskinesias, highlighting the need for precise dosage adjustments and sometimes combination therapies to optimize patient outcomes. Physical therapy plays a critical role in addressing the motor symptoms of PD, including bradykinesia, muscle rigidity, tremors, postural instability, and akinesia. PT techniques are tailored to improve mobility, balance, strength, and overall quality of life. Strategies such as gait and balance training, strengthening exercises, stretching, and functional training are employed to mitigate symptoms and enhance functional independence. Specialized approaches like proprioceptive neuromuscular facilitation (PNF), the Bobath concept, and the use of assistive devices are also integral to the rehabilitation process, aimed at improving patients' ability to perform daily activities and reducing the risk of falls. Innovations in technology have introduced robotic-assisted gait training (RAGT) and other assistive devices, offering new possibilities for patient care. These tools provide targeted support and feedback, allowing for more intensive and personalized rehabilitation sessions. Despite these advancements, high costs and accessibility issues remain challenges that need addressing. The inclusion of exercise and activity beyond structured PT sessions is encouraged, with evidence suggesting that regular physical activity can have neuroprotective effects, potentially slowing disease progression. Activities such as treadmill walking, cycling, and aquatic exercises not only improve physical symptoms but also contribute to emotional well-being and social interactions. In conclusion, treating PD requires a holistic approach that combines medical, surgical, and therapeutic strategies. While there is no cure, the goal is to maximize patients' functional abilities and quality of life through personalized treatment plans. This integrated approach, along with ongoing research and development of new therapies, offers hope for improving the management of PD and the lives of those affected by this challenging disease.
Topics: Humans; Parkinson Disease; Physical Therapy Modalities; Independent Living; Gait; Deep Brain Stimulation; Quality of Life; Exercise Therapy
PubMed: 38792894
DOI: 10.3390/medicina60050711 -
International Journal of Molecular... May 2024In recent years, particular attention has been paid to the serotonin 4 receptor, which is well expressed in the brain, but also peripherally in various organs. The... (Review)
Review
In recent years, particular attention has been paid to the serotonin 4 receptor, which is well expressed in the brain, but also peripherally in various organs. The cerebral distribution of this receptor is well conserved across species, with high densities in the basal ganglia, where they are expressed by GABAergic neurons. The 5-HT receptor is also present in the cerebral cortex, hippocampus, and amygdala, where they are carried by glutamatergic or cholinergic neurons. Outside the central nervous system, the 5-HT receptor is notably expressed in the gastrointestinal tract. The wide distribution of the 5-HT receptor undoubtedly contributes to its involvement in a plethora of functions. In addition, the modulation of this receptor influences the release of serotonin, but also the release of other neurotransmitters such as acetylcholine and dopamine. This is a considerable asset, as the modulation of the 5-HT receptor can therefore play a direct or indirect beneficial role in various disorders. One of the main advantages of this receptor is that it mediates a much faster antidepressant and anxiolytic action than classical selective serotonin reuptake inhibitors. Another major benefit of the 5-HT receptor is that its activation enhances cognitive performance, probably via the release of acetylcholine. The expression of the 5-HT receptor is also altered in various eating disorders, and its activation by the 5-HT agonist negatively regulates food intake. Additionally, although the cerebral expression of this receptor is modified in certain movement-related disorders, it is still yet to be determined whether this receptor plays a key role in their pathophysiology. Finally, there is no longer any need to demonstrate the value of 5-HT receptor agonists in the pharmacological management of gastrointestinal disorders.
Topics: Humans; Receptors, Serotonin, 5-HT4; Animals; Brain Diseases; Serotonin 5-HT4 Receptor Agonists; Brain
PubMed: 38791281
DOI: 10.3390/ijms25105245 -
International Journal of Molecular... May 2024Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their...
Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their role in dopamine (DA) homeostasis remains understudied. In the present study, we investigated the kinetic and molecular mechanisms of DA transport in cultured striatal astrocytes of adult rats. Kinetic uptake experiments were performed using radiolabeled [H]-DA, whereas mRNA expression of the dopamine, norepinephrine, organic cation and plasma membrane monoamine transporters (DAT, NET, OCTs and PMAT) and DA receptors D1 and D2 was determined by qPCR. Additionally, astrocyte cultures were subjected to a 24 h treatment with the DA receptor agonist apomorphine, the DA receptor antagonist haloperidol and the DA precursor L-DOPA. [H]-DA uptake exhibited temperature, concentration and sodium dependence, with potent inhibition by desipramine, nortriptyline and decynium-22, suggesting the involvement of multiple transporters. qPCR revealed prominent mRNA expression of the NET, the PMAT and OCT1, alongside lower levels of mRNA for OCT2, OCT3 and the DAT. Notably, apomorphine significantly altered NET, PMAT and D1 mRNA expression, while haloperidol and L-DOPA had a modest impact. Our findings demonstrate that striatal astrocytes aid in DA clearance by multiple transporters, which are influenced by dopaminergic drugs. Our study enhances the understanding of regional DA uptake, paving the way for targeted therapeutic interventions in dopaminergic disorders.
Topics: Animals; Astrocytes; Dopamine; Rats; Corpus Striatum; Haloperidol; Kinetics; Dopamine Plasma Membrane Transport Proteins; Apomorphine; Cells, Cultured; Male; Receptors, Dopamine D1; Biological Transport; Levodopa
PubMed: 38791173
DOI: 10.3390/ijms25105135 -
Biomedicines May 2024Osteoporosis is the most common metabolic bone disorder and is characterized by decreased bone density, which has a relationship with the quality of life among the aging...
Osteoporosis is the most common metabolic bone disorder and is characterized by decreased bone density, which has a relationship with the quality of life among the aging population. Previous research has found that activation of the dopamine D1 receptor can improve bone mass formation. SKF38393 is an agonist of dopamine D1 receptors. However, as a small-molecule drug, SKF38393 is unstable and releases quickly. The aim of this study was to prototype polylactic-co-glycolic acid (PLGA)/SKF38393 microspheres and assess their potential osteogenic effects compared to those under the free administration of SKF38393. The cytocompatibility of PLGA/SKF38393 was determined via CCK-8 and live/dead cell staining; the osteogenic effects in vitro were determined with ALP and alizarin red staining, qRT-PCR, and Western blotting; and the in vivo effects were assessed using 25 Balb/c mice. We also used a PCR array to explore the possible signaling pathway changes after employing PLGA/SKF38393. Our experiments demonstrated that the osteogenic effect of D1Rs activated by the PLGA/SKF38393 microsphere was better than that under free administration, both in vitro and in vivo. According to the PCR array, this result might be associated with six signaling pathways (graphical abstract). Ultimately, in this study, we prototyped PLGA/SKF38393, demonstrated its effectiveness, and preliminarily analyzed its mechanism of action.
PubMed: 38791008
DOI: 10.3390/biomedicines12051046 -
JMIR Human Factors May 2024The fastest-growing neurological disorder is Parkinson disease (PD), a progressive neurodegenerative disease that affects 10 million people worldwide. PD is typically...
BACKGROUND
The fastest-growing neurological disorder is Parkinson disease (PD), a progressive neurodegenerative disease that affects 10 million people worldwide. PD is typically treated with levodopa, an oral pill taken to increase dopamine levels, and other dopaminergic agonists. As the disease advances, the efficacy of the drug diminishes, necessitating adjustments in treatment dosage according to the patient's symptoms and disease progression. Therefore, remote monitoring systems that can provide more detailed and accurate information on a patient's condition regularly are a valuable tool for clinicians and patients to manage their medication. The Parkinson's Remote Interactive Monitoring System (PRIMS), developed by PragmaClin Research Inc, was designed on the premise that it will be an easy-to-use digital system that can accurately capture motor and nonmotor symptoms of PD remotely.
OBJECTIVE
We performed a usability evaluation in a simulated clinical environment to assess the ease of use of the PRIMS and determine whether the product offers suitable functionality for users in a clinical setting.
METHODS
Participants were recruited from a user sign-up web-based database owned by PragmaClin Research Inc. A total of 11 participants were included in the study based on the following criteria: (1) being diagnosed with PD and (2) not being diagnosed with dementia or any other comorbidities that would make it difficult to complete the PRIMS assessment safely and independently. Patient users completed a questionnaire that is based on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale. Interviews and field notes were analyzed for underlying themes and topics.
RESULTS
In total, 11 people with PD participated in the study (female individuals: n=5, 45%; male individuals: n=6, 55%; age: mean 66.7, SD 7.77 years). Thematic analysis of the observer's notes revealed 6 central usability issues associated with the PRIMS. These were the following: (1) the automated voice prompts are confusing, (2) the small camera is problematic, (3) the motor test exhibits excessive sensitivity to the participant's orientation and position in relation to the cameras, (4) the system poses mobility challenges, (5) navigating the system is difficult, and (6) the motor test exhibits inconsistencies and technical issues. Thematic analysis of qualitative interview responses revealed four central themes associated with participants' perspectives and opinions on the PRIMS, which were (1) admiration of purpose, (2) excessive system sensitivity, (3) video instructions preferred, and (4) written instructions disliked. The average system usability score was calculated to be 69.2 (SD 4.92), which failed to meet the acceptable system usability score of 70.
CONCLUSIONS
Although multiple areas of improvement were identified, most of the participants showed an affinity for the overarching objective of the PRIMS. This feedback is being used to upgrade the current PRIMS so that it aligns more with patients' needs.
Topics: Humans; Parkinson Disease; Male; Female; Middle Aged; Aged; User-Computer Interface; Monitoring, Physiologic
PubMed: 38787603
DOI: 10.2196/54145 -
Journal of Endocrinological... May 2024Cabergoline (CAB) has shown to have benefic effects on the metabolism in different clinical settings but its metabolic role in acromegaly disease has not been studied...
PURPOSE
Cabergoline (CAB) has shown to have benefic effects on the metabolism in different clinical settings but its metabolic role in acromegaly disease has not been studied yet. Aim of our study was to evaluate the impact of CAB on glucose metabolism and weight in patients with acromegaly.
METHODS
All patients with acromegaly undergoing continuous treatment with CAB for at least 6 months were retrospectively screened. Exclusion criteria were discontinuation of CAB for more than one month, change of antidiabetic or other therapy for acromegaly, concomitant untreated hormonal deficiency, initiation of pregnancy and/or breastfeeding. All patients were evaluated in terms of biochemical disease control, glucose metabolism and weight at baseline (T0) and after the introduction of CAB therapy at 6 (T6) and 12 months (T12).
RESULTS
Twenty-six patients (15 females and 11 males) were evaluated at T0 and T6 and 19 patients (12 females and 7 males) were also evaluated at T12. Insulin-like growth factor I (IGF-I) and prolactin (PRL) levels were significantly lower at T6 and T12 compared to baseline (p < 0.001 for IGF-I, p < 0.05 for PRL) even if no further differences were observed between T12 and T6. Considering the entire cohort, no differences were appreciated regarding the metabolic parameters but a significant reduction in weight and body mass index (BMI) was observed at both T6 (p = 0.009 for weight, p = 0.021 for BMI) and T12 (p = 0.014 for weight, p = 0.017 for BMI) compared to baseline.
CONCLUSION
Our results confirm the efficacy of CAB in providing a significant improvement in the biochemical disease control but do not demonstrate a marked benefit on glucose metabolism of acromegaly patients. In such patients, CAB appears to have a rapid effect on weight and BMI, with significant changes noticeable as early as 6 months and persisting for at least 12 months.
PubMed: 38787507
DOI: 10.1007/s40618-024-02396-1