RESUMEN
BACKGROUND: The management of multidrug-resistant tuberculosis (MDR-TB) remains challenging. Treatment outcome is influenced by multiple factors; the specific roles of diabetes and glycemic control remain uncertain. This study aims to assess the impact of glycemic control on drug exposure, to investigate the association between drug exposure and treatment outcomes, and to identify clinically significant thresholds predictive of treatment outcome, among patients with diabetes. METHODS: This multicenter prospective cohort study involved patients with confirmed MDR-TB and diabetes. Drug exposure level was estimated by noncompartmental analysis. The minimum inhibitory concentrations (MICs) were determined for the individual Mycobacterium tuberculosis isolates. The influence of poor glycemic control (glycated hemoglobin ≥7%) on drug exposure and the associations between drug exposure and treatment outcome were evaluated by univariate and multivariate analysis. Classification and regression tree analysis was used to identify the drug exposure/susceptibility thresholds. RESULTS: Among the 131 diabetic participants, 43 (32.8%) exhibited poor glycemic control. Poor glycemic control was independently associated with decreased exposure to moxifloxacin, linezolid, bedaquiline, and cycloserine, but not clofazimine. Additionally, a higher ratio of drug exposure to susceptibility was found to be associated with a favorable MDR-TB treatment outcome. Thresholds predictive of 6-month culture conversion and favorable outcome were bedaquiline area under the concentration-time curve (AUC)/MIC ≥245 and moxifloxacin AUC/MIC ≥67, demonstrating predictive accuracy in patients, regardless of their glycemic control status. CONCLUSIONS: Glycemic control and optimal TB drug exposure are associated with improved treatment outcomes. This dual management strategy should be further validated in randomized controlled trials of patients with MDR-TB and diabetes.
Asunto(s)
Antituberculosos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Masculino , Femenino , Estudios Prospectivos , Antituberculosos/uso terapéutico , Persona de Mediana Edad , China/epidemiología , Adulto , Resultado del Tratamiento , Mycobacterium tuberculosis/efectos de los fármacos , Diabetes Mellitus/tratamiento farmacológico , Moxifloxacino/uso terapéutico , Linezolid/uso terapéutico , Cicloserina/uso terapéutico , Diarilquinolinas/uso terapéutico , Anciano , Clofazimina/uso terapéutico , Hemoglobina Glucada/análisisRESUMEN
Neurodevelopmental disorders such as autism spectrum disorder (ASD) have a heterogeneous etiology but are largely associated with genetic factors. Robust evidence from recent human genetic studies has linked mutations in the Shank2 gene to idiopathic ASD. Modeling these Shank2 mutations in animal models recapitulates behavioral changes, e.g. impaired social interaction and repetitive behavior of ASD patients. Shank2-deficient mice exhibit NMDA receptor (NMDAR) hypofunction and associated behavioral deficits. Of note, NMDARs are strongly implicated in cognitive flexibility. Their hypofunction, e.g. observed in schizophrenia, or their pharmacological inhibition leads to impaired cognitive flexibility. However, the association between Shank2 mutations and cognitive flexibility is poorly understood. Using Shank2-deficient mice, we explored the role of Shank2 in cognitive flexibility measured by the attentional set shifting task (ASST) and whether ASST performance in Shank2-deficient mice can be modulated by treatment with the partial NMDAR agonist D-cycloserine (DCS). Furthermore, we investigated the effects of Shank2 deficiency, ASST training, and DCS treatment on the expression level of NMDAR signaling hub components in the orbitofrontal cortex (OFC), including NMDAR subunits (GluN2A, GluN2B, GluN2C), phosphoglycerate dehydrogenase and serine racemase. Surprisingly, Shank2 deficiency did not affect ASST performance or alter the expression of the investigated NMDAR signaling hub components. Importantly, however, DCS significantly improved ASST performance, demonstrating that positive NMDAR modulation facilitates cognitive flexibility. Furthermore, DCS increased the expression of GluN2A in the OFC, but not that of other NMDAR signaling hub components. Our findings highlight the potential of DCS as a pharmacological intervention to improve cognitive flexibility impairments downstream of NMDAR modulation and substantiate the key role of NMDAR in cognitive flexibility.
Asunto(s)
Cicloserina , Ratones Noqueados , Proteínas del Tejido Nervioso , Receptores de N-Metil-D-Aspartato , Animales , Cicloserina/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas del Tejido Nervioso/genética , Ratones , Masculino , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Ratones Endogámicos C57BL , Cognición/efectos de los fármacos , Cognición/fisiología , Modelos Animales de Enfermedad , Atención/efectos de los fármacos , Atención/fisiologíaRESUMEN
RATIONALE: Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability. OBJECTIVES: After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective. RESULTS: We found resistant reconsolidation impairment by the α2-adrenergic receptor agonist clonidine or cannabidiol, a major non-psychotomimetic Cannabis sativa component. However, pre-retrieval administration of D-cycloserine, a partial agonist at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex, facilitated their impairing effects on reconsolidation. A similar reconsolidation blockade by clonidine or cannabidiol was achieved following exposure to a non-conditioned but generalized context after D-cycloserine administration. This suggests that sufficient memory destabilization can accompany generalized fear expression. Combining clonidine with cannabidiol without potentiating memory destabilization by D-cycloserine was ineffective. CONCLUSIONS: These findings highlight the importance of NMDA receptor signaling in memory destabilization and underscore the efficacy of a dual-step pharmacological intervention in attenuating traumatic-like memories, even in a context different from the original learning environment.
Asunto(s)
Cannabidiol , Clonidina , Cicloserina , Miedo , Animales , Cicloserina/farmacología , Masculino , Femenino , Cannabidiol/farmacología , Ratas , Clonidina/farmacología , Miedo/efectos de los fármacos , Memoria/efectos de los fármacos , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo , Factores SexualesRESUMEN
We review the literature on various strategies to augment cognitive-behavioral therapy (CBT). Although traditional pharmacotherapy has only a small additive effect, research demonstrates that it is possible to select interventions that potentiate known mechanisms of CBT. D-cycloserine appears to potentiate activity at the N-methyl D-ethyl aspartate receptor and thereby facilitates fear extinction. Exercise may increase neural plasticity and thereby increase the efficacy of CBT for depression and anxiety. Noninvasive brain stimulation is thought to target the specific cortical regions needed for CBT response, but results have been mixed. Several other compounds appear promising but await controlled research before their efficacy as an augmentation strategy can be determined.
Asunto(s)
Terapia Cognitivo-Conductual , Humanos , Terapia Cognitivo-Conductual/métodos , Cicloserina/uso terapéutico , Terapia Combinada , Trastornos de Ansiedad/terapia , Trastorno Depresivo/terapiaRESUMEN
Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring.
Asunto(s)
Antituberculosos , Clofazimina , Cicloserina , Interacciones Farmacológicas , Isoniazida , Levofloxacino , Linezolid , Tuberculosis Resistente a Múltiples Medicamentos , Clofazimina/farmacocinética , Clofazimina/uso terapéutico , Humanos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto , Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Masculino , Femenino , Linezolid/farmacocinética , Linezolid/uso terapéutico , Isoniazida/farmacocinética , Isoniazida/uso terapéutico , Levofloxacino/farmacocinética , Levofloxacino/uso terapéutico , Cicloserina/farmacocinética , Cicloserina/uso terapéutico , Persona de Mediana Edad , Sudáfrica , Adulto Joven , Quimioterapia CombinadaRESUMEN
Oxidative stress plays a pivotal role in the pathogenesis of several neurodegenerative diseases. Retinal degeneration causes irreversible death of photoreceptor cells, ultimately leading to vision loss. Under oxidative stress, the synthesis of bioactive sphingolipid ceramide increases, triggering apoptosis in photoreceptor cells and leading to their death. This study investigates the effect of L-Cycloserine, a small molecule inhibitor of ceramide biosynthesis, on sphingolipid metabolism and the protection of photoreceptor-derived 661W cells from oxidative stress. The results demonstrate that treatment with L-Cycloserine, an inhibitor of Serine palmitoyl transferase (SPT), markedly decreases bioactive ceramide and associated sphingolipids in 661W cells. A nontoxic dose of L-Cycloserine can provide substantial protection of 661W cells against H2O2-induced oxidative stress by reversing the increase in ceramide level observed under oxidative stress conditions. Analysis of various antioxidant, apoptotic and sphingolipid pathway genes and proteins also confirms the ability of L-Cycloserine to modulate these pathways. Our findings elucidate the generation of sphingolipid mediators of cell death in retinal cells under oxidative stress and the potential of L-Cycloserine as a therapeutic candidate for targeting ceramide-induced degenerative diseases by inhibiting SPT. The promising therapeutic prospect identified in our findings lays the groundwork for further validation in in-vivo and preclinical models of retinal degeneration.
Asunto(s)
Apoptosis , Ceramidas , Cicloserina , Estrés Oxidativo , Esfingolípidos , Estrés Oxidativo/efectos de los fármacos , Cicloserina/farmacología , Animales , Ceramidas/metabolismo , Ceramidas/farmacología , Ratones , Esfingolípidos/metabolismo , Apoptosis/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patología , Serina C-Palmitoiltransferasa/metabolismo , Serina C-Palmitoiltransferasa/antagonistas & inhibidores , Peróxido de Hidrógeno/toxicidad , Peróxido de Hidrógeno/farmacología , Línea Celular , Degeneración Retiniana/metabolismo , Degeneración Retiniana/prevención & control , Degeneración Retiniana/patología , Degeneración Retiniana/tratamiento farmacológico , Western Blotting , Inhibidores Enzimáticos/farmacología , Supervivencia Celular/efectos de los fármacosRESUMEN
Although bacterial peptidoglycan (PG) is highly conserved, some natural variations in PG biosynthesis and structure have evolved. Understanding the mechanisms and limits of such variation will inform our understanding of antibiotic resistance, innate immunity, and the evolution of bacteria. We have explored the constraints on PG evolution by blocking essential steps in PG biosynthesis in Vibrio fischeri and then selecting mutants with restored prototrophy. Here, we attempted to select prototrophic suppressors of a D-glutamate auxotrophic murI racD mutant. No suppressors were isolated on unsupplemented lysogeny broth salts (LBS), despite plating >1011 cells, nor were any suppressors generated through mutagenesis with ethyl methanesulfonate. A single suppressor was isolated on LBS supplemented with iso-D-gln, although the iso-D-gln subsequently appeared irrelevant. This suppressor has a genomic amplification formed by the creation of a novel junction that fuses proB to a gene encoding a putative broad-spectrum racemase of V. fischeri, bsrF. An engineered bsrF allele lacking the putative secretion signal (ΔSS-bsrF) also suppressed D-glu auxotrophy, resulting in PG that was indistinguishable from the wild type. The ΔSS-bsrF allele similarly suppressed the D-alanine auxotrophy of an alr mutant and restored prototrophy to a murI alr double mutant auxotrophic for both D-ala and D-glu. The ΔSS-bsrF allele increased resistance to D-cycloserine but had no effect on sensitivity to PG-targeting antibiotics penicillin, ampicillin, or vancomycin. Our work helps define constraints on PG evolution and reveals a periplasmic broad-spectrum racemase in V. fischeri that can be co-opted for PG biosynthesis, with concomitant D-cycloserine resistance. IMPORTANCE: D-Amino acids are used and produced by organisms across all domains of life, but often, their origins and roles are not well understood. In bacteria, D-ala and D-glu are structural components of the canonical peptidoglycan cell wall and are generated by dedicated racemases Alr and MurI, respectively. The more recent discovery of additional bacterial racemases is broadening our view and deepening our understanding of D-amino acid metabolism. Here, while exploring alternative PG biosynthetic pathways in Vibrio fischeri, we unexpectedly shed light on an unusual racemase, BsrF. Our results illustrate a novel mechanism for the evolution of antibiotic resistance and provide a new avenue for exploring the roles of non-canonical racemases and D-amino acids in bacteria.
Asunto(s)
Alanina Racemasa , Ácido Glutámico , Ácido Glutámico/metabolismo , Aliivibrio fischeri/genética , Aliivibrio fischeri/metabolismo , Racemasas y Epimerasas/metabolismo , Cicloserina , Peptidoglicano/metabolismo , Aminoácidos/metabolismo , Alanina Racemasa/metabolismoRESUMEN
IlvA1, a pyridoxal phosphate-dependent (PLP) enzyme, catalyzes the deamination of l-threonine and l-serine to yield 2-ketobutyric acid or pyruvate. To gain insights into the function of IlvA1, we determined its crystal structure from Pseudomonas aeruginosa to 2.3 Å. Density for a 2-ketobutyric acid product was identified in the active site and a putative allosteric site. Activity and substrate binding assays confirmed that IlvA1 utilizes l-threonine, l-serine, and L-allo-threonine as substrates. The enzymatic activity is regulated by the end products l-isoleucine and l-valine. Additionally, the efficiency of d-cycloserine and l-cycloserine inhibitors on IlvA1 enzymatic activity was examined. Notably, site-directed mutagenesis confirmed the active site residues and revealed that Gln165 enhances the enzyme activity, emphasizing its role in substrate access. This work provides crucial insights into the structure and mechanism of IlvA1 and serves as a starting point for further functional and mechanistic studies of the threonine deaminase in P. aeruginosa.
Asunto(s)
Butiratos , Pseudomonas aeruginosa , Treonina Deshidratasa , Cristalografía por Rayos X , Cicloserina , Fosfatos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Fosfato de Piridoxal/metabolismo , Treonina/metabolismo , Treonina Deshidratasa/genética , Treonina Deshidratasa/metabolismoRESUMEN
The partial N-methyl-D-aspartate receptor (NMDAR) agonist D-Cycloserine (DCS) has been evaluated for the treatment of a wide variety of psychiatric disorders, including dementia, schizophrenia, depression and for the augmentation of exposure-based psychotherapy. Most if not all of the potential psychiatric applications of DCS target an enhancement or restitution of cognitive functions, learning and memory. Their molecular correlate is long-term synaptic plasticity; and many forms of synaptic plasticity depend on the activation of NMDA receptors. Here, we comprehensively examined the modulation of different forms of synaptic plasticity in the hippocampus by DCS and its mechanism. We found that DCS positively modulates NMDAR-dependent forms of long-term synaptic plasticity (long-term synaptic potentiation, LTP, and long-term synaptic depression, LTD) in hippocampal brain slices of juvenile rats without affecting basal synaptic transmission. DCS binds to the D-serine/glycine binding site of the NMDAR. Pharmacological inhibition of this site prevented the induction of LTP, whereas agonism at the D-serine/glycine binding site augmented LTP and could functionally substitute for weak LTP induction paradigms. The most probable origin of endogenous D-serine are astrocytes, and its exocytosis is regulated by astrocytic metabotropic glutamate receptors (mGluR1). Functional eradication of astrocytes, inhibition of mGluR1 receptors and G-protein signaling in astrocytes adjacent to postsynaptic neurons prevented the induction of NMDAR-dependent forms of LTP and LTD. Our results support the enhancement of a bidirectional range of NMDAR-dependent hippocampal synaptic plasticity by DCS and D-serine-mediated gliotransmission. Therefore, the D-serine/glycine-binding site in NMDAR is a major target for psychopharmacological interventions targeting plasticity-related disorders.
Asunto(s)
Cicloserina , Receptores de N-Metil-D-Aspartato , Humanos , Animales , Ratas , Cicloserina/farmacología , Plasticidad Neuronal , Serina , Glicina , HipocampoRESUMEN
OBJECTIVES: This study aimed to investigate the association between drug exposure and adverse events (AEs) during the standardized multidrug-resistant tuberculosis (MDR-TB) treatment, as well as to identify predictive drug exposure thresholds. METHODS: We conducted a prospective, observational multicenter study among participants receiving standardized MDR-TB treatment between 2016 and 2019 in China. AEs were monitored throughout the treatment and their relationships to drug exposure (e.g., the area under the drug concentration-time curve from 0 to 24 h, AUC0-24 h) were analyzed. The thresholds of pharmacokinetic predictors of observed AEs were identified by boosted classification and regression tree (CART) and further evaluated by external validation. RESULTS: Of 197 study participants, 124 (62.9%) had at least one AE, and 15 (7.6%) experienced serious AEs. The association between drug exposure and AEs was observed including bedaquiline, its metabolite M2, moxifloxacin and QTcF prolongation (QTcF >450â ms), linezolid and mitochondrial toxicity, cycloserine and psychiatric AEs. The CART-derived thresholds of AUC0-24 h predictive of the respective AEs were 3.2 mg·h/l (bedaquiline M2); 49.3 mg·h/l (moxifloxacin); 119.3 mg·h/l (linezolid); 718.7 mg·h/l (cycloserine). CONCLUSIONS: This study demonstrated the drug exposure thresholds predictive of AEs for key drugs against MDR-TB treatment. Using the derived thresholds will provide the knowledge base for further randomized clinical trials of dose adjustment to minimize the risk of AEs.
Asunto(s)
Antituberculosos , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Antituberculosos/efectos adversos , Antituberculosos/farmacocinética , Cicloserina/efectos adversos , Diarilquinolinas/uso terapéutico , Linezolid/efectos adversos , Moxifloxacino/uso terapéutico , Estudios Prospectivos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
There are no pharmacokinetic data in children on terizidone, a pro-drug of cycloserine and a World Health Organization (WHO)-recommended group B drug for rifampicin-resistant tuberculosis (RR-TB) treatment. We collected pharmacokinetic data in children <15 years routinely receiving 15-20 mg/kg of daily terizidone for RR-TB treatment. We developed a population pharmacokinetic model of cycloserine assuming a 2-to-1 molecular ratio between terizidone and cycloserine. We included 107 children with median (interquartile range) age and weight of 3.33 (1.55, 5.07) years and 13.0 (10.1, 17.0) kg, respectively. The pharmacokinetics of cycloserine was described with a one-compartment model with first-order elimination and parallel transit compartment absorption. Allometric scaling using fat-free mass best accounted for the effect of body size, and clearance displayed maturation with age. The clearance in a typical 13 kg child was estimated at 0.474 L/h. The mean absorption transit time when capsules were opened and administered as powder was significantly faster compared to when capsules were swallowed whole (10.1 vs 72.6 min) but with no effect on bioavailability. Lower bioavailability (-16%) was observed in children with weight-for-age z-score below -2. Compared to adults given 500 mg daily terizidone, 2022 WHO-recommended pediatric doses result in lower exposures in weight bands 3-10 kg and 36-46 kg. We developed a population pharmacokinetic model in children for cycloserine dosed as terizidone and characterized the effects of body size, age, formulation manipulation, and underweight-for-age. With current terizidone dosing, pediatric cycloserine exposures are lower than adult values for several weight groups. New optimized dosing is suggested for prospective evaluation.
Asunto(s)
Cicloserina , Tuberculosis Resistente a Múltiples Medicamentos , Adulto , Humanos , Niño , Cicloserina/uso terapéutico , Cicloserina/farmacocinética , Rifampin/farmacocinética , Antituberculosos/farmacocinética , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
Pseudomonas aeruginosa is a major human pathogen in the healthcare setting. The emergence of multi-drug-resistant and extensive drug-resistant P. aeruginosa is of great concern, and clearly indicates that new alternatives to current first-line antibiotics are required in the future. Inhibition of d-alanine-d-alanine production presents as a promising avenue as it is a key component in the essential process of cell wall biosynthesis. In P. aeruginosa, d-alanine-d-alanine production is facilitated by two isoforms, d-alanine-d-alanine ligase A (PaDdlA) and d-alanine-d-alanine ligase B (PaDdlA), but neither enzyme has been individually characterised to date. Here, we present the functional and structural characterisation of PaDdlA and PaDdlB, and assess their potential as antibiotic targets. This was achieved using a combination of in vitro enzyme-activity assays and X-ray crystallography. The former revealed that both isoforms effectively catalyse d-alanine-d-alanine production with near identical efficiency, and that this is effectively disrupted by the model d-alanine-d-alanine ligase inhibitor, d-cycloserine. Next, each isoform was co-crystallised with ATP and either d-alanine-d-alanine or d-cycloserine, allowing direct comparison of the key structural features. Both isoforms possess the same structural architecture and share a high level of conservation within the active site. Although residues forming the d-alanine pocket are completely conserved, the ATP-binding pocket possesses several amino acid substitutions resulting in a differing chemical environment around the ATP adenine base. Together, these findings support that the discovery of dual PaDdlA/PaDdlB competitive inhibitors is a viable approach for developing new antibiotics against P. aeruginosa.
Asunto(s)
Antibacterianos , Cicloserina , Humanos , Antibacterianos/farmacología , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Alanina , Estudios Prospectivos , Péptido Sintasas/química , Isoformas de Proteínas , Adenosina Trifosfato/químicaRESUMEN
BACKGROUND: Over a decade and a half of research has resulted in inconsistent evidence for the efficacy of d-cycloserine (DCS), a partial glutamatergic N-methyl-D-aspartate agonist, for augmenting exposure-based cognitive behavioral therapy (CBT) for anxiety- and fear-based disorders. These variable findings have motivated the search for moderators of DCS augmentation efficacy. METHODS: In this secondary analysis of a previous randomized clinical trial, we evaluated the value of de novo threat conditioning outcomes-degree of threat acquisition, extinction, and extinction retention-for predicting treatment response to exposure-based CBT for social anxiety disorder, applied with and without DCS augmentation in a sample of 59 outpatients. RESULTS: We found that average differential skin conductance response (SCR) during extinction and extinction retention significantly moderated the prediction of clinical response to DCS: participants with poorer extinction and extinction retention showed relatively improved treatment response with DCS. No such effects were found for expectancy ratings, consistent with accounts of DCS selectively aiding lower-order but not higher-order extinction learning. CONCLUSIONS: These findings provide support for extinction and extinction retention outcomes from threat conditioning as potential pre-treatment biomarkers for DCS augmentation benefits. Independent of DCS augmentation, the current study did not support threat conditioning outcomes as useful for predicting response to exposure-based CBT.
Asunto(s)
Terapia Cognitivo-Conductual , Cicloserina , Humanos , Trastornos de Ansiedad/tratamiento farmacológico , Terapia Cognitivo-Conductual/métodos , Terapia Combinada , Cicloserina/uso terapéutico , Extinción Psicológica , Resultado del TratamientoRESUMEN
INTRODUCTION: The aim of the study was to investigate the role of D-cycloserine (DCS) in the adaptation process and maintenance of motion sickness (MS). METHODS: In experiment 1, 120 SD rats were used to study the promoting effect of DCS on the adaptation process of MS in rats. They were randomly divided into four groups, DCS-rotation (DCS-Rot), DCS-static, saline-rotation (Sal-Rot), and saline-static, and further divided into three subgroups according to the adaptation time (4 days, 7 days, and 10 days) in each group. After being given DCS (0.5 mg/kg) or 0.9% saline, they were rotated or kept static according to the group. Their fecal granules, total distance, and total activity of spontaneous activity were recorded and analyzed. In experiment 2, other 120 rats were used. The experimental grouping and specific experimental method were the same as experiment 1. According to the grouping of the adaptive maintenance duration, the animals of 14 days, 17 days, and 21 days groups were measured on the corresponding date of the changes in the animals' exploratory behavior. RESULTS: In experiment 1, the fecal granules, total distance, and total activity of spontaneous activity of Sal-Rot returned to the control level on 9 days, and the DCS-Rot group returned to the control level on 6 days, indicating that DCS could shorten the adaptation time of MS rats from 9 days to 6 days. In experiment 2, the Sal-Rot could not maintain the adaptive state after 14 days' absence from the seasickness environment. The fecal granules of DCS-Rot increased significantly, and total distance and total activity of spontaneous activity of DCS-Rot decreased significantly from 17 days. These illustrate that DCS can prolong the adaptive maintenance time from within 14 days to 17 days in MS rats. CONCLUSION: 0.5 mg/kg DCS injected intraperitoneally can shorten the MS adaptation process and extend the maintenance time of adaptation of SD rats.
Asunto(s)
Cicloserina , Extinción Psicológica , Ratas , Animales , Cicloserina/farmacología , Cicloserina/uso terapéutico , Ratas Sprague-Dawley , Conducta Animal , Receptores de N-Metil-D-AspartatoRESUMEN
D-cycloserine inhibits pyridoxal-5'-phosphate (PLP)-dependent enzymes. Inhibition effect depend on organization of the active site and mechanism of the catalyzed reaction. D-cycloserine interacts with the PLP form of the enzyme similarly to the substrate (amino acid), and this interaction is predominantly reversible. Several products of the interaction of PLP with D-cycloserine are known. For some enzymes formation of a stable aromatic product - hydroxyisoxazole-pyridoxamine-5'-phosphate at certain pH - leads to irreversible inhibition. The aim of this work was to study the mechanism of D-cycloserine inhibition of the PLP-dependent D-amino acid transaminase from Haliscomenobacter hydrossis. Spectral methods revealed several products of interaction of D-cycloserine with PLP in the active site of transaminase: oxime between PLP and ß-aminooxy-D-alanine, ketimine between pyridoxamine-5'-phosphate and cyclic form of D-cycloserine, and pyridoxamine-5'-phosphate. Formation of hydroxyisoxazole-pyridoxamine-5'-phosphate was not observed. 3D structure of the complex with D-cycloserine was obtained using X-ray diffraction analysis. In the active site of transaminase, a ketimine adduct between pyridoxamine-5'-phosphate and D-cycloserine in the cyclic form was found. Ketimine occupied two positions interacting with different active site residues via hydrogen bonds. Using kinetic and spectral methods we have shown that D-cycloserine inhibition is reversible, and activity of the inhibited transaminase from H. hydrossis could be restored by adding excess of keto substrate or excess of cofactor. The obtained results confirm reversibility of the inhibition by D-cycloserine and interconversion of various adducts of D-cycloserine and PLP.
Asunto(s)
Aminoácidos , Transaminasas , Transaminasas/química , Cicloserina/farmacología , Cicloserina/química , Piridoxamina/química , Fosfato de PiridoxalRESUMEN
OBJECTIVE: N-methyl-d-aspartate receptor (NMDAR) antagonist antidepressants have known potential for abuse liability. The aim of this study was to evaluate the abuse liability of D-cycloserine (DCS), using a self-administration paradigm in which DCS was tested for its efficacy in substituting for ketamine in ketamine-dependent rats. METHODS: A standard intravenous self-administration study was conducted in male adult Sprague-Dawley rats to study abuse liability. Potential for self-administration was assessed in ketamine-habituated subjects. Subjects were trained to press a lever to obtain food, prior to connection of the lever to the intravenous drug administration apparatus. DCS was provided for self-infusion by test subjects at doses of 1.5, 5.0, and 15 mg/kg per lever press. RESULTS: S-ketamine was seen to substitute for ketamine and to result in self-administration at the same frequency. DCS was not seen to result in self-administration at any of the test doses. The self-infusion behavior of DCS was similar to control (saline). CONCLUSION: D-cycloserine, a partial agonist of the NMDAR glycine site, which has been shown to have antidepressant and anti-suicidal properties in clinical studies, has no apparent potential for abuse liability in a standard rodent self-administration model.
Asunto(s)
Cicloserina , Ketamina , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Ketamina/farmacología , Antidepresivos/uso terapéutico , Administración Intravenosa , Receptores de N-Metil-D-AspartatoRESUMEN
Trauma-focused psychotherapy (tf-PT) is the first-line treatment for posttraumatic stress disorder (PTSD). Tf-PT focuses on processing and modulating trauma memories. Not all patients benefit, however, and there is room for improvement of efficacy. Pharmacologically augmenting trauma memory modulation in the context of tf-PT may help optimise treatment outcome. To systematically review effects of pharmacologically augmented memory modulation in the context of tf-PT for PTSD (PROSPERO preregistration ID: CRD42021230623). We conducted a systematic review of randomised controlled trials of psychotherapy treatment for PTSD. We included placebo-controlled studies that augmented at least one treatment session pharmacologically targeting memory extinction or reconsolidation. We calculated post-treatment between group (pharmacological augmentation vs placebo control) effect sizes of PTSD symptom severity. We included 13 RCTs. There was large heterogeneity in augmentation procedure and methodological quality. Four studies showed significantly greater PTSD symptom reduction in the pharmacological augmentation group (propranolol, hydrocortisone, dexamethasone, D-cycloserine) compared to placebo. Seven studies showed no significant effect of pharmacological augmentation compared to placebo (D-cycloserine, rapamycin, mifepristone, propranolol, mifepristone combined with D-cycloserine, methylene blue). Two studies showed significantly smaller PTSD symptom reduction in the pharmacological augmentation group (D-cycloserine, dexamethasone) compared to placebo. Results of pharmacological augmentation were mixed overall and heterogenous for the pharmacological agents tested in more than one study. Additional studies and replications are needed to identify which pharmacological agents work, in which combination and to identify patient groups that benefit most to tailor PTSD treatment.
Asunto(s)
Trastornos por Estrés Postraumático , Humanos , Cicloserina , Dexametasona , Mifepristona/farmacología , Mifepristona/uso terapéutico , Propranolol/farmacología , Propranolol/uso terapéutico , Psicoterapia/métodos , Trastornos por Estrés Postraumático/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Tuberculosis (TB) is the second leading cause of death by a single infectious disease behind COVID-19. Despite a century of effort, the current TB vaccine does not effectively prevent pulmonary TB, promote herd immunity, or prevent transmission. Therefore, alternative approaches are needed. We seek to develop a cell therapy that produces an effective antibiotic in response to TB infection. D-cycloserine (D-CS) is a second-line antibiotic for TB that inhibits bacterial cell wall synthesis. We have determined D-CS to be the optimal candidate for anti-TB cell therapy due to its effectiveness against TB, relatively short biosynthetic pathway, and its low-resistance incidence. The first committed step towards D-CS synthesis is catalyzed by the L-serine-O-acetyltransferase (DcsE) which converts L-serine and acetyl-CoA to O-acetyl-L-serine (L-OAS). To test if the D-CS pathway could be an effective prophylaxis for TB, we endeavored to express functional DcsE in A549 cells as a human pulmonary model. We observed DcsE-FLAG-GFP expression using fluorescence microscopy. DcsE purified from A549 cells catalyzed the synthesis of L-OAS as observed by HPLC-MS. Therefore, human cells synthesize functional DcsE capable of converting L-serine and acetyl-CoA to L-OAS demonstrating the first step towards D-CS production in human cells.
Asunto(s)
COVID-19 , Tuberculosis , Humanos , Cicloserina/farmacología , Cicloserina/metabolismo , Serina/metabolismo , Acetilcoenzima A/metabolismo , AntibacterianosRESUMEN
Agents that act at the N-methyl-D-aspartate receptor (NMDAR), such as ketamine, have gained increasing attention as rapid-acting antidepressants; however, their use has been limited by potential neurotoxicity. Recent FDA guidance requires a demonstration of safety on histologic parameters prior to the initiation of human studies. D-cycloserine (DCS) is a partial NMDA agonist that, along with lurasidone, is being investigated as a treatment for depression. The current study was designed to investigate the neurologic safety profile of DCS. To this end, female Sprague Dawley rats (n = 106) were randomly divided into 8 study groups. Ketamine was administered via tail vein infusion. DCS and lurasidone were administered via oral gavage in escalating doses to a maximum of 2000 mg/kg DCS. To ascertain toxicity, dose escalation with 3 different doses of D-cycloserine/lurasidone was given in combination with ketamine. MK-801, a known neurotoxic NMDA antagonist, was administered as a positive control. Brain tissue was sectioned and stained with H&E, silver, and Fluoro-Jade B stains. No fatalities were observed in any group. No microscopic abnormalities were found in the brain of animal subjects given ketamine, ketamine followed by DCS/lurasidone, or DCS/lurasidone alone. Neuronal necrosis, as expected, was seen in the MK-801 (positive control) group. We conclude that NRX-101, a fixed-dose combination of DCS/lurasidone, when administered with or without prior infusion of IV ketamine was tolerated and did not induce neurotoxicity, even at supratherapeutic doses of DCS.
Asunto(s)
Ketamina , Humanos , Ratas , Animales , Femenino , Ketamina/toxicidad , Cicloserina/farmacología , Cicloserina/uso terapéutico , Clorhidrato de Lurasidona , Maleato de Dizocilpina/toxicidad , N-Metilaspartato , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistasRESUMEN
Although cycloserine is a recommended drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) according to World Health Organization (WHO), few studies have reported on pharmacokinetics (PK) and/or pharmacodynamics (PD) data of cycloserine in patients with standardized MDR-TB treatment. This study aimed to estimate the population PK parameters for cycloserine and to identify clinically relevant PK/PD thresholds, as well as to evaluate the current recommended dosage. Data from a large cohort with full PK curves was used to develop a population PK model. This model was used to estimate drug exposure in patients with MDR-TB from a multicentre prospective study in China. The classification and regression tree was used to identify the clinically relevant PK/PD thresholds. Probability of target attainment was analyzed to evaluate the currently recommended dosing strategy. Cycloserine was best described by a two-compartment disposition model. A percentage of time concentration above MICs (T>MIC) of 30% and a ratio of area under drug concentration-time curve (AUC0-24h) over MIC of 36 were the valid predictors for 6-month sputum culture conversion and final treatment outcome. Simulations showed that with WHO-recommended doses (500 mg and 750 mg for patients weighing <45 kg and ≥45 kg), the probability of target attainment exceeded 90% at MIC ≤16 mg/L in MGIT for both T>MIC of 30% and AUC0-24h/MIC of 36. New clinically relevant PK/PD thresholds for cycloserine were identified in patients with standardized MDR-TB treatment. WHO-recommended doses were considered adequate for the MGIT MIC distribution in our cohort of Chinese patients with MDR-TB.