Prev Chronic Dis

2006681

Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression

Scientific evidence that circadian rhythms affect pharmacokinetics and pharmacodynamics has highlighted the importance of drug dosing-time. Circadian oscillations alter drug absorption, distribution, metabolism, and excretion (ADME) as well as intracellular signaling systems, target molecules (e.g., receptors, transporters, and enzymes), and gene transcription. Although several antidepressant drugs are clinically available, less than 50% of depressed patients respond to first-line pharmacological treatments. Chronotherapeutic approaches to enhance the effectiveness of antidepressants are not completely known. Even so, experimental results found until this day suggest a positive influence of drug dosing-time on the efficacy of depression therapy. On the other hand, antidepressants have also demonstrated to modulate circadian rhythmicity and sleep-wake cycles. This review aims to evidence the potential of chronotherapy to improve the efficacy and/or safety of antidepressants. It includes pre-clinical and clinical studies that demonstrate the relevance of determining the most appropriate time of administration for antidepressant drugs. In parallel, their positive influence on the resynchronization of disrupted circadian rhythms is also herein discussed. It is expected that this review will promote the investigation of chronotherapy for the treatment of depression, contribute to a better understanding of the relationship between antidepressants and circadian rhythms, and consequently promote the development of new therapeutics

Pre-Clinical Assessment of the Nose-to-Brain Delivery of Zonisamide After Intranasal Administration

Zonisamide clinical indications are expanding beyond the classic treatment of epileptic seizures to Parkinson's disease and other neurodegenerative diseases. However, the systemic safety profile of zonisamide may compromise its use as a first-line drug in any clinical condition. Since zonisamide is marketed as oral formulations, the present study aimed at exploring the potential of the intranasal route to centrally administer zonisamide, evaluating the systemic bioavailability of zonisamide and comparing its brain, lung and kidney pharmacokinetics after intranasal, oral and intravenous administrations

Therapeutic Drug Monitoring of Amikacin in Neutropenic Oncology Patients

Amikacin is the antibiotic of choice for the treatment of Gram-negative infections, namely, those in neutropenic oncology patients. No populational pharmacokinetic studies are currently available reporting amikacin pharmacokinetics in neutropenic oncology patients despite their specific pathophysiological features and treatments. A large-scale retrospective study was herein conducted to specifically investigate the effects that tumor diseases have on the pharmacokinetic parameters of amikacin and identify whether chemotherapy, the lag time between administration of chemotherapy and amikacin, age and renal function contribute to amikacin pharmacokinetics in neutropenic cancer patients. A total of 1180 pharmacokinetic analysis from 629 neutropenic patients were enrolled. The daily dose administered to oncology patients was higher than that administered to non-oncology patients (p p < 0.0001). Chemotherapy influenced amikacin pharmacokinetics and drug clearance decreased as the lag time enhanced. The elderly group revealed no statistical differences between the doses administered to both the oncology groups, suggesting that the impact of ageing is stronger than chemotherapy. Our research suggests that cancer patients require higher initial doses of amikacin, as well as when chemotherapy is received less than 30 days before amikacin treatment has started

Pharmacokinetic Monitoring of Levetiracetam in Portuguese Refractory Epileptic Patients: Effect of Gender, Weight and Concomitant Therapy

Levetiracetam is a second-generation antiepileptic drug, widely used in the treatment of focal and generalized epilepsy due to its pharmacokinetic and safety profiles. Its pharmacokinetic monitoring is ascribed as useful to personalize its dosing regimen. The aim of the present study was to describe, for the first time, the pharmacokinetics of levetiracetam in Portuguese refractory epileptic patients. Therefore, a retrospective study was carried out on 65 Portuguese refractory epileptic patients (pharmacokinetic study: 48; validation study: 17) admitted to the Refractory Epilepsy Centre of the Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. The pharmacokinetic parameters of levetiracetam were estimated by applying a one-compartment model with first-order absorption and elimination analysis. Male patients showed higher distribution volume (Vd/F) and oral clearance (CL/F) than female patients (median Vd/F: 52.40 L in males and 38.60 L in females, p = 0.011; median CL/F: 4.71 L/h in males and 3.91 L/h in females, p = 0.028). Higher values of Vd/F (p = 0.026) and CL/F (p = 0.003) were also found in overweight patients relative to normal weight and obese patients. Carbamazepine was the co-administered antiepileptic drug that mostly affected the pharmacokinetics of levetiracetam, increasing both Vd/F (61.30 L with carbamazepine and 39.10 L without carbamazepine, p = 0.007) and CL/F (6.71 L/h with carbamazepine and 3.91 L/h without carbamazepine, p < 0.001). The pharmacokinetics of levetiracetam was affected by gender, body mass index, and co-administration of carbamazepine. This study highlights the impact of several factors on the CL/ and Vd/F of levetiracetam when administered to refractory epileptic patients. The importance of its pharmacokinetic monitoring in clinical pharmacy stands out, thereby enabling the optimization of antiepileptic drug therapy

Encapsulated Escitalopram and Paroxetine Intranasal Co-Administration: In Vitro/In Vivo Evaluation

Depression is a common mental disorder. Its treatment with selective serotonin reuptake inhibitors (SSRIs) is effective only in a fraction of patients, and pharmacoresistance is increasing steadily. Intranasal (IN) drug delivery to the brain stands out as a promising strategy to improve current therapeutic approaches by operating as a shuttle to overcome the blood-brain barrier. This work aimed to simultaneously administer escitalopram and paroxetine by IN route to mice. For this purpose, three nanostructured lipid carriers (NLC1, NLC2, and BorNLC) and one nanoemulsion (NE) were tested for drug loading. After their characterization, investigation of their impact on nasal cell viability and SSRI permeability assays were performed, using a human nasal RPMI 2650 cell line in air-liquid interface. In vitro assays demonstrated that NLCs, including borneol (BorNLC), significantly increased escitalopram permeability (p < 0.01) and paroxetine recovery values (p < 0.05) in relation to the other formulations and non-encapsulated drugs. IN and intravenous (IV) pharmacokinetic studies performed in vivo with a single dose of 2.38 mg/kg demonstrated similar results for escitalopram brain-to-plasma ratios. IN administrations delayed escitalopram peak concentrations in the brain for 15-60 min and no direct nose-to-brain delivery was detected. However, encapsulation with BorNLC considerably decreased escitalopram exposure in the lungs (124 μg min/g) compared with free escitalopram by IN (168 μg min/g) and IV (321 μg min/g) routes. Surprisingly, BorNLC IN instillation increased concentration levels of paroxetine in the brain by five times and accelerated brain drug delivery. Once again, lung exposure was considerably lower with BorNLC (AUCt = 0.433 μg min/g) than that with IV administration (AUCt = 1.01 μg min/g) and non-encapsulated IN formulation (AUCt = 2.82 μg min/g). Direct nose-to-brain delivery was observed for paroxetine IN administration with a direct transport percentage (DTP) of 56.9%. If encapsulated, it increases to 74.2%. These results clearly emphasize that nose-to-brain delivery and lung exposure depend on the formulation and on the characteristics of the drug under investigation. NLCs seem to be an advantageous strategy for nose-to-brain delivery of lipophilic molecules, since they reduce systemic and lung exposure, thereby decreasing adverse effects. For hydrophilic compounds, NLCs are particularly important to decrease lung exposure after IN administration

QbD-driven development of intranasal lipid nanoparticles for depression treatment

Depression is a life-threatening psychiatric disorder and a multifactorial global public health concern. Current pharmacological treatments present limited efficacy, and are associated with several harmful side effects and development of pharmacoresistance mechanisms. Developing more effective therapeutic options is therefore a priority. This work aims at efficiently designing an antidepressant therapeutic surrogate relying on a dual strategy supported on lipid nanoparticles and intranasal delivery. For that purpose, the formulation was comprehensively optimized following a quality by design perspective. Critical quality attributes (CQAs) ranged from physicochemical to intranasal performance features. The optimized formulation was administered to mice in order to assess the antidepressive and anxiolytic effects by applying the forced swimming and marble-burying tests, respectively. A cross-analysis of the predictive models established for the set of 12 CQAs elicited the formulation containing similar proportion of solid and liquid lipids and lower surfactant concentration as the optimal one. Despite increasing the liquid lipid amount yielded smaller and more homogeneous particle size, and higher release rate, nanostructured lipid carriers (NLCs) provided an earlier and superior pig nasal mucosa permeability than nanoemulsions, along with better stability and cytotoxic profiles. Importantly, the intranasal delivery of the optimal lipid nanoparticle formulation reduced both depressive and anxiety-like behaviors, which positions these intranasal nanosystems in line with the hypothesis of provisioning timely and better acting antidepressant therapies

Population Pharmacokinetic Analysis of Perampanel in Portuguese Patients Diagnosed with Refractory Epilepsy

Perampanel is a promising antiepileptic drug (AED) for refractory epilepsy treatment due to its innovative mechanism of action. This study aimed to develop a population pharmacokinetic (PopPK) model to be further used in initial dose optimization of perampanel in patients diagnosed with refractory epilepsy. A total of seventy-two plasma concentrations of perampanel obtained from forty-four patients were analyzed through a population pharmacokinetic approach by means of nonlinear mixed effects modeling (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic profiles of perampanel. Interpatient variability (IPV) was entered on clearance (CL), while the residual error (RE) was modeled as proportional. The presence of enzyme-inducing AEDs (EIAEDs) and body mass index (BMI) were found as significant covariates for CL and volume of distribution (V), respectively. The mean (relative standard error) estimates for CL and V of the final model were 0.419 L/h (5.56%) and 29.50 (6.41%), respectively. IPV was 30.84% and the proportional RE was 6.44%. Internal validation demonstrated an acceptable predictive performance of the final model. A reliable population pharmacokinetic model was successfully developed, and it is the first enrolling real-life adults diagnosed with refractory epilepsy

Clinical Application of Pharmacokinetics to Appraise Adherence to Levetiracetam in Portuguese Epileptic Patients

Adherence to antiseizure drug treatment determines its effectiveness and safety, and consequently affects patients&rsquo; quality of life. Herein, we assessed adherence to levetiracetam in Portuguese patients with refractory epilepsy (n = 115), with resort to a pharmacokinetic drug monitoring approach. The pharmacokinetic parameters of levetiracetam in each patient were determined in steady-state while admitted to the hospital. Then, adherence was assessed by comparing the plasma concentration of the drug observed on the first day of hospitalization with the predicted plasma concentration, considering previously determined pharmacokinetic parameters. The rate of adherence was assessed according to gender, age, diagnosis, and antiseizure drug regimen. Among 115 enrolled patients, 49 (42.6%) were identified as non-adherent, 30 (26.1%) classified as under-consumers, and 19 (16.5%) as over-consumers. A relationship between adherence, daily dose and plasma concentrations was herein reported for the first time. Adherent patients received higher daily doses of levetiracetam [2500 (2000&ndash;3000) mg] than non-adherent over-consumers [1500 (1000&ndash;2000) mg] and non-adherent under-consumers [2000 (1500&ndash;3000) mg]. Higher average steady-state plasma concentrations of levetiracetam were found in non-adherent under-consumers [27.28 (15.33&ndash;36.36) mg/L], followed by adherent patients [22.05 (16.62&ndash;29.81) mg/L] and non-adherent over-consumers [17.50 (10.69&ndash;24.37) mg/L]. This study demonstrates that adherence (or lack thereof) influences the plasma concentrations of levetiracetam in steady-state and its pharmacological effects. Moreover, it emphasizes the importance of educating patients to encourage adherence to therapy. Otherwise, the risk of developing toxic and subtherapeutic concentrations is undeniable, compromising the therapeutic effect and safety of treatment