The Pharmacokinetic Study of Progesterone and Allopregnanolone in Refractory Epilepsy : Phase II Study

Abstract Background: Progesterone belongs to a class of neurosteroids used for the reduction of seizure frequency in patients with refractory epilepsy. However, the pharmacokinetics of progesterone and its active derivative, allopregnanolone, have never been studied in these patients. Objectives: This study was aim to explore the pharmacokinetic parameters of progesterone 400 mg every 12 h, for 3 months, in patients with refractory epilepsy as an add-on therapy to control seizures. Phoenix® WinNonlin® was used to analyse the pharmacokinetic parameters. Results: Twelve patients were recruited. From a therapeutic drug monitoring, the serum progesterone and allopregnanolone levels after taking the first dose of progesterone were characterised by a time to maximum concentration (Tmax) median of 1 and 2.5 h, a maximum concentration (Cmax) median of 274.97 and 3.81 ng/mL, and a minimum concentration (Cmin) median of 56.93 and 1.06 ng/mL, respectively. The median values of the pharmacokinetic parameters of progesterone and allopregnanolone during the steady state were as follows: t1/2 of 2.4 and 2.0 h, Cmax of 964.35 and 8.92 ng/mL, and Cmin of 64.67 and 1.86 ng/mL, respectively. By examining the relationship between the progesterone or allopregnanolone concentrations with seizure-controlling ability, we could identify a responder patient group with 6- to 7-fold higher serum concentrations of progesterone and allopregnanolone than the non-responders. Conclusions: We could establish higher serum levels of both progesterone and allopregnanolone, which could consequently relate to lowering the seizure frequency in patients with refractory epilepsy. The suggested progesterone dose was 400 mg orally every 12 h against refractory epilepsy Trial registration: This study has been registered on the Thai Clinical Trials Registry (No. TCTR20200710005, 10 July 2020)

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Ictal aggression in severely mentally handicapped people

Irish Journal of Psychological Medicine ◽

10.1017/s0790966700013227 ◽

1993 ◽

Vol 10 (1) ◽

pp. 12-15 ◽

Cited By ~ 5

Author(s):

Mary Creaby ◽

Mary Warner ◽

Nahla Jamil ◽

Sudad Jawad

Keyword(s):

Therapeutic Drug Monitoring ◽

Seizure Frequency ◽

Drug Monitoring ◽

Aggressive Behaviour ◽

Therapeutic Drug ◽

Neuroleptic Drugs ◽

Partial Seizures ◽

Mentally Handicapped ◽

Handicapped People ◽

The Relationship

AbstractObjective: To study the relationship between epilepsy and aggression in a population of severely mentally handicapped people. Methods: Comparing epilepsy and aggression variables in people with epilepsy without aggression, people with aggression without epilepsy, and people with both. The epilepsy variables were: seizure frequency, classification, anticonvulsant drugs, therapeutic drug monitoring, and neuroleptic drugs. Aggression variables were: frequency, direction, type, and neuroleptic drugs. Results: Prevalence of aggressive behaviour was similar in people with and without epilepsy (36%). Partial seizures were less prevalent in people with epilepsy and aggression. People with epilepsy were more likely to manifest unprovoked aggression directed against property. Conclusion: Some episodes of aggressive behaviour in people with epilepsy may be ictal in origin.

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Evaluation of the Relationship Between Celiac Disease and Refractory Epilepsy in Patients Referred to Imam Khomeini Hospital of Urmia

Basic and Clinical Neuroscience Journal ◽

10.32598/bcn.2021.3341.1 ◽

2021 ◽

pp. 1-15

Author(s):

Hanieh Mollazadeh ◽

◽

Surena Nazarbaghi ◽

Mohammad Reza Pashaei ◽

◽

...

Keyword(s):

Celiac Disease ◽

Serum Level ◽

Refractory Epilepsy ◽

Serum Levels ◽

Control Group ◽

Cross Sectional ◽

Statistical Population ◽

Significant Difference ◽

The Mean ◽

The Relationship

Objective: Celiac disease can be associated with other diseases, including neurological disorders. In this study, the relationship between celiac disease and refractory epilepsy was evaluated in patients referred to Imam Khomeini Hospital of Urmia. Material & Methods: In this cross-sectional study, patients with refractory epilepsy referred to the neurology clinic of Imam Khomeini Hospital of Urmia, during the second half of 2019 and controlled epilepsy were studied as a control group. The statistical population of the present study included 50 patients with refractory seizures and 50 patients with controlled seizures. The mean age of patients was 32.96 ± 11.35 years. Five ml blood samples were taken from the patients, and a serum anti-tTG test was performed using the ELISA kit. Then, in patients with positive anti-tTG, a duodenal biopsy sample was prepared using an endoscopy. Results: This study showed that the mean serum level of anti-tTG in patients with refractory epilepsy was higher than in patients with controlled epilepsy. Anti-tTG test results were positive in five of fifty patients with refractory epilepsy, and it was positive in two of fifty patients with controlled epilepsy. There was no significant difference between the two groups in terms of serum levels anti-tTG (p=0.14). Also, there was no significant relationship between serum level anti-tTG, age and genus (p>0.05). Biopsy results in three patients in the refractory epilepsy group and one patient in the controlled epilepsy group was in favor of a definitive diagnosis of the celiac disease. Patients in whom the celiac disease was confirmed by endoscopy had higher anti-tTG levels (p=0.006). Conclusion: There was no significant difference between the celiac disease in the group with refractory epilepsy and controlled epilepsy.

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Preliminary study of the association between the elimination parameters of phenytoin and phenobarbital

Drug Metabolism and Personalized Therapy ◽

10.1515/dmpt-2017-0017 ◽

2017 ◽

Vol 32 (3) ◽

Author(s):

Janthima Methaneethorn ◽

Duangchit Panomvana ◽

Thaveechai Vachirayonstien

Keyword(s):

Steady State ◽

Medical Records ◽

Maximum Rate ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Regression Equations ◽

Simple Linear Regression ◽

Epileptic Patients ◽

Preliminary Study ◽

The Relationship

AbstractBackground:Therapeutic drug monitoring is essential for both phenytoin and phenobarbital therapy given their narrow therapeutic indexes. Nevertheless, the measurement of either phenytoin or phenobarbital concentrations might not be available in some rural hospitals. Information assisting individualized phenytoin and phenobarbital combination therapy is important. This study’s objective was to determine the relationship between the maximum rate of metabolism of phenytoin (VMethods:Data on phenytoin and phenobarbital concentrations of 19 epileptic patients concurrently receiving both drugs were obtained from medical records. Phenytoin and phenobarbital pharmacokinetic parameters were studied at steady-state conditions. The relationship between the elimination parameters of both drugs was determined using simple linear regression.Results:A high correlation coefficient between VConclusions:Regression equations were established for estimating V

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Multiple Dose Pharmacokinetics of Oral Transmucosal Fentanyl Citrate in Healthy Volunteers

Anesthesiology ◽

10.1097/00000542-200003000-00009 ◽

2000 ◽

Vol 92 (3) ◽

pp. 665-673 ◽

Cited By ~ 35

Author(s):

Talmage D. Egan ◽

Amarnath Sharma ◽

Michael A. Ashburn ◽

Jur Kievit ◽

Nathan L. Pace ◽

...

Keyword(s):

Plasma Concentration ◽

Maximum Concentration ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Pharmacokinetic Models ◽

Multiple Dosing ◽

Fentanyl Citrate ◽

Minimum Concentration ◽

Intravenous Fentanyl ◽

Oral Transmucosal Fentanyl Citrate

Background Oral transmucosal fentanyl citrate (OTFC) is a solid form of fentanyl that delivers the drug through the oral mucosa. The clinical utility of multiple doses of OTFC in the treatment of "breakthrough" cancer pain is under evaluation. The aim of this study was to test the hypothesis that the pharmacokinetics of OTFC do not change with multiple dosing. Methods Twelve healthy adult volunteers received intravenous fentanyl (15 microg/kg) or OTFC (three consecutive doses of 800 microg) on separate study sessions. Arterial blood samples were collected for determination of fentanyl plasma concentration by radioimmunoassay. The descriptive pharmacokinetic parameters (maximum concentration, minimum concentration, and time to maximum concentration) were identified from the raw data and subjected to a nonparametric analysis of variance. Population pharmacokinetic models for all subjects and separate models for each subject were developed to estimate the pharmacokinetic parameters of fentanyl after multiple OTFC doses. Results The shapes of the profiles of plasma concentration versus time for each dose of OTFC were grossly similar. No change was noted for maximum concentration or time to maximum concentration over the three doses, while minimum concentration did show a significantly increasing trend. Terminal half-lives for intravenous fentanyl and OTFC were similar. A two-compartment population pharmacokinetic model adequately represented the central tendency of the data from all subjects. Individual subject data were best described by either two- or three-compartment pharmacokinetic models. These models demonstrated rapid and substantial absorption of OTFC that did not change systematically with time and multiple dosing. Conclusions The pharmacokinetics of OTFC were similar among subjects and did not change with multiple dosing. Multiple OTFC dosing regimens within the dosage schedule examined in this study can thus be formulated without concern about nonlinear accumulation.

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UHPLC-MS/MS Analysis of Cannabidiol and Its Metabolites in Serum of Patients with Resistant Epilepsy Treated with CBD Formulations

Pharmaceuticals ◽

10.3390/ph14070630 ◽

2021 ◽

Vol 14 (7) ◽

pp. 630

Author(s):

Sara Malaca ◽

Massimo Gottardi ◽

Federica Pigliasco ◽

Sebastiano Barco ◽

Alessia Cafaro ◽

...

Keyword(s):

High Performance ◽

Serum Levels ◽

European Medicines Agency ◽

Therapeutic Drug ◽

Blood Levels ◽

Childhood Onset ◽

Serum Samples ◽

First Time ◽

The Relationship ◽

Promising Therapeutic Agent

Cannabidiol (CBD) is a promising therapeutic agent with analgesic, myorelaxant, and anti-epileptic actions. Recently, a purified form of CBD (Epidiolex®) has been approved by the European Medicines Agency (EMA) for the treatment of two highly-refractory childhood-onset epilepsies (Dravet and Lennox-Gastaut syndrome). Given the interindividual response and the relationship between the dose administered and CBD blood levels, therapeutic drug monitoring (TDM) is a valuable support in the clinical management of patients. We herein report for the first time a newly developed and validated method using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS) to evaluate CBD and its metabolites (i.e., cannabidiol-7-oic acid (7-COOH-CBD), 7-hydroxycannabidiol (7-OH-CBD), 6-α-hydroxycannabidiol (6-α–OH–CBD) and 6-β-hydroxycannabidiol (6-β–OH–CBD)) in serum samples. The method reached the sensitivity needed to detect minimal amounts of analytes under investigation with limits of quantification ranging from 0.5 to 20 ng/mL. The validation results indicated in this method were accurate (average inter/intra-day error, <15%), precise (inter/intra-day imprecision, <15%), and fast (8 min run time). The method resulted to be linear in the range of 1–10,000 ng/mL for CBD-COOH, 1–500 ng/mL for 7-OH-CBD and CBD and 1–25 ng/mL for 6-α–OH–CBD and 6-β–OH–CBD. Serum levels of CBD (88.20–396.31 and 13.19–170.63 ng/mL) as well as of 7-OH-CBD (27.11–313.63 and 14.01–77.52 ng/mL) and 7-COOH-CBD (380.32–10,112.23 and 300.57–2851.82 ng/mL) were significantly higher (p < 0.05) in patients treated with GW pharma CBD compared to those of patients treated with galenic preparations. 6-α–OH–CBD and 6-β–OH–CBD were detected in the first group and were undetectable in the second group. 7-COOH-CBD was confirmed as the most abundant metabolite in serum (5–10 fold higher than CBD) followed by 7-OH-CBD. A significant correlation (p < 0.05) between the dose administrated and a higher bioavailability was confirmed in patients treated with a GW pharma CBD preparation.

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Evaluation of the Relationship Between Serum levels of Zinc, Vitamin B12, Vitamin D and Clinical outcomes in Patients with COVID‐19

Journal of Medical Virology ◽

10.1002/jmv.27277 ◽

2021 ◽

Author(s):

Habibesadat Shakeri ◽

Amir Azimian ◽

Hamed Ghasemzadeh‐Moghaddam ◽

Mohammadreza Safdari ◽

Mehdi Haresabadi ◽

...

Keyword(s):

Vitamin D ◽

Vitamin B12 ◽

Clinical Outcomes ◽

Serum Levels ◽

The Relationship

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Personalized antibiotic therapy – a rapid high performance liquid chromatography–tandem mass spectrometry method for the quantitation of eight antibiotics and voriconazole for patients in the intensive care unit

LaboratoriumsMedizin ◽

10.1515/labmed-2020-0052 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Tony Böhle ◽

Ulrike Georgi ◽

Dewi Fôn Hughes ◽

Oliver Hauser ◽

Gudrun Stamminger ◽

...

Keyword(s):

Intensive Care ◽

Antibiotic Therapy ◽

High Performance ◽

High Specificity ◽

Serum Levels ◽

Turnaround Time ◽

Target Range ◽

Therapeutic Drug ◽

Monitoring Method ◽

Adjustment Procedure

AbstractObjectivesFor a long time, the therapeutic drug monitoring of anti-infectives (ATDM) was recommended only to avoid the toxic side effects of overdosing. During the last decade, however, this attitude has undergone a significant change. Insufficient antibiotic therapy may promote the occurrence of drug resistance; therefore, the “one-dose-fits-all” principle can no longer be classified as up to date. Patients in intensive care units (ICU), in particular, can benefit from individualized antibiotic therapies.MethodsPresented here is a rapid and sufficient LC-MS/MS based assay for the analysis of eight antibiotics (ampicillin, cefepime, cefotaxime, ceftazidime, cefuroxime, linezolid, meropenem, and piperacillin) applicated by continuous infusion and voriconazole. In addition a dose adjustment procedure for individualized antibiotic therapy has been established.ResultsThe suggested dose adjustments following the initial dosing of 121 patient samples from ICUs, were evaluated over a period of three months. Only a minor percentage of the serum levels were found to be within the target range while overdosing was often observed for β-lactam antibiotics, and linezolid tended to be often underused. The results demonstrate an appreciable potential for β-lactam savings while enabling optimal therapy.ConclusionsThe presented monitoring method provides high specificity and is very robust against various interferences. A fast and straightforward method, the developed routine ensures rapid turnaround time. Its application has been well received by participating ICUs and has led to an expanding number of hospital wards participating in ATDM.

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Effect of polyaspartic acid on pharmacokinetics of gentamicin after single intravenous dose in the dog.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.5.1237 ◽

1996 ◽

Vol 40 (5) ◽

pp. 1237-1241 ◽

Cited By ~ 8

Author(s):

T Whittem ◽

K Parton ◽

K Turner

Keyword(s):

Aspartic Acid ◽

Elimination Rate ◽

Volume Of Distribution ◽

Intravenous Dose ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Peripheral Compartment ◽

Single Intravenous Dose ◽

Polyaspartic Acid ◽

Peripheral Tissues

The effects of poly-L-aspartic acid on the pharmacokinetics of gentamicin were examined by using a randomized crossover trial design with the dog. When analyzed according to a three-compartment open model, poly-L-aspartic acid reduced some first-order rate equation constants (A3, lambda 1, and lambda 3), the deep peripheral compartment exit microconstant (k31), the elimination rate constant (k(el)), and the area under the concentration-time curve from 0 to 480 h (AUC0-480) (0.21-, 0.60-, 0.26-, 0.27-, 0.72-, and 0.76-fold, respectively; P < 0.05) but increased the volume of distribution at steady state (Vss), the volume of distribution calculated by the area method (V(area)), the apparent volume of the peripheral compartment (Vp), and all mean time parameters. These results suggested that poly-L-aspartic acid increased the distribution of gentamicin to or binding within the deep peripheral compartment and that poly-L-aspartic acid may have delayed gentamicin transit through the peripheral tissues. In contrast, poly-L-aspartic acid did not alter pharmacokinetic parameters relevant to the central or shallow peripheral compartments to a clinically significant extent. Although gentamicin's pharmacokinetic parameters of relevance to therapeutic drug monitoring were not directly altered, this study has provided pharmacokinetic evidence that poly-L-aspartic acid alters the peripheral distribution of gentamicin. This pharmacokinetic interaction occurred after a single intravenous dose of each drug. Therefore, this interaction should be investigated further, before polyaspartic acid can be considered for use as a clinical nephroprotectant.

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Sufentanil Disposition and Pharmacokinetic Model-Based Dosage Regimen for Sufentanil in Ventilated Full-Term Neonates

Pharmacology ◽

10.1159/000515787 ◽

2021 ◽

pp. 1-6

Author(s):

Pavla Pokorná ◽

Martin Šíma ◽

Birgit Koch ◽

Dick Tibboel ◽

Ondřej Slanař

Keyword(s):

Linear Regression ◽

Dosage Regimen ◽

Regression Models ◽

Drug Disposition ◽

Prospective Trial ◽

Full Term ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Linear Regression Models ◽

Term Neonates

Introduction: Sufentanil is a potent synthetic opioid used for analgesia in neonates; however, data concerning drug disposition of sufentanil and dosage regimen are sparse in this population. Therefore, the aim of the study was to explore sufentanil disposition and to propose optimal loading and maintenance doses of sufentanil in ventilated full-term neonates. Methods: Individual sufentanil pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a 2-compartmental model. Linear regression models were used to explore the covariates. Results: The median (IQR) central volume of distribution (Vdc) and clearance (CL) for sufentanil were 4.7 (4.1–5.4) L/kg and 0.651 (0.433–0.751) L/h/kg, respectively. Linear regression models showed relationship between Vdc (L) and GA (r2 = 0.3436; p = 0.0452) as well as BW (r2 = 0.4019; p = 0.0268). Median optimal sufentanil LD and MD were 2.13 (95% CI: 1.78–2.48) μg/kg and 0.29 (95% CI: 0.22–0.37) μg/kg/h, respectively. Median daily COMFORT-B (IQR) scores ranged from 6 to 23 while no significant relationship between pharmacokinetic parameters and COMFORT-B scores was found. Discussion/Conclusion: Body weight and gestational age were found as weak covariates for sufentanil distribution, and the dosage regimen was developed for a prospective trial.

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Assessment of the relationship of serum liver enzymes activity with general and abdominal obesity in an urban Bangladeshi population

Scientific Reports ◽

10.1038/s41598-021-86216-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nurshad Ali ◽

Abu Hasan Sumon ◽

Khandaker Atkia Fariha ◽

Md Asaduzzaman ◽

Rahanuma Raihanu Kathak ◽

...

Keyword(s):

General Population ◽

Abdominal Obesity ◽

Liver Enzymes ◽

Serum Levels ◽

General Obesity ◽

Enzymes Activity ◽

Elevated Liver Enzymes ◽

Bangladeshi Population ◽

Relationship Of ◽

The Relationship

AbstractObesity is a global health concern because of its increasing trend both in developed and developing countries. A limited number of studies have evaluated the association of liver enzymes with both general and abdominal obesity in the general population; data for the Bangladeshi population are not available yet. This study aimed to assess the relationship of serum liver enzymes activity with both general and abdominal obesity in Bangladeshi adults. In total, 540 blood samples were obtained from the participants (388 males and 152 females) and analyzed for serum levels of ALT, AST, GGT, and ALP using standard methods. General obesity was defined as body mass index (BMI) ≥ 27.5 kg/m2 and abdominal obesity was defined as waist circumference (WC) ≥ 90 cm in males and ≥ 80 cm in females. The relationship between liver enzymes and obesity was evaluated by multivariate logistic regression models. Overall, 58% of participants in the general obesity group and 55% of the participants in the abdominal obesity group had at least one or more elevated levels of liver enzymes. The prevalence of elevated liver enzymes was significantly higher in the obesity group compared to the normal BMI and WC groups (p < 0.05 for all cases). The mean level of serum ALT, AST and GGT were significantly higher in the obesity group than the normal BMI group (p < 0.05). In the WC groups, mean AST and GGT were significantly higher in the obesity group compared to the normal group (p < 0.05). In regression analysis, serum levels of ALT showed an independent and significant association with general obesity, whereas, serum GGT showed a significant association with both general and abdominal obesity. In conclusion, a high prevalence of elevated liver enzymes was observed among participants included in the present study. Of the four enzymes, serum GGT was independently associated with both general and abdominal obesity. Further studies are required to understand the complex relationship between liver enzymes and obesity in the general population.

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