Phenytoin-Induced Purple Glove Syndrome: A Case Report and Review of the Literature

Objective:

To present a case report and literature review of phenytoin-induced purple glove syndrome (PGS).

Case summary:

A 54-year-old African American male presented to our hospital’s emergency department (ED) following a seizure episode, cardiac arrest, and loss of consciousness. On arrival to the ED, the patient’s total phenytoin level was subtherapeutic at 4.1 mcg/mL and his corrected total phenytoin level was subtherapeutic at 5.1 mcg/mL. In the ED, the patient received a loading dose of intravenous (IV) phenytoin 1,000 mg once via the left cephalic vein, at a rate of 50 mg/min, and was admitted to the medicine service. A day following IV phenytoin administration, a nurse noticed an IV fluid infiltration on the skin tissue around the left cephalic vein. The area appeared dark blue and purple in color, swollen, erythematous, and warm to touch. An ultrasound of the left upper extremity was performed and revealed subcutaneous fluid collection without evidence of thrombosis.

Discussion:

The Naranjo Adverse Drug Reaction Probability Scale assigned a score of 7, indicating phenytoin as the probable cause of purple glove syndrome (PGS). The patient’s PGS was managed with a combination of dry dressing material, left forearm elevation, collagenase topical cream, 0.1% IV bupivacaine, and IV fentanyl. The patient’s injury was resolving at the time of discharge to a rehabilitation facility.

Conclusion:

PGS is a rare complication of IV phenytoin therapy. The risk of PGS for this patient may have been abated by decreasing the phenytoin infusion rate from 50 mg/min to less than 25 mg/min.     

Population pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium in pediatric patients, adult patients, and healthy volunteers

Purpose

We performed a population pharmacokinetic analysis of phenytoin after intravenous administration of fosphenytoin sodium in healthy, neurosurgical, and epileptic subjects, including pediatric patients, and determined the optimal dose and infusion rate for achieving the therapeutic range.

Methods

We used pooled data obtained from two phase I studies and one phase III study performed in Japan. The population pharmacokinetic analysis was performed using NONMEM software. The optimal dose and infusion rate were determined using simulation results obtained using the final model. The therapeutic range for total plasma phenytoin concentration is 10–20 μg/mL.

Results

We used a linear two-compartment model with conversion of fosphenytoin to phenytoin. Pharmacokinetic parameters of phenytoin, such as total clearance and central and peripheral volume of distribution were influenced by body weight. The dose simulations are as follows. In adult patients, the optimal dose and infusion rate of phenytoin for achieving the therapeutic range was 22.5 mg/kg and 3 mg/kg/min respectively. In pediatric patients, the total plasma concentration of phenytoin was within the therapeutic range for a shorter duration than that in adult patients at 22.5 mg/kg (3 mg/kg/min). However, many pediatric patients showed phenytoin concentration within the toxic range after administration of a dose of 30 mg/kg.

Conclusions

The pharmacokinetics of phenytoin after intravenous administration of fosphenytoin sodium could be described using a linear two-compartment model. The administration of fosphenytoin sodium 22.5 mg/kg at an infusion rate of 3 mg/kg/min was optimal for achieving the desired plasma phenytoin concentration.     

Toxicity from a clonidine suspension

Background

Clonidine is frequently prescribed to children. Clonidine overdose in children has resulted in major clinical effects and deaths.

Case Report

A 3.5-year-old male with a history of a seizure disorder and night terrors presented following difficulty walking, excessive sleeping, agitation when awake, and possible seizure activity. Chronic medications were valproic acid (VPA) and clonidine. On presentation, he alternated between poor responsiveness and agitation, with initial vitals: blood pressure, BP 144/76 mmHg; heart rate, 65 bpm; respiratory rate, 18 bpm; temperature 99.5°F; and pulse oximetry 96% on room air. VPA level was 35 μg/mL. A toxicology consult the next day noted a dry mouth, 2-mm pupils, intermittent gasping, and central nervous system (CNS) depression, with a diagnostic impression of clonidine overdose. The caregiver had been giving 1 mL (0.1 mg) qd of a pharmacy-compounded clonidine suspension by a provided syringe. The pharmacy procedure record agreed with the physicians order. The amount dispensed was a 30-day supply but the bottle was empty on day 19, leading us to suspect a possible accelerated dosing error. The concentration in the bottle thus could not be confirmed. The child slowly returned to his baseline state over 48 hours. A serum clonidine level drawn approximately 18 hours after his last dose later returned at 300 ng/mL (reference range = 0.5–4.5 ng/mL).

Case Discussion

Compounding and liquid dosing errors are common in children and may result in massive overdoses. There was an accelerated dosing error, but whether a compounding or suspension error or even an acute overdose occurred as well is unknown.

Conclusion

Particular care should be taken with medications that have low therapeutic indices, that are extemporaneously compounded, and are prepared as liquids, where medication errors are more likely.     

Evaluation of a New Vancomycin Dosing Protocol in Morbidly Obese Patients

Background:

Optimal dosing of vancomycin in morbidly obese patients (>100 kg and at least 140% of their ideal body weight) has not been determined. Conventional dosing strategies have led to the observation of supratherapeutic trough concentrations (>20 mcg/mL).

Objective:

To evaluate the effectiveness of a new vancomycin dosing protocol in morbidly obese patients in achieving therapeutic trough concentrations between 10 and 20 mcg/mL and to determine patient-specific factors influencing the trough concentration attained.

Methodology:

A single-center, retrospective chart review included morbidly obese adult patients with a pharmacy-to-dose vancomycin consult and at least 1 trough concentration obtained at steady state. Patients were excluded if they had a creatinine clearance (CrCl) less than 35 mL/min or unstable renal function, were not dosed according to the revised protocol, or received vancomycin prior to initiation of the protocol.

Results:

Of the 48 patients included, 17 (35.4%) achieved a therapeutic vancomycin trough concentration. Subtherapeutic concentrations (<10 mcg/mL) were observed in 27 patients (56.3%) and supratherapeutic concentrations were observed in 4 (8.3%) patients. Age less than 45 years and CrCl greater than 100 mL/min were associated with subtherapeutic trough concentrations.

Conclusion:

This study demonstrates that the revised vancomycin dosing protocol led to the attainment of therapeutic trough concentrations in 35.4% of patients. The majority had subtherapeutic concentrations, which increases the risk of treatment failures and resistance. Further study is needed to determine the optimal dosing strategy in this patient population.     

Use of neostigmine for the management of drug induced ileus in severe poisonings

Introduction

Effective whole bowel irrigation may be difficult in the presence of drug-induced ileus. Neostigmine, which inhibits the enzymatic degradation of acetylcholine, has been suggested to improve drug-induced ileus. We present two poisoning cases in which neostigmine was used to facilitate gut decontamination complicated by ileus.

Case Reports

A 47-year-old woman, after overdose with sodium valproate, venlafaxine, and ibuprofen, developed ileus that prevented whole bowel irrigation. Neostigmine, 2.5 mg intravenously followed by 1.25 mg three hours later, led to improved bowel transit and successful whole bowel irrigation. A 25-year-old man developed ileus after overdose with venlafaxine, dothiepin, and ethanol. Neostigmine administration led to improved intestinal motility and successful whole bowel irrigation.

Discussion

We demonstrate facilitated gut decontamination temporally associated with administration of neostigmine in two patients judged to have drug-induced ileus following overdose. No significant adverse events related to neostigmine were observed.     

The role of cortisol and psychopathy in the cycle of violence

Rationale

Child abuse and neglect are universal risk factors for delinquency, violence, and aggression; this phenomenon is known as the cycle of violence. Additional factors—psychopathy, impulsiveness, and disruptions in the hypothalamic–pituitary–adrenal (HPA) axis—play a role in aggressive behavior but have rarely been examined in the same conceptual and experimental framework.

Objectives

We sought to examine the above-mentioned risk factors for aggression in a prospective study employing psychopharmacologic and psychometric techniques.

Methods

Sixty-seven adult participants were given an acute dose of 20 mg cortisol in a placebo-controlled, within-subject, counter-balanced dosing design. Salivary cortisol was measured at baseline and at regular intervals across a 5 h testing period. Following dosing, state-aggressive behavior was measured by a laboratory task, the Point-Subtraction Aggression Paradigm. History of child abuse/neglect, psychopathy, impulsivity, and a trait measure of aggression were assessed through self-report questionnaires.

Results

Using multiple regression, a model including abuse/neglect, psychopathy, impulsivity, and baseline cortisol explained 58 % of the variance in trait aggression and 26 % of the variance in state aggression. Abuse/neglect predicted diminished HPA-axis reactivity and HPA-axis reactivity showed a trend toward predicting state and trait aggression, although it was not a significant mediating variable between abuse/neglect and aggression.

Conclusions

The results indicate that child maltreatment, psychopathy and HPA-axis reactivity interact to provide a confluence over aggressive behavior, and intervention efforts need to consider all these factors.     

Factitious lithium toxicity secondary to lithium heparin-containing blood tubes

Introduction

Lithium concentrations analyzed from blood collected in inappropriate tubes may lead to misdiagnosis and lead to unnecessary hospitalization and intervention. We sought to assess the magnitude of falsely elevated lithium levels in green top lithium heparin-containing blood tubes.

Methods

Serum lithium concentrations from two types of commonly used standard green top tubes were evaluated against a control tube. Blood samples obtained from 5 healthy volunteers who have never ingested pharmaceuticals containing lithium were aliquoted into a control serum separator tube (SST), a light green heparin-containing tube, and a dark green heparin tube at the following volumes: full draw, 2cc, and 1cc. Serum lithium levels in lithium heparin blood tubes were compared to standard blood tubes.

Results

All levels are reported as mmol/L. Mean serum lithium level for the control was 0.16 [range: 0.1–0.2]. Levels for the light-green tubes at full-draw, 2cc, and 1cc were 1.05 [1.0–1.1], 1.99 [1.68–2.3], and 3.31 [2.8–4.2] respectively. Levels for the dark-green tubes at full-draw, 2cc, and 1cc were 1.07 [1.0–1.14], 2.35 [2.1–2.55], and 4.04 [3.8–4.4] respectively.

Conclusions

Falsely elevated lithium levels may occur when using green-top lithium containing blood tubes and may contribute as much as 4 mmol/L to the level in tubes not completely filled.     

MCP-1 and fetuin A levels in patients with PCOS and/or obesity before and after metformin treatment

Background/Aims

The aim of the study was to investigate MCP-1 and fetuin A levels in women with PCOS and/or obesity before and after metformin treatment.

Materials/Methods

In the study consisted of 59 patients. Anthropometric measurements and biochemical tests, including MCP-1 and fetuin A measurement, were performed. For patients that were diagnosed with insulin resistance and started metformin treatment all the laboratory tests and anthropometric measurements were repeated after 6 months.

Results

MCP-1 and fetuin A levels did not differ between patients with obesity with and without PCOS, between patients with PCOS with and without obesity, insulin resistance, arterial hypertension, dyslipidemia or menstrual disturbances. MCP-1 levels were significantly higher in patients with hyperandrogenemia than in patients without (456.3±141.1pmol/L vs. 372.5±108.5 pmol/L), while fetuin A levels were significantly higher in patients with metabolic syndrome (MetS) than in patients without MetS (278.5±41.1 mcg/ml vs. 240.0±42.0 mcg/ml). There was no significant change in MCP-1 and fetuin A levels after of metformin treatment.

Conclusions

MCP- 1 levels are higher in patients with hyperandrogenemia and fetiun A levels are higher in patients with metabolic syndrome. MCP-1 and fetuin A levels do not change significantly after metformin treatment.     

Insulin & C-peptide levels in sulfonylurea-induced hypoglycemia: A systematic review

Objectives

We will describe insulin and C-peptide levels observed in sulfonylurea-induced hypoglycemia and determine whether these levels differed if obtained before or after hypoglycemic therapy.

Methods

We performed a systematic review of the English literature to identify Medline articles containing “sets” (glucose < 60 mg/dL with insulin and C-peptide levels). These “sets” were categorized as being obtained BEFORE, AFTER, or UNKNOWN with respect to hypoglycemic therapy.

Results

22 articles, 76 patients, and 97 “sets” were included. Mean glucose (mg/dL), insulin (μIU/mL), and C-peptide (ng/mL) for all “sets” were 28.6 (±12.6; 26.1 to 31.2), 54.4 (±126.3; 28.3 to 80.5), 7.2 (±6.2; 5.9 to 8.5).

1. The BEFORE measures were 24.3 (±7.3; 18.7 to 30.0), 36.6 (±26.2; 16.5 to 56.7), 5.4 (±4.6; 1.5 to 9.2).
2. The AFTER measures were 33.1 (±9.8; 28.2 to 38.0), 126.7 (±278.1; 0 to 265.0), 10.3 (±10.5; 5.1 to 15.4).
3. The UNKNOWN measures were 28.0 (±13.5; 24.7 to 31.3), 37.1 (±21.8; 31.7 to 42.5), 6.5 (±4.3; 5.4 to 7.6).
4. Only one “set” (glucose 49 mg/dL) had insulin < 3.9 μIU/mL and C-peptide < 1.4 ng/mL.

Conclusions

Insulin ≥ 3.9 μIU/mL, C-peptide ≥ 1.4 ng/mL, and glucose < 49 mg/dl are consistent with sulfonylurea-induced hypoglycemia. BEFORE levels were lower, but they were consistent with sulfonylurea-induced hypoglycemia.     

Weight loss dynamics during combined fluoxetine and olanzapine treatment

Background

Fluoxetine and olanzapine combination therapy is rapidly becoming an effective strategy for managing symptoms of treatment-resistant depression. Determining drug-drug interactions, drug metabolism and pharmacokinetics is of particular interest for revealing potential liabilities associated with drug augmentation in special patient populations. In the current studies, we chronically administered fluoxetine and olanzapine in non-stressed rats to extend our previous findings regarding body weight dynamics.

Results

Chronic fluoxetine (10 mg/kg) and olanzapine (5 mg/kg and 0.5 mg/kg) treatment decreased weight gain irrespective of olanzapine dosing. At the 10 mg/kg and 5 mg/kg dose, respectively, fluoxetine and olanzapine also significantly reduced food and water consumption. This pharmacodynamic event-related effect, however, was not observed at the 10 mg/kg and 0.5 mg/kg dosing paradigm suggesting differences in tolerability rates as a function of olanzapine dose. The decrease in weight gain was not associated with apparent changes in glucose metabolism as vehicle- and drug-treated rats showed undistinguishable serum glucose levels. The combination of fluoxetine and olanzapine in rats yielded drug plasma concentrations that fell within an expected therapeutic range for these drugs in psychiatric patients.

Conclusions

These data suggest that fluoxetine and olanzapine treatment decreases weight gain in rats; a pharmacodynamic event-related effect that differs considerably from what is observed in the clinical condition. The possibility of mismatched models regarding body weight changes during drug augmentation therapy should be seriously considered.     

Higher mycophenolate dose requirements in children undergoing hematopoietic cell transplant (HCT)

Little is known about dosing of mycophenolate mofetil in pediatric hematopoietic cell transplant recipients; therefore, dosing strategies using other settings have been extended to this population. The authors studied pharmacokinetics in 19 children (median 17 months) undergoing myeloablative hematopoietic cell transplant and receiving prophylactic mycophenolate and cyclosporine. All subjects except 2 received mycophenolate 15 mg/kg intravenously every 8 hours. The median (range) total mycophenolic acid area under the concentration-time curve (AUC)(0-8) was 12.6 mcg.h/mL (4.9-49.2), and unbound mycophenolic acid AUC(0-8) was 0.274 mcg.h/mL (0.037-1.4). Total and unbound mycophenolic acid trough concentrations were 0.27 (0.03-2.9) and 0.005 (0-0.034) mcg/mL, respectively. Mycophenolic acid trough concentrations were not good surrogates for overall exposure (AUC(0-8)), r(2) < or = 0.55. Mycophenolate dose requirements are higher in pediatric hematopoietic cell transplant recipients relative to pediatric organ transplant recipients. Children undergoing hematopoietic cell transplant should receive a mycophenolate mofetil dose of at least 15 mg/kg intravenously every 8 hours when used in combination with cyclosporine to achieve systemic concentrations near those proposed to be therapeutic in the adult hematopoietic cell transplant population.     

A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray

Purpose

A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ⁹-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects.

Methods

Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a minimum of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatography-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated.

Results

Δ⁹-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concentration (C_max) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concentration (T_max) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported.

Conclusions

The mean C_max values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated C_max values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.     

The impact of sustained and intermittent docetaxel chemotherapy regimens on cognition and neural morphology in healthy mice

Rationale

A subset of cancer survivors demonstrates impairments in cognition long after chemotherapy completion. At present, it is unclear whether these changes are due to direct neurotoxic effects of chemotherapy.

Objectives

This study examined the impact of variable docetaxel (DTX) chemotherapy dosing on brain DTX exposure via analyses of neural morphology and changes in cognition.

Methods

Male CD-1 mice were treated with DTX either intermittently (8 mg/kg i.p. weekly) or via a sustained delivery system (DTX-PoLi_gel), which continuously releases DTX. Both groups received total DTX doses of 32 mg/kg. Mice were assessed on the novel object recognition (NOR) task and the Morris water maze (MWM) shortly after treatment.

Results

Post-treatment behavioral testing demonstrated impaired NOR in mice treated with either dosing schedule relative to controls. No differences were observed between groups in MWM training and initial testing, though control mice performed better than chance while DTX-treated mice did not. Appreciable amounts of DTX were found in the brain after both treatment regimens. DTX treatment did not significantly increase levels of apoptosis within the CNS. However, some elevation in neural autophagy was observed following DTX treatment. Analysis of astrocytic activation demonstrated that intermittent DTX treatment resulted in an elevation of GFAP-positive astrocytes for 48 h after administration. Sustained chemotherapy demonstrated prolonged but lower levels of astrocyte activation over 9 days following implantation.

Conclusions

DTX treatment induced cognitive impairment shortly after treatment. Further, these findings suggest an association between DTX dosing, neurotoxicity, and cognitive effects.     

Studies on the transplacental passage of cefotaxime in late pregnancy

The transplacental passage of a single intravenous dose of cefotaxime (CTX), 1,000 mg, was examined in 11 pregnant women undergoing delivery at term by cesarean section. The results were as follows. 1. Measurements by HPLC: After a single 1,000 mg intravenous dose, the maternal blood level of CTX took the following course: 40.1 +/- 3.4 mcg/ml (mean +/- S.E.) at 15 minutes, 22.5 +/- 1.9 mcg/ml at 30 minutes, 10.8 +/- 0.9 mcg/ml at 60 minutes and 3.2 +/- 0.4 mcg/ml at 120 minutes. Slightly high maternal blood levels of 0.7 and 1.1 mcg/ml were obtained at child deliveries made at 200 minutes, but only a trace amount was found at a child delivery at 356 minutes. The CTX level in the umbilical cord blood was comparatively high until the measurement at 222 minutes, and then declined. IN the amniotic fluid, peak levels were observed at 222 to 252 minutes, thereafter decreasing slowly. Desacetyl-CTX, a metabolite of CTX, showed maternal blood levels of 5.8 +/- 0.5 mcg/ml at 15 minutes, 6.3 +/- 0.6 mcg/ml at 30 minutes, 6.8 +/- 0.7 mcg/ml at 60 minutes and 4.9 +/- 0.7 mcg/ml at 120 minutes. Thus, the maternal blood level of desacetyl-CTX showed an increasing tendency until 60 minutes after intravenous administration, and decreased rapidly from 120 minutes onwards. No consistent tendency was noted in desacetyl-CTX levels in the umbilical cord blood and the amniotic fluid. 2. Measurements by bioassay: Maternal blood levels of CTX determined by bioassay were 45.2 +/- 3.3 mcg/ml at 15 minutes, 25.8 +/- 2.2 mcg/ml at 30 minutes, 12.4 +/- 1.0 mcg/ml at 50 minutes adn 4.0 +/- 0.5 mcg/ml at 120 minutes. At the time of child delivery, maternal blood levels of CTX were 1.1 and 2.6 mcg/ml at 200 minutes, and then decreased slowly. Trace levels were noted at 336 minutes and CTX was undetectable at 356 minutes. 3. The HPLC study demonstrated that the level of CTx remained comparatively high in the umbilical cord blood and the amniotic fluid even 6 hours after administration (0.3--0.4 mcg/ml and 4.0 mcg/ml, respectively). This result suggests, in consideration of CTX's MIC values for causative organisms, that CTX will produce a sufficient clinical effect in perinatal infections. No side effects were observed in the mothers or their babies.     

Population pharmacokinetics of intravenous busulfan in children: revised body weight-dependent NONMEM® model to optimize dosing

Purpose

We developed a new population pharmacokinetic (PopPK) model for intravenous (i.v.) busulfan in children to evaluate the optimal method to personalize its dosing without concentration-time data.

Methods

PopPK analyses were done with NONMEM® 7.2. First, a model from Trame et al. was evaluated using an external dataset consisting of 24 children. Second, a revised model was built in a separate dataset of 82 children. Model evaluation was performed by using a standardized visual predictive check (SVPC) procedure and a bootstrap analysis (internal evaluation) and by comparison to an external dataset (external validation).

Results

The final model included body surface area (BSA) as an exponential function on volume of distribution (V) and actual body weight (ABW) as an allometric function on clearance (CL). The dosing nomogram for every 6 h administration derived from the final model is: dose[mg]?=?target AUC[mg?×?h/L]?×?3.04L/h?×?(ABW/16.1)^0.797. Compared to other dosing strategies, differences were observed for the very small and obese patients.

Conclusions

We revised our prior dosing nomogram after validation in a separate cohort of children. This dosing nomogram can be used to personalize i.v. busulfan doses without concentration-time data, but an additional prospective evaluation in the very small and obese children is needed.     

Seizures in a pediatric patient with a tiagabine overdose

Introduction

Tiagabine (TGB) is a novel antiepileptic that decreases GABA uptake. The literature contains one report of an adult with epilepsy who ingested up to 1 gram of TGB and developed status epilepticus. We reported on a pediatric patient who ingested significantly less TGB but still developed tonic-clonic seizures.

Case report

A previously healthy, 13 kg, two-year-old girl developed generalized tonic-clonic seizure activity at home approximately 1 hour after ingesting 90 mg of her grandmother’s TGB (forty five 2 mg tablets). At the hospital she had two 5 minute seizures at 1.5 and 3.5 hours post ingestion. Her serum TGB levels were 530 and 130 ng/ml approximately 5 and 11 hours post-ingestion (5–70 ng/ml trough levels with most probable range for seizure control). She was discharged 27 hours post ingestion, and she was in good condition.

Conclusion

An overdose of TGB, a novel anti-epileptic, can cause convulsive seizures.     

The dopaminergic stabilizer pridopidine is to a major extent N-depropylated by CYP2D6 in humans

Purpose

The influence of the cytochrome P450 enzyme CYP2D6 in the metabolism of the novel dopaminergic stabilizer pridopidine was investigated in healthy Swedish Caucasians.

Methods

Six extensive metabolizers (EM) and six poor metabolizers (PM) of debrisoquine were given a single oral dose of pridopidine (EM, 50?mg; PM, 25?mg).

Results

The mean total plasma clearance of pridopidine was 541?and 138?mL/min in EM and PM, respectively (p?=?0.003), and was slightly higher in PM than the mean renal plasma clearance (105?mL/min; p?=?0.11). The mean plasma area under the time–concentration curve between time zero and 32 h (AUC_0-32h) of the N-depropyl metabolite ACR30 was higher in EM than in PM (1,377 vs. 61?nmol h/mL, respectively; p?max) was not statistically different in EM and PM; consequently, the oral absorption of pridopidine was close to complete.

Conclusions

Following a single dose of pridopidine, the drug is N-depropylated by CYP2D6 in EM, while in PM the most important elimination pathway is renal glomerular filtration. Results of studies examining the effects of multiple repeat dosing suggest that the CYP2D6 enzyme is at least partly inactivated by pridopidine.     

Design and prospective validation of a dosing instrument for continuous infusion of vancomycin: a within-population approach

Introduction

The clinical application of continuous infusion (CoI) of vancomycin has gained interest in recent years. Since no international guidelines on initial dosing of vancomycin CoI exist, there is a need for methods to facilitate the switch from intermittent to continuous vancomycin dosing algorithms in clinically infected populations. Therefore, the aim of this study was to design and validate an a priori dosing schedule for CoI of vancomycin in clinical practice.

Methods

A dosing table for CoI of vancomycin based on estimated glomerular filtration rate (eGFR) was developed by simulation of continuous infusion of vancomycin using pharmacokinetic (PK) software and a PK population model designed from historical within-population data in intermittently dosed patients. The target range for the first vancomycin serum concentrations drawn approximately 24 h after start of infusion’ (C24) was set at 15–20 mg/L corresponding with an area under the curve (AUC) of at least 350 mg·h·L^?1. The performance of the dosing schedule was primarily assessed by describing the percentages of patients attaining the predefined target.

Results

An eGFR-derived dosing schedule for CoI of vancomycin was established and implemented in clinical practice. Prospective assessment in 35 general ward and 45 intensive care unit patients showed that the C24 target was reached in 69 and 63 % and the AUC target was attained in 80 and 72 % of patients, respectively.

Conclusions

An easy method to design and validate an eGFR-derived dosing algorithm for the continuous infusion of vancomycin to switch from intermittent to continuous dosing of vancomycin was developed.     

Pharmacokinetics of sumatriptan nasal spray in children

The authors studied the pharmacokinetics of sumatriptan nasal spray after a single dose in children migraineurs outside of migraine attack. Seventeen subjects (9 females) ages 6 to 11 years were given one dose of sumatriptan nasal spray based on age and weight; children 6 to 8 years of age weighing 25 kg and children ages 9 to 11 years of age weighing 40 kg received 20 mg (n = 4). Plasma sumatriptan concentrations were determined in serial blood samples obtained over 8 hours. Pharmacokinetic analysis included both noncompartmental and population modeling methods. The pharmacokinetic parameter estimates (geometric mean [95% confidence interval]) following 5, 10, and 20 mg sumatriptan were, respectively, as follows: maximum concentration = 8.1 ng/mL (3.6-18.4), 10.8 ng/mL (7.7-15.4), and 12.3 ng/mL (7.6-19.9); half-life = 1.4 hours (1.2-1.8), 1.7 hours (1.4-2.0), and 1.7 hours (1.3-2.3); and AUC = 27.8 ng*h/mL (9.7-79.8), 42.4 ng*h/mL (30.6-58.8), and 49.2 ng*h/mL (32.9-73.7). The median time to maximum concentration for all groups was 2 hours. Population pharmacokinetic modeling included pooled data from this study and from an adolescent study (n = 16). Clearance (CL/F) was 197 L/h for a 30-kg child with between-subject variability of 28%, and the volume of distribution was 751 L, normalized for an 11-year-old child with variability of 43%. The covariate analysis showed that volume increases with age and clearance increases with body size. The absorption was complex, often displaying double-peak plasma concentrations, with a rapid absorption phase and a delayed and rate-limited absorption phase. The dosing scheme based on age and weight resulted in maximal concentrations (C(max)) and systemic exposure (AUC) that were comparable to those observed in adolescents and adults treated with 20 mg. The age- and weight-adjusted dosing scheme appears to an appropriate initial dosing regimen for children with migraine headache. Appropriate safety and efficacy trials will need to be completed in children prior to recommending its use in children.