Predicting Unbound Phenytoin Concentrations: Effects of Albumin Concentration and Kidney Dysfunction.

STUDY OBJECTIVE: Several methods are available to predict unbound (free) phenytoin concentrations in patients with hypoalbuminemia; however, predictive methods have not been evaluated in patients with concurrent hypoalbuminemia and kidney dysfunction or in patients with mild to moderate (estimated glomerular filtration rate [eGFR] 30-90 ml/min/1.73 m2 ) kidney dysfunction alone. Thus the objective was to evaluate the accuracy and precision of predictive methods to estimate free phenytoin concentrations in patients with varying albumin concentrations and/or kidney dysfunction. DESIGN: Retrospective chart review. SETTING: Large academic medical center. PATIENTS: A total of 344 patients with free and total phenytoin, albumin, and serum creatinine concentrations obtained between November 2012 and May 2017. MEASUREMENTS AND MAIN RESULTS: Free phenytoin concentrations were estimated in patients without kidney dysfunction using the Winter-Tozer, Anderson, Kane, and Cheng equations. For the analysis in patients with eGFR lower than 90 ml/min/1.73 m2 , free phenytoin concentrations were estimated using the Shiner-Tozer derivation with adjusted affinity coefficients (C = 0.15, 0.20, 0.25, and 0.30). For both analyses, accuracy of predictive methods was evaluated by P20, the proportion of estimations within 20% of the measured free phenytoin concentration. In 158 patients with normal kidney function/normal albumin concentrations, 73 with normal kidney function/hypoalbuminemia, or 47 with mild kidney dysfunction/normal albumin concentrations, the Anderson method had the highest accuracy (86%, 82%, and 92%, respectively) and highest precision compared with the other methods. In 47 patients with normal albumin concentrations and mild kidney dysfunction or 13 with moderate kidney dysfunction, the free fraction was unchanged, and total phenytoin concentrations accurately reflected free concentrations. In 17 patients with hypoalbuminemia and mild or 17 with moderate kidney dysfunction, the Winter-Tozer (67% and 50%, respectively) and the Anderson (56% and 67%, respectively) methods had the highest accuracy compared with other methods with significantly lower accuracy compared with patients with normal kidney function. In the 14 patients with severe kidney dysfunction and hypoalbuminemia, none of the coefficients had a P20 accuracy greater than 45%. CONCLUSION: In patients with normal albumin concentrations, with or without mild or moderate kidney dysfunction and not receiving a protein-binding displacer, the free fraction of phenytoin is unchanged, and it is not necessary to measure a free phenytoin concentration. Free phenytoin concentrations should be measured directly in patients with hypoalbuminemia and kidney dysfunction.

Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections.

The lack of new antibiotics is among the most critical challenges facing medicine. The problem is particularly acute for Gram-negative bacteria. An unconventional antibiotic strategy is to target bacterial nutrition and metabolism. The metal gallium can disrupt bacterial iron metabolism because it substitutes for iron when taken up by bacteria. We investigated the antibiotic activity of gallium ex vivo, in a mouse model of airway infection, and in a phase 1 clinical trial in individuals with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infections. Our results show that micromolar concentrations of gallium inhibited P. aeruginosa growth in sputum samples from patients with CF. Ex vivo experiments indicated that gallium inhibited key iron-dependent bacterial enzymes and increased bacterial sensitivity to oxidants. Furthermore, gallium resistance developed slowly, its activity was synergistic with certain antibiotics, and gallium did not diminish the antibacterial activity of host macrophages. Systemic gallium treatment showed antibiotic activity in murine lung infections. In addition, systemic gallium treatment improved lung function in people with CF and chronic P. aeruginosa lung infection in a preliminary phase 1 clinical trial. These findings raise the possibility that human infections could be treated by targeting iron metabolism or other nutritional vulnerabilities of bacterial pathogens.

Pharmacokinetic Factors to Consider in the Selection of Antiseizure Drugs for Older Patients with Epilepsy.

The incidence of epilepsy is highest in the older adult age group. Seizures in older adults can be more difficult to diagnose because their presentation is often subtle and can easily be mistaken for other conditions. Fortunately, new-onset epilepsy in the older adult is often pharmaco-responsive, with as many as 80-85% of patients achieving remission, often with monotherapy at modest doses. Many physiological and pathological changes occur with aging that can alter the pharmacokinetics of antiseizure drugs (ASDs). For the majority of the old- and new-generation ASDs, a decrease in dose may be needed to maintain concentrations equivalent to those found in young adults. The risk of drug interactions with ASDs is substantial, as polypharmacy is common. The first-generation ASDs (carbamazepine, phenytoin, phenobarbital, and valproic acid) have the potential to interact with many drugs, but many newer ASDs either do not have significant interactions or are selective inhibitors and inducers of specific hepatic enzymes. The differences in adverse effects between younger and older adults are not just due to dosing and pharmacokinetics. Older adults are more susceptible to the gait, balance, and cognitive effects of ASDs. Overall, the improved tolerability and decreased drug interaction potential of the newer-generation ASDs, such as lamotrigine and levetiracetam, have demonstrated their superiority in the treatment of seizures in older adults and, as such, are clearly favored for new-onset epilepsy in older adults.

Methods of Estimating Kidney Function for Drug Dosing in Special Populations.

International guidelines recommend the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method to monitor kidney function in chronic kidney disease using either creatinine- or cystatin C-based estimation methods. The choice of an estimation method to determine dosage for renally eliminated drugs is not as clear. For the majority of currently marketed drugs, the Cockcroft-Gault equation with the Jaffe method, a non-isotope dilution mass spectrometry, standardized serum creatinine, was used to estimate kidney function to recommend dosing adjustment in kidney impairment. As the Cockcroft-Gault equation cannot be converted for isotope dilution mass spectrometry-traceable creatinine values and clinical laboratories now report estimated glomerular filtration (eGFR) rate by the Modified Diet in Renal Disease (MDRD) Equation or CKD-EPI, the eGFR is now more widely accepted for dosage adjustment recommendations. Cockcroft-Gault, MDRD Equation, and CKD-EPI creatinine-based methods were developed in specific populations, which included either none or a low proportion of obese individuals, pregnant women, older adults, and those with significant comorbid conditions. Clinical studies in these special populations have identified significant decreased accuracy, precision, and bias in the creatinine-based methods. Newer cystatin C-based estimation methods may significantly improve the ability to estimate kidney function to determine doses in the future. At this time, the increased cost and lack of standardization of serum cystatin C hinder routine use.

An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers.

OBJECTIVES: The co-primary objectives of this study were to determine the human pharmacokinetics (PK) of oral NR and the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels. BACKGROUND: Though mitochondrial dysfunction plays a critical role in the development and progression of heart failure, no mitochondria-targeted therapies have been translated into clinical practice. Recent murine studies have reported associations between imbalances in the NADH/NAD+ ratio with mitochondrial dysfunction in multiple tissues, including myocardium. Moreover, an NAD+ precursor, nicotinamide mononucleotide, improved cardiac function, while another NAD+ precursor, nicotinamide riboside (NR), improved mitochondrial function in muscle, liver and brown adipose. Thus, PK studies of NR in humans is critical for future clinical trials. METHODS: In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed. RESULTS: Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008). CONCLUSIONS: Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases.

Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products.

Tobacco smoke contains a large number of compounds in the form of metals, volatile gases and insoluble particles, as well as nicotine, a highly addictive alkaloid. Marijuana is the most widely used illicit drug of abuse in the world, with a significant increase in the USA due to the increasing number of states that allow medical and recreational use. Of the over 70 phytocannabinoids in marijuana, Δ9-tetrahydrocannabinol (Δ9THC), cannabidiol (CBD) and cannibinol are the three main constituents. Both marijuana and tobacco smoking induce cytochrome P450 (CYP) 1A2 through activation of the aromatic hydrocarbon receptor, and the induction effect between the two products is additive. Smoking cessation is associated with rapid downregulation of CYP1A enzymes. On the basis of the estimated half-life of CYP1A2, dose reduction of CYP1A drugs may be necessary as early as the first few days after smoking cessation to prevent toxicity, especially for drugs with a narrow therapeutic index. Nicotine is a substrate of CYP2A6, which is induced by oestrogen, resulting in lower concentrations of nicotine in females than in males, especially in females taking oral contraceptives. The significant effects of CYP3A4 inducers and inhibitors on the pharmacokinetics of Δ9THC/CBD oromucosal spray suggest that CYP3A4 is the primary enzyme responsible for the metabolism of Δ9THC and CBD. Limited data also suggest that CBD may significantly inhibit CYP2C19. With the increasing use of marijuana and cannabis products, clinical studies are needed in order to determine the effects of other drugs on pharmacokinetics and pharmacodynamics.

Modified-Release Formulations of Second-Generation Antiepileptic Drugs: Pharmacokinetic and Clinical Aspects.

Modified-release or extended-release (XR) formulations are used to decrease the frequency of dosing for drugs with rapid elimination, to improve convenience and adherence. Use of a modified-release formulation can decrease the peak to trough fluctuations in serum concentrations and theoretically improve the therapeutic benefit of the drug, by decreasing adverse events associated with the higher peak concentrations. Once-daily formulations of lamotrigine (Lamictal XR(®)), levetiracetam (Keppra XR(®)), oxcarbazepine (Oxtellar XR(®), Apydan(®) extent) and topiramate (Qudexy XR™, Trokendi XR™) are approved for the treatment of focal and/or generalized onset seizures. Other seizure medications have been approved for non-epileptic symptoms. Gabapentin XR (Gralise(®)) is approved for the treatment of post-herpetic neuralgias. Gabapentin enacarbil XR (Horizant(®)) is a prodrug of gabapentin and is indicated for treatment of post-herpetic neuralgia and restless leg syndrome, a novel indication. For all but Qudexy XR™, the tablets/capsules must be swallowed whole, without cutting, crushing or chewing, in order to maintain the XR properties of the formulation. Qudexy XR™ can be swallowed intact or the capsules can be opened and sprinkled onto soft food for those with swallowing difficulties, for example, children and the elderly. The bioavailability of Gralise(®) and Horizant(®) is significantly affected by food, specifically fat content, and should be taken with a meal to maximize absorption. Overall, the primary advantage of the newly released XR formulations is the once-daily dosing to improve convenience and adherence, with very limited data suggesting improved tolerability.

A behavioral and histological comparison of fluid percussion injury and controlled cortical impact injury to the rat sensorimotor cortex.

Our primary goal was to evaluate the behavioral and histological outcome of fluid percussion injury (FPI) and cortical contusion injury (CCI) to the sensorimotor cortex (SMC). The SMC has been used to evaluate neuroplasticity following CCI, but has not been extensively examined with FPI. In both the CCI and FPI models, a mechanical force of 4mm in diameter was applied over the SMC, allowing for a direct comparison to measure the relative rates of histology and recovery of function in these models. Gross behavioral deficits were found on the sensory task (tactile adhesive removal task) and multiple motor assessments (forelimb asymmetry task, forelimb placing task, and rotorod). These sensorimotor deficits occurred in the absence of cognitive deficits in the water maze. The CCI model creates focal damage with a localized injury wheras the FPI model creates a more diffuse injury causing widespread damage. Both behavioral and histological deficits ensued following both models of injury to the SMC. The neuroplastic changes and ease at which damage to this area can be measured behaviorally make this an excellent location to assess traumatic brain injury (TBI) treatments. No injury model can completely mimic the full spectrum of human TBI and any potential treatments should be validated across both focal and diffuse injury models. Both of these injury models to the SMC produce severe and enduring behavioral deficits, which are ideal for evaluating treatment options.

Effect of Traumatic Brain Injury, Erythropoietin, and Anakinra on Hepatic Metabolizing Enzymes and Transporters in an Experimental Rat Model.

In contrast to considerable data demonstrating a decrease in cytochrome P450 (CYP) activity in inflammation and infection, clinically, traumatic brain injury (TBI) results in an increase in CYP and UDP glucuronosyltransferase (UGT) activity. The objective of this study was to determine the effects of TBI alone and with treatment with erythropoietin (EPO) or anakinra on the gene expression of hepatic inflammatory proteins, drug-metabolizing enzymes, and transporters in a cortical contusion impact (CCI) injury model. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Plasma cytokine and liver protein concentrations of CYP2D4, CYP3A1, EPHX1, and UGT2B7 were determined. There was no effect of TBI, TBI + EPO, or TBI + anakinra on gene expression of the inflammatory factors shown to be associated with decreased expression of hepatic metabolic enzymes in models of infection and inflammation. IL-6 plasma concentrations were increased in TBI animals and decreased with EPO and anakinra treatment. There was no significant effect of TBI and/or anakinra on gene expression of enzymes or transporters known to be involved in drug disposition. TBI + EPO treatment decreased the gene expression of Cyp2d4 at 72 h with a corresponding decrease in CYP2D4 protein at 72 h and 7 days. CYP3A1 protein was decreased at 24 h. In conclusion, EPO treatment may result in a significant decrease in the metabolism of Cyp-metabolized drugs. In contrast to clinical TBI, there was not a significant effect of experimental TBI on CYP or UGT metabolic enzymes.

A Combination Therapy of Nicotinamide and Progesterone Improves Functional Recovery following Traumatic Brain Injury.

Neuroprotection, recovery of function, and gene expression were evaluated in an animal model of traumatic brain injury (TBI) after a combination treatment of nicotinamide (NAM) and progesterone (Prog). Animals received a cortical contusion injury over the sensorimotor cortex, and were treated with either Vehicle, NAM, Prog, or a NAM/Prog combination for 72 h and compared with a craniotomy only (Sham) group. Animals were assessed in a battery of behavioral, sensory, and both fine and gross motor tasks, and given histological assessments at 24 h post-injury to determine lesion cavity size, degenerating neurons, and reactive astrocytes. Microarray-based transcriptional profiling was used to determine treatment-specific changes on gene expression. Our results confirm the beneficial effects of treatment with either NAM or Prog, demonstrating significant improvements in recovery of function and a reduction in lesion cavitation, degenerating neurons, and reactive astrocytes 24 h post-injury. The combination treatment of NAM and Prog led to a significant improvement in both neuroprotection at 24 h post-injury and recovery of function in sensorimotor related tasks when compared with individual treatments. The NAM/Prog-treated group was the only treatment group to show a significant reduction of cortical loss 24 h post-injury. The combination appears to affect inflammatory and immune processes, reducing expression of a significant number of genes in both pathways. Further preclinical trials using NAM and Prog as a combination treatment should be conducted to identify the window of opportunity, determine the optimal duration of treatment, and evaluate the combination in other pre-clinical models of TBI.

Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol).

Ethanol (alcohol) is one of the most widely used legal drugs in the world. Ethanol is metabolized by alcohol dehydrogenase (ADH) and the cytochrome P450 (CYP) 2E1 drug-metabolizing enzyme that is also responsible for the biotransformation of xenobiotics and fatty acids. Drugs that inhibit ADH or CYP2E1 are the most likely theoretical compounds that would lead to a clinically significant pharmacokinetic interaction with ethanol, which include only a limited number of drugs. Acute ethanol primarily alters the pharmacokinetics of other drugs by changing the rate and extent of absorption, with more limited effects on clearance. Both acute and chronic ethanol use can cause transient changes to many physiologic responses in different organ systems such as hypotension and impairment of motor and cognitive functions, resulting in both pharmacokinetic and pharmacodynamic interactions. Evaluating drug interactions with long-term use of ethanol is uniquely challenging. Specifically, it is difficult to distinguish between the effects of long-term ethanol use on liver pathology and chronic malnutrition. Ethanol-induced liver disease results in decreased activity of hepatic metabolic enzymes and changes in protein binding. Clinical studies that include patients with chronic alcohol use may be evaluating the effects of mild cirrhosis on liver metabolism, and not just ethanol itself. The definition of chronic alcohol use is very inconsistent, which greatly affects the quality of the data and clinical application of the results. Our study of the literature has shown that a significantly higher volume of clinical studies have focused on the pharmacokinetic interactions of ethanol and other drugs. The data on pharmacodynamic interactions are more limited and future research addressing pharmacodynamic interactions with ethanol, especially regarding the non-central nervous system effects, is much needed.

Pharmacokinetic of antiepileptic drugs in patients with hepatic or renal impairment.

Many factors influence choice of antiepileptic drugs (AEDs), including efficacy of the drug for the indication (epilepsy, neuropathic pain, affective disorder, migraine), tolerability, and toxicity. The first-generation AEDs and some newer AEDs are predominately eliminated by hepatic metabolism. Other recent AEDs are eliminated by renal excretion of unchanged drug or a combination of hepatic metabolism and renal excretion. The effect of renal and hepatic disease on the dosing will depend on the fraction of the AED eliminated by hepatic and/or renal excretion, the metabolic isozymes involved, as well as the extent of protein binding, if therapeutic drug monitoring is used. For drugs that are eliminated by renal excretion, methods of estimating creatinine clearance can be used to determine dose adjustments. For drugs eliminated by hepatic metabolism, there are no specific markers of liver function that can be used to provide guidance in dosage adjustments. Based on studies with probe drugs, the hepatic metabolic enzymes are differentially affected depending on the cause and severity of hepatic disease, which can aid in predicting dose adjustment when clinical data are not available. Several AEDs are also associated with laboratory markers of mild hepatic dysfunction and, rarely, more severe hepatic injury. In contrast, the risk of renal injury from AEDs is generally low. In general, co-morbid hepatic or renal diseases influence the decision for the selection of an AED. For some patients dosing changes to their existing AEDs may be appropriate. For others, a change to another AED may be a better option.

Comparison of the effect of minocycline and simvastatin on functional recovery and gene expression in a rat traumatic brain injury model.

The goal of this study was to compare the effects of minocycline and simvastatin on functional recovery and brain gene expression after a cortical contusion impact (CCI) injury. Dosage regimens were designed to provide serum concentrations in a rat model in the range obtained with clinically approved doses; minocycline 60 mg/kg q12h and simvastatin 10 mg/kg q12h for 72 h. Functional recovery was assessed using motor and spatial learning tasks and neuropathological measurements. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Gene Ontology analysis (GOA) was used to evaluate the effect on relevant biological pathways. Both minocycline and simvastatin improved fine motor function, but not gross motor or cognitive function. Minocycline modestly decreased lesion size with no effect of simvastatin. At 24 h post-CCI, GOA identified a significant effect of minocycline on chemotaxis, blood circulation, immune response, and cell to cell signaling pathways. Inflammatory pathways were affected by minocycline only at the 72 h time point. There was a minimal effect of simvastatin on gene expression 24 h after injury, with increasing effects at 72 h and 7 days. GOA identified a significant effect of simvastatin on inflammatory response at 72 h and 7 days. In conclusion, treatment with minocycline and simvastatin resulted in significant effects on gene expression in the brain reflecting adequate brain penetration without producing significant neurorestorative effects.

Comparison of the effects of erythropoietin and anakinra on functional recovery and gene expression in a traumatic brain injury model.

The goal of this study was to compare the effects of two inflammatory modulators, erythropoietin (EPO) and anakinra, on functional recovery and brain gene expression following a cortical contusion impact (CCI) injury. Dosage regimens were designed to provide serum concentrations in the range obtained with clinically approved doses. Functional recovery was assessed using both motor and spatial learning tasks and neuropathological measurements conducted in the cortex and hippocampus. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Ingenuity Pathway Analysis was used to evaluate the effect on relevant functional categories. EPO and anakinra treatment resulted in significant changes in brain gene expression in the CCI model demonstrating acceptable brain penetration. At all three time points, EPO treatment resulted in significantly more differentially expressed genes than anakinra. For anakinra at 24 h and EPO at 24 h, 72 h, and 7 days, the genes in the top 3 functional categories were involved in cellular movement, inflammatory response and cell-to-cell signaling. For EPO, the majority of the genes in the top 10 canonical pathways identified were associated with inflammatory and immune signaling processes. This was true for anakinra only at 24 h post-traumatic brain injury (TBI). The immunomodulation effects of EPO and anakinra did not translate into positive effects on functional behavioral and lesion studies. Treatment with either EPO or anakinra failed to induce significant beneficial effects on recovery of function or produce any significant effects on the prevention of injury induced tissue loss at 30 days post-injury. In conclusion, treatment with EPO or anakinra resulted in significant effects on gene expression in the brain without affecting functional outcome. This suggests that targeting these inflammatory processes alone may not be sufficient for preventing secondary injuries after TBI.

A comparison of the effects of nicotinamide and progesterone on functional recovery of cognitive behavior following cortical contusion injury in the rat.

The primary goal of this study was to compare clinically relevant doses of progesterone and nicotinamide within the same injury model. Progesterone has been shown to reduce edema and inflammation and improve functional outcomes following brain injury. Nicotinamide has also been shown to be an effective neuroprotective agent in a variety of neurological injury models. In the current study, nicotinamide was administered beginning 4 h post-cortical contusion injury (CCI) with a loading dose (75 mg/kg, i.p.) combined with continuous infusion (12 mg/h/kg, s.c.) for 72 h post-injury. Progesterone was administered beginning 4 h post-CCI at a dose of 10 or 20 mg/kg, i.p. every 12 h for 72 h. This resulted in the following groups: Injured-nicotinamide treated, Injured-progesterone-10 treated, Injured-progesterone-20 treated, Injured-vehicle treated, and Sham. Functional recovery was assessed with two spatial memory tasks in the Morris water maze (MWM) the acquisition of a reference memory task and a reversal learning task. Neuropathological assessments were conducted in the cortex and hippocampus. It was found that both progesterone (10 mg/kg) and nicotinamide improved reference memory acquisition and reversal learning in the MWM compared with vehicle treatment. The lower dose of progesterone and nicotinamide also reduced tissue loss in the injured cortex and ipsilateral hippocampus compared with vehicle. The beneficial effects of progesterone appear to be dose dependent with the lower 10 mg/kg dose producing significant effects that were not observed at the higher dose. Direct comparison between nicotinamide and low dose progesterone appears to suggest that both are equally effective. The general findings of this study suggest that both nicotinamide and progesterone produce significant improvements in recovery of function following CCI.

Is ethnicity associated with morphine's side effects in children? Morphine pharmacokinetics, analgesic response, and side effects in children having tonsillectomy.

OBJECTIVES/AIMS: To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid-related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non-Latino Caucasian (NL) children. BACKGROUND: Morphine has high interindividual variability in its analgesic response and side effects profile. Earlier studies suggest that morphine response may vary by race and ethnicity. METHODS: Prospective cohort study in L and NL children, 3-17 years of age comparing pain scores, occurrence of side effects, plasma morphine, morphine-6- and morphine-3-glucuronide concentrations measured after a single morphine IV bolus administration. Noncompartmental pharmacokinetic analysis and genotyping for 28 polymorphisms in eight genes (UGT1A8, UGT2B7, ABCB1, COMT, STAT6, MC1R, OPRM1, and ARRB2) were performed. RESULTS: We enrolled 68 children (33 L, 35 NL). There were no differences in pain scores or need for rescue analgesia. Statistically significant differences in the occurrence of side effects were documented: While 58% of L children experienced at least one side effect only 20% of NL did (P = 0.001). Pruritus was four times (P = 0.006) and emesis seven times (P = 0.025) more frequent in L compared with NL. PK parameters were similar between groups. None of the assessed polymorphisms mediated the association between ethnicity and side effects. CONCLUSIONS: We found statistically significant differences in the occurrence of side effects after morphine administration between L and NL children. Neither differences in morphine or metabolite concentrations, nor the genetic polymorphisms examined explain these findings. Studies are needed to further investigate reasons for the increase in morphine side effects by Latino ethnicity.

Current oral and non-oral routes of antiepileptic drug delivery.

Antiepileptic drugs are commonly given orally for chronic treatment of epilepsy. The treatment of epilepsy requires administration of medications for both acute and chronic treatment using multiple types of formulations. Parenteral routes are used when the oral route is unavailable or a rapid clinical response is required. Lorazepam and midazolam can be administered by the buccal, sublingual or intranasal routes. Consensus documents recommend rectal diazepam, buccal midazolam or intranasal midazolam for the out-of-hospital treatment of early status epilepticus. In the United States, diazepam is the only FDA approved rectal formulation. With the lack of parenteral, buccal or intranasal formulations for many of the antiepileptic drugs, the use of the rectal route of delivery to treat acute seizures or to maintain therapeutic concentrations is suitable for many, but not all antiepileptic medications. There is a significant need for new non-oral formulations of the antiepileptic drugs when oral administration is not possible.

The red blood cell participates in regulation of the circulation by producing and releasing epoxyeicosatrienoic acids.

Red blood cells (RBCs) have an important function in regulation of the circulation by producing and releasing epoxyeicosatrienoic acids (EETs) in response to a low O2 environment such as encountered in the cardiac microcirculation during exercise. RBCs, in their role as sensors of low pO2, release ATP and critical lipid mediators, the EETs. Both cis- and trans-EETs are synthesized and stored in RBCs and are hydrolyzed by soluble epoxide hydrolases (sEH). The trans-EETs differ from cis-EETs in their higher vascular potencies and more rapid metabolism by sEH. Thus, inhibition of sEH results in greater trans-EET levels and increased positive vascular effects of trans-EETs vs cis-EETs. The trans-EETs are responsible for a significant decline in the elevated blood pressure in the spontaneously hypertensive rat on treatment with a sEH inhibitor to raise EET levels. We predict that trans-EETs and cis-EETs will occupy important therapeutic roles in a broad spectrum of diseases and abnormal physiological conditions such as that resulting from high salt intake and hypertension.

The effect of progesterone dose on gene expression after traumatic brain injury.

Microarray-based transcriptional profiling was used to determine the effect of progesterone in the cortical contusion (CCI) model. Gene ontology (GO) analysis then evaluated the effect of dose on relevant biological pathways. Treatment (vehicle, progesterone 10 mg/kg or 20 mg/kg given i.p.) was started 4 h post-injury and administered every 12 h post-injury for up to 72 h, with the last injection 12 hr prior to death for the 24 h and 72 h groups. In the CCI-injured vehicle group compared to non-injured animals, expression of 1,114, 4,229, and 291 distinct genes changed >1.5-fold (p<0.05) at 24 h, 72 h, and 7 days, respectively. At 24 h, the effect of low-dose progesterone on differentially expressed genes was <20% the effect of higher dose compared to vehicle. GO analysis identified a significant effect of low- and high-dose progesterone treatment compared to vehicle on DNA damage response. At 72 h, high-dose progesterone treatment compared to vehicle affected expression of almost twice as many genes as did low-dose progesterone. Both low- and high-dose progesterone resulted in expression of genes regulating inflammatory response and apoptosis. At 7 days, there was only a modest difference in high-dose progesterone compared to vehicle, with only 14 differentially expressed genes. In contrast, low-dose progesterone resulted in 551 differentially expressed genes compared to vehicle. GO analysis identified genes for the low-dose treatment involved in positive regulation of cell proliferation, innate immune response, positive regulation of anti-apoptosis, and blood vessel remodeling.