Consideration of Aggressive and Strategic Approaches to Address Declining Enrollment in US Pharmacy Schools.

Members from Cohort 13 of the Academic Leadership Fellows Program (ALFP) 2016-2017 were challenged to present a debate on the topic: "In Turbulent Times, Pharmacy Education Leaders Must Take Aggressive Action to Prevent Further Declines in Enrollment" at the American Association of Colleges of Pharmacy INfluence 2017 meeting in Rio Grande, Puerto Rico. This paper is the result of thoughtful insights emerging from this debate. We present a discussion of the question of whether pharmacy education leaders must take aggressive action or strategic approaches to prevent further declines in enrollment. There are many thoughts regarding current declines in enrollment. Some educators contend that a more aggressive approach is needed while others argue that, while aggressive actions might lead to short-term gains, a more viable approach involves strategic actions targeting the underlying causes for decreasing enrollment. This paper explores themes of enrollment challenges, current and future workforce needs, and financial issues for both pharmacy programs and students. In summation, both aggressive actions and a strategic, sustainable approach are urgently needed to address declining enrollment.

An interactive lesson in acid/base and pro-drug chemistry using sodium gamma-hydroxybutyrate and commercial test coasters.

OBJECTIVE: To develop a classroom activity that applied pertinent pharmaceutical concepts to examine the use and limitations of a commercially available test drink coaster in detecting the presence of a date-rape drug, sodium gamma-hydroxybutyrate (NaGHB), in beverages. DESIGN: An activity exercise involving a combination of self-study, hands on participation, and classroom discussion was developed. Topics incorporated into the activity were drug-assisted rape, the concepts of false positives and negatives, and prodrug and pH chemistry. ASSESSMENT: Based on questionnaires completed by the students, the intended concepts were reinforced and students demonstrated an increased awareness of the potential shortcomings of the commercial test devices. The activity was well received by the majority of students. CONCLUSION: The developed activity stimulated student awareness and interest in several principles relevant in pharmaceutical education, including drug-assisted rape, consumer-based drug testing of NaGHB, and the chemical basis for its limitations. The activity requires no special equipment other than the drink coasters and can be easily completed in one 2-hour classroom session.

Feasibility of D-glucuronate to enhance gamma-hydroxybutyric acid metabolism during gamma-hydroxybutyric acid toxicity: pharmacokinetic and pharmacodynamic studies.

Gamma-Hydroxybutyric acid (GHB) is a drug of abuse. Literature studies showed that D-glucuronate acts as an oxidative stimulator of GHB metabolism following in vivo GHB tracer doses. The present proof-of-concept study investigates if D-glucuronate enhances GHB metabolism and inhibits blood-brain barrier (BBB) carrier-mediated transport of GHB for clinically relevant and toxicological concentrations of GHB. In a randomized cross-over study with a 3 day washout period, rats were intravenously administered GHB (200, 400 or 800 mg/kg) with either saline or D-glucuronate (830 mg/kg i.v. bolus followed by a constant infusion of 1.39 g/kg-h). Systemic and renal GHB pharmacokinetics, as well as onset, offset and duration of GHB sedative/hypnotic effects were measured following each GHB dose. In situ brain perfusion was used to determine if D-glucuronate inhibited GHB BBB transport. D-Glucuronate did not alter GHB sedative/hypnotic effects at all three GHB doses. A model independent approach revealed that GHB systemic (AUC, CL(Total), CL(Metabolism), V(SS), T(1/2)) and renal (CL(Renal), f(e)) pharmacokinetic parameters were unaltered by D-glucuronate administration. GHB influx clearance was unaltered by D-glucuronate suggesting a lack of transport inhibition. These observations suggest that although previously shown to be promising at GHB tracer doses, D-glucuronate lacks therapeutic benefit in the treatment of GHB toxicity.

Pharmacokinetics and pharmacodynamics of gamma-hydroxybutyric acid during tolerance in rats: effects on extracellular dopamine.

gamma-Hydroxybutyrate (GHB) is a potent sedative/hypnotic and drug of abuse. Tolerance develops to GHB's sedative/hypnotic effects. It is hypothesized that GHB tolerance may be mediated by alterations in central nervous system pharmacokinetics or neurotransmitter response. Rats were dosed daily with GHB (548 mg/kg s.c. q.d. for 5 days), and sleep time was measured as an index of behavioral tolerance. Plasma and brain GHB pharmacokinetics on days 1 and 5 were monitored using blood and microdialysis sampling. Extracellular (ECF) striatal dopamine levels were measured by microdialysis as a pharmacodynamic endpoint of tolerance. Pharmacokinetic (PK)/pharmacodynamic (PD) modeling was performed to describe the plasma and brain disposition using an indirect response model with inhibition of dopamine synthesis rate to describe the pharmacodynamic response. GHB plasma and brain ECF concentration versus time profiles following acute or chronic exposure were not significantly different. GHB sedative/hypnotic tolerance was observed by day 5. Acute GHB administration resulted in a decrease in striatal ECF dopamine (DA) levels compared with baseline levels. GHB tolerance was reflected by a 60% decrease in dopamine area under the curve (effect and baseline): acute, 10.1 +/- 15.3% basal DA/min/10(-3) versus chronic, 4.73 +/- 1.49% basal DA/min/10(-3) (p < 0.05, n = 5; unpaired Student's t test). The PK/PD model revealed an increase in the IC50 following chronic exposure indicating decreased dopaminergic sensitivity toward the inhibitory effects of GHB. Our findings indicate that GHB pharmacokinetics do not contribute to behavioral tolerance; however, changes in neurotransmitter responsiveness may suggest specific neurochemical pathways involved in the development and expression of tolerance.

Alterations in neuronal transport but not blood-brain barrier transport are observed during gamma-hydroxybutyrate (GHB) sedative/hypnotic tolerance.

PURPOSE: To investigate if gamma-Hydroxybutyrate (GHB) tolerance is mediated by alterations in GHB systemic pharmacokinetics, transport (blood brain barrier (BBB) and neuronal) or membrane fluidity. MATERIALS AND METHODS: GHB tolerance in rats was attained by repeated GHB administration (5.31 mmol/kg, s.c., QD for 5 days). GHB sedative/hypnotic effects were measured daily. GHB pharmacokinetics were determined on day 5. In separate groups, on day 6, in situ brain perfusion was performed to assess BBB transport alterations; or in vitro studies were performed (fluorescence polarization measurements of neuronal membrane fluidity or [3H]GABA neuronal accumulation). RESULTS: GHB sedative/hypnotic tolerance was observed by day 5. No significant GHB pharmacokinetic or BBB transport differences were observed between treated and control rats. Neuronal membrane preparations from GHB tolerant rats showed a significant decrease in fluorescence polarization (treated-0.320 +/- 0.009, n = 5; control-0.299 +/- 0.009, n = 5; p < 0.05). [3H]GABA neuronal transport Vmax was significantly increased in tolerant rats (2,110.66 +/- 91.06 pmol/mg protein/min vs control (1,612.68 +/- 176.03 pmol/mg protein/min; n = 7 p < 0.05). CONCLUSIONS: Short term GHB administration at moderate doses results in the development of tolerance which is not due to altered systemic pharmacokinetics or altered BBB transport, but might be due to enhanced membrane rigidity and increased GABA reuptake.

Potential gamma-hydroxybutyric acid (GHB) drug interactions through blood-brain barrier transport inhibition: a pharmacokinetic simulation-based evaluation.

Recreational abuse or overdose of gamma-hydroxybutyric acid (GHB) results in dose-dependent central nervous system (CNS) effects including death. As GHB undergoes monocarboxylic acid transporter (MCT)-mediated transport across the blood-brain barrier (BBB), one possible strategy for the management of GHB toxicity/overdose involves inhibition of GHB BBB transport. To test this strategy, interactions between GHB and MCT substrates (salicylic acid or probenecid) were simulated. Competitive, noncompetitive and uncompetitive inhibition mechanisms were incorporated into the GHB-MCT substrate interaction model for inhibitor dosing either pre-, concurrent or post-GHB administration. Simulations suggested that salicylic acid was the better candidate to limit GHB accumulation in the CNS. A time window of effect (> 10% change) was observed for salicylic acid pre- and post-administration, with maximal transport inhibition occurring within 12 hr of pre- and 2 hr of post-administration. Consistent with the prediction that reduced GHB brain concentrations could translate to decreased pharmacodynamic effects, a pilot study in rats showed that the pronounced GHB sedative/hypnotic effects (24.0 +/- 6.51 min; n = 4) in the control group (1.58 mmol/kg GHB plus saline) were significantly (p < 0.05) abrogated by salicylic acid (1.25 mmol/kg) coadministration.

GHB (gamma-hydroxybutyrate) carrier-mediated transport across the blood-brain barrier.

gamma-Hydroxybutyrate (sodium oxybate, GHB) is an approved therapeutic agent for cataplexy with narcolepsy. GHB is widely abused as an anabolic agent, euphoriant, and date rape drug. Recreational abuse or overdose of GHB (or its precursors gamma-butyrolactone or 1,4-butanediol) results in dose-dependent central nervous system (CNS) effects (respiratory depression, unconsciousness, coma, and death) as well as tolerance and withdrawal. An understanding of the CNS transport mechanisms of GHB may provide insight into overdose treatment approaches. The hypothesis that GHB undergoes carrier-mediated transport across the BBB was tested using a rat in situ brain perfusion technique. Various pharmacological agents were used to probe the pharmacological characteristics of the transporter. GHB exhibited carrier-mediated transport across the BBB consistent with a high-capacity, low-affinity transporter; averaged brain region parameters were V(max) = 709 +/- 214 nmol/min/g, K(m) = 11.0 +/- 3.56 mM, and CL(ns) = 0.019 +/- 0.003 cm(3)/min/g. Short-chain monocarboxylic acids (pyruvic, lactic, and beta-hydroxybutyric), medium-chain fatty acids (hexanoic and valproic), and organic anions (probenecid, benzoic, salicylic, and alpha-cyano-4-hydroxycinnamic acid) significantly inhibited GHB influx by 35 to 90%. Dicarboxylic acids (succinic and glutaric) and gamma-aminobutyric acid did not inhibit GHB BBB transport. Mutual inhibition was observed between GHB and benzoic acid, a well known substrate of the monocarboxylate transporter MCT1. These results are suggestive of GHB crossing the BBB via an MCT isoform. These novel findings of GHB BBB transport suggest potential therapeutic approaches in the treatment of GHB overdoses. We are currently conducting "proof-of-concept" studies involving the use of GHB brain transport inhibitors during GHB toxicity.

Nitric oxide neurotoxicity in neurodegenerative diseases.

Nitric oxide (nitrogen monoxide; NO) is a simple molecule with diverse biological functions. NO and related reactive nitrogen oxide species (RNOS) mediate intricate physiological and pathophysiological effects in the central nervous system. Depending on environmental conditions, NO and RNOS can initiate and mediate neuroprotection or neurotoxicity either exclusively or synergistically with other effectors. The focus of this review is limited to the neuroprotectant/neurotoxic role of NO in Acquired Immune Deficiency Syndrome (AIDS) Dementia Complex (aka HIV--Associated Dementia; HAD) Amyotrophic Lateral Sclerosis (aka Lou Gehrig's Disease), Alzheimer's Disease, Huntington's Disease, Multiple Sclerosis and Parkinson's Disease. This review will shed light on the question: "How important is NO in neurodegenerative diseases?"

Neuroinflammatory role of prostaglandins during experimental meningitis: evidence suggestive of an in vivo relationship between nitric oxide and prostaglandins.

Nitric oxide (NO) and prostaglandins are inflammatory mediators produced during meningitis. The purpose of the present study was to pharmacologically inhibit cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) to 1) explore the prostaglandin contribution to blood-cerebrospinal fluid barrier permeability alterations and 2) elucidate the in vivo concentration relationship between prostaglandin E2 (PGE2) and NO during experimental meningitis. Intracisternal injection of lipopolysaccharides (LPSs, 200 microg) induced neuroinflammation. Rats were dosed with nimesulide (COX-2 inhibitor), aminoguanidine (iNOS inhibitor), or vehicle. Evans blue was used to assess blood-cerebrospinal fluid barrier permeability. Meningeal NO and cerebrospinal fluid PGE2 were assayed using conventional methods. (Results are expressed as mean +/- S.E.M. of 5-9 rats/group.) Nimesulide failed to prevent blood-cerebrospinal fluid barrier disruption [cerebrospinal fluid Evans blue (micrograms per milliliter): control, 0.22 +/- 0.22*; LPS, 11.58 +/- 0.66; LPS + nimesulide, 10.58 +/- 0.86; *p < 0.05; ANOVA]. Although nimesulide decreased PGE2 (picograms per microliter; p < 0.01) in LPS + nimesulide rats (13.9 +/- 1.96) versus LPS + vehicle (73.8 +/- 12.4), meningeal NO production (picomoles/30 min/10(6) cells; p < 0.01) increased unexpectedly in LPS + nimesulide rats (439 +/- 47) versus LPS + vehicle rats (211 +/- 31). In contrast, aminoguanidine inhibited meningeal NO (picomoles/30 min/10(6) cells; p < 0.005) in LPS + aminoguanidine (111 +/- 20) versus LPS (337 +/- 48) but had no effects (p > 0.05) on PGE2. The in vivo relationship between PGE2 and NO was mathematically described by a biphasic, bell-shaped curve (r2 = 0.42; n = 27 rats; p < 0.0001). Based on these results, inhibition of prostaglandin synthesis not only fails to prevent blood-cerebrospinal fluid barrier disruption during neuroinflammation and but also promotes increased meningeal NO production. The in vivo concentration relationship between PGE2 and NO is biphasic, suggesting that inhibition of COX-2 alone may promote NO toxicity through enhanced NO synthesis.

In vivo measurement of blood-brain barrier permeability.

This unit describes various protocols for the in vivo quantitation of drug permeability across the rodent blood-brain barrier. Methods for the measurement of drug influx and efflux are described, and support protocols are provided for determining intravascular capillary volume and cerebral perfusion flow. An in situ perfusion technique is also provided for assessing whether transport of a test compound occurs by carrier-mediated or saturable transport.