Marc G. Sturgill

RATIONAL USE OF CALCIUM-CHANNEL ANTAGONISTS IN RAYNAUD'S PHENOMENON

Raynauds phenomenon (RP) is a peripheral circulatory disorder characterized by sudden episodes of digital artery spasm, often precipitated by cold temperature or emotional stress. Although the cause of RP is not fully known, it appears to involve inappropriate adrenergic response to cold stimuli. Treatment of RP is conservative in most patients, but in patients with severe disease includes the use of agents that promote digital vasodilation. The calcium-channel antagonists, particularly the dihydropyridine derivative nifedipine, are the most thoroughly studied drug class for the treatment of RP. Approximately two thirds of patients respond favorably, with significant reductions in the frequency and severity of vasospastic attacks. Nifedipine use is often limited by the appearance of adverse vasodilatory effects such as headache or peripheral edema. The newer second-generation dihydropyridines such as amlodipine, isradipine, nicardipine, and felodipine also appear to be effective in patients with RP and may be associated with fewer adverse effects.

Pharmacokinetics of intravenous recombinant human granulocyte colony-stimulating factor (rhG-CSF) in children receiving myelosuppressive cancer chemotherapy: Clearance increases in relation to absolute neutrophil count with repeated dosing

Limited evidence suggests increased efficacy of rhG‐CSF by subcutaneous (SQ) compared with intravenous (IV) administration. To examine the possibility that rapid elimination of IV rhG‐CSF could substantially shorten the duration of systemic exposure and could explain a difference in pharmacodynamics, we characterized the pharmacokinetic profile of IV rhG‐CSF for comparison to that previously reported for SQ administration. Twelve children were randomly assigned to receive 10 or more days of IV rhG‐CSF at dosages of 5 or 10 μg/kg a day beginning 24 hr after chemotherapy. Enzyme‐linked immunosorbent assay (ELISA) was used to measure rhG‐CSF concentrations in timed serum samples on days 1 and 10. Pharmacokinetic parameters were estimated by nonlinear, least squares regression. All serum concentration‐time profiles were best described by a two‐compartment model of elimination. Mean t1/2β values ranged from 3.68 ± 0.86 to 22.4 ± 12.0 hr. ANC was correlated with log CLT (r = 0.72, P < 0.05), and inversely with log dose‐adjusted AUC (r = −0.75, P < 0.05) and log dose‐adjusted Cmax (r = −0.65, P < 0.05). Estimated duration of serum rhG‐CSF concentrations above 1 ng/ml exceeded 24 hr for all but the 5 μg/kg cohort on day 1. Pharmacokinetic parameters of IV rhG‐CSF are similar to those previously reported for SQ administration in children treated with myelosuppressive cancer chemotherapy. Daily IV administration should be suitable alternative route of administration in this patient population. Am. J. Hematol. 54:124–130, 1997

Effects of Yohimbine on Autonomic Measures are Determined by Individual Values for Area Under the Concentration—Time Curve

A study was conducted to examine tolerability and pharmacodynamics of single doses of yohimbine in healthy volunteers using measures of mood, heart rate, blood pressure, and serum catecholamine levels. Participants were given single oral doses of yohimbine hydrochloride as high as 21.6 mg. Plasma concentrations of yohimbine, epinephrine, norepinephrine, and MHPG (3‐methoxy‐4‐hydroxyphenylethylene‐glycol) were quantified by means of high‐performance liquid chromatography with electrochemical detection. Mood was assessed by visual analogue scale (VAS), the Profile of Mood States, and the Spielberger State Anxiety Index. Yohimbine was well tolerated and rapidly absorbed and eliminated. Dose‐related increases in area under the concentration—time curve (AUC) were observed. Administration of yohimbine in the presence of a high fat meal diminished both the rate and extent of drug absorption. Significant intersubject variability in the pharmacokinetic parameters of yohimbine was observed, with some individuals exhibiting greatly increased oral bioavailability of yohimbine. Increases in blood pressure, respiratory rate, plasma catecholamine levels, and total VAS score were observed in participants with elevated AUC values. The AUC of yohimbine had the largest effect on total VAS score. The results indicate that higher doses of yohimbine are both well tolerated and produce dose‐related increases in AUC, which are associated with more pronounced autonomic effects. Increases in respiratory rate and plasma MHPG appear to be the most reliable pharmacodynamic measures for single oral doses of yohimbine. Individual differences in the pharmacokinetics of yohimbine are important in determining pharmacodynamic effects and should be considered in evaluations of its clinical effectiveness.

Trimethoprim/Sulfamethoxazole Does Not Affect the Steady-State Disposition of Indinavir

This study evaluates the safety and potential pharmacokinetic interaction between indinavir and trimethoprim/sulfamethoxazole (TMP/SMZ). In a randomized, three‐period crossover fashion, 12 healthy adults received 1 week of indinavir sulfate 400 mg orally every 6 hours with placebo, TMP 160 mg/SMZ 800 mg orally every 12 hours with placebo, and indinavir sulfate with TMP/SMZ. Plasma indinavir, SMZ, and TMP concentrations were determined after the last dose of each treatment period. Concomitant administration resulted in a 17% decrease in geometric mean trough plasma indinavir concentrations (p = 0.032), an 18% increase in geometric mean AUC0‐12h and Cmax TMP values (p = 0.031 and 0.030, respectively), and a 5% increase in geometric mean AUC0‐12h SMZ values (p = 0.039). None of these effects was considered clinically significant. The combination of indinavir sulfate and TMP/SMZ is generally well tolerated, with no clinically significant pharmacokinetic interaction being noted.

The effect of ABO and Rh blood type on the response to intravenous immune globulin (IVIG) in children with immune thrombocytopenic purpura (ITP).

Purpose Immune thrombocytopenic purpura (ITP) is a common childhood illness characterized by thrombocytopenia secondary to shortened platelet survival. Medical therapy includes corticosteroids, intravenous immune globulin (IVIG), and IV Rho (D) immunoglobulin (anti-D). Individuals with Rh-negative blood generally do not respond to treatment with anti-D, but little information is currently available regarding the potential relationship between blood type and response to IVIG. This study was designed to characterize the relationship between ABO and Rh blood type and the response to IVIG in children and adolescents with newly diagnosed ITP. Patients and Methods A retrospective chart review was performed for 52 children and adolescents with newly diagnosed ITP initially treated with IVIG by the Division of Pediatric Hematology-Oncology at Robert Wood Johnson University Hospital in New Brunswick, New Jersey. Results There were no significant differences in response rate or clinical outcome by ABO blood group or Rh type in children with ITP who received IVIG monotherapy as their initial treatment. Conclusions ABO blood group and Rh type do not appear to be prognostic factors when IVIG monotherapy is the initial treatment for childhood ITP.

Extravascular Administration of Interferon Alfa-N3 Increases Serum Exposure and 2–5(A) Synthetase Activity

The objective of this study was to evaluate the pharmacokinetics, pharmacodynamic response, and safety of single intravenous (IV), intramuscular (IM), and subcutaneous (SQ) doses of interferon alfa‐n3. Six healthy adults received 10 million units of IV, IM, and SQ interferon alfa‐n3 in a randomized three‐period crossover fashion. Serum interferon alfa‐n3 concentrations and 2′‐5′‐oligoadenylate synthetase (2–5[A] synthetase) activity in peripheral blood mononuclear cells were determined after each dose. Extravascular administration significantly increased mean serum interferon alfa‐n3 AUC values (1152 ± 214, 944 ± 209, and 576 ± 188 U·h/mL, p < 0.001, with SQ, IM, and IV administration, respectively) and 2–5(A) synthetase activity at 36 and 48 hours after dosing. Mild to moderate flu‐like symptoms were reported by all 6 subjects, with no route‐related difference in type or incidence. Interferon alfa‐n3 is generally well tolerated by the IV, IM, and SQ routes, with IM and SQ administration maximizing serum exposure and 2–5(A) synthetase activity.

Extracellular dopamine, acetylcholine, and activation of dopamine D1 and D2 receptors after selective breeding for cocaine self-administration in rats

RationaleThe low self-administration (LS)/Kgras (LS) and high self-administration (HS)/Kgras (HS) rat lines were generated by selective breeding for low- and high-intravenous cocaine self-administration, respectively, from a common outbred Wistar stock (Crl:WI). This trait has remained stable after 13 generations of breeding.ObjectiveThe objective of the present study is to compare cocaine preference, neurotransmitter release, and dopamine receptor activation in LS and HS rats.MethodsLevels of dopamine, acetylcholine, and cocaine were measured in the nucleus accumbens (NA) shell of HS and LS rats by tandem mass spectrometry of microdialysates. Cocaine-induced locomotor activity and conditioned-place preference were compared between LS and HS rats.ResultsHS rats displayed greater conditioned-place preference scores compared to LS and reduced basal extracellular concentrations of dopamine and acetylcholine. However, patterns of neurotransmitter release did not differ between strains. Low-dose cocaine increased locomotor activity in LS rats, but not in HS animals, while high-dose cocaine augmented activity only in HS rats. Either dose of cocaine increased immunoreactivity for c-Fos in the NA shell of both strains, with greater elevations observed in HS rats. Activation identified by cells expressing both c-Fos and dopamine receptors was generally greater in the HS strain, with a similar pattern for both D1 and D2 dopamine receptors.ConclusionsDiminished levels of dopamine and acetylcholine in the NA shell, with enhanced cocaine-induced expression of D1 and D2 receptors, are associated with greater rewarding effects of cocaine in HS rats and an altered dose-effect relationship for cocaine-induced locomotor activity.

Cytokine profiles in pediatric multiple sclerosis

BackgroundThe immunopathogenesis of pediatric multiple sclerosis (MS) is not well understood.MethodsWe studied the cytokine profile in pre-treatment serum specimens of 19 pediatric MS patients, 25 adult MS patients, and 22 age- and gender-matched pediatric healthy controls. In addition to IL-2, IL-12p40, IL-12p70, IL-18, IL-23, IL-6, TNF-α, TGF-β-1, IFN-γ, IL-17A, IL-21, IL-10, IL-4, IL-5, IL-13, and GM-CSF, we measured osteopontin and soluble VCAM-I.ResultsIn children with MS, significantly lower levels of IL-6 were present compared to age- and gender-matched healthy control children (p < 0.05). Moreover, significantly higher levels of osteopontin (p < 0.02) and sVCAM-1 (p < 0.02) and lower levels of IL-6 (p < 0.01) were present, with trends toward lower levels of IL-12p70 (p = 0.074) and IL-17a (p = 0.05) compared to adults with MS.ConclusionsThese findings indicate important differences in cytokine signatures in children with MS and suggest an unexpected possible lower inflammatory cytokine profile in children with MS.

Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil

BACKGROUND In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil. METHODS Twelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5 mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at .0, .18, and .36 mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites. RESULTS Intravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30 minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (.18 mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (.36 mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo-treated participants. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE We conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil. (Am J Addict 2016;25:392-399).

Augmentation of hepatic doxorubicin extraction with extracorporeal filtration avoids the dose-dependent, nonlinear increase in AUC observed with systemic administration

Purpose: Regional therapy of primary or metastatic liver cancer with low hepatic extraction ratio drugs such as doxorubicin is constrained by development of systemic toxicity. To examine the effect of augmentation of hepatic drug extraction, a swine model of hepatic artery infusion (HAI) with minimally invasive hepatic venous isolation and hepatic venous drug extraction (HVDE) was developed to study the comparative pharmacokinetic profiles of regional and systemically administered doxorubicin. Methods: Doxorubicin 0.5–9 mg/kg was administered to 31 pigs over 90 min either by HAI with simultaneous HVDE or by standard systemic vein infusion. Systemic artery and hepatic vein plasma samples were collected periodically (0 to 240 min) for determination of doxorubicin concentrations by high-performance liquid chromatography. Pharmacokinetic profiles were modeled with PCNONLIN 4.2. Results: Concentration-time data were best described in all pigs by a two-compartment open model of elimination. Independent of the route of administration, AUC and Cmax values increased with dose. Mean systemic AUC and Cmax values were consistently lower with regional administration, with statistically significant decreases at the 0.5 and 3 mg/kg doses, whereas there was no relationship between hepatic vein parameters and route of administration. There was a linear relationship between mean systemic AUC values and dose in pigs receiving doxorubicin via HAI with HVDE, whereas mean systemic AUC values increased exponentially at doses of 5 mg/kg or above with systemic vein administration. Conclusions: Administration of doxorubicin by HAI with simultaneous HVDE signifiantly decreases systemic exposure in comparison with standard systemic vein drug infusion, and may protect against nonlinear increases in exposure at higher doses.