David J. Freeman

Corticosteroid Pharmacokinetics in the Inner Ear Fluids: An Animal Study Followed by Clinical Application

Objective: Autoimmune disease (e.g., Cogan syndrome) and other inflammatory inner ear diseases may ravage the labyrinth if not treated aggressively with antiinflammatory medication. Corticosteroids are the mainstay of treatment, yet, partly because of the existence of the blood—labyrinthine barrier, the ideal drug, dose, and route of administration are currently unknown. Study Design: In the present study, we established cochlear fluid pharmacokinetic profiles of hydro‐cortisone, methylprednisolone, and dexamethasone in the guinea pig following oral, intravenous, and topical (intratympanic) administration. High‐performance liquid chromatography was used to determine the drug concentrations, and comparisons were made with simultaneous pharmacokinetic profiles from blood and cerebrospinal fluid. Results: Our findings demonstrated a much higher penetration of all three drugs into the cochlear fluids following topical application as compared with systemic administration, with methylprednisolone showing the best profile. Discussion: The results suggested that intratympanic administration of corticosteroids might be more efficacious while avoiding high blood levels and therefore the deleterious side effects of systemic use. Clinical Application: Thirty‐seven patients with various inner ear disorders causing sensorineural hearing loss were subsequently treated using intratympanic corticosteroids, 20 with dexamethasone, and 17 with methlyprednisolone. Patients with immune‐mediated hearing losses showed the best results, with notable improvement also seen in several cases of a “sudden deafness.” No benefit was seen in patients with cochlear hydrops or those with sudden deterioration of a preexisting hearing loss. Three patients developed a transient otitis media related to the treatments, easily controlled with antibiotics. There were no cases of treatment‐induced hearing loss and no permanent tympanic membrane perforations. Conclusions: Overall, injection of intratympanic corticosteroids for the treatment of hearing loss in inner ear disorders appears to be both safe and highly effective for certain disorders. The concept of this technique is supported by animal experimental data. The findings from the present study warrant further clinical application and experimental investigation.

Pre–B-Cell Colony–Enhancing Factor Regulates NAD+-Dependent Protein Deacetylase Activity and Promotes Vascular Smooth Muscle Cell Maturation

Conversion of vascular smooth muscle cells (SMCs) from a proliferative state to a nonproliferative, contractile state confers vasomotor function to developing and remodeling blood vessels. Using a maturation-competent human SMC line, we determined that this shift in phenotype was accompanied by upregulation of pre–B-cell colony–enhancing factor (PBEF), a protein proposed to be a cytokine. Knockdown of endogenous PBEF increased SMC apoptosis and reduced the capacity of synthetic SMCs to mature to a contractile state. In keeping with these findings, human SMCs transduced with the PBEF gene had enhanced survival, an elongated bipolar morphology, and increased levels of h-caldesmon, smoothelin-A, smoothelin-B, and metavinculin. Notwithstanding some prior reports, PBEF did not have attributes of a cytokine but instead imparted the cell with increased nicotinamide phosphoribosyltransferase activity. Intracellular nicotinamide adenine dinucleotide (NAD+) content was increased in PBEF-overexpressing SMCs and decreased in PBEF-knockdown SMCs. Furthermore, NAD+-dependent protein deacetylase activity was found to be essential for SMC maturation and was increased by PBEF. Xenotransplantation of human SMCs into immunodeficient mice revealed an increased capacity for PBEF-overexpressing SMCs to mature and intimately invest nascent endothelial channels. This microvessel chimerism and maturation process was perturbed when SMC PBEF expression was lowered. These findings identify PBEF as a regulator of NAD+-dependent reactions in SMCs, reactions that promote, among other potential processes, the acquisition of a mature SMC phenotype.

Grapefruit‐felodipine interaction: Effect of unprocessed fruit and probable active ingredients

To determine whether unprocessed grapefruit can cause a drug interaction, whether the active ingredients are naturally occurring, and whether specific furanocoumarins or flavonoids are involved.

Nitrous Oxide-Induced Increased Homocysteine Concentrations Are Associated with Increased Postoperative Myocardial Ischemia in Patients Undergoing Carotid Endarterectomy

Nitrous oxide anesthesia causes increased postoperative plasma homocysteine levels. Acute increases in plasma homocysteine are associated with impaired endothelial function and procoagulant effects. This nitrous oxide-induced plasma homocysteine increase may therefore affect the risk of perioperative cardiovascular events. This prospective, randomized study was therefore designed to evaluate the effect of nitrous oxide anesthesia and postoperative plasma homocysteine levels on myocardial ischemia in patients undergoing carotid endarterectomy. After institutional review board approval and written informed consent, 90 ASA Class I–III patients presenting for elective carotid endarterectomy were randomized to receive general anesthesia with or without nitrous oxide. Prior to induction, on arrival in the postanesthesia care unit, and after 48 h, blood samples were obtained for homocysteine analysis. Three hours prior to induction and for 48 h postoperatively patients were monitored by a three-channel, seven-lead Holter monitor. Postoperatively in the postanesthesia care unit and at 48 h the nitrous oxide group had increased mean plasma homocysteine concentrations of 15.5 ± 5.9 and 18.8 ± 14.7 when compared with the nonnitrous group of 11.4 ± 5.2 and 11.3 ± 4.0 &mgr;mol/L, P < 0.001. The nitrous oxide group had an increased incidence of ischemia (46% vs. 25%, P < 0.05), significantly more ischemia (63 ± 71 vs. 40 ± 68 min, P < 0.05), had more ischemic events (82 vs. 53, P < 0.02), and had more ischemic events lasting 30 min (23 vs. 14, P < 0.05) than the nonnitrous group. This study reconfirmed that intraoperative nitrous oxide is associated with postoperative increases in plasma homocysteine concentration. This was associated with an increase in postoperative myocardial ischemia. Implications Use of nitrous oxide during carotid artery surgery induces increases in postoperative plasma homocysteine concentration and is associated with increases in postoperative myocardial ischemia.

Grapefruit juice-felodipine interaction : Effect of naringin and 6', 7'-dihydroxybergamottin in humans

To test whether naringin or 6′,7′‐dihydroxybergamottin is a major active substance in grape‐fruit juice‐felodipine interaction in humans.

Plasma Homocyst(e)ine Concentration, But Not MTHFR Genotype, Is Associated With Variation in Carotid Plaque Area

BACKGROUND AND PURPOSE Elevated plasma homocyst(e)ine [H(e)] concentration is associated with premature atherosclerosis. A common cause of elevated plasma H(e) concentration is a thermolabile mutation (677T) in the gene encoding methylenetetrahydrofolate reductase (MTHFR). We sought to determine whether plasma H(e) concentration or MTHFR genotype would be more strongly associated with carotid plaque area (CPA), a potential intermediate phenotype of atherosclerosis. METHODS In 307 subjects who were ascertained through a premature atherosclerosis clinic, we measured CPA with 2-dimensional ultrasound and also determined traditional atherosclerosis risk factors, in addition to plasma H(e) concentration and MTHFR genotypes. RESULTS We found that the frequency of the MTHFR 677T allele was 0.363 in this sample. Mean plasma H(e) concentration was significantly higher in 677T/T homozygotes than in 677T/C heterozygotes and 677C/C homozygotes (17. 1+/-13.7 versus 13.5+/-6.1 versus 12.6+/-5.9 micromol/L, respectively, P<0.001). Analysis of variance showed that CPA was significantly associated with age, sex, smoking, diabetes, hypertension, and hyperlipidemia (each P<0.05). When plasma H(e) concentration was included in the model, it was significantly associated with CPA (P<0.05). However, when the MTHFR genotype was included in the model, it was not associated with CPA (P=0.50). Furthermore, there was a significant correlation of CPA with plasma H(e) (r=0.23, P<0.0001). However, the mean CPA did not differ between subjects according to genotype. CONCLUISONS: Thus, plasma H(e), but not MTHFR genotype, is significantly associated with carotid atherosclerosis, suggesting that the biochemical test may be sufficient to identify patients who may be at increased risk of atherosclerosis through this mechanism.

Will Routine Therapeutic Drug Monitoring Have a Place in Clozapine Therapy

SummaryClozapine is an atypical antipsychotic medication with proven efficacy in the management of refractory schizophrenia. It is also recommended for patients who do not tolerate the extrapyramidal adverse effects of traditional antipsychotic medications. However, the therapeutic promise of clozapine has been limited by a higher incidence of agranulocytosis.Currently, plasma clozapine concentrations are not routinely used in clinical management. Therapeutic effects are monitored empirically during a 6 to 8 week titration period in which the dosage is raised to 300 to 450 mg/day. Clozapine nevertheless fulfils a number of criteria which make it a candidate for therapeutic monitoring. These include an identifiable therapeutic range, an unpredictable dose-concentration relationship between patients, a potential for clinically relevant pharmacokinetic interaction with other drugs and a high probability of patient noncompliance.The therapeutic threshold plasma concentration appears to be about 400 μg/L. Concentrations above 1000 μg/L increase the risk of adverse effects on the central nervous system (confusion, delirium and generalised seizures). There is no evidence to link increased concentrations of clozapine or its metabolite to the development of agranulocytosis.We conclude that therapeutic drug monitoring can play a useful role in the clinical management of patients treated with clozapine. The clinician is advised to primarily use clinical judgement during dosage escalation, but intermittent monitoring is recommended to quickly optimise a therapeutic dosage for each patient. At steady state, occasional measurements could be made when clinical signs indicate possible toxicity or lack of effect (possibly caused by a lack of compliance or drug interaction). Long term monitoring would, in our view, not be necessary.

Reinstalling Antitumor Immunity by Inhibiting Tumor-Derived Immunosuppressive Molecule IDO through RNA Interference

Tumor-derived immune suppression is a major impediment to successful immune/gene cancer therapy. In the present study, we describe a novel strategy to disrupt tumor-derived immune suppression by silencing a tolerogenic molecule of tumor origin, IDO, using small interfering RNA (siRNA). Silencing of IDO in B16F10 cells in vitro using IDO-siRNA prevented catabolism of tryptophan and inhibited apoptosis of T cells. IDO-siRNA treatment of B16F10 cells in vitro inhibited subsequent growth, tumor formation, and the size of tumor formed, by those cells when transplanted into host mice. In vivo treatment of B16F10 tumor-bearing mice successfully postponed tumor formation time and significantly decreased tumor size. Furthermore, in vivo IDO-siRNA treatment resulted in recovery of T cells responses and enhancement of tumor-specific killing. Thus, silencing IDO may break tumor-derived immune suppression. These data indicate that RNA interference has potential to enhance cancer therapy by reinstalling anticancer immunity.

Tolerance to nicotinic acid flushing

The mechanism of tolerance to nicotinic acid flushing was determined in subjects during a 5‐day course of treatment. Objective measures of skin blood flow were used to confirm the development of tolerance. Plasma levels of nicotinic acid showed marked intraindividual variability but were not decreased with the development of tolerance. However plasma levels of 9‐α 11‐β prostaglandin F2, a stable metabolite of prostaglandin D2, became undetectable in most subjects with the development of tolerance. Thus tolerance is not associated with decreased levels of nicotinic acid or development of tolerance to the prostaglandin mediator, but with decreased levels of the mediator.

The Use of Intraoperative Nitrous Oxide Leads to Postoperative Increases in Plasma Homocysteine

Hyperhomocysteinemia is an independent risk factor for coronary artery and cerebrovascular disease, but its significance in the perioperative period is unknown.Nitrous oxide inhibits methionine synthase, which aids in the conversion of homocysteine to methionine. In this prospective, controlled, randomized study, we determined the effect of intraoperative nitrous oxide exposure on postoperative plasma homocysteine concentrations. Twenty ASA physical status I-III patients, aged >18 yr, presenting for elective craniotomy, were randomized to receive general anesthesia with or without nitrous oxide (inspired nitrous oxide >50%). Plasma was sampled before the induction of anesthesia, on arrival in the postanesthesia care unit (PACU) after discontinuation of nitrous oxide, and 24 h after induction. There was a significant increase (22.6 +/- 11.4 vs 13.0 +/- 4.7 [micro sign]mol/L; P = 0.0038 for postoperative versus preinduction values) in plasma homocysteine concentrations in the nitrous oxide group on arrival in the PACU and for 24 h. In the nonnitrous oxide group, mean plasma homocysteine concentrations did not change (9.5 +/- 1.9 vs 9.8 +/- 1.6 [micro sign]mol/L; P = 0.86 for postoperative versus preinduction values). The change in plasma homocysteine concentrations in the nitrous oxide group was significantly different from that in the nonnitrous group (P = 0.0031). We conclude that the use of intraoperative nitrous oxide leads to significant increases in perioperative plasma homocysteine concentrations. Implications: Short-term exposure to nitrous oxide led to significant increases in plasma homocysteine. Further investigations are required to determine the clinical significance of this change. (Anesth Analg 1998;87:711-3)