Regulatory and scientific issues regarding use of foreign data in support of new drug applications in the United States: an FDA perspective.

Globalization of clinical research has led to an increase in clinical trials conducted outside of the United States that are submitted to the US Food and Drug Administration (FDA) in new drug applications. This article discusses the FDA's experience with these submissions in specific therapeutic areas, including the extent of this practice, differences between the effectiveness and safety outcomes of studies conducted inside and outside the United States, and the FDA's approach to acceptance of these trials.

The role of ethnicity in variability in response to drugs: focus on clinical pharmacology studies.

Ethnicity is one factor that may account for the observed differences in both pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, resulting in variability in response to drug therapy. Given that the applicability of clinical study results to the treatment of an individual patient is a critical consideration in a physician's choice of drug therapy, drug development should seek to ensure that a clinical pharmacologic evaluation includes a population that is representative of the target therapeutic population. Ethnic diversity in drug response with respect to safety and efficacy and the resulting differences in recommended doses have been well described for some drugs. Some of these differential responses may be related to the pharmacogenomics of a particular drug. Pharmacogenomic techniques have recently enjoyed widespread use in studies of drug exposure and response. The clinical relevance of variability in drug response due to pharmacogenomics of drug-metabolizing enzymes was considered at a September 2004 workshop cosponsored by the US Food and Drug Administration (FDA), Johns Hopkins University, and the Pharmaceutical Research and Manufacturers of America (http://www.fda.gov/cder/Offices/OCPB/workshops.htm).

The use of imaging in the early development of neuropharmacological drugs: a survey of approved NDAs.

The aim of the study was to evaluate the use of imaging in the development of neuropharmacological drugs. All New Drug Applications (NDAs) approved from 1995 through 2004 in the Division of Neuropharmacological Drug Products at the Food and Drug Administration were surveyed for imaging studies. Imaging literature was also reviewed with respect to antipsychotics and antidepressants. One hundred and six NDAs (35 new molecular entities (NMEs)) were approved; 15 of these NDAs (10 NMEs) had imaging studies. The primary imaging modality was positron emission tomography. Imaging was primarily conducted for drugs used in schizophrenia, depression, multiple sclerosis, and migraine. The majority evaluated receptor occupancy or proof of concept. Examples (including literature) are discussed as pertinent to dosage, efficacy, safety, or further development of a drug or class of drugs. Imaging contributes to optimal clinical development of central nervous system (CNS)-active drugs. Opportunities are available for its broader use, contributing to improved understanding of the clinical pharmacology of CNS-active drugs.

Olanzapine-induced rhabdomyolysis.

OBJECTIVE: To report a possible case of olanzapine-induced rhabdomyolysis with concomitant lithium-induced pseudo-infarction electrocardiogram changes. CASE SUMMARY: A 13-year-old white boy was admitted to the hospital with profound weakness and electrocardiogram (EGG) changes suggestive of myocardial damage after starting olanzapine and lithium. An adverse medication effect was not considered at the time of the patient's admission. The time course of onset of weakness was coincident with administration of olanzapine. ECG abnormalities are a known manifestation of lithium therapy DISCUSSION: This is a case description of olanzapine-induced rhabdomyolysis. Although other antipsychotic agents have been reported to cause rhabdomyolysis, an adverse drug reaction was not initially part of this patient's differential diagnosis. The patient had begun reporting rnyalgias six days after starting olanzapine. Fourteen days later, these symptoms forced him to bed rest; lithium was added for behavior misinterpreted as disobedience and oppositional disorder. Only when medications were considered as cause of the weakness and EGG changes, was the true nature of the patient's illness discovered. CONCLUSIONS: Olanzapine, like other neuroleptic agents, can cause rhabdomyolysis. Lithium can cause multiple EGG changes that can be misinterpreted as myocardial damage. Medication effects and adverse effects must always be considered in any disease complex.

Visual hallucination and tremor induced by sertraline and oxycodone in a bone marrow transplant patient.

The authors report a case of probable serotonin syndrome caused by the coadministration of sertraline and oxycodone. A 34 year-old male patient experienced visual hallucinations and severe tremor after dramatically increasing his dosage of oxycodone while on stable amounts of sertraline and cyclosporin. Discontinuation of cyclosporin did not result in resolution of his symptoms. Consideration of a possible sertraline-oxycodone interaction led to withholding sertraline, which resulted in symptom resolution. Serotonin syndrome has been noted with sertraline in combination with other drugs, but this is the first report in combination with a narcotic analgesic. Possible pharmacological mechanisms are discussed. In complicated patients that are taking multiple medications, physicians should be aware of this possible interaction to avoid delay in the diagnosis of serotonin syndrome.

Determination of clemastine in human plasma by gas chromatography with nitrogen-phosphorus detection.

A method for the quantitative determination of clemastine in human plasma has been developed and validated. The assay uses gas chromatography with nitrogen-phosphorus detection and a HP-1 capillary column (25 mx0.22 mm, film thickness 0.33 mm) coated with dimethylpolysiloxane. Clemastine (with orphenadrine as internal standard) was isolated from human plasma using liquid-liquid extraction. A linear relationship was observed between 0.1 and 12.8 ng/ml using the peak area ratio of clemastine to orphenadrine with a correlation coefficient greater than 0.99 (the detection limit for clemastine was 0.06 ng/ml). The intra- and inter-day coefficients of variation were less than 11%. The developed method was used for the analysis of plasma samples from healthy volunteers (n = 19) to examine the pharmacokinetics of the antihistamine clemastine after single and multiple oral doses of clemastine fumarate.

Quantification of human H1 histamine receptor mRNA from peripheral blood.

STUDY OBJECTIVE: To develop a reverse transcription (RT)-polymerase chain reaction (PCR) technique to detect and quantify human histamine1 (H1) receptor mRNA in peripheral blood. METHODS: Primer pairs were based on the human H1 receptor nucleotide sequence. A competitive reference standard (CRS) was developed that used the same primers as wild-type mRNA but contained a 92-bp deletion. RT-PCR was performed with 5 microg of total RNA obtained from venous blood of six subjects that was added to known concentrations of CRS RNA. Linear regression comparing wild-type with CRS product was used to quantify wild-type mRNA. MEASUREMENTS AND MAIN RESULTS: Three subjects had detectable H1 mRNA, with a range of 31-435 pg. In three subjects PCR product was not detected, although the presence of RNA was confirmed. Redesigned primer pairs showed mRNA to H1 receptor in two of the remaining subjects, but it was undetectable in the third. CONCLUSION: RT-PCR can be used to detect and quantify human H1 receptor mRNA from peripheral blood.

Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes.

Anticholinergic effects are presumed to be the mechanism for the efficacy of chlorpheniramine in symptomatic relief of the common cold. Terfenadine, a second-generation antihistamine, reportedly lacks anticholinergic side effects. We evaluated affinities of two commonly used over-the-counter antihistamines, brompheniramine and chlorpheniramine, as well as terfenadine in comparison with atropine at the five human muscarinic cholinergic receptor subtypes using CHO cells stably transfected with the individual subtypes. Atropine was more potent than all three drugs at m1-m5 (p<0.01). No significant difference was observed between chlorpheniramine and brompheniramine. Atropine, brompheniramine, and chlorpheniramine could not discriminate between m1-m5. Terfenadine demonstrated subtype selectivity at m3. In vitro comparisons in human muscarinic receptor subtypes could potentially be used to predict clinical anticholinergic effects of antihistamines and to target receptor-specific effects of such agents.

Adenosine A1-receptor occupancy predicts A1-receptor antagonist effects of N-0861.

OBJECTIVE: To evaluate the relationship between dose of N-0861 ([+/-]N6-endo-norbornan-2-yl-9-methyladenine), N-0861 plasma concentrations, and antagonism of adenosine-induced slowing of atrioventricular nodal conduction and to evaluate A1-receptor occupancy by antagonist present in plasma of subjects after administration of N-0861 to determine A1-selectivity of these effects. METHODS: The study was conducted in patients undergoing a clinically indicated electrophysiology study to evaluate atrioventricular nodal conduction. Nineteen subjects were enrolled in the study and received adenosine (60 to 140 microg/kg) before or during a bolus dose and maintenance infusion of specific doses of N-0861. Adenosine-induced slowing of atrioventricular nodal conduction was determined by measuring A-H intervals on the intracardiac electrocardiograms. Plasma concentrations of N-0861 were determined with an HPLC method. A1-Receptor occupancy by antagonist present in plasma from identical time points was determined with use of a radioreceptor assay. RESULTS: A linear relationship was shown between plasma concentration and dose of N-0861. A-H interval lengthening by 60 microg/kg adenosine was reduced by administration of N-0861. A linear relationship was observed between A1 occupancy and N-0861 concentration and between occupancy and antagonism of adenosine-induced A-H prolongation. CONCLUSION: The results suggest that the effect of N-0861 on antagonism of adenosine-induced prolongation of A-H interval, at the doses used in this study, were the result of effects at the A1 receptor.

Amiodarone-induced lymphocyte toxicity and mitochondrial function.

Amiodarone is one of the most effective antiarrhythmic drugs available. However, its use is often limited by potentially life-threatening toxicities, including hepatotoxicity and pulmonary toxicity. We have used human lymphocytes as a system in which to study amiodarone-induced cytotoxicity. Using a tetrazolium dye reduction assay, we observed amiodarone-induced cytotoxicity with a lethal dose (LD)50 of 10.0 +/- 31.1 microM (mean +/- SD, n = 5) with a cellular concentration of 2.2 +/- 0.2 million/ml and of 55.5 and 39.2 microM with cellular concentrations of 8.9 and 7.2 million/ml, respectively, after only 2.75 h of drug exposure. Damage to mitochondria, but not other organelles, was observed with electron microscopy at an amiodarone concentration of 7.3 microM. Alterations in ATP synthesis and lactate dehydrogenase (LDH) release from cells had concentration-response curves similar to those for cytotoxicity. However, we did not observe extracellular accumulation of adenine nucleotides. These results suggest that amiodarone may have a direct toxic effect on mitochondria, beginning at < 10 microM, with membrane-damaging effects at higher drug concentrations.

Chlorpheniramine plasma concentration and histamine H1-receptor occupancy.

The plasma concentration-response relationship of the antihistamine chlorpheniramine is poorly characterized. This study examined concurrently the concentrations of chlorpheniramine and presence of H1-receptor antagonist in plasma after administration of 8 mg chlorpheniramine in normal volunteers. Six extensive metabolizers and five poor metabolizers, as judged by CYP2D6 phenotype (dextromethorphan metabolic ratio), were enrolled in the study. More than 80% occupancy of H1-receptors by antagonist in plasma was observed for 12 hours after the dose in extensive metabolizers and greater than 60% from 12 to 30 hours in poor metabolizers, when plasma concentrations had fallen below those that should result in 50% occupancy of receptors. The results suggest that (+/-)-chlorpheniramine plasma concentrations do not predict H1-receptor antagonist in plasma. In addition, a role is suggested for CYP2D6 in formation of a potent active metabolite of chlorpheniramine.

Reducing inappropriate prescribing of sublingual nifedipine.

OBJECTIVE: To report a program to reduce the practice of prescribing sublingual nifedipine. MONITORING AND EDUCATIONAL PROGRAM: Pharmacy records were used to identify orders for sublingual nifedipine at Georgetown University Medical Center. Initial review showed 30-40 orders/month, or approximately 11% of all nifedipine orders. A newsletter was published outlining Pharmacy and Therapeutics Committee guidelines for the use of nifedipine when rapid onset of action is desired. Further educational efforts involved correspondence with each attending physician responsible for the sublingual nifedipine orders. A reduction in orders for sublingual nifedipine to approximately 10 orders/month (3.9% of total nifedipine orders) was observed after using this educational approach. The reduction in orders has been maintained by frequent contact with the attending physicians. CONCLUSIONS: Repeated educational measures have resulted in a reduction in the inappropriate prescribing of sublingual nifedipine.

d-sotalol reduces heart rate in vivo through a beta-adrenergic receptor-independent mechanism.

d-Sotalol was developed as an antiarrhythmic agent with a relative lack of antagonist activity at beta-adrenergic receptors. Exercise heart rate reduction has been observed after administration to humans. The purpose of this study was to determine directly whether this effect of d-sotalol was attributable to beta-blockade. Plasma samples from normal volunteers who randomly received either atenolol, d-sotalol, or placebo were used in an in vitro radioreceptor assay to determine occupancy of beta 1-adrenergic receptors by antagonist present in the plasma. Occupancy was compared with the observed pharmacologic effects. A reduction in exercise heart rate of 7.7% +/- 3.8% for d-sotalol and 15.9% +/- 3.0% for atenolol occurred with beta 1-adrenergic receptor occupancy of 0% and 33.9% +/- 21.4%, respectively. Absence of antagonist effect in the radioreceptor assay eliminates the potential role of beta 1-blockade in d-sotalol-induced heart rate reduction. This effect is most likely a result of prolongation of the sinus node action potential duration.

Nimodipine in the treatment of subarachnoid hemorrhage.

Nimodipine, a calcium-channel antagonist with a relatively selective vasodilatory effect on cerebral blood vessels, has recently been approved for improvement of neurologic deficits due to spasm following subarachnoid hemorrhage. Nimodipine has low oral bioavailability (2.7-27.9 percent), a short half-life (2 h), is highly protein bound (98-99 percent), and is hepatically metabolized. Clinical studies have evaluated topical, intravenous, and oral administration of nimodipine for the treatment of cerebral artery spasm associated with subarachnoid hemorrhage. These studies document some benefit of the drug in reducing the occurrence of severe neurologic deficit, although this effect is not universal. Few adverse effects have been noted. Further studies are necessary to evaluate the pharmacologic and pharmacokinetic characteristics, the appropriate dose and route of administration, adverse effects, drug interactions, and the therapeutic efficacy of nimodipine before routine use can be recommended.