Measurement of human cerebral blood flow with [15O]butanol and positron emission tomography.

Although H2(15)O is widely used for CBF measurement by positron tomography, it underestimates CBF, especially at elevated flow rates. Several tracers, including butanol, overcome this problem, but the short half-life of 15O provides advantages that cause water to remain the tracer of choice. We report the first use and evaluation of 15O-labeled butanol for CBF measurement. Flow measurements made in a similar fashion with water and butanol at 10-min intervals were compared in normal volunteers under resting and hypercapnic conditions. Regional analysis showed good agreement between the tracers at low flows, and significant underestimation of flow by water relative to butanol in regions of elevated flow. The observed relationship between the tracers and the curve-fitted permeability-surface area product for water (133 ml.100 g-1.min-1) follow the known relationship between water and true flow. These observations indicate that [15O]-butanol provided accurate measurements of human regional CBF under conditions of elevated perfusion. We conclude that butanol is a convenient and accurate method for routine CBF determination by positron emission tomography.

Comparison of the effect of temafloxacin, ciprofloxacin, or placebo on cerebral blood flow, glucose, and oxygen metabolism in healthy subjects by means of positron emission tomography.

STUDY OBJECTIVE: To determine the cause of the central nervous system effect of the fluorinated quinolones temafloxacin and ciprofloxacin by measuring cerebral blood flow and metabolism by use of positron emission tomography. DESIGN: This was a prospective, randomized, double-blind, placebo-controlled study. PATIENTS: The patients were 13 healthy, nonsmoking volunteers whose ages ranged from 18 to 40 years. RESULTS: We measured brain blood flow and metabolism by use of positron emission tomography before and after a five-dose course of 750 mg ciprofloxacin, 600 mg temafloxacin, or placebo given every 12 hours. Quinolone administration produced no significant effect on visual (qualitative) reading of the positron emission tomography scans. CONCLUSIONS: We conclude that short-term administration of temafloxacin, ciprofloxacin, or placebo does not significantly alter cerebral glucose or oxygen metabolism. Subjects treated with ciprofloxacin demonstrated a significant decrease in brain blood flow compared with baseline and with temafloxacin- or placebo-treated subjects.

Global cerebral blood flow, blood volume, and oxygen metabolism in patients with migraine headache.

OBJECTIVE: Migraine headaches with and without aura are representative of vascular headache states traditionally thought to be mediated by alterations in vascular tone. Validation of this theory has been hampered in part by technical difficulties inherent in the measurement of cerebral blood flow (CBF). The purpose of this study was to compare CBF measured during migraine and migraine-free states using PET. METHODS: Patients with a minimum of one migraine headache without aura per month (International Headache Society [IHS] criteria) underwent measurement of CBF, cerebral blood volume (CBV), oxygen extraction, and metabolism during an episode of spontaneous migraine headache. Imaging was repeated during a migraine-free period of at least 48 hours. PET radiotracers used were: CBF, H(2)15O; CBV, C15O; oxygen metabolism, 15O2. RESULTS: In nine patients (seven female and two male), global CBF (mL/min/100 g [SD]) was measured as 52.70 (6.9) during migraine and 59.65 (10.6) in the migraine-free state; p=0.028. CBV (mL/100 g [SD]) was 3.6 (0.43) during the symptomatic state and 3.8 (0.55) after the migraine; p=0.047. Oxygen metabolism (mL/min/100 g [SD]) was 3.68 (0.9) during migraine and 3.38 (1.02) without headache; p=0.211. The oxygen extraction ratio was 0.48 (0.15) and 0.41 (0.12) during migraine and migraine-free states, respectively; p=0.132. CONCLUSIONS: In patients experiencing migraine without aura, CBF and CBV are reduced during the headache phase. Cerebral oxygen metabolism and oxygen extraction are not significantly affected.

High-dose cyclophosphamide-induced myocardial damage during BMT: assessment by positron emission tomography.

Despite its potential to cause myocardial damage, high-dose CY in doses up to 200 mg/kg is an integral part of preparative regimens for BMT. Conventional tests, such as an electrocardiogram or echocardiogram, have lacked sensitivity in prediction of cardiotoxicity in this patient population. We prospectively compared serial electrocardiograms and positron emission tomography scans before and after CY administration to investigate the possible changes in 13N-ammonia perfusion and 18F-2-deoxyglucose metabolism after CY administration in 12 consecutive patients undergoing BMT. Neither global nor regional changes in myocardial N-13 ammonia and 18-fluorodeoxyglucose were significant when compared with baseline studies and control studies (p < 0.05). In a single patient, however, a substantial increase in 13N-ammonia perfusion was seen in the inferior region simultaneously with electrocardiographic T wave inversions in the inferior leads. These changes may be due to alterations in myocardial blood flow or membrane permeability. PET scanning may be a useful adjunct in evaluating CY cardiotoxicity, although further investigations are needed to elucidate its role in clinical practice.

An assessment of cerebral blood flow and metabolism after fleroxacin therapy.

Cerebral blood flow (CBF), glucose (FDG), and oxygen metabolism (OM) were evaluated by positron emission tomography (PET) in 18 healthy volunteers who were randomized to a 72-hour course of either 600 mg/d of fleroxacin or placebo. Such studies attempted to assess potentially serious, yet unexplained, central nervous system adverse effects of the fluorinated quinolone class. Baseline and postplacebo values for CBF (mL/min/100 g) and FDG (mg/min/100 g) were: 53 +/- 6 and 5.7 +/- 1.8; and 49.6 +/- 4.4, and 5.2 +/- 1.2, respectively. Identical values for fleroxacin were: 53.9 +/- 4.8 and 6.3 +/- 1.1; and 54.4 +/- 2.2 and 6.8 +/- 1.5, respectively. The differences between fleroxacin and placebo were not significant. There was also no effect seen in OM between placebo and the active drug. The authors conclude that short-term administration of fleroxacin does not alter CBF, FDG, or OM in healthy volunteers.

Assessment of the effects of ciprofloxacin and nalidixic acid on cerebral blood flow and metabolism in healthy subjects by positron emission tomography.

STUDY OBJECTIVES: The mechanism by which the fluorinated quinolones produce central nervous system effects is unknown. Using positron emission tomography (PET), we evaluated the effects of two quinolones on brain blood flow as well as on oxygen and glucose metabolism. These determinations were done in conjunction with ophthalmologic and neuro-ophthalmologic testing. DESIGN: Randomized, double-blind, placebo-controlled, 7-day course of ciprofloxacin 750 mg (C750) or 500 mg (C500) every 12 hours, or nalidixic acid (NA) 1 g every 6 hours. POPULATION: Twenty-four healthy male volunteers, six in each treatment arm. RESULTS: [table: see text] CONCLUSIONS: Compared with baseline values, NA significantly reduced brain glucose uptake, whereas C500, C750, and placebo produced no detectable effect. No compound significantly altered brain blood flow or oxygen metabolism compared with baseline or other treatments. No significant effect on electroretinographic, electro-oculographic, or other neuro-ophthalmologic tests was observed.

Comparative assessment of the effect of lomefloxacin, ciprofloxacin, and placebo on cerebral blood flow, and glucose and oxygen metabolism in healthy subjects by positron emission tomography.

The mechanism by which the fluorinated quinolones produce central nervous system (CNS) effects is currently unknown. We measured the effect of lomefloxacin on cerebral blood flow and metabolism using positron emission tomography. Eighteen healthy, nonsmoking volunteers were randomized to receive lomefloxacin 400 mg, ciprofloxacin 750 mg, or placebo given in a single-blind fashion every 12 hours for 72 hours, the time window for maximum lomefloxacin CNS effects. Subjects receiving lomefloxacin had a mean (+/- SEM) cerebral blood flow (CBF) of 46 (2.9) ml/min/100 g, glucose metabolism (FDG) 4.7 (0.4) mg/min/100 g, oxygen metabolism (OM) 3.3 (0.3) ml/min/100 g, and oxygen extraction (%OM) 0.4 (0.04). Posttreatment values were 43 (3.6) ml/min/100 g, 4.2 (0.4) mg/min/100 g, 2.6 (0.3) ml/min/100 g, and 0.4 (0.03), respectively. Values for subjects receiving ciprofloxacin were CBF 44.8 (1.6) ml/min/100 g, FDG 4.9 (0.7) mg/min/100 g, OM 4.1 (0.4) ml/min/100 g, and %OM 0.6 (0.03) at baseline, and 40.3 (3.5), 4.5 (0.6), 3.4 (0.4), and 0.5 (0.09), respectively, after treatment. For placebo-treated subjects, baseline values were CBF 41.4 (1.9) ml/min/100 g, FDG 4.9 (0.5) mg/min/100 g, OM 3.3 (0.4) ml/min/100 g, and %OM 0.5 (0.07), and respective posttreatment values were 42.1 (2.3), 5.0 (0.6), 3.5 (0.3), and 0.5 (0.02). No effect was observed on visual (qualitative), blinded reading of the scans. No significant effect on cerebral blood flow or metabolism was detected. We conclude that short-term administration of lomefloxacin or ciprofloxacin to healthy volunteers does not have a significant effect on cerebral blood flow, or on oxygen or glucose metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized, prospective trial of fenoldopam vs sodium nitroprusside in the treatment of acute severe hypertension. Fenoldopam Study Group.

OBJECTIVE: To compare the safeties and efficacies of IV fenoldopam (FNP) vs sodium nitroprusside (NTP) in severe acute hypertension. METHODS: A prospective, randomized, open-label, multicenter international trial, at 24 academic medical centers, was conducted. The participants were adult patients (21-80 years of age) who had supine diastolic blood pressures (DBPs) > or = 120 mm Hg, were capable of written informed consent, and did not have selected exclusion criteria. The subjects were randomized to either FNP or NTP therapy; DBP was titrated to 95-110 mm Hg, or a maximum reduction of 40 mm Hg for very high pressures. Infusions were maintained for at least six hours, then the patients were weaned off the IV therapy and oral medication was started. Measurements included BP, heart rate, and duration of study drug infusion and frequency of side effects or complications. RESULTS: A total of 183 patients (90 FNP, 93 NTP) were enrolled. Fifteen patients from each arm were excluded from efficacy analysis due to protocol violation. There was no significant difference in baseline characteristics. The two antihypertensive agents were equivalent in controlling and maintaining DBP. Systolic blood pressure (SBP) was reduced to a slightly greater degree for the NTP-treated patients during the initial (0.5-1-hr) study period, and both SBP and DBP were reduced more for the FNP-treated patients in the subset receiving infusions during the 12-24-hour period. The adverse effect profiles of the drugs were similar, as were the times to achieve target pressure, with no clinically relevant difference. CONCLUSIONS: For patients who had acute severe hypertension, FNP and NTP were equivalent in terms of efficacy and acute adverse events. Because of a unique mechanism of action, FNP may have advantages in selected subsets of patients. Further studies may be indicated in patient populations with pure "hypertensive emergencies."

Regression of nifedipine-induced gingival hyperplasia following switch to a same class calcium channel blocker, isradipine.

Patients with nifedipine-induced gingival hyperplasia (GH) often require continued calcium channel blocker therapy. Switches to diltiazem and verapamil have been described; however, these drugs are of a different chemical class and present therapeutic limitations in some patients. The purpose of this study was to evaluate the effect on nifedipine-induced GH of a switch to a dihydropyridine derivative with a low incidence of GH. Fourteen patients with nifedipine-induced GH were given a medical exam and a periodontal exam. The following parameters were assessed: probing depth (PD), gingival margin (GM), gingival thickness (GT), plaque index (PI), and gingival index (GI). Intraoral photographs, study models, and a gingival biopsy for histological examination were taken. Following baseline measures, patients were randomized to continued treatment with nifedipine or an equivalent dose of isradipine in a single-blind fashion. Biweekly periodontal parameters were taken for 8 weeks. At the end of 8 weeks, some patients elected to receive 4 weeks of open label isradipine therapy, with biweekly examination continuing through the open label phase. The isradipine treatment arm showed a mean decrease in PD of 0.59 mm at week 8 (P < 0.05). No other measured parameter (GM, GT, PI, GI) was significantly changed, compared either to baseline or to the alternate treatment arm. Clinically, 60% of patients treated with isradipine exhibited a decrease in hyperplasia, while 66% of patients treated with nifedipine demonstrated an increase in hyperplasia, a significant difference (P < 0.05). When combined with open label data, patients switching therapy to isradipine exhibited an increase in GM (increase in recession) of 0.74 mm from baseline to week 12 (P < 0.05). No patients treated with isradipine exhibited an increase in gingival overgrowth. All patients exhibited adequate control of hypertension. We conclude that in hypertensive patients with nifedipine-induced GH, switching hypertensive therapy to isradipine may result in a regression of GH. When coupled with aggressive oral hygiene treatment, this drug may provide a reasonable option for patients requiring dihydropyridine treatment.

Establishment of a drug information service on a public-access computer bulletin board.

OBJECTIVE: Computerized bulletin board services (BBSs) have existed for several decades; in recent years there has been increased use and acceptance. We have established a drug information service called The Pharmacy on a local public-access BBS, the Cleveland FreeNet. The goal of this service is to provide drug information to the lay public as well as healthcare professionals. DESCRIPTION: The Pharmacy is divided into 4 areas: (1) About the Pharmacy, which provides instructions for use; (2) Drug Information, which contains postings on selected drug information topics that are prepared by the BBS staff; (3) Pharmacy Questions, the most popular feature, where FreeNet users are invited to post questions, the answers to which are provided by clinical, staff, and consultant pharmacists, as well as baccalaureate and graduate pharmacy students; and (4) Investigational Studies, where patient recruitment for investigational studies is done. RESULTS: A total of 259 questions have been posted in the first 3 years of operation. An average of 5.2, 7.78, and 8.7 questions/month have been posted in 1992, 1993, and 1994, respectively. Four drug information monographs have been prepared and posted, and approximately 5 investigational studies have been advertised. CONCLUSIONS: A computerized BBS is a new means of distributing drug information to the public and healthcare professionals. In addition to meeting a need for a public service of drug information in the community, it permits increased visibility for pharmacists and a unique learning experience for students.

Positron emission tomography: from production and distribution to drug research and clinical applications.

The radiopharmaceutical FDG has had a major impact on PET imaging in clinical medicine, particularly in the detection and staging of certain cancers. PET isotopes offer unparalleled insight into in vivo distribution of labeled drugs. PET imaging of blood flow, metabolism, and neuroreceptor characteristics may provide new perspectives on the mechanism of action and effects of drugs.

Anaphylactic reaction to streptokinase with first exposure: case report and review of the literature.

Thrombolytic therapy has become an accepted part of the management of acute myocardial infarction. One agent with widespread use in this setting is streptokinase. We report the case of a 62-year-old man who experienced an anaphylactic reaction with cardiopulmonary arrest immediately after receiving streptokinase 1.5 million units iv administered for an acute anterior wall myocardial infarction. The patient had no history of prior exposure to streptokinase, chronic allergic reactions, or reactive airway disease. Five other cases of anaphylaxis to streptokinase are also reviewed.

Principles and clinical applications of positron emission tomography.

The basics of positron emission tomography (PET) are presented, including the physics, instrumentation, and radiopharmaceuticals involved; the clinical and research applications; and the cost. In PET, organic molecules labeled with positron-emitting radionuclides are injected or inhaled, and the high-energy photons produced by annihilation events are detected by paired, integrated crystal detectors. A computer uses the lines of origin of these photons to reconstruct a three-dimensional map of a functioning organ system. The positron-emitting radionuclides most often used are carbon 11, oxygen 15, nitrogen 13, fluorine 18, and rubidium 82. PET imaging centers usually consist of a cyclotron facility, a radiochemistry facility, a PET scanner, and computers for image reconstruction. Radiopharmaceuticals used in PET may be divided into blood flow-imaging agents, metabolic imaging agents, and drug receptor-imaging agents. Although PET is still primarily a research tool, it has shown diagnostic potential in neurology, cardiology, and oncology. It has also shown promise as a tool for pharmacologic assessment, as in studies of the effects of the fluorinated quinolones on cerebral blood flow and glucose metabolism. PET may become important in drug development because it yields specific information relatively noninvasively. A single study carries an average break-even price tag of $1500-$2000; rigorous cost-benefit analyses should be conducted before society is asked to subsidize such costs. Positron emission tomography is a frontier technology for which valuable clinical applications are being discovered. Pharmacists can contribute enormously to PET applications and at the same time establish a unique subspecialty for the profession.

Brain blood flow in the nitroglycerin (GTN) model of migraine: measurement using positron emission tomography and transcranial Doppler.

Nitroglycerin has been widely used as a model of experimental migraine. Studies combining measurement of flow velocity using transcranial Doppler (TCD) concurrently with measures of cerebral blood flow (CBF) are uncommon. We report the results of a study combining TCD and positron emission tomography (PET). Healthy volunteers with no personal or family history of migraine underwent measurement of CBF using H215O PET, and velocity using TCD. Measurements were done at baseline, and following i.v. nitroglycerin at 0.125, 0.25 and 0.5 micro g/kg per min. Subcutaneous sumatriptan (6 mg) was injected, with CBF and velocity measured 15, 30, and 60 min later. Nitroglycerin was terminated and measurements obtained 30 min later. Six male and six female subjects were studied. Nitroglycerin increased global CBF while flow velocities decreased. Sumatriptan did not have a significant effect on these values. Regions of increased flow included the anterior cingulate, while regions of decreased flow included the occipital cortex. Our data suggest that nitroglycerin induces regional changes in CBF that are similar to changes reported in spontaneous migraine, but produces distinctly different effects on global CBF and velocity.

Hyperventilation-induced reduction in cerebral blood flow: assessment by positron emission tomography.

The use of positron emission tomography (PET) has been well documented as a relatively noninvasive method of measuring cerebral blood flow (CBF), both globally and regionally. The utility of readily detecting alterations in CBF is apparent, particularly when applied to the evaluation of therapeutic interventions thought to influence CBF. We report the effects of hypocapnia, an experimental condition of known cerebral vasoconstriction, in ten normal volunteers. Subjects had brain blood flow evaluated utilizing H215O as the positron emitter before and after approximately five minutes of hyperventilation. Baseline CBF was measured as a mean +/- SD of 61.2 +/- 16.3 mL/min/100 g of tissue. Mean baseline arterial blood gas values were PaO2 107.4 +/- 14 mm Hg, PaCO2 37.7 +/- 0.89 mm Hg, and pH 7.39 (calculated from mean [H+]). Post hyperventilation, global CBF was measured as 31.1 +/- 10.8 mL/min/100 g. Mean arterial blood gas values were PaO2 141.7 +/- 21 mm Hg, PaCO2 19.7 +/- 5 mm Hg, and pH 7.63 (calculated from mean [H+]). CBF decreased by a mean of 49.5 +/- 11 percent. Data analysis using the Student's t-test showed a significant change over baseline in PaCO2 (p less than 0.001) and CBF (p less than 0.001), in the hyperventilated state. Correlations were noted between the decrease in CBF and change in PaCO2 (r = 0.81) as well as between hyperventilation PaCO2 and the change in CBF (r = 0.97). We conclude that, as measured by PET, CBF decreases significantly during a state of artificial hyperventilation to a degree consistent with results seen using other methods. PET appears to be a valuable tool in the assessment of interventions that could influence CBF.

Assessment of intravenous fenoldopam mesylate in the management of severe systemic hypertension.

To evaluate the acute BP response to iv fenoldopam mesylate (FNP), 14 patients with severe hypertension (diastolic BP 120 to 170 mm Hg) were studied in an open-label trial. Initial infusion rate of FNP was 0.1 microgram/kg.min. Titration to diastolic BP goal (95 to 110 mm Hg) was followed by a constant infusion phase (greater than or equal to 6 h), a detitration phase (2 h), and a postinfusion phase. FNP reduced BP by 27/29 mm Hg (p less than .001) with no significant effect on heart rate. Maintenance of the BP effect was noted through the 6 h of constant rate infusion. Mild, transient vasodilating-associated adverse effects were noted with FNP. We conclude that FNP is an effective, well-tolerated iv antihypertensive agent for acute BP reduction in a severely hypertensive population.