Lack of effect of reboxetine on cardiac repolarization.

OBJECTIVE: The effect of reboxetine on electrocardiographic parameters, particularly the QTc interval, was assessed in 20 healthy subjects (15 male, 5 female). METHODS: In a 5-way crossover study, subjects received placebo, 2 mg, 4 mg, or 6 mg reboxetine, or 6 mg reboxetine and 200 mg ketoconazole twice daily for 7 days. Plasma samples, vital signs, and 12-lead electrocardiograms (ECGs) were obtained during one dosing interval of days 1, 4, and 7. Additional ECGs were recorded immediately after an exercise paradigm, so that the RR versus QT relationship might be used in calculating QTc. Plasma concentrations of R,R (-)reboxetine and the more active S,S (+)reboxetine were measured by HPLC-dual mass spectrometry. RESULTS: No statistically significant differences among treatments in mean dose-corrected pharmacokinetic parameters were observed, except that the dose-corrected area under the concentration-time curve from time zero to 12 hours and the peak plasma concentration were significantly increased on days 4 and 7 in the presence of ketoconazole. As expected, heart rate increased from baseline (approximately 8-11 beats/min) at > or =8 mg reboxetine daily. No statistically significant prolongation of QTc (Fridericia correction) occurred after any of the treatments. No relationships between DeltaQTc and plasma concentrations of reboxetine enantiomers were apparent. Similar results were obtained with Bazett's correction and two linear corrections that relied on exercise data generated before drug administration. CONCLUSIONS: Reboxetine, at systemic exposures approximately twice the recommended dose, did not significantly affect cardiac repolarization in healthy subjects. Use of QT versus RR relationship in the drug-free state to correct QT for heart rate in the drug-treated state may provide an acceptable alternative to classic correction equations.

Pharmacokinetics and tolerability of a novel 5-HT1D agonist, PNU-142633F.

OBJECTIVES: The objectives of this study were to characterize the safety, tolerability and pharmacokinetics of a single, oral dose of PNU-142633F escalating over the range of 1.0 mg to 100 mg (free base equivalents). METHODS: This was a randomized, double-blind, single-dose, placebo-controlled, dose-escalation trial, with each dose group (1.0, 3.0, 10, 30, 50, 75 and 100 mg) having eight volunteers (six PNU-142633F and two placebo). Clinical laboratory tests, electrocardiogram, Holter monitoring, and assessment of adverse events were used to gauge the tolerability of PNU-142633. Serial blood samples and urine collections were obtained and plasma and urine PNU-142633 concentrations were determined by a validated HPLC fluorescence method. RESULTS: PNU-142633 was well tolerated after oral administration. There were no reports of serious or unexpected adverse events. The most common adverse event that was possibly medication-related was transient dizziness. There were no clinically significant or dose-related effects of PNU-142633 on any vital sign parameters (aural temperature, systolic and diastolic blood pressure, pulse rate or respiratory rate), at any study time or dose. There were no clinically significant ECG changes. Only sporadic abnormalities in clinical chemistry values and hematology were noted. After the 1.0 mg and 3.0 mg doses, plasma concentrations of PNU-142633 were either below or only slightly above the lower limit of quantitation (2 ng/ml). At higher doses (30-100 mg) the terminal half-life was relatively constant at approximately 11 hours. Neither Cmax nor AUC(0-infinity) increased proportionally with the administered dose. The mean percentage of the dose excreted in the urine as intact PNU-142633 increased from 14.3% after the 1 mg dose to 49.3% after the 100 mg dose. CONCLUSIONS: The clinical safety and pharmacokinetic data support the study of this agent as a potential treatment for migraine attacks.

Effect of systemic corticoid and antihistamine alone or in combination on elements of the response to a two dose nasal allergen challenge.

This study examined the effects of low dose systemic corticoid (methylprednisolone, MP), standard dose antihistamine (terfenadine, TF) or the combination on response to out-of-season acute allergen challenge. We feel that a single dose challenge delivered to the nose may represent real disease imperfectly and in this study used two doses given 1 hour apart, hoping to approximate better the circumstances of natural allergen stimulation. The study used clinical endpoints only: measured nasal airway resistance (NAR), sneeze count, and weight of blown nasal secretions. Subjects showed similar NAR, sneezing, and secretion response to both challenges. With placebo treatment, NAR rose after the first allergen provocation and returned to baseline about 30 minutes later. Antihistamine pretreatment appeared to delay but did not prevent this rise; low dose corticoid partially inhibited it, and the combination totally ablated the response. All active treatments suppressed sneezing and secretion better than placebo. Combination corticoid/antihistamine treatment showed no greater effect on sneeze/ secretion than did antihistamine alone; this differs from our findings in separate studies comparing analogous drug combinations in naturally-acquired ragweed hayfever.

Physiology and pharmacokinetics of a novel hemoglobin-based oxygen carrier in humans.

OBJECTIVE: To evaluate the physiology and pharmacokinetics of a novel hemoglobin-based oxygen carrier of bovine origin. DESIGN: Randomized, single-blind, placebo-controlled, dose-escalation study. SETTING: The Upjohn Research Clinics (Kalamazoo, MI). SUBJECTS: Normal healthy adult men between the ages of 18 and 45 yrs. There were 18 subjects who received active treatment and 23 controls. INTERVENTIONS: All subjects had phlebotomy of 15% of blood volume (performed in <15 mins) followed by isovolemic hemodilution (3:1, Ringer's lactate to the volume of whole blood removed) over a 90-min period, and either active drug (polymerized bovine hemoglobin) or a control infusion of lactated Ringer's solution (each infusion given over a total of 4.3 hrs). The subjects randomized to active treatment received a loading dose and a continuous infusion of polymerized bovine hemoglobin for a total dose of 16.5, 24.1, 30.2, 38.0, or 45.0 g. All subjects had an indwelling radial artery catheter (for blood pressure and arterial blood gas measurements), determination of cardiac function (by impedance plethysmography), serial pulmonary function tests (spirometry and diffusion capacity), and metabolic cart measurements. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetics of the plasma bovine hemoglobin demonstrated that the elimination of the hemoglobin-based oxygen carrier was a linear, first-order process and that there was no renal excretion. Peak plasma concentrations were between 1 to 2 g/dL and plasma half-life approached 20 hrs at the highest doses given. Diffusion capacity of oxygen was increased up to 20% above baseline in the 38.0 and 45.0 g groups in comparison with controls (approximately 14% below baseline) between 2 and 24 hrs after the infusion (p < .01). Other pulmonary function tests and arterial blood gas measurements were unremarkable. Arterial oxygen content and oxygen delivery tended to be greater in active groups than in controls. CONCLUSIONS: The plasma concentrations of bovine hemoglobin were directly proportional to the doses administered. An increase in diffusion capacity paralleled the plasma bovine hemoglobin concentrations. Dosing of the hemoglobin-based oxygen carrier of bovine origin to a target plasma hemoglobin concentration can be achieved using pharmacokinetic principles with measurable effects on oxygen physiology.

Effects of a novel hemoglobin-based oxygen carrier on percent oxygen saturation as determined with arterial blood gas analysis and pulse oximetry.

STUDY OBJECTIVE: Hemoglobin-based oxygen carrier 201 (HBOC-201) is a polymerized hemoglobin of bovine origin being developed for use in hemorrhage during surgery or trauma. Pulse oximetry is commonly used in clinical practice to assess percent saturation of hemoglobin (Spo2). The ability to measure Spo2 in the presence of HBOC-201 will be important for the use of this compound in patient care. METHODS: We carried out a randomized, single-blind, placebo-controlled study at the Upjohn Research Clinics in Kalamazoo, Michigan, with normal, healthy adult men and women as subjects. The members of four groups of adult subjects (N=24) each received 45 g of HBOC-201 (nine each, men and women) or a control solution (Ringer's lactate) (three each, men and women). Each subject underwent phlebotomy (about 15% of estimated blood volume) followed by 3:1 hemodilution with Ringer's lactate and then either HBOC-201 or control solution. An indwelling arterial catheter in the radial artery was used for serial arterial blood gas sampling. Arterial blood gas measurements were made with a cooximeter (Instrumentation Laboratories). Fingertip pulse oximetry was used (Criticare 504-US; Criticare, Incorporated). Paired pulse oximetry and arterial blood gas sampling were made serially (at approximately hourly intervals) over 24 hours. RESULTS: The mean +/- SEM difference for Spo2 for arterial blood gas analysis compared with the pulse oximetry reading in the presence of HBOC-201 was 1.1% +/- 0.75%; in controls it was .1% +/- 0.64% (P<.001) for each) over the 24 hours after dosing. This relationship was constant despite increased concentrations of plasma hemoglobin (between 1 and 2g/dl [10 to 20 g/L]) in the HBOC-201 groups. CONCLUSION: Accurate determinations of Spo2 can be made with pulse oximetry in subjects given HBOC-201 over the normal range of Spo2.

Hemoglobin-based oxygen carrier preserves submaximal exercise capacity in humans.

OBJECTIVE: The objective of this study was to evaluate the exercise capacity of subjects given an autologous transfusion or a polymerized bovine hemoglobin solution to define the pharmacodynamics and pharmacokinetics of a new hemoglobin-based oxygen carrier (HBOC-201). METHODS: Six normal healthy male subjects (ages 25 to 45 years) participated in this randomized, single-blind, two-way crossover study, which took place at Upjohn Research Clinics in Kalamazoo, Mich. A radial artery catheter was inserted in each subject before serial cardiac output and pulmonary function tests and phlebotomy of 15% blood volume (750 ml plus another 250 ml for study laboratories yields 1000 ml, or about 150 gm human hemoglobin). This was followed by isovolemic hemodilution with Ringer's lactate plus an autologous blood transfusion (or HBOC-201) and 1 week later 45 gm bovine hemoglobin of HBOC-201 (or autologous transfusion). Bicycle exercise stress tests to anaerobic threshold (approximately 65% of predicted maximum aerobic capacity) were done before phlebotomy and at approximately 45 minutes after the autologous transfusion or HBOC-201 infusion. RESULTS: Subjects had similar exercise and diffusion capacity but lower lactate levels (for up to 24 hours) during HBOC-201 (which paralleled plasma HBOC-201 levels) than during autologous transfusion periods. Oxygen use (uptake) and carbon dioxide production at rest were greater during the HBOC-201 infusion than during the autologous transfusion period. The half-life of HBOC-201 was about 23 hours. CONCLUSIONS: Exercise capacity and diffusion capacity were similar after HBOC-201 and autologous transfusion. HBOC-201 resulted in greater oxygen (or uptake) and carbon dioxide production and lower lactate levels compared with autologous transfusion. Under the conditions of the study, the physiologic effects of 1 gm bovine hemoglobin of HBOC-201 were similar to 3 gm human hemoglobin from autologous transfusion.

Lifibrol: a novel lipid-lowering drug for the therapy of hypercholesterolemia. Lifibrol Study Group.

OBJECTIVE: To determine the effects of lifibrol on serum lipids in adult patients with primary hypercholesterolemia. METHODS: These were two double-blind, randomized placebo-controlled studies. Each patient in each study had an 8-week dietary lead-in period on the American Heart Association Step I diet before administration of lifibrol or placebo. The first study consisted of active dosing of 4 weeks, and the second study had 12 weeks of active dosing. The setting for the study involved outpatients in private or university hospitals in the United States. All patients had primary hypercholesterolemia with low-density lipoprotein (LDL) cholesterol levels of > 160 mg/dl after the dietary lead-in period. There were 155 patients in the 4-week study and 336 patients in the 12-week study. In the first study, patients were randomly assigned to receive either 150, 300, 450, 600, or 900 mg lifibrol as a single daily dose for 4 weeks. In the second study, patients were randomized to receive either 150, 300, or 600 mg lifibrol for 12 weeks. Efficacy was determined by serial measurements of serum lipids either on a weekly or biweekly basis during each study. RESULTS: Compared with baseline, lifibrol reduced LDL cholesterol (> 40%, p < 0.0001) and apolipoprotein B (approximately 40%, p < 0.0001) by 4 weeks in both studies. After 6 weeks, high-density lipoprotein (HDL) cholesterol levels increased in the placebo and 150 and 300 mg lifibrol groups. In the 600 mg lifibrol group, triglycerides (approximately 25%, p < 0.001), lipoprotein (a) (approximately 30%, p < 0.001), and HDL cholesterol (approximately 5%, p < 0.002) decreased. Lifibrol reduced key sterol intermediates (e.g., lanosterol, lathosterol, beta-sitosterol, and campesterol) and increased serum bile acids, but it had no effect on urinary mevalonic acid excretion. The pharmacokinetics of lifibrol are independent of dose and are similar in men and women. Lifibrol was well tolerated. The most frequent medical event in both studies was skin rash. CONCLUSIONS: Lifibrol is a potent lipid-lowering drug in patients with hypercholesterolemia.

Lack of effects of beta-carotene on lipids and sex steroid hormones in hyperlipidemics.

Beta-carotene in doses of up to 300 mg daily raises high-density lipoprotein cholesterol levels within 2 to 4 weeks in healthy subjects. The authors, in this study, investigate the short-term effects of high-dose beta-carotene upon serum lipids, lipoproteins, and selected sex steroid hormones in 59 adult patients with Type IIa or IIb hyperlipidemia and 36 healthy subjects. Volunteers took beta-carotene (300 mg) or wheat germ oil capsules daily for 30 days. Lipids were measured on days 1, 14, 21, and 30. Beta-carotene, retinol, free and total testosterone, and estradiol levels were measured on days 1 and 30. Total high-density lipoprotein cholesterol levels increased 10% (p < 0.01) over baseline in all groups by day 14 but returned to baseline by day 30. Total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels transiently increased between days 14 and 21 by up to 9%, 8%, and 20%, respectively, only in the patients with hyperlipidemia treated with beta-carotene, but returned to baseline on day 30. Apolipoproteins A and B were unchanged. Despite 20-fold increases of plasma beta-carotene levels there, were no reports of carotenodermia and no alteration in sex steroid hormones, retinol levels, hepatic transaminases, or persistent changes in serum lipids that were attributable to beta-carotene.

Phlebotomy of 500 or 750 milliliters of whole blood followed by isovolemic hemodilution or autologous transfusion yields similar hemodynamic, hematologic, and biochemical effects.

The purpose of this study was to evaluate the effects of phlebotomy of 500 or 750 ml of whole blood followed by isovolemic hemodilution or autologous transfusion on hemodynamic, hematologic, and biochemical parameters in healthy subjects. Four groups of normovolemic male subjects (n = 6 or 7 per group), aged 18 to 41 years, participated in this 10-day study at Upjohn Research Clinics, Kalamazoo, Mich. On day 1 two groups had phlebotomy of 500 ml; of these, one group underwent immediate postphlebotomy autologous transfusion (group 1) and the other underwent immediate postphlebotomy isovolemic hemodilution and then autologous transfusion on day 3 (group 2). Two other groups had 750 ml phlebotomy, also on day 1; of these, one group underwent immediate postphlebotomy autologous transfusion (group 3) and one underwent immediate postphlebotomy isovolemic hemodilution followed by autologous transfusion on day 3 (group 4). Noninvasive measurement of vital signs, blood pressure, and cardiac function; oximetry; and select hematologic and biochemical parameters were made. On day 1 in groups 2 and 4 transient reductions in hematocrit, hemoglobin, red blood cell count, fibrinogen, and albumin were seen concurrent with prolongation of coagulation studies. Erythropoietin was increased severalfold on day 3 (groups 2 and 4, p < 0.001). The physiologic response to phlebotomy of 500 or 750 ml was similar and was well tolerated in normal subjects.

Effect of vasoconstrictor pre-treatment on obstruction, secretion and sneezing after nasal challenge with threshold and suprathreshold allergen doses.

Acute nasal allergen challenge produces airway obstruction which varies in amount and timing with the allergen dose delivered. To see whether different mechanisms might contribute variably to mucosal swelling with different amounts of allergen, we challenged sensitive volunteers with threshold and 10-times threshold allergen doses, with and without topical vasoconstrictor pre-treatment. The vasoconstrictor effectively eliminated obstruction at both allergen dose levels, suggesting that acute vascular changes were responsible for all the measurable obstruction seen with acute allergen provocation. Alpha-adrenergic vasoconstrictor pre-treatment was associated with increased weight of secretion and numbers of sneezes.

Oral methylprednisolone acetate (Medrol Tablets) for seasonal rhinitis: examination of dose and symptom response.

The authors compared the effect of several doses an oral corticosteroid on symptom profile and severity in ragweed hay fever. Thirty-one patients were randomized to receive 0, 6, 12, or 24 mg methylprednisolone (Medrol Tablets [MP], Upjohn, Kalamazoo, MI). A baseline week in which no treatment was given preceded the treatment comparison. At the end of this week, symptom diaries showed that most of the subjects were experiencing moderate or severe symptoms. The corticoid produced dose-related reduction in all symptoms. The difference between placebo and 24 mg MP was significant for all the symptoms monitored, except itching, which benefited marginally. With 6 mg MP, congestion, drainage, and eye symptoms showed significant drug-placebo differences but itching, running/blowing, and sneezing did not. Not all rhinitis symptoms responded equally to corticoid treatment. Those that responded least could reflect histamine effect, which was not effectively suppressed by low-dose, short-term corticoid treatment.

A double stopcock technique for repeated sampling of venous blood.

Repeated sampling for measurement of venous blood levels of hemoglobin, hematocrit, plasma hemoglobin, potassium and ibuprofen with a novel method of phlebotomy, the double stopcock technique (DST), was compared to heparin lock (HPL), Angiocath with obturator (AOB) and direct venipuncture (DVP) techniques. There were 12 normal subjects in this randomized, three-way crossover trial. During each portion of the crossover, simultaneous samples for hemoglobin, hematocrit, plasma hemoglobin, potassium and ibuprofen were taken from each phlebotomy site prior to and after oral dosing with 400 mg ibuprofen. The DST was the best acceptable method based on the assessment of comfort by the subjects, followed by the AOB, HPL and DVP techniques. The least amount of blood waste was with the DST. The degree of hemolysis (as shown by plasma hemoglobin and potassium) was comparable across all techniques. Across all of the techniques, measurement of hemoglobin, hematocrit and ibuprofen levels using DST, HPL and AOB yielded lower levels than DVP. These changes were small and were not clinically significant, although statistically significant in some cases. The authors conclude that when there is need for frequent, rapid and repetitive venous blood sampling with minimal blood wastage and patient discomfort, the DST should be considered.

Pharmacokinetics and pharmacodynamics of oral diazepam: effect of dose, plasma concentration, and time.

Eleven healthy subjects received single oral doses of placebo, 2 mg diazepam, 5 mg diazepam, and 10 mg diazepam in a randomized four-way crossover study. Plasma diazepam levels, the Digit Symbol Substitution Test (DSST), and fraction of total electroencephalographic (EEG) amplitude falling in the sigma plus beta (13 to 31 Hz) frequency range were determined during the 12 hours after drug administration. Peak plasma diazepam concentration and area under the 12-hour curve were proportional to dose; time of peak was independent of dose. Baseline percentage of EEG amplitude falling in the 13 to 31 Hz range averaged 15.7% and did not differ among the four trials. The percentage of EEG amplitude falling in the 13 to 31 Hz range did not change over baseline with placebo or 2 mg diazepam but was increased 1/4 to 2 1/2 hours after 5 mg diazepam, (maximum, +7.3%) and 3/4 to 12 hours after 10 mg diazepam (maximum, +15.2%). The increase in the percentage of EEG amplitude falling in the 13 to 31 Hz range was highly correlated with plasma diazepam concentration. DSST scores for placebo and 2 mg diazepam were nearly identical. DSST decrements with 5 and 10 mg diazepam paralleled and were correlated with the changes in the percentage of EEG amplitude falling in the 13 to 31 Hz range and with plasma diazepam levels. Thus the EEG analysis provides objective quantitation of benzodiazepine central nervous system effects, in turn reflecting plasma levels and other clinical measures.

Synergistic effects of oral nonsteroidal drugs and topical corticosteroids in the therapy of sunburn in humans.

The ability to modify skin injury due to ultraviolet light (UVB) by the nonsteroidal anti-inflammatory drugs (NSAIDs) oral ibuprofen (IB) or indomethacin (IN) plus topical betamethasone dipropionate (BD) was studied in 24 subjects in this open-label, four-way, cross-over trial. All subjects received UVB at weekly intervals: group 1 was randomized to IB, BD, IB + BD or control, and group 2 to IN, BD, IN + BD or control. Oral medications were given prior to and after exposure to UVB, but BD was applied only afterwards. The skin response to UVB [erythema and increased skin blood flow (SBF)] was measured serially for 96 h. A skin biopsy was taken at 24 h after each dosing with UVB. At maximum erythema (8-12 h after UVB), the following approximate reductions in SBF (compared to control responses) were noted: 42-58% for combination therapies, 33-40% for IB or IN alone, and 17% for BD alone. SBF tended to equalize across all treatments by 24 h and remained until 96 h. Skin biopsy results were consistent with the noninvasive findings. Thus, we observed a synergistic effect of reduction of UVB-induced erythema and SBF with combinations of oral NSAIDs and topical corticosteroids. This study could have implications for the therapy of sunburn in humans.

Effects of fish oil and endorphins on the cold pressor test in hypertension.

The effects of fish oil and naloxone on blood pressure, catecholamines, and endorphins during the cold pressor test were evaluated in a randomized, double-blind, placebo-controlled, two-way crossover trial of normotensive and medication-free hypertensive men (n = 13 each). Subjects were given 5 gm omega-3 fatty acids per day or placebo for 30 days with a 1-month washout between interventions. The cold pressor test (hand in ice water for 5 minutes) was done at the end of the treatment periods. Intravenous naloxone (10 mg) or placebo was given before the cold pressor test. Fish oil-treated, normotensive, or hypertensive groups had similar changes in blood pressure, plasma catecholamine levels, and beta-endorphins during the cold pressor test, but naloxone treatment was associated with fivefold and tenfold increases in plasma epinephrine and cortisol levels, respectively. Naloxone may modulate sympathomedullary discharge through blockade of endorphin activity. It is unlikely that endorphins are involved in the blood pressure increase during the cold pressor test or that fish oil alters this response.

Unilaterality of obstruction after acute nasal allergen provocation. Relation of allergen dose, nasal reactivity and the nasal cycle.

We examined unilaterality of obstruction after acute bilateral nasal allergen provocation in two groups of pollen-sensitive volunteers studied out of season. One group was challenged on one occasion with a threshold allergen dose and on another with placebo. We measured nasal airway resistance (NAR) unilaterally for 3.5 hr before the challenges and for 40 min after. Most subjects' noses had marked asymmetry of response. Over half showed marked obstruction on one side and none at all on the other side. The side which showed higher resistance and greater lability before challenge was typically more obstructed after. In a second group we compared responses to threshold and x 10 threshold doses. Threshold challenge produced results similar to those seen with the first group. After the higher allergen dose, there was some obstruction in the less responsive side and the rate of rise was much slower. Obstructive response after acute threshold allergen challenge is typically one-sided. This pattern may be related to the stage of the nasal cycle in which the challenge was delivered. Higher allergen doses produce more obstruction in the less responsive side but the response is still asymmetrical.

Evaluation of intraosseous vs intravenous antibiotic levels in a porcine model.

OBJECTIVES: To compare intraosseous vs intravenous routes of administration and their effects on serum levels of four antibiotics in an animal model. DESIGN: Prospective controlled study comparing two routes of drug administration. SETTING: Research laboratories of a large pharmaceutical company. PARTICIPANTS: Twenty male and female domestic swine weighing 10 to 20 kg. INTERVENTIONS: The animals were anesthetized and treated with controlled ventilation. The animals were divided into one of four groups: (1) intravenous and intraosseous cefotaxime sodium (50 mg/kg), (2) intravenous and intraosseous chloramphenicol sodium succinate (25 mg/kg), (3) intravenous and intraosseous vancomycin hydrochloride (15 mg/kg), or (4) intravenous and intraosseous tobramycin sulfate (2.5 mg/kg). There was a 24-hour clearance period for groups 1 and 2 and a 48-hour clearance period for groups 3 and 4. Serum drug levels were measured at 1, 15, 30, 45, 60, 90, and 120 minutes after intravenous and intraosseous administration of the respective antibiotics. Control and treated tibias were sampled for drug levels at the end of the experiment. MEASUREMENTS AND MAIN RESULTS: - Peak serum concentrations for intravenously administered antibiotics were within the therapeutic range. Peak serum levels after intravenous and intraosseous administration were 102 and 82 mg/L, respectively for cefotaxime; 13.9 and 6.3 mg/L, respectively, for chloramphenicol; 24.5 and 3.8 mg/L, respectively, for vancomycin; and 7.1 and 1.3 mg/L, respectively, for tobramycin. CONCLUSIONS: Cefotaxime may be administered intraosseously when intravenous access is not possible. We cannot recommend chloramphenicol or vancomycin for intraosseous administration, because serum levels were not comparable with those following intravenous administration. Findings with tobramycin suggested a lack of achievement of serum levels comparable with those following intravenous administration.

Beta-carotene's effects on serum lipoproteins and immunologic indices in humans.

Doses of beta-carotene for cancer-prevention trials have been chosen based on epidemiologic data. Mechanisms of the putative antineoplastic effects by beta-carotene are unknown but may involve modulation of the immune system. We measured plasma carotenoid concentrations and selected immunologic indices at baseline and at 2 and 4 wk in 50 healthy humans (5 groups of 10 each) ingesting 0, 15, 45, 180, or 300 mg beta-carotene/d for 1 mo in this randomized placebo-controlled, open-label, parallel study. Plasma beta-carotene concentrations were markedly increased by 2 wk and were correlated with dose. Beta-carotene concentrations plateaued between 2 and 4 wk except for the 300-mg group. Thus, we developed a dose-concentration curve to optimize beta-carotene-dose selection to achieve target plasma concentrations. We were unable to identify any effects of beta-carotene ingestion on the immunologic indices studied, but modest increases in high-density-lipoprotein cholesterol were observed in all beta-carotene-treated groups.