Evaluation of dextrose 50 % as a medium for injection-assisted polypectomy.

BACKGROUND AND STUDY AIMS: Injection-assisted polypectomy (IAP) is traditionally carried out by using normal saline as the submucosal fluid cushion. However, normal saline, being isotonic, does not maintain the elevation of the mucosa for prolonged periods. It was hypothesized that dextrose 50 %, as a hypertonic solution, might be an ideal medium for IAP. This study evaluated the efficacy and safety of dextrose 50 % for performing IAP. PATIENTS AND METHODS: All patients undergoing IAP during gastroscopy or colonoscopy were randomly assigned on a prospective basis to receive either normal saline or dextrose 50 % as the submucosal fluid cushion. The endoscopist was blinded to the type of solution injected. The volume of solution and number of sites injected to elevate the lesion, the number of times IAP was interrupted to inject more fluid to maintain elevation, the rates of en bloc and complete resections, and the complication rates were compared in the two groups. The mean follow-up period was 10 months. RESULTS: Fifty-two sessile lesions were removed in 50 patients. In comparison with normal saline, smaller volumes (median 7 ml vs. 5 ml; P = 0.02) and fewer injections (median 2 vs. 1; P = 0.003) were required to perform IAP when dextrose 50 % was used. The en bloc resection rate was higher with dextrose 50 % than with normal saline (82 % vs. 44 %; P = 0.01). Elevation of the submucosal area persisted even after completion of IAP in 96 % of the patients randomly assigned to dextrose 50 %, compared with 20 % of those receiving normal saline ( P < 0.001). There were no significant differences in the rates of complete resection or complications between the two groups. CONCLUSIONS: Dextrose 50 % is superior to normal saline as a submucosal fluid cushion, as it allows better en bloc resection during injection-associated polypectomy.

Botulinum toxin versus pneumatic dilatation in the treatment of achalasia: a randomised trial.

BACKGROUND: Intrasphincteric injection of botulinum toxin is a new treatment option for achalasia. AIMS: To compare the immediate and long term efficacy of botulinum toxin with that of pneumatic dilatation. METHODS: Symptomatic patients with achalasia were randomised to botulinum toxin (22 patients, median age 57 years) or pneumatic dilatation (20 patients, median age 56 years). Symptom scores were assessed initially, and at one, three, six, nine, and 12 months after treatment. Objective assessment included oesophageal manometry initially and at one month, and barium oesophagram initially and at one, six, and 12 months post-treatment. RESULTS: Pneumatic dilatation resulted in a significantly (p=0.02) higher cumulative remission rate. At 12 months, 14/20 (70%) pneumatic dilatation and 7/22 (32%) botulinum toxin treated patients were in symptomatic remission (p=0.017). Failure rates were similar initially, but failure over time was significantly (p=0.01) higher after botulinum toxin (50%) than pneumatic dilatation (7%). Pneumatic dilatation resulted in significant (p<0.001) reduction in symptom scores, and lower oesophageal sphincter pressure, oesophageal barium column height, and oesophageal diameter. Botulinum toxin produced significant reduction in symptom scores (p<0.001), but no reduction in objective parameters. CONCLUSIONS: At one year pneumatic dilatation is more effective than botulinum toxin. Symptom improvement parallels objective oesophageal measurements after pneumatic dilatation but not after botulinum toxin treatment for achalasia.

Economic impact of aminoglycoside toxicity and its prevention through therapeutic drug monitoring.

Therapeutic drug monitoring (TDM) of aminoglycoside antibacterials with the goal of minimising toxicity and maximising effectiveness has become routine. Successful management of serious infections requires the ability to achieve therapeutic peak concentrations, while maintaining low trough concentrations will assist in avoiding nephrotoxicity. Reported nephrotoxicity rates range from 1.7 to 58% and depend on the definition used, the patient group studied, concomitant drug therapy used and whether TDM services have been provided. TDM services have been shown to reduce aminoglycoside nephrotoxicity. The costs of providing TDM averages $US301.87 (1997 values) per patient and the cost for each use of nephrotoxicity is estimated at $US4583 (1997 values). In order for the costs of providing a TDM service to 100 patients ($US30,187) to be offset by cost savings due to decreasing nephrotoxicity, the service would need to be able to reduce nephrotoxicity by 6.6%, resulting in a saving of $US30,248. The ability to achieve this saving is dependent on the characteristics of the population in which aminoglycoside therapy is used. In populations where high rates of nephrotoxicity (e.g. > 15%) would be expected, TDM services are cost justified. In populations where nephrotoxicity is low (e.g. < 5%), TDM service is not justified for this purpose. In order to provide a cost-efficient approach to TDM, resources should be focused on providing service to high risk patient groups.

The influence of multiple dosing and age on the pharmacokinetics and pharmacodynamics of glipizide in patients with type II diabetes mellitus.

STUDY OBJECTIVES: To determine the pharmacokinetics and pharmacodynamics of glipizide after a single dose and 12 weeks of dosing in patients with type II diabetes mellitus, and evaluate the influence of aging. DESIGN: Comparison of single and multiple doses of glipizide. SETTING: University-affiliated outpatient internal medicine clinic and diabetes care unit. PATIENTS: Twenty patients (11 men, 9 women, mean age 55.2 +/- 9.9 yrs) with type II diabetes mellitus who were currently receiving oral hypoglycemic agents or were hyperglycemic with diet. INTERVENTIONS: A 24-hour pharmacokinetic evaluation of glipizide was assessed after a 5-mg dose at the start of therapy and after 12 weeks of therapy. Pharmacokinetic parameters were assessed using compartmental population analysis techniques. Glipizide pharmacodynamic evaluation was assessed by serum glucose, insulin, and C-peptide responses during a 4-hour Sustacal tolerance test performed at baseline before instituting glipizide therapy, with the first 5-mg dose, and at week 12 of therapy. Glipizide dosages were titrated to a targeted goal of fasting plasma glucose of 7.8 mmol/L or less or to reach maximum daily doses of 40 mg. MEASUREMENTS AND MAIN RESULTS: No significant differences in time to peak concentration, apparent volumes of distribution for the central and peripheral compartments, apparent oral clearance from the central compartment, distributional clearance between the central and peripheral compartments, or terminal elimination half-life were observed with a single dose and long-term dosing. The mean +/- SD terminal elimination half-lives were 9.67 +/- 5.6 and 9.35 +/- 4.6 hours after a single dose and 12 weeks, respectively. Fasting plasma glucose concentrations decreased from 12.3 +/- 3.6 mmol/L before the first dose of glipizide to 9.2 +/- 1.7 mmol/L after 12 weeks of treatment. The values for area under the serum concentration-time curve from zero to 4 hours for glucose (AUC0-4.glucose) were significantly reduced at week 12 (baseline 49.8 +/- 15.6, week 12 37.8 +/- 9.8 mmol/L/hr). Glipizide provoked an increase in serum insulin and C-peptide concentrations (AUC0-4.insulin: baseline 698 +/- 327, single dose 954 +/- 461, long-term dosing 945 +/- 600 pmol/L/hr). No significant change in insulin response was observed between single and multiple doses. No age-related differences in the pharmacokinetic parameters or the pharmacodynamic responses of glipizide were observed. CONCLUSIONS: Long-term dosing and aging have little effect on the pharmacokinetic profile of glipizide. In addition, glipizide stimulates insulin secretion to a similar extent following glucose challenge after a single dose and long-term administration.

Itraconazole and hydroxyitraconazole serum concentrations are reduced more than tenfold by phenytoin.

OBJECTIVE: To study the disposition of single doses of phenytoin and itraconazole when administered alone and after chronic treatment with the other drug. METHODS: Healthy male volunteers were randomized to two groups and studied in parallel. In group 1, a single 200 mg oral dose of itraconazole was administered on two occasions (alone and after 15 days of 300 mg oral phenytoin once daily). Subjects in group 2 were given a single 300 mg oral dose of phenytoin before and after 15 days of itraconazole (200 mg once daily). Blood was collected for 96 hours after each single dose of phenytoin or itraconazole. Serum was assayed for itraconazole and hydroxyitraconazole concentration by HPLC and for phenytoin concentration by fluorescence polarization immunoassay. RESULTS: Phenytoin decreased the area under the concentration-time curve (AUC) of itraconazole by more than 90%, from 3203 to 224 ng.hr/ml, accompanied by a decrease in half-life from 22.3 to 3.8 hours. Similar changes were observed for hydroxyitraconazole AUC (decreased from 6224 to 315 ng.hr/ml) and half-life (11.3 versus 2.9 hours). Itraconazole increased the AUC of phenytoin (10.3%; p < 0.05), with no change in any other pharmacokinetic parameter. CONCLUSIONS: The striking decrease in itraconazole concentrations with phenytoin is due to induction of metabolism combined with a reduction in the degree of saturable metabolism normally exhibited by itraconazole at this dose. The magnitude of interaction likely accounts for reports of therapeutic failures in patients with fungal infections who are receiving both itraconazole and phenytoin.

Diabetes and related metabolic risk factors among Arab Americans.

OBJECTIVE: To estimate the incidence of noninsulin-dependent diabetes mellitus (NIDDM) and associated metabolic abnormalities such as impaired glucose tolerance, increased blood pressure, hyperinsulinemia, and obesity in the Arab-American community in the Detroit metropolitan area. METHODS: Subjects were selected randomly from a computer-generated list provided by the Arab-American Center for Economic and Social Services. Laboratory studies included a 2-hour, 75-g oral glucose tolerance test with glucose, insulin, and C-peptide determinations. RESULTS: Of the 105 volunteers studied, 57 were women and 48 were men. Mean +/- SD age was 46.0 +/- 13.0 years. Body mass index was 30.4 +/- 6.8 kg/m2, with 68% of subjects having a body mass index of 27 kg/m2 or more. Of the study participants, 33% had NIDDM, 8.6% had impaired glucose tolerance, and 58% had normal glucose tolerance. Subjects with diabetes, compared with subjects who had normal glucose tolerance, exhibited increased fasting insulin (98 +/- 69 vs 55 +/- 31 pmol/L; p = 0.00056); higher cholesterol (6.03 +/- 1.03 vs 5.09 +/- 1.22 mmol/L; p = 0.00073); marginally lower high-density lipoprotein cholesterol (0.98 +/- 0.21 vs 1.14 +/- 0.31 mmol/L; p = 0.054); higher triglycerides (7.84 +/- 5.79 vs 3.83 +/- 2.15 mmol/L; p = 0.00002); and higher diastolic (83.7 +/- 8.9 vs 78.3 +/- 8.0 mm Hg; p = 0.014) as well as systolic (132.5 +/- 16.0 vs 119.0 +/- 10.6 mm Hg; p = 0.00001) blood pressures CONCLUSIONS: This pilot study demonstrates that diabetes may be a frequent medical problem in the Arab-American community. A well-designed epidemiologic study is warranted to validate these results and to elucidate the underlying mechanisms responsible for these findings.

Recent advances: the cytochrome P450 enzymes.

Successful application of information on cytochrome P450 to prevent drug interactions and improve the therapeutic risk: benefit ratio can occur only if we know which enzyme is responsible for the metabolism of a drug. Until recently, this information was not usually available when new drugs reached the market. It is not enough to know the fraction of a dose metabolized versus excreted unchanged or the metabolic pathways by which a compound is degraded. Studies conducted during drug development must identify the enzyme or enzymes involved in the metabolism of new drugs. In addition, the ability of new drugs to inhibit or induce the activity of the key P450 enzymes must be known if we are to take full advantage of our current knowledge of how the cytochrome P450 system works.

Comparison of pharmacokinetics and pharmacodynamics of short- and long-term glyburide therapy in NIDDM.

OBJECTIVE: To examine the pharmacokinetics and pharmacodynamics of glyburide after single- and multiple-dose administration in patients with type II diabetes. RESEARCH DESIGN AND METHODS: Twenty patients with type II diabetes between 40 and 70 years of age participated in the study. A 24-h pharmacokinetic evaluation including a 4-h Sustacal tolerance test was conducted before instituting glyburide therapy (baseline), after the first 2.5-mg test dose of glyburide and at weeks 6 and 12 of chronic glyburide therapy. Glyburide doses were titrated with a target goal of achieving a fasting plasma glucose of < or = 7.8 mmol/l or to reach maximum daily doses of 20 mg. RESULTS: A significant prolongation in the elimination half-life (t1/2: week 0, 4.0 +/- 1.9 h; week 6, 13.7 +/- 10.5 h; and week 12, 12.1 +/- 8.2 h) and an increased volume of distribution of glyburide was observed during chronic dosing. These results strongly suggest possible drug accumulation. No differences in pharmacokinetic parameters were noted between evaluations at week 6 or week 12. Changes in pharmacodynamic response of glucose, insulin, and C-peptide to chronic glyburide therapy were observed. Glyburide therapy significantly reduced plasma glucose levels at weeks 6 and 12 (percent changes in AUC0-->4. glucose from baseline: week 0, -3 +/- 11%; week 6, -29 +/- 13%; and week 12, -26 +/- 19%). Pancreatic insulin secretion was acutely enhanced and maintained during long-term therapy. Responsiveness to therapy as assessed by the ratio of AUC0-->4.glucose:AUC0-->4.C-peptide was significantly improved at all weeks compared with baseline. No pharmacodynamic response differences were observed between the week 6 and the week 12 evaluations. CONCLUSIONS: This study demonstrates that significant differences in glyburide pharmacokinetics and pharmacodynamics exist between single-dose and steady-state conditions. These differences support the need for careful dosage titration of glyburide to achieve a desired therapeutic response in patients with type II diabetes.

Vancomycin pharmacokinetics in a patient population: effect of age, gender, and body weight.

The effects of age, gender, and body weight on the pharmacokinetics of vancomycin were examined using data collected as part of routine therapeutic drug monitoring in patients. One thousand eighty-five sets of steady-state peak and trough serum concentrations obtained from 704 different patients were used to calculate elimination rate constant (k), volume of distribution (V), and clearance (Cl) using a one-compartment model. The median half-life of vancomycin was 6.5 h. Clearance was significantly correlated with creatinine clearance as estimated using the Cockcroft-Gault equation [Cl = 0.771 (Clcr) + 18.9; r = 0.63]. V averaged 0.69 L/kg ideal body weight (IBW) with increased values in females, patients over age 60, and obese patients. V ranged from 0.58 L/kg IBW in normal weight males under age 40 to 1.17 L/kg IBW in obese females over age 60. V was not different in underweight patients and those of normal weight (43.8 vs. 44.4 L). Regression analysis indicated that V was more predictable in women than in men and that vancomycin distributed into excess body weight (EBW) to a greater extent in women. However, the correlation coefficients from multiple regression analysis of V with IBW, EBW, and age did not exceed 0.60, and the high root mean square error values of 11-15 L suggest considerable variability in V is not accounted for by these factors alone. Despite these limitations, dosing of vancomycin may be improved by adjusting initial estimates of V for patient age, gender, and obesity.

Treatment of achalasia: the best of both worlds.

OBJECTIVE: To conduct a retrospective analysis of one center's experience with treating achalasia over 4 yr with skilled gastroenterologists using primarily the Rigiflex balloon dilator and with a senior surgeon performing Heller myotomies. METHODS: Newly diagnosed cases of achalasia were identified by a computer search of hospital records. Charts were reviewed for the presence/severity of dysphagia, regurgitation, heartburn, and chest pain. Weight loss was also recorded. Esophageal manometries and barium swallows were reviewed. Choice of treatment was made freely by patients. With an a priori definition of success, follow-up was conducted by telephone interviews. RESULTS: A total of 45 achalasia patients (mean age, 46 yr; 32 females, 13 males) were identified with a symptoms-frequency as follows: dysphagia, 100%; regurgitation, 78%; heartburn, 50%; and chest pain, 42%. Mean weight loss was 17.5 pounds. Primary treatment was pneumatic dilation in 36 patients and surgery in nine patients. In a total of 45 pneumatic dilations, three (6.6%) were complicated by perforation. Five (14%) patients required repeat dilation. Mean duration of follow-up for pneumatic dilation and surgery was 27 months and 20.8 months, respectively. The overall excellent-good success rates were: pneumatic dilation 88% and surgery 89%. In comparing the efficacy of pneumatic dilation versus surgery, all symptoms were improved significantly (p < 0.01) in both groups, except heartburn, which increased postmyotomy. CONCLUSIONS: If both procedures are available by skilled operators, pneumatic dilation and surgery are equally effective in the treatment of achalasia.

Clinical interventions provided by doctor of pharmacy students.

OBJECTIVE: To assess the types, perceived benefit, and cost impact of the interactions provided by two-year post-B.S. Pharm.D. students on clerkship rotations. DESIGN: Information was obtained through voluntary reporting by students on a standardized data collection form. Cost analysis and peer review were performed on a subset of interventions. SETTING: The setting of the study included hospital clerkship sites (general medicine and specialty rotations) and an ambulatory care site (general medicine). PARTICIPANTS: Six second-year Pharm.D. students. RESULTS: Reports that were completed totaled 951, including 612 intervention, 335 information, and 4 unknown events. Most events were drug related and student initiated. Follow-up was predominantly to physicians. Intervention events primarily involved changes in drug therapy regimens (63.5 percent), changes in dose (29.5 percent), and identification of potential adverse drug reactions (7 percent). Acceptance rate of recommendations was 78.7 percent. Antibiotics, cardiovascular agents, and central nervous system drugs accounted for 55.5 percent of all interventions. Almost 80 percent of disease states encountered included cardiovascular, infectious, neurologic, pulmonary, gastrointestinal, and endocrine diseases. Overall, peer review scores tended to show a positive impact, with physician scoring higher than pharmacy faculty scoring. Medication-related costs were reduced modestly by accepted student interventions. CONCLUSIONS: This study demonstrates substantial clinical involvement of two-year post-B.S. Pharm.D. students on clerkships. The results indicate that the curriculum of Pharm.D. programs should emphasize cardiology, infectious disease, neurology, and gerontology.

The effect of stress on glycemic control in patients with type II diabetes during glyburide and glipizide therapy.

Stress adversely affects glycemic control in patients with type II diabetes mellitus. In addition, stress reduction with relaxation techniques or medication use in the management of hyperglycemia has been recommended. This study examined the relationship of glycemic control to self-reported stress in 19 patients with type II diabetes mellitus who were randomly allocated to receive either glyburide or glipizide for 16 weeks in a double-blind crossover design. Each treatment phase was preceded by a 2-week washout period. A previously designed and validated nine-item stress questionnaire was used to assess areas such as safety, financial wellbeing, energy level, health, etc. These areas were evaluated as more/less, better/worse, or no change. The stress questionnaire, fasting blood glucose (FBG), and glycosylated hemoglobin (GHb) concentrations were completed or measured at the end of glyburide and glipizide treatment periods. By assigning a value of 1, 2, or 3 to a positive, no change, or negative response, respectively, a composite stress score was computed and compared with glycemic control as assessed by FBG and GHb. Regression analysis showed highly significant correlations (P < .05) between stress scores and FBG (r = .70) as well as GHb (r = 0.84) with glipizide therapy. No such correlation was noted with glyburide (FBG: r = 0.29; GHb: r = 0.29). These findings suggest that during glyburide treatment, in contrast to glipizide, an increase in stress was not associated with a corresponding rise in blood glucose or worsening of metabolic control.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics and pharmacodynamics of 12 weeks of glyburide therapy in obese diabetics.

We have studied the pharmacokinetics and pharmacodynamics of glyburide during long-term therapy in 20 patients with type II diabetes mellitus. The patients were divided according to body mass index (BMI) into an obese group [n = 12, age 55(13) y, BMI 36.2(9.2) kg.m-2, total body weight (TBW) 100(23) kg], and a non-obese group [n = 8, age 61(13) y, BMI 24.5(2.1) kg.m-2, TBW 73(7) kg]. The dosages of glyburide were titrated to achieve specified therapeutic goals based upon serum glucose concentrations or to a maximum dosage of 20 mg per day. The pharmacokinetics of glyburide were determined at week 12 of treatment. On the study day, the patients took a 2.5 mg liquid test dose of glyburide with a Sustacal meal challenge. The elimination rate constant (lambda z), clearance (CL), and apparent volume of distribution (Vz) were 0.08 h-1, 3.3 l.h-1, and 47.0 l in the obese group, and 0.07 h-1, 3.1 l.h-1, and 56.8 l in the non-obese group. These values were not statistically significantly different. However, there were differences between the groups when the volume and clearance were corrected by TBW or BMI but not by ideal body weight (IBW) or fat-free mass (FFM). Regression analysis between the pharmacokinetic variables and body weight status revealed statistically significant correlations between volume or clearance and body weight. However, due to large inter-patient variability, these relations were relatively weak and were considered to be non-predictive.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of renal failure on hepatic drug clearance.

It is known that loss of renal function decreases the hepatic clearance of some drugs, but the mechanisms by which this occurs are unclear. Knowledge of which drugs display reduced hepatic metabolism may be important for appropriate dosing of these drugs in uremic patients. Although no firm conclusions can be made regarding common pharmacokinetic and metabolic characteristics of drugs that display decreased hepatic metabolism in renal failure, certain observations deserve consideration. It appears that drugs metabolized by oxidation, conjugation, or both may be predisposed to decreased hepatic clearance in renal failure. Drugs that undergo oxidation by the P-450IID6 isozyme may be more likely to exhibit inhibition whereas those metabolized by the P-450IIIA4 isozyme may be spared. Future studies designed to clarify the mechanisms of decreased hepatic clearance in renal failure should take into account the multiplicity of P-450 enzymes for drugs that are oxidatively metabolized. The phenomenon of reduced hepatic drug clearance in uremia should be considered when evaluating the influence of renal failure on drug disposition.

Pharmacokinetics and pharmacodynamics of methylprednisolone in obesity.

Methylprednisolone pharmacokinetics and its directly suppressive effects on plasma cortisol, blood histamine (basophils), and circulating helper T cells were evaluated in six obese (at least 35% above ideal body weight) men and six nonobese male volunteers. Methylprednisolone doses of 0.6 mg/kg total body weight were administered as the 21-succinate sodium salt. Absolute clearance (in liters per hour) of methylprednisolone was 40% less in the obese subjects. Total volume of distribution (Vss) of methylprednisolone was unchanged (about 120 L), but when normalized for total body weight, Vss per kilogram was less in obesity. The patterns of cortisol, blood histamine, and helper T cell responses after methylprednisolone administration were similar in both groups, but more profound effects were observed in the obese subjects. Pharmacodynamic models were applied for these immediate effects of methylprednisolone based on the premise that receptor interactions of steroids are followed by rapid suppression of the circadian rhythm of cortisol and recirculation of basophils and helper T cells, which persist until inhibitory concentrations (IC50) of methylprednisolone disappear. Similar IC50 values for the three effects were obtained in both groups, indicating no intrinsic pharmacodynamic differences in sensitivity to these methylprednisolone effects in obesity. However, methylprednisolone should be administered on the basis of ideal body weight, and the dosing interval should be potentially lengthened because of decreased methylprednisolone clearance in obesity.

Steroid dose sparing: pharmacodynamic responses to single versus divided doses of methylprednisolone in man.

Inhibitory drug interactions affecting the metabolism of methylprednisolone (MP) may produce either steroid sparing or adverse effects partly by increasing the exposure time to the steroid. This phenomenon can be mimicked by administering MP in divided doses. Two types of responses were compared after a single MP dose (40 mg bolus) and a divided regimen (20 mg bolus and a 5 mg bolus 8 hours later) in six healthy male volunteers. The suppression of basophils measured as whole blood histamine and plasma cortisol concentrations was assessed during 32 hours. The 37.5% reduction in dose produced a 23% overall decreased blood histamine response. A pharmacodynamic model for basophil cell distribution to and from an extravascular compartment describes the effects of MP after both regimens. A slower initial decline in blood histamine after the divided regimen may be related to incomplete suppression of basophil cell return to blood. The 50% inhibitory concentrations of MP of about 5 ng/ml were similar for both regimens. The decline and return of cortisol concentrations were similar between MP treatments with suppression continuing for 24 hours. The 50% inhibitory concentrations of MP values for adrenal suppression were about 1 ng/ml. Pharmacodynamic modeling is useful in quantitating corticosteroid responses and generally predicted the "dose-sparing" effects that were achieved by prolonging MP plasma concentrations. This study supports previous clinical observations that patients may require morning through evening exposure to MP to optimize efficacy while adrenal suppression is being minimized.

Comparison of assay procedures used to measure total and unbound concentrations of quinidine.

Individualized quinidine dosing through the assessment of serum concentrations is warranted because of the wide variability observed in its pharmacokinetic behavior and its reported narrow therapeutic index. The free fraction of quinidine also varies widely. Thus the development of procedures that could be widely used to determine quinidine free concentrations would be highly desirable. It was the purpose of this study to evaluate several procedures available to determine total serum quinidine concentrations (rate nephelometry [ICS], homogenous enzyme immunoassay [EMIT], and high-performance liquid chromatography [HPLC]). Furthermore, in samples from 46 patients, equilibrium dialysis and ultrafiltration procedures were compared for their ability to estimate quinidine free fraction. Finally, unbound concentrations of quinidine were compared using a modified EMIT procedure and a standard HPLC method to quantitate quinidine in ultrafiltrates from patient samples. For the measurement of total quinidine concentrations, reasonable agreement was seen when EMIT and ICS systems were compared with HPLC (ICS = 1.03.HPLC + 0.96, r = 0.93; EMIT = 1.08.HPLC + 0.38, r = 0.93) The mean errors, however, for these procedures were high (ICS +70 percent, range +7 to +233 percent; EMIT +35 percent, range 0 to 110 percent). Quinidine free fractions (QFF) determined by equilibrium dialysis (E) and ultrafiltration (U) showed good agreement (QFF(U) = 1.11.QFF(E) +0.0; r = 0.96). Unbound quinidine concentration determined by EMIT analysis of ultrafiltrate substantially overestimated the values obtained by HPLC analysis (mean error by EMIT 104 +/- 59 percent). It is concluded that HPLC is the method of choice for determining both total and unbound serum quinidine concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects.

Pharmacodynamic models for "directly suppressive" effects of methylprednisolone are based on the premise that receptor interactions of steroids are followed by immediate suppression of either the circadian secretion of cortisol or the constant rate recirculation of histamine-containing basophils that persists until inhibitory concentrations of methylprednisolone disappear. Methylprednisolone doses of 0, 10, 20, and 40 mg were given as the 21-succinate sodium salt in a balanced crossover study to six normal men. Plasma steroid concentrations and blood histamine were measured simultaneously. Both forms of methylprednisolone exhibited linear kinetic parameters. One dynamic model quantitates the baseline circadian pattern and the decline and return of cortisol with similar parameter estimates for all three dose levels. A similar model describes the monoexponential decline and the log-linear return to steady-state baseline of blood histamine. Similar inhibitory concentration values for both effects approximated the equilibrium dissociation constant of in vitro steroid receptor binding. The new models are more physiologically appropriate for these steroid effects than three other models that are commonly employed in pharmacodynamics. Steroid effects generally appear to be receptor mediated with either nongene immediate responses or gene-mediated delayed effects. These models allow quantitation of the rapid effects of steroids with simple equations and common fitted parameters for all steroid dose levels.

Steroid-specific effects of ketoconazole on corticosteroid disposition: unaltered prednisolone elimination.

Ketoconazole inhibits the clearance of methylprednisolone by 60 percent and extends cortisol suppression beyond that produced by methylprednisolone alone. This study examined prednisolone pharmacokinetics and cortisol suppression in four healthy male volunteers following administration of prednisone 20 mg. Studies were performed with and without ketoconazole 200 mg po for six days. Blood samples were obtained serially over 24 hours and serum prednisone, prednisolone, and cortisol concentrations were determined by HPLC. Prednisolone clearance before and after ketoconazole therapy was not significantly different (160 +/- 38 vs. 148 +/- 23 mL/h/kg). In addition, no significant differences were found in mean residence time (5.03 +/- 0.69 vs. 6.18 +/- 1.77 h), terminal slope (0.23 +/- 0.03 vs. 0.19 +/- 0.05 h-1), or volume of distribution (0.79 +/- 0.11 vs. 0.84 +/- 0.12 L/kg). The ratio of cortisol area under the concentration versus time curve (AUC) 0-24 hours after prednisone administration to the AUC under baseline conditions was used as a measure of adrenal suppression. This ratio was not significantly different after prednisolone with and without ketoconazole (0.40 +/- 0.10 vs. 0.45 +/- 0.03). Renal excretion of prednisone and prednisolone was not significantly changed with ketoconazole. Based on this preliminary study, ketoconazole minimally alters prednisolone clearance in contrast to the significant ketoconazole-methylprednisolone interaction previously reported.