Patellofemoral arthroplasty versus total knee arthroplasty for patients with patellofemoral osteoarthritis: equal function and satisfaction but higher revision rate for partial arthroplasty at a minimum eight years' follow-up.

AIMS: The primary aim of this study was to compare the knee-specific functional outcome of patellofemoral arthroplasty with total knee arthroplasty (TKA) in the management of patients with patellofemoral osteoarthritis. PATIENTS AND METHODS: A total of 54 consecutive Avon patellofemoral arthroplasties were identified and propensity-score-matched to a group of 54 patients undergoing a TKA with patellar resurfacing for patellofemoral osteoarthritis. The Oxford Knee Score (OKS), the 12-Item Short-Form Health Survey (SF-12), and patient satisfaction were collected at a mean follow up of 9.2 years (8 to 15). Survival was defined by revision or intention to revise. RESULTS: There was no significant difference in the mean OKS (p > 0.60) or SF-12 scores (p > 0.28) between the groups. There was a lower rate of satisfaction at the final follow-up for the TKA group (78% vs 87%) but this was not statistically significant (odds ratio 0.56, p = 0.21). Length of stay was significantly shorter (p = 0.008) for the Avon group (difference 1.8 days, 95% confidence interval (CI) 0.4 to 3.2). The ten-year survival for the Avon group was 92.3% (95% CI 87.1 to 97.5) and for the TKA group was 100% (95% CI 93.8 to 100). This difference was not statistically significant (log-rank test, p = 0.10). CONCLUSION: Patients undergoing an Avon patellofemoral arthroplasty have a shorter length of stay, and a functional outcome and rate of satisfaction that is equal to that of TKA. The benefits of the Avon arthroplasty need to be balanced against the increased rate of revision when compared with TKA.

Total knee replacement in patients with haemophilia: the Scottish experience.

INTRODUCTION: Patients with haemophilia commonly develop arthropathy secondary to recurrent haemarthroses. Although modern treatment with replacement coagulation factors has reduced the prevalence of end-stage arthropathy, total joint replacement is still required in a small group of patients. These patients may be at higher risk of complications and the outcome of surgery may not be comparable to reports of outcomes of total joint replacement in the general population. The purpose of this study was to describe the change in function in patients undergoing total knee replacement for haemophilic arthropathy. PATIENTS AND METHODS: Patients undergoing total knee arthroplasty in a tertiary centre had prospective evaluations of patient reported outcome measures and range of movement. Their post-operative function was evaluated in a combined orthopaedic-haematology clinic. Eight male patients underwent 13 total knee replacements from 1999 to 2007 and were followed up for a median of 78 months (range 17-116). RESULTS: The median Oxford knee score improved from 45.5 pre-operatively to 28 (p = 0.049). There was a similar improvement in SF-12 physical (p = 0.017) and Knee Society scores (objective p = 0.001; function p = 0.002). Four total knee replacements were performed in patients with inhibitor antibodies and were treated with recombinant activated factor VIIa. These patients had reduced range of movement (p = 0.047). No patients suffered deep infection. CONCLUSIONS: Total knee replacement in patients with haemophiliac arthropathy resulted in improvement in range of movement and function. The presence of factor VIII inhibitors resulted in reduced range of movement, but similar patient reported outcome measures.

A new gas chromatography-mass spectrometry method for simultaneous determination of total and free trans-3'-hydroxycotinine and cotinine in the urine of subjects receiving transdermal nicotine.

trans-3'-Hydroxycotinine (THOC) has been recognized as the most abundant metabolite of nicotine. In an attempt to assess THOC and cotinine (COT) concentrations during nicotine transdermal therapy, we developed a new quantitative gas chromatography-mass spectrometry (GC-MS) method for simultaneous determination of total and free THOC and COT in human urine. The method utilizes the following: (a) hydrolysis of conjugated THOC and COT by beta-glucuronidase; (b) basic extraction of THOC and COT with mixed dichloromethane and n-butyl acetate; (c) derivatization of THOC with bis(trimethylflurosilyl)acetamide; and (d) separation and identification by GC-MS with selective ion monitoring. Lower limits of quantification for the assay were 50 and 20 microg/L for THOC and COT, respectively. The intra- and interassay CVs were 4.4% and 11% for THOC, and 3.9% and 10% for COT at 1000 microg/L. The results from six consecutive 24-h urine collections in 71 subjects administered daily transdermal nicotine doses of 11, 22, and 44 mg showed that, on average, free THOC was 76% of total THOC and free COT was 48% of total COT in all subjects. THOC is the major metabolite of nicotine and constitutes 20% of total nicotine intake at steady state, whereas urinary nicotine and COT excretion were 8% and 17%, respectively. The method is useful for simultaneous determination of free and total THOCand COT and can be used to assess the urinary excretion of these metabolites during transdermal nicotine therapy.

Peripheral nerve reconstruction using freeze-thawed muscle grafts: a comparison with group fascicular nerve grafts in a large animal model.

There is evidence to suggest that the 'freeze-thawed muscle graft' may function as an alternative to established methods of nerve reconstruction. Using a large animal model we compared this method with group fascicular nerve grafting in peripheral nerve reconstruction. We excised a 3 cm segment of right median nerve in 10 anaesthetized sheep. The resulting gaps were repaired with either group fascicular cable grafts (GFCGs) or freeze-thawed muscle grafts (FTMGs). After six months the right (grafted) and left (control) median nerves of each sheep were exposed and assessed for nerve blood flow, nerve conduction velocity and morphological indices of recovery. Nerve blood flow was reduced by 40% in those repaired with FTMGs. All the repaired nerves contained a population of significantly smaller nerve fibres and displayed a reduced peak nerve conduction velocity. Those repaired with FTMGs (mean velocity 30.96 m/s) had a peak velocity significantly faster than the GFCG group (mean 13.16 m/s). This study shows that peripheral nerve reconstruction with freeze-thawed muscle grafts compares well with repair using nerve grafts.

Application of serum nicotine and plasma cotinine concentrations to assessment of nicotine replacement in light, moderate, and heavy smokers undergoing transdermal therapy.

As part of a clinical trial investigating the level of nicotine replacement with different doses of transdermal therapy for smoking cessation, peak and trough serum nicotine and plasma cotinine concentrations were measured in 70 subjects while they were actively smoking (baseline) and daily for 6 consecutive inpatient days while they were receiving transdermal nicotine. Subjects were randomly assigned to a daily 24-hour patch delivering a transdermal nicotine dose of 0, 11, 22, or 44 mg and stratified by self-reported smoking rate as either light (10-15 cigarettes per day), moderate (16-30 cigarettes per day), or heavy (>30 cigarettes per day). Steady-state concentrations of nicotine and cotinine were attained in 1 and 3 days, respectively, at all doses and were independent of baseline smoking rate. Mean percentage replacement of nicotine was calculated by dividing steady-state peak nicotine or cotinine concentrations by their respective baseline concentrations. Significant underreplacement occurred in subjects receiving the 11 mg/day patch regardless of baseline smoking rate. Underreplacement also occurred in moderate and heavy smokers receiving 22 mg/day and in light smokers at this same dose. Complete replacement occurred only in subjects receiving the 44 mg/day patch. These results have several implications for transdermal nicotine therapy. First, with the higher nicotine and cotinine levels observed with heavier smoking, it is inherent that one size does not fit all, and there is a need to consider more individualization of dosage for nicotine patch therapy. Second, there is substantial underreplacement with the 22 mg/day dose in moderate to heavy smokers and in some light smokers. Third, even with twice the usual dose (i.e., 44 mg/day), there was no accumulation of either nicotine or cotinine. Plasma cotinine levels after achievement of steady state (i.e., after 3 days of patch therapy) can be collected at any time and used to calculate percent replacement using baseline levels.

Application of urine nicotine and cotinine excretion rates to assessment of nicotine replacement in light, moderate, and heavy smokers undergoing transdermal therapy.

As part of a clinical trial investigating the level of nicotine replacement with different doses of transdermal therapy for smoking cessation, urine excretion rates of nicotine and cotinine were measured in 70 subjects while they were actively smoking (baseline) and for 6 consecutive inpatient days while they were receiving transdermal nicotine therapy. Subjects were stratified according to baseline smoking rate as light (10-15 cigarettes per day), moderate (16-30 cigarettes per day), or heavy (>30 cigarettes per day) smokers and randomly assigned to a daily 24-hour patch delivering a transdermal nicotine dose of 0, 11, 22, or 44 mg. Steady-state excretion rates of nicotine and cotinine were attained in 2 and 3 days, respectively, at all doses and were independent of smoking rate. Percentage replacement of nicotine was calculated by dividing steady-state nicotine or cotinine excretion rates by their respective baseline excretion rates. Significant underreplacement occurred with the 11-mg/day dose, particularly in moderate and heavy smokers (<50%). At a dose of 22 mg/day, nicotine replacement was still <100% in the majority of subjects. Only at a dose of 44 mg/day did mean replacement exceed 100% regardless of baseline smoking rate.

Immediate and delayed nerve repair using freeze-thawed muscle autografts in complex nerve injuries. Associated arterial injury.

Five sheep underwent repair of the median nerve along with the establishment and repair of a brachial artery defect adjacent to the site of nerve injury. The defect in the brachial artery was of similar length to the nerve defect and lay in parallel with it. It was repaired using a reversed vein autograft harvested from one of the superficial veins of the arm. A further five sheep underwent similar treatment with the repair of the nerve delayed for 30 days after the establishment of the complicating vascular injury. Six months after the nerve repair, each group of sheep was assessed using electrophysiological and morphometric methods in order to establish objective indices of nerve recovery and regeneration. These results were compared with those from other sheep which had undergone nerve repair both immediate and delayed with no complicating injury and groups in which the complicating injury consisted of a cavity, fibrosis and haematoma. It was found that delay in the nerve repair and the presence of a complicating arterial injury, both separately and additively, contributed to a poorer outcome in recovery of nerve function and maturation. The effect of an arterial injury, in both of these respects, was to produce a worse outcome than the presence of a cavity with fibrosis and haematoma.

Immediate and delayed nerve repair using freeze-thawed muscle allografts. Associated long-bone fracture.

Six sheep underwent repair of the median nerve in the forearm using freeze-thawed muscle autografts, along with the establishment and repair of a "fracture" adjacent to the site of nerve injury. The "fracture" was created by making a transverse osteotomy of the radius. It was repaired using an 8-hole dynamic compression plate. A further six sheep underwent similar treatment with the repair of the nerve delayed for 30 days after the establishment of the long-bone injury. Six months after the nerve repair, each group of sheep was assessed using electrophysiological and morphometric methods in order to establish objective indices of nerve recovery and regeneration. It was found that delay of the nerve repair and the presence of a complicating long-bone injury, both separately and additively, contributed to a poorer outcome in recovery of nerve function and maturation.

A solid phase extraction method for determination of nicotine in serum and urine by isotope dilution gas chromatography/mass spectrometry with selected ion monitoring.

A rapid method for measuring nicotine concentration in serum and urine is described. Deuterated nicotine is used as an internal standard. Nicotine and deuterated nicotine are extracted using a copolymeric-bonded phase silica column. The extract is analysed by gas chromatography coupled with mass spectrometry (GC/MS) operating in selected ion monitoring mode. The method has a lower limit of detection of approximately 2 micrograms/L and is linear to at least 2000 micrograms/L. Within-run percentage coefficients of variation (% CV) are < 4 in both assays over a nicotine concentration range of 10-2000 micrograms/L. Between-run % CV in the serum assay are 5.4, 5.2, 4.8 and 5.9, respectively, at nicotine concentrations of 10, 15, 25, and 50 micrograms/L. Between-run % CV in the urine assay are 5.9, 4.5, 2.7 and 5.2, respectively, at nicotine concentrations of 100, 250, 500, and 2000 micrograms/L. The absolute recovery of nicotine is 61 +/- 6% (mean +/- SD) over the range of 10-250 micrograms/L. The assay has been used to measure serum nicotine concentrations and 24-h urinary excretion of nicotine to monitor the extent of replacement in subjects receiving transdermal nicotine therapy for smoking cessation.

A dose-ranging pharmacokinetic study of nicotine tartrate following single-dose delayed-release oral and intravenous administration.

BACKGROUND: Ulcerative colitis is predominantly a disease of non-smokers, and transdermal nicotine is therapeutic but often results in side-effects. Administration of nicotine tartrate as a liquid enema decreases systemic nicotine absorption and may be effective for treatment of active distal ulcerative colitis. Ileocolonic delivery of nicotine tartrate via a delayed release oral capsule would be the preferred route to deliver nicotine to the colon. AIM: To determine the bioavailability and pharmacokinetic parameters of delayed-release oral nicotine tartrate capsules (Eudragit S100 coated) at doses of 3 mg and 6 mg nicotine. METHODS: Twenty healthy human subjects received delayed-release oral nicotine tartrate at one of two doses (each group n = 10): 3 mg and 6 mg nicotine. All subjects also received intravenous nicotine tartrate (at a dose of 15 micrograms nicotine base/kg) during a separate study period. Serum nicotine concentrations were determined by gas chromatography-mass spectrometry. In addition, concentrations of serum cotinine (major nicotine metabolite) were determined by high-performance liquid chromatography in all samples for two subjects (both given 6 mg nicotine). Adverse reactions were determined by questionnaire. RESULTS: The mean bioavailabilities of nicotine after ileocolonic nicotine tartrate administration via delayed-release oral capsules at doses 3 mg and 6 mg nicotine were 41% and 42%, respectively. The ratios (after adjusting for nicotine dose) of cotinine area under the curve (AUC) for delayed-release oral nicotine to cotinine AUC for intravenous nicotine were 1.5 and 1.6 for the two subjects undergoing cotinine pharmacokinetics, demonstrating significant first-pass metabolism. Serum nicotine concentrations did not predict adverse reactions. CONCLUSIONS: Nicotine tartrate delivered to the ileocolon as a delayed-release oral capsule at doses of 3 mg and 6 mg nicotine considerably reduced systemic nicotine bioavailability. This reduction in bioavailability appears to be a result of first-pass hepatic metabolism rather than poor mucosal absorption of nicotine. The therapeutic potential of an ileocolonic delivery formulation of nicotine tartrate, which can potentially limit toxicity by local delivery of high doses of nicotine, should be investigated in patients with ulcerative colitis.

Prolonged exercise decreases serum leptin concentrations.

Serum leptin and free fatty acid concentrations were determined in two groups of subjects undergoing strenuous exercise: 12 men who fasted overnight and then pedaled a stationary ergometer for 2 hours, and 14 nonfasting ultramarathon runners. Blood samples were collected before exercise, immediately after cessation of exercise, and 6 to 24 hours after the end of the exercise period. Two hours of strenuous pedaling following an overnight fast significantly reduced mean leptin levels by 8.3%; free fatty acids were highly increased and correlated well with the decrease in serum leptin (r = .737, P = .01). After 6 hours of rest and refeeding, leptin concentrations recovered to preexercise levels and free fatty acid concentrations were decreased to less than preexercise levels. A similar decrease in serum leptin levels (12.3%) occurred in subjects who fasted overnight and then for a period corresponding to the cycle exercise period. The prolonged exercise of an ultramarathon significantly reduced leptin concentrations by 32% in comparison to prerace levels; free fatty acid concentrations were highly increased, but did not correlate with the change in serum leptin concentrations (r = .366, P = .20). Leptin and free fatty acid concentrations all trended toward prerace levels in blood samples collected 18 to 24 hours after cessation of racing. The results suggest that the negative energy balance of exercise can reduce serum leptin concentrations, but that the significant decrease occurs only at extremes of severity/duration of the exercise-induced negative balance. The possible physiological role of reduced leptin concentrations in response to energy balance and the role of free fatty acids in mediating the response are discussed.

Nicotine tartrate liquid enemas for mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy: a pilot study.

BACKGROUND: Ulcerative colitis is predominantly a disease of non-smokers, and transdermal nicotine is therapeutic but often results in side-effects. Administration of nicotine as a liquid rectal enema results in less systemic nicotine absorption. AIM: To determine the safety and clinical response of nicotine tartrate liquid enemas for active left-side ulcerative colitis in a pilot study. METHODS: Ten non-smoking patients with mildly to moderately active left-sided ulcerative colitis unresponsive to first-line therapy were treated in an open protocol with nightly nicotine tartrate liquid enemas at a dose of 3 mg nicotine base for 1 week then 6 mg for 3 weeks. Clinical assessments were determined at baseline and 4 weeks by endoscopy, physician assessment and a patient diary of daily symptoms. Peak and trough serum nicotine and trough plasma cotinine were determined by gas chromatography/mass spectrometry and high performance liquid chromatography, respectively. RESULTS: After 4 weeks of treatment, 5/7 patients (71%) showed clinical and sigmoidoscopic improvement (per protocol analysis). The other three patients discontinued therapy within 7 days because of inability to retain the liquid enemas. No patients showed histologic improvement. Six of the patients who completed the 4-week study had peak and trough serum nicotine concentration determined, only 1 of 6 patients had a detectable peak nicotine concentration (value 2.3 ng/mL), and all six patients had undetectable trough nicotine concentrations. The mean trough plasma cotinine concentration was 13 +/- 10 ng/mL. Transient and mild adverse events occurred in 4/10 patients (nausea, lightheadedness, tremor, sleep disturbance). Given the low or undetectable serum nicotine concentrations, these adverse events are not likely to be related to the nicotine enemas. CONCLUSIONS: Nicotine tartrate liquid enemas administrated at a dose of 3 mg nicotine base/day for 1 week and then 6 mg/day for 3 weeks are safe and appear to result in clinical improvement in some patients with mildly to moderately active, left-sided ulcerative colitis unresponsive to first-line therapy. Placebo-controlled trials are warranted to confirm these preliminary findings.

Pharmacokinetics of nicotine tartrate after single-dose liquid enema, oral, and intravenous administration.

Ulcerative colitis is predominantly a disease of nonsmokers, and transdermal nicotine is therapeutic but often results in adverse reactions. Colonic administration of nicotine tartrate as a liquid enema could decrease systemic nicotine absorption and adverse reactions. The purpose of the current study was to determine the bioavailability and pharmacokinetic parameters of nicotine after administration by hydrophilic liquid enema (acidic and basic), hydrophobic liquid enema (acidic and basic), and by oral and intravenous routes. Thirty healthy volunteers received 45 micrograms nicotine base/kg (as nicotine tartrate) in one of five formulations (each n = 6): hydrophilic acidic liquid enema, hydrophilic basic liquid enema, hydrophobic acidic liquid enema, hydrophobic basic liquid enema, and oral solution. All participants also received 15 micrograms nicotine base/kg (as nicotine tartrate) intravenously during a separate study period. Serum concentrations of nicotine were determined by gas chromatography with mass spectrometry. The mean (+/-SD) bioavailabilities of nicotine after administration in the liquid enema formulations (hydrophilic acidic 17 +/- 18%, hydrophilic basic 16 +/- 16%, hydrophobic acidic 25 +/- 17%, hydrophobic basic 15 +/- 12%) were similar to the bioavailability of nicotine after administration by oral solution (20 +/- 25%). The bioavailabilities of nicotine for all five nonintravenous formulations were significantly less than for intravenous nicotine (100%). Serum concentrations of nicotine did not predict adverse reactions. Nicotine tartrate administered as either a liquid enema or as an oral solution had low bioavailability and was well tolerated. The therapeutic potential of nicotine tartrate liquid enemas, which can potentially limit toxicity by local (colonic) delivery of high doses of nicotine should be investigated in patients with left-sided ulcerative colitis.

Transdermal nicotine for mildly to moderately active ulcerative colitis. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Ulcerative colitis is predominantly a disease of nonsmokers. Transdermal nicotine may help control clinical manifestations of this condition. OBJECTIVE: To determine the efficacy of transdermal nicotine for controlling clinical disease activity in active ulcerative colitis. DESIGN: Randomized, double-blind, placebo-controlled, single-center clinical trial. SETTING: Multispecialty group serving as an academic tertiary referral center. PATIENTS: 64 nonsmoking patients with mildly to moderately active ulcerative colitis despite the use of medication. INTERVENTION: Patients were stratified on the basis of smoking history, extent of disease, and concomitant medical therapy. After stratification, patients were randomly assigned to daily treatment with transdermal nicotine (n = 31) at the highest tolerated dose (11 mg for 1 week and then < or = 22 mg for 3 weeks) or placebo (n = 33). MEASUREMENTS: Clinical features were assessed at baseline and 4 weeks by endoscopy, physician assessment, and a patient diary of daily symptoms. Serum concentrations of nicotine were determined by using gas chromatography and mass spectrometry, and plasma concentrations of cotinine were measured by using high-performance liquid chromatography. RESULTS: At 4 weeks, 12 of 31 patients (39%) who received nicotine showed clinical improvement compared with 3 of 33 patients (9%) who received placebo (P = 0.007). Four patients receiving nicotine discontinued therapy because of side effects (contact dermatitis [n = 2], nausea [n = 1], and acute pancreatitis [n = 1]). At week 4, the nicotine group had a mean (+/-SD) trough serum nicotine concentration of 11.3 +/- 8.4 ng/mL and a mean trough plasma cotinine concentration of 192 +/- 95 ng/mL. CONCLUSIONS: Transdermal nicotine administered at the highest tolerated dosage (< or = 22 mg/d) for 4 weeks is efficacious for controlling clinical manifestations of mildly to moderately active ulcerative colitis.

Capillary electrophoretic detection of metabolites in the urine of patients receiving hypoglycemic drug therapy.

Micellar electrokinetic chromatography (MEKC) in tandem with diode array detection (DAD) has been exploited as an analytical method for the separation and detection of sulfonylurea drugs. The ultimate goal is the development of an assay to detect these drugs or their metabolites in urine as a means of diagnosing sulfonylurea drug abuse. Using a separation buffer consisting of 5 mM borate/5 mM phosphate/75 mM sodium cholate, separation of both the second and third generation sulfonylurea drugs can be achieved. The characteristic absorbance spectra associated with each of the third generation drugs, glipizide and glyburide, allow for their identification in mixtures. Coinjection of glyburide, its primary metabolite, hydroxy glyburide, and glipizide demonstrated that the metabolite was resolved from the parent drug but shared its absorbance spectral properties. MEKC analysis of a series of solid phase-extracted urine samples from patients prescribed glipizide or glyburide, as well as from control patients not ingesting the drug, showed that the parent compounds were difficult to detect in the urine. However, the use of DAD allowed for detection of metabolites in the urine of these patients. With glyburide patients, only primary metabolites were detected, while urine from patients on glipizide showed a series of peaks whose absorbance spectra was consistent with the presence of both primary and secondary metabolites. In addition, the intensity of the metabolite peaks corresponded reasonably well with the respective dose and in vivo time interval associated with the urine collection. This study shows that MEKC with DAD has potential for further exploration as a clinical assay for detecting surreptitious abuse of sulfonylurea drugs.

Reducing the potential morbidity of an unintentional spinal anaesthetic by aspirating cerebrospinal fluid.

We describe two cases where we attempted to reduce the adverse effects of inadvertent spinal anaesthesia by aspirating local anaesthetic-contaminated cerebrospinal fluid (CSF). Analysis of this CSF for its local anaesthetic concentration revealed that we were able to recover 51% and 39% of the administered lignocaine. It is suggested that such aspiration may be a helpful additional measure to the supportive management of this complication.

Clinical response does not correlate with intestinal or blood cyclosporine concentrations in patients with Crohn's disease treated with high-dose oral cyclosporine.

OBJECTIVE: High-dose ( >5 mg/kg/d) oral cyclosporine may be effective treatment for Crohn's disease, whereas low-dose oral cyclosporine ( < or = 5 mg/kg/d) is not. This study determined the correlation between blood and intestinal tissue cyclosporine concentrations and clinical response in patients with Crohn's disease treated with cyclosporine 8 mg/kg/day. METHODS: Twelve patients with inflammatory Crohn's disease were treated for 6 wk with oral cyclosporine 8 mg/kg/day, adjusted to a whole blood cyclosporine concentration (chromatography) of 200-300 ng/ml. Response was determined by the Crohn's disease activity index. Cyclosporine was measured in intestinal tissue biopsies obtained by colonoscopy at week 6 (chromatography). RESULTS: Eight patients responded and four did not respond. There were no significant differences between the responders and nonresponders in the mean whole blood or intestinal tissue cyclosporine concentrations. Similarly, there were no significant correlations between change in the Crohn's disease activity index score (baseline to week 6) and whole blood or intestinal tissue cyclosporine concentrations. Cyclosporine side effects, including nephrotoxicity and peroneal nerve palsy, were common. CONCLUSIONS: Clinical response did not correlate with whole blood or intestinal tissue cyclosporine concentrations in patients treated with high-dose cyclosporine for Crohn's disease. Cyclosporine side effects, including a significant decrease in renal function, were common.

High-dose nicotine patch therapy. Percentage of replacement and smoking cessation.

OBJECTIVE: To assess the level of nicotine replacement, evidence of nicotine toxicity, and withdrawal symptom relief with placebo and 11-, 22-, and 44-mg/d doses of transdermal nicotine. A secondary objective was to assess short- and long-term smoking cessation rates. DESIGN: Randomized, double-blind, placebo-controlled inpatient/outpatient trial. SUBJECTS: Seventy-one cigarette smokers stratified according to light (n = 23), moderate (n = 24), and heavy (n = 24) smoking rates. INTERVENTIONS: After baseline measures were obtained, subjects were randomly assigned to placebo or an 11-, 22-, or 44-mg/d dose of transdermal nicotine and admitted to a special hospital unit for intensive inpatient treatment of nicotine dependence. During the 6-day inpatient stay, daily nicotine and cotinine levels were determined from trough and peak blood samples. Outpatient patch therapy continued for 7 weeks following the hospital stay, and those initially assigned to placebo were randomly assigned to 11 or 22 mg/d. At week 4, the dosage of those initially assigned to 44 mg/d was reduced to 22 mg/d. MAIN OUTCOME MEASURES: Percentage of replacement of cotinine was calculated by dividing the steady-state levels attained during patch therapy by the corresponding baseline levels. Abstinence from smoking was verified by expired air carbon monoxide. Withdrawal symptoms and nicotine toxicity were assessed daily through questionnaires during the inpatient stay. Follow-up visits were at 3, 6, 9, and 12 months. RESULTS: There was a statistically significant relationship between baseline smoking rate and baseline trough and peak blood cotinine levels (rs = 0.39, rs = 0.45; P < .001 in both instances). A dose-response relationship was observed with higher patch doses, which produced a higher percentage of cotinine replacement and better withdrawal symptom relief. Only one subject (a light smoker assigned to the 44-mg dose) developed signs of nicotine toxicity. There was a positive association between the week 2 patch dose and the biochemically confirmed abstinence at the end of patch therapy (P = .007) but not for subsequent follow-up times. A higher percentage of cotinine replacement was associated with the higher 8-week smoking abstinence rate (P = .03), an association not found at long-term follow-up. CONCLUSION: A 44-mg/d dose of nicotine patch therapy appears to be safe for use in heavy smokers. Cigarette smoking rates can be used to estimate the initial nicotine patch dose. Monitoring blood cotinine levels at baseline and steady state can be used for assessing the adequacy of nicotine replacement. Withdrawal symptom relief can be improved with more complete nicotine replacement. Achieving a greater percentage of nicotine replacement may increase the efficacy of nicotine patch therapy.

Concentration and separation of hypoglycemic drugs using solid-phase extraction-capillary electrophoresis.

Solid-phase extraction-capillary electrophoresis (SPE-CE) is a technique whereby very dilute analytes may be selectively extracted from a sample matrix and concentrated on-line for analysis. This study describes the first phase in the development of a method exploiting this technique for the direct analysis of hypoglycemic drugs in urine. Effective separation and detection of six sulfonylurea drug standards at concentrations below the detection limit of conventional capillary electrophoretic techniques is shown to be attainable. Since surfactant interfered with the on-line concentration process, non-MEKC (micellar electrokinetic chromatography) separation conditions were defined. Using 250 mM borate/5 mM phosphate at pH 8.4, all drugs in a mixture at 285 ng/ml were effectively extracted, concentrated from an injected volume of 2.5 microliters, non-selectively desorbed with an organic-based elution buffer and electrophoretically resolved. Sample loading was found to be linear in the 0.12-1.9 microliters range and drugs in a volume of up to 190 microliters could be concentrated and detected with a sensitivity of approximately 5 ng/ml. Not only was resolution of the desorbed material uncompromised by the presence of the SPE-tip, but separation of glipizide and glyburide was observed despite the fact that these drugs were unresolved under the same separation conditions by standard capillary zone electrophoresis (CZE). From these results, it is clear that SPE-CE not only increases the sensitivity for detection but that selectivity may be altered due to chromatographic processes occurring on the solid-phase resin.

Detection of hypoglycemic drugs in human urine using micellar electrokinetic chromatography.

Micellar electrokinetic chromatography (MEKC) is evaluated as a potential analytical method for the separation and detection of a series of sulfonylurea drugs used in the treatment of hyperglycemia. These drugs are often surreptitiously abused, producing extremely low blood glucose levels and symptoms indistinguishable from those associated with an insulin-secreting tumor. Separation buffer containing 50 mM sodium dodecyl sulfate (SDS) was found to be adequate for the MEKC separation of the third generation drugs (glipizide and glyburide) but not the second generation drugs (acetohexamide chlorpropamide, tolazamide, and tolbutamide). At a pH of 8.5 in the presence of 20 mM borate/20 mM phosphate and 150 mM SDS, all seven components were adequately resolved with an analysis time of 17 min. Altering the concentration of the buffering components to either 5 mM borate/5 mM phosphate or 40 mM borate alone reduced the analysis time to less than 10 min with no observable loss in resolution. A series of other micelle-forming surfactants were evaluated, and only sodium cholate provided an improvement over the SDS-based system. Optimal separation was obtained with 75 mM sodium cholate and led to complete analysis with baseline resolution of all seven components in less than 8 min. These conditions were shown to be adequate for the detection of the hypoglycemic drugs spiked into normal urine and in patients taking these drugs. The precision associated with nine consecutive injections of six samples (n = 54) was found to be acceptable with percent coefficient of variance for absolute migration times (MTabs) for all peaks averaging 0.89 with peak area and peak height being 8.49 and 8.26, respectively. The between-sample precision was found to average 0.92% for MTabs and 8.56% and 8.45%, respectively, for the relative peak area and peak height. With a detection limit for the drugs in urine (following extraction) in the 50 ng/mL range, the potential exists for an MEKC-based assay for the detection of sulfonylurea drugs in urine.