Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet.

BACKGROUND: This study compared directly the renal effects of two selective cyclooxygenase (COX)-2 inhibitors (rofecoxib and celecoxib) with naproxen (dual COX-1/COX-2 inhibitor) and placebo in healthy elderly subjects on a sodium-replete diet. METHODS: A total of 67 elderly subjects stabilized in the clinic for weight and urinary sodium on a controlled 200-mEq sodium diet were randomized in a double-blind fashion to receive rofecoxib, 25 mg daily (n = 17); celecoxib, 200 mg twice daily (n = 17); naproxen, 500 mg twice daily (n = 17); or matching placebo (n = 16) for 28 days. Subjects were sequestered in the clinic for the first 14 treatment days on the controlled diet. RESULTS: Daily urinary sodium excretion during the first 72 hours of treatment (primary endpoint) significantly decreased in rofecoxib, celecoxib, and naproxen groups compared with baseline (P < or =.05). Rofecoxib and celecoxib decreases in urinary sodium excretion rates that were comparable with each other, on the basis of predefined boundaries (-39.5 versus -27.1 mEq/d, respectively) and to naproxen (-40.6, mEq/d). Rofecoxib, celecoxib, and naproxen increased mean systolic blood pressure to a similar degree (3.4, 4.3, and 3.1 mm Hg, respectively, versus -1.3 mm Hg for placebo) after 14 days of treatment; small changes also occurred in diastolic blood pressure (0.3, 0.8, and -0.4 mm Hg, respectively, versus -1.4 mm Hg for placebo). Changes from baseline in creatinine clearance, body weight, and urinary potassium excretion among active treatments were similar. After 28 days of treatment, findings were generally consistent with those at 14 days. No subject reported edema or discontinued treatment as the result of an adverse experience. CONCLUSION: In healthy elderly subjects on a sodium-replete diet, the COX-2 inhibitors rofecoxib and celecoxib did not differ from a nonselective nonsteroidal anti-inflammatory drug (naproxen), in influencing renal function as measured by urinary sodium excretion, systolic and diastolic blood pressure, creatinine clearance, or weight change.

Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthritis patients.

Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (COX-2). Methotrexate is a disease-modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double-blind, placebo-controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days -1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7-hydroxymethotrexate. The AUC(0-infinity) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/day -1, and day 21/day -1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day -1). All AUC(0-infinity), GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.

Noise levels of orthopedic instruments and their potential health risks.

Exposure to intense levels of noise has been identified as a potential workplace risk for the development of hearing impairment for health care workers. With this knowledge a noise level survey was performed on selected orthopedic equipment. Several instruments produced threshold levels of 95 dBA to 106 dBA. Often these levels remained as high as 90 dBA at 4 ft from the source. Based on the results of this survey, audiometric tests were conducted on five cast technicians to determine the prevalence of noise-induced hearing loss (NIHL). Audiometric measurements of the cast technicians indicated that, in the absence of other risk factors for hearing loss, there was an association between the presence of NIHL and the years of exposure. NIHL was most evident on the side of the dominant hand used for holding the cast cutter. These findings suggest there may be a risk of NIHL from the occupational exposure to various orthopedic instruments. Further, this level of risk may warrant the use of an individual hearing protection device or the development of quieter instruments.

Treatment of delayed unions and nonunions of the proximal fifth metatarsal with pulsed electromagnetic fields.

Nine delayed unions and nonunion of the proximal fifth metatarsal were treated with pulsed electromagnetic fields (PEMF). All fractures healed in a mean time of 4 months (range 2-8 months). Those fractures treated with both pulsed electromagnetic fields and a nonweightbearing cast healed in a mean time of 3 months (range 2-4 months). The average duration of follow-up was 39 months (range 24-60 months). There were no refractures. When compared with reported healing times and morbidity for conventional casting, medullary curettage with inlay bone, and closed axial intramedullary screw fixation, pulsed electromagnetic fields provided an effective alternative for the treatment of delayed unions and nonunion of the proximal fifth metatarsal.

Fractures and dislocations of the foot and ankle in diabetics associated with Charcot joint changes.

This study was undertaken to evaluate the occurrence of Charcot joint changes in diabetic patients after fractures and/or dislocations of the foot and ankle. There were 20 fracture/dislocations of the foot and ankle in 18 patients, with an average follow-up of 27 months (range 14-70 months). There were eight fractures of the midfoot, six fractures of the ankle, four fractures of the hindfoot, and two fractures of the forefoot. Eight fractures were followed by the development of Charcot changes: five in the midfoot and one each in the forefoot, hindfoot, and ankle. Of nine fractures recognized early and initially treated by early immobilization or ORIF, seven healed uneventfully. Two fractures, both open injuries, developed soft tissue infection and osteomyelitis, respectively. Of the 11 fractures in which there was a delay in diagnosis and treatment, eight developed Charcot changes. The early recognition and appropriate treatment of fractures in diabetic patients appears to be important in the prevention of Charcot joint changes.

Quantitative determination of intermetatarsal pressure.

Pain, plantar to the metatarsophalangeal joints, is a common location for the presentation of pain in the forefoot. In the absence of fractures or specific inflammatory conditions common causes of pain in this area include: (1) nonspecific metatarsalgia, (2) plantar fat pad atrophy, and (3) interdigital (intermetatarsal) neuroma. The aggravation and possibly the etiology of these forms of forefoot pain may be related to acute or chronic extrinsic pressure to the forefoot. The role of nonweightbearing, compression of the metatarsal heads, weightbearing, and toe-stance (on the metatarsal heads) on the intermetatarsal pressure of the third interspace was measured in eleven asymptomatic volunteers. Intermetatarsal pressures were recorded using the Stryker Miniaturized Digital Fluid Pressure Monitor. Intermetatarsal pressures for nonweightbearing, nonweightbearing with medial-lateral compression of the metatarsal heads, weightbearing, and toe stance averaged 21 mm Hg, 22 mm Hg, 29 mm Hg, and 36 mm Hg, respectively. In comparison to nonweightbearing, significant increases in intermetatarsal pressures were measured with weightbearing (P = .0027) and toe stance (P = .0002). The change noted from weightbearing to toe-stance was also significant (P = .0005). These findings support the proposition that increases in forefoot plantar pressures convey greater pressures to the intermetatarsal space and metatarsal heads. Increased pressures to the intermetatarsal space may likewise lead to or exacerbate the symptoms of patients with fat pad atrophy, nonspecific metatarsalgia and Morton's neuroma.

Bioequivalence of verapamil hydrochloride extended-release pellet-filled capsules when opened and sprinkled on food and when swallowed intact.

A study was performed to determine whether verapamil hydrochloride administered in extended-release pellet-filled capsules is bioequivalent to the same formulation administered by sprinkling the contents of the capsules onto food. Thirty-two healthy subjects participated in the randomized, two-way crossover study. In treatment A, the subjects swallowed the contents of a verapamil hydrochloride extended-release pellet-filled capsule, 240 mg, that had been sprinkled on applesauce. In treatment B, the subjects swallowed the same type of capsule intact. Blood samples were drawn at baseline, every hour for 10 hours, and at 12, 15, 24, 30, 36, and 48 hours after each dose administration. The plasma was analyzed for verapamil and norverapamil by high-performance liquid chromatography. The following calculations were performed: AUC0-48, AUC0-infinity, Cmax, tmax, and k. Results for the two treatments were compared by analysis of variance. There were no significant differences between the AUC0-48, AUC0-infinity, Cmax, tmax, and k for the two methods of dose administration. For verapamil the differences for all variables were less than 5%, and for norverapamil the differences were less than 4% for all variables except tmax (9.5%). The 90% confidence intervals were within acceptable limits for all variables except the norverapamil tmax comparison. Sprinkling the contents of extended-release pellet-filled capsules onto food provides verapamil hydrochloride that is bioequivalent to that obtained from the intact capsules.

Fractures of the talar neck. A mechanical study of fixation.

Anatomical reduction and rigid internal fixation of fractures of the talar neck allow early mobilization of the ankle and subtalar joints. Forty fresh tali from cadavera were fractured across the talar neck and were internally fixed with one of four methods. The specimens were again loaded to failure, and mean yield loads, yield deformations, stiffness, and energy absorbed were compared. The two configurations of screws that were inserted posterior to anterior provided yield loads superior to those of screws inserted anterior to posterior. All combinations of screws were stronger than Kirschner wires. Comparisons of yield deformations, stiffness, and energy absorbed corroborated these results. The calculated theoretical maximum shear force across the talar neck during active motion was 1129 newtons. This exceeded the strength that was provided by Kirschner wires and anteriorly inserted screws but not that provided by screws that were placed posteriorly.

Possible epidemiological factors associated with rupture of the posterior tibial tendon.

Rupture of the posterior tibial tendon has been postulated to occur, in part, as a result of degenerative changes to the tendon. This possibility was examined by a review of 67 patients (average age 57 years) diagnosed with rupture of the posterior tibial tendon. Forty-five of the 67 patients (60%) had one or more of the following positive medical histories: (1) hypertension, (2) obesity, (3) diabetes mellitus, (4) previous surgery or trauma about the medial aspect of the foot, or (5) steroid exposure. Thirty-five patients (52%) had either hypertension, diabetes mellitus, or obesity. A statistical correlation was demonstrated between rupture of the posterior tibial tendon and obesity (P = .005) and to a lesser extent hypertension (P = .025). These disorders have been uniformly associated with an acceleration of the degenerative processes associated with aging, commonly via an acceleration of microvascular and macrovascular diseases. An additional vascular risk is implicated by the known zone of hypovascularity of the posterior tibial tendon and risk of rupture secondary to systemic or local injections of corticosteroids. The prevalence of posterior tibial tendon rupture parallels the degenerative processes of aging, hypertension, diabetes mellitus, and obesity. Additionally, the effects of corticosteroids and local surgical procedures may further be associated with local vascular impairment and eventual rupture.

The effects of wearing high heeled shoes on pedal pressure in women.

The purpose of this study was to investigate the effects of increased heel height in women's shoes on foot pressure during walking. An increase in heel height increased the maximum peak pressure under the metatarsal heads in the forefoot, decreased the time to maximum peak pressure under the metatarsal heads, and increased the rate of loading to the metatarsals during early support. The higher pressures noted with increased heel height were accompanied by a more uniform distribution of pressure beneath the forefoot. These findings may denote increased stress to the various tissues in the foot when walking in high heeled shoes, which may contribute to deleterious orthopaedic changes. Quantitative studies need to be conducted to determine whether orthopaedic changes occur with prolonged wearing of high heeled shoes.

Practical considerations for the use of the pedobarograph.

The pedobarograph functions as a device for the dynamic, quantitative measurement of pedal pressures. To date, little attention has been paid to various practical questions concerning its operation. For example, the number and timing of trials sufficient to provide meaningful information upon which to reliably base investigational or management decisions has yet to be addressed. Twenty volunteers were used for the measurement of pedal pressures for 15 trials during three separate sessions. Statistical analysis for the determination of MIVQUE(0) estimates and maximum likelihood estimates were used to determine the individual variability, the variability of the specific area of the foot, the daily variability, and the trial-to-trial variability. This analysis indicated that for the assessment of pedal pressures in a clinical setting, the variance factors were sufficiently minimized by obtaining multiple measurements. The improvement in the estimate of error by obtaining trials on different days was overshadowed by the potential benefit of doing extra trials on a single day. Three trials on 1 day should sufficiently reduce estimates of error for both clinical and investigational purposes.

Discontinuation of phenytoin and carbamazepine in patients receiving felbamate.

Five patients participated in a controlled discontinuation of phenytoin (PHT) and carbamazepine (CBZ) after a study in which all subjects had felbamate (FBM) added to both PHT and CBZ. Four subjects (three women and 1 man aged 23-36 years) completed the protocol. Mean total seizure frequency per day with PHT and CBZ was 1.33 +/- 0.93 (mean +/- SEM), decreasing to 0.87 +/- 0.71 with addition of FBM, and 0.82 +/- 0.78 after discontinuation of PHT. Only one subject tolerated discontinuation of CBZ; the other three had dosage reductions of 33, 54, and 63%. Toxicity attributable to FBM was not observed, and patients often described less severe seizures. Results from four refractory patients indicated that FBM was able to replace PHT and reduce the need for CBZ. In addition, as PHT dosages were reduced, FBM clearance decreased 21%. As the CBZ dosages were reduced. FBM clearance decreased an additional 16.5%.

Chronic rupture of the Achilles tendon: a new technique of repair.

A new operative technique is described for the treatment of patients who have a rupture of the Achilles tendon. The large gap between the proximal and distal stumps of the Achilles tendon in seven patients was bridged by use of the tendon of the flexor digitorum longus as the graft. At the most recent follow-up examination (average follow-up, thirty-nine months; range, two to six years), the result was excellent or good in six patients and fair in one. Postoperatively, two patients needed an adjuvant procedure: one, a local rotation flap and the other, a split-thickness skin graft. Both patients had excellent restoration of function. The patient who had a fair result had a persistent limp and residual discomfort. There were no re-ruptures.

Surgical management of foot disorders: bunions and bunionettes.

Pathologic conditions of the metatarsophalangeal joints comprise the majority of painful conditions of the forefoot. Clinical manifestations commonly include hallux valgus (bunion), bunionette ("tailor's bunion"), and metatarsalgia. Conservative treatment remains the hallmark of initial management of these disorders. Conservative measures emphasize the adequate accommodation of the forefoot within the toe box of the shoe and the even distribution of plantar pressures by various metatarsal pads or bars and soft insoles. Numerous and sometimes controversial surgical procedures have been developed when conservative measures fail to achieve significant pain relief. In general, these procedures can be grouped as 1) soft tissue realignment procedures, 2) bony realignment procedures, 3) combined bony and soft tissue realignment procedures (ie, osteotomy), 4) bony and joint resection, 5) arthrodesis techniques, and 6) Silastic joint replacement techniques.

A quantitative assessment of the effect of metatarsal pads on plantar pressures.

The treatment of metatarsalgia secondary to the plantar prominence of the metatarsal heads has lead to the development of numerous orthotic devices designed to decrease pressures in these areas. In spite of the considerable cost of some of these devices, there has yet to be much objective evidence of their efficacy. This study assessed the effect of a simple metatarsal pad on pressures transmitted to the metatarsal heads. Quantitative measurements of dynamic peak pressures for 10 asymptomatic subjects with and without metatarsal pads were made using the pedobarograph. Female volunteers had a reduction in peak metatarsal pressures from 12% to 60% when a small metatarsal pad was appropriately applied to the foot. In two of five males there was a decrease in metatarsal pressure of 14% to 44%. One male had no change in pressure, while two others had an increase in pressure from 8% to 28%. When properly positioned and appropriately monitored, metatarsal pads can be an inexpensive and effective means of reducing metatarsal pressures.

Absorption of valproic acid suppositories in human volunteers.

The absorption of valproic acid administered by rectal suppository was studied in six male volunteers. Valproic acid was incorporated into a synthetic lipid base in our pharmacy. Each subject received 500 mg of valproic acid by rectal suppository and 500 mg of oral valproate sodium syrup one week apart; 13 blood samples were drawn to determine serum concentrations over 48 hours after administration of each formulation. Significant differences were evident in the amount absorbed, maximum serum concentration, and time to achieve maximum serum concentration between the oral and rectal formulations. Mean absorption after rectal suppository was 80%. Maximum serum concentration was 43.4 mg/L after oral administration and 29.2 mg/L after rectal suppository. The time to achieve maximum serum concentration was 1.0 hour after oral syrup and 3.1 hours after rectal suppository. Absorption of the rectal suppository was consistent and complete within 3 hours. The use of valproate sodium in rectal suppository form can be a more convenient and satisfactory method of administering valproic acid when the oral route is impossible. Dosage increases may be necessary, and serum concentrations should be monitored.

Relative bioavailability of rectally administered phenobarbital sodium parenteral solution.

Rectal administration of antiepileptic drugs may be a useful alternative route when oral administration is not possible due to illness, surgery, or status epilepticus. Although parenteral administration often replaces oral administration in these circumstances, there is not always a desirable intravenous line available or repeated intramuscular injections may not be practical. The purpose of this study was to determine the relative bioavailability and time course of absorption of the commercially available parenteral phenobarbital sodium solution administered rectally in comparison with the same preparation given intramuscularly. Seven healthy adult volunteers were given phenobarbital 5 mg/kg intramuscularly and rectally five weeks apart. Eighteen blood samples were drawn over 288 hours. Pharmacokinetic parameters following intramuscular versus rectal administration were the following: area under the curve 5916 vs. 5253 mumol.h/L; half-life 112 vs. 113 h; time to maximum concentration 2.1 vs. 4.4 h; and maximum serum concentration 36.2 vs. 31.4 mumol/L. Mean relative bioavailability for rectal phenobarbital was 90 percent. Therefore, the parenteral phenobarbital sodium solution given rectally is well absorbed and provides a useful alternative route of administration.

Effect of felbamate on phenytoin and carbamazepine serum concentrations.

Felbamate (FBM) is a novel antiepileptic drug (AED) undergoing clinical trials in the United States. During a double-blind, cross-over clinical trial, patients received concomitant phenytoin (PHT) and carbamazepine (CBZ). Dosages of PHT and CBZ were adjusted to maintain serum concentrations +/- 20 and +/- 25% of baseline values. All patients required a PHT dosage decrease of 10-30% during active FBM treatment to maintain stable concentrations. CBZ serum concentrations decreased significantly in patients receiving active FBM. The mean decrease was 1.3 micrograms/ml and occurred in 30 of 32 patients. Therefore, FBM apparently causes a bidirectional effect on the serum concentrations of PHT and CBZ when all three drugs are taken concomitantly.

Pharmacokinetics of felbamate, a novel antiepileptic drug: application of mixed-effect modeling to clinical trials.

Felbamate is a novel antiepileptic drug currently undergoing clinical trials in the United States. Serum felbamate concentration data from a phase II safety and efficacy trial were analyzed using NONMEM. A one-compartment, open model with first-order absorption and elimination was used. Body weight, sex, concurrent folic acid therapy, and phenytoin dose and dose:concentration ratio did not affect the estimates for felbamate clearance (Cl). Carbamazepine dose and dose:concentration ratio (CDCR) led to significant improvements in the objective function. The final models for felbamate clearance and volume of distribution (Vd) were as follows: Cl(L/hr) = 2.43 + 0.429*CDCR/240, Vd (L) = 51. The coefficient of variation of clearance was only about 12%, which may be indicative of the highly selective patient population. The clearance estimates are similar to those obtained in healthy volunteers and in patients receiving lower dosages of felbamate. The volume of distribution estimate, however, is slightly smaller than that reported previously. Valuable pharmacokinetic information can be obtained from the routine monitoring of serum concentrations during safety and efficacy trials.