Accuracy of fluoroscopy in closed reduction and percutaneous fixation of simulated Bennett's fracture.

PURPOSE: Restoration of joint congruity has been shown to be an important factor in the prevention of arthritis in patients with Bennett's fracture. It is for this reason that surgical management is generally recommended for displaced intra-articular fractures of the base of the thumb metacarpal. Adequacy of closed reduction after pinning of Bennett's fracture is usually evaluated by fluoroscopic examination. The purpose of this study is to determine the accuracy of fluoroscopic examination compared to plain radiographs and direct visualization in closed reduction and percutaneous pin fixation of simulated Bennett's fractures. METHODS: In 8 fresh-frozen cadaveric hands, Bennett's fractures were created and the incisions were closed. Under fluoroscopic visualization the fractures were close reduced and pinned using 1.14-mm (0.045-in) K-wires. These reductions were all judged to be acceptably aligned with fracture stepoff and displacement less than 1.5 mm under fluoroscopy. Anteroposterior and lateral plain radiographic films were then taken to assess the reduction. Finally, the carpometacarpal joint was opened and visualized to directly assess the reduction for fracture stepoff, displacement, and gap. RESULTS: After percutaneous fixation, all closed reductions were deemed acceptable. Examination with plain radiographs demonstrated an average anteroposterior view displacement of 0 mm, lateral view gap of 0.1 mm, and articular stepoff of 1.1 mm. Direct examination of the joints showed an average articular gap of 0.9 mm, stepoff of 2.1 mm, and displacement of 3.1 mm. The values for stepoff and displacement were significantly different when the direct measurements were compared to the fluoroscopic measurements. Radiographic measurements were significantly different from direct measurements for displacement of the fracture fragments. CONCLUSIONS: After closed reduction and percutaneous pinning of simulated Bennett's fractures in a cadaver model, the assessment of the articular gap, stepoff, and displacement as detected by fluoroscopy is often in error compared to that detected by plain radiographs and direct examination.

Biomechanical stability of four fixation constructs for distal radius fractures.

Implants available for distal radius fracture fixation include dorsal nonlocked plating (DNLP), volar locked plating (VLP), radial-ulnar dual-column locked plating (DCPs), and locked intramedullary fixation (IMN). This study examines the biomechanical properties of these four different fixation constructs. In 28 fresh-frozen radii, a wedge osteotomy was performed, creating an unstable fracture model and the four fixation constructs employed (DNLP, VLP, DCPs, and IMN). Dorsal bending loads were applied and bending stiffness, load to yield 5 mm displacement, and ultimate failure were measured. Bending stiffness for VLP (16.7 N/mm) was significantly higher than for DNLP (6.8 N/mm), while IMN (12.6 N/mm) and DCPs (11.8 N/mm) were similar. Ultimate load to failure occurred at 278.2 N for the VLP, 245.7 N for the IMN, and 52.0 N for the DNLP. The VLP was significantly stronger than the DNLP and DCPs, and the IMN and DCPs were stronger than the DNLP. The VLP has higher average bending stiffness, ultimate bending strength, and resistance to 5 mm displacement than the other constructs and significantly higher ultimate bending strength than the DCPs and DNLP. There was no statistically significant difference between the VLP and IMN. VLP and IMN fixation of distal radius fractures can achieve comparable stability.

Minifragment screw fixation of oblique metacarpal fractures: a biomechanical analysis of screw types and techniques.

The lag screw technique has historically been a successful and accepted way to treat oblique metacarpal fractures. However, it does take additional time and involve multiple steps that can increase the risk of fracture propagation or comminution in the small hand bones of the hand. An alternate fixation technique uses bicortical interfragmentary screws. Other studies support the clinical effectiveness and ease of this technique. The purpose of this study is to biomechanically assess the strength of the bicortical interfragmentary screw versus that of the traditional lag screw. Using 48 cadaver metacarpals, oblique osteotomies were created and stabilized using one of four methods: 1.5 mm bicortical interfragmentary (IF) screw, 1.5 mm lag technique screw, 2.0 mm bicortical IF screw, or 2.0 mm lag technique screw. Biomechanical testing was performed to measure post cyclic displacement and load to failure. Data was analyzed using one-way analysis of variance (ANOVA). There was no significant difference among the fixation techniques with regard to both displacement and ultimate failure strength. There was a slight trend for a higher load to failure with the 2.0 mm IF screw and 2.0 mm lag screw compared to the 1.5 mm IF and 1.5 mm lag screws, but this was not significant. Our results support previously established clinical data that bicortical interfragmentary screw fixation is an effective treatment option for oblique metacarpal fractures. This technique has clinical importance because it is an option to appropriately stabilize the often small and difficult to control fracture fragments encountered in metacarpal fractures.

Hemicondylar hamate replacement arthroplasty for proximal interphalangeal joint fracture dislocations: an assessment of graft suitability.

PURPOSE: Proximal interphalangeal (PIP) joint fracture-dislocations are complex injuries, and successful surgical treatment can be challenging. The hamate appears to be an appropriate graft based on its general shape and dimensions. The purpose of this study was to evaluate the rationale and suitability of the hamate as an autograft for proximal interphalangeal joint fracture-dislocations and to determine the inherent stability of the donor site after graft harvesting. METHODS: Fresh-frozen cadaveric hand specimens were used to evaluate the hamate as a suitable graft source for defects of the middle phalanx based on macroscopic, radiographic, and biomechanical properties. Radiographic measurements were made of the articular contours of the hamate and the base of middle phalanx of digits 2 through 5. Hemicondylar hamate replacement arthroplasty (HHRA) was performed in cadavers for defects created in the middle phalanges. Biomechanical stability testing of the hamate-metacarpal joint was then assessed in additional specimens before and after HHRA. Fluoroscopic examination with a 22.2-N load applied in a 45 degrees dorsal-proximal direction was used to assess stability of the carpometacarpal joints. A servohydraulic testing machine was then used to determine the amount of translation induced with a similarly directed force before and after harvesting of the hamate graft. RESULTS: The cadaveric HHRA reconstructions restored joint stability with no tendency to subluxate. Radiographic measurement showed that the hamate has a central ridge and bicondylar facet with articular contours that are similar to the base of the middle phalanx. The removal of a central portion of the hamate did not induce dislocation or create obvious clinical instability of the carpometacarpal joint. CONCLUSIONS: The HHRA technique is used for treatment of fracture-dislocations of the proximal interphalangeal joint. This study demonstrated the suitability of using the dorsal portion of the hamate as an osteochondral autograft for middle phalangeal base fractures; the technique creates minimal donor site morbidity.

Variation in digital rotation and alignment in normal subjects.

PURPOSE: The purpose of this study is to quantify finger/digit rotation, overlap, parallelism, and convergence to the scaphoid tuberosity in normal volunteers to establish standards for comparison. METHODS: We examined 240 uninjured fingers in 30 volunteers. There were 14 men and 16 women with an average age of 35 years. Rotation was determined with the palm flat and fingers extended. Digit overlap, parallelism (angular relationship between the index, ring, and small fingers with respect to the middle finger) and scaphoid convergence were determined with simultaneous flexion of metacarpophalangeal and proximal interphalangeal joints. Linear and angular measurements were performed with imaging software. RESULTS: Rotation, parallelism, and scaphoid convergence measurements were similar comparing left with right hands. Rotation: All digits were found to be in supination relative to the horizontal plane; the small fingers averaged 9 degrees, the ring fingers 4 degrees, the middle fingers 8 degrees, and the index fingers 12 degrees. Parallelism: Angular measurements between the middle finger and the small finger averaged 19 degrees, between the middle finger and the ring finger 9 degrees, and between the middle finger and the index finger 11 degrees. Scaphoid convergence: In no hand did all 4 fingers converge onto scaphoid tuberosity. Whereas small and ring finger trajectories averaged -0.1 to 1.2 mm from the scaphoid tubercle, the middle finger averaged 4.0 to 4.6 mm and the index finger 8.1 to 9.5 mm. Overlap: Ninety percent of individuals demonstrated digit overlap, although none covered more than 50% of the adjacent nail plate. Seventy-seven percent of these were bilateral, and 73% were asymmetric. CONCLUSIONS: This study establishes the normal parameters for digit rotation, overlap, parallelism, and scaphoid convergence. For digit rotation, parallelism, and scaphoid convergence, the contralateral (uninjured) hand can be used reliably for comparison. However, for digit overlap, the contralateral hand should not be used for comparison because of side-to-side asymmetry and variability. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV.

Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks.

BACKGROUND: Antiretroviral tolerability is a critical factor contributing to treatment outcome. The T-20 Versus Optimized Background Regimen Only (TORO) studies assessed the safety and efficacy of enfuvirtide in treatment-experienced HIV-1-infected patients. METHODS: A total of 997 patients were randomized at a 2:1 ratio to an optimized background antiretroviral regimen plus enfuvirtide (n = 663) or an optimized background regimen alone (control group; n = 334). Control patients could switch to enfuvirtide on virologic failure. RESULTS: In total, 26.5% of patients randomized to enfuvirtide and 36.6% to the control group discontinued study treatment before week 48; the percentage of patients withdrawn for safety reasons (including adverse events [AEs], deaths, and laboratory abnormalities) was 14.0% in the enfuvirtide group and 11.6% in the control group. Injection site reactions (ISRs) occurred in 98% of enfuvirtide patients and led to treatment discontinuation in 4.4%. Treatment-related (defined as possibly, probably, or remotely) AE rates per 100 patient-years were lower with enfuvirtide (96.2) than in the control group (149.9); diarrhea, nausea, and fatigue, the most frequently reported AEs, were significantly less frequent with enfuvirtide than in the control group. Pneumonia was significantly more frequent in patients treated with enfuvirtide (6.7 vs. 0.6 events per 100 patient-years), although the incidence was within expected ranges for this population. Lymphadenopathy was also higher in enfuvirtide-treated patients (7.1 vs. 1.2 events per 100 patient-years) for control patients. CONCLUSION: The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in <5% of patients.

Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus type 1-infected patients.

INTRODUCTION: Enfuvirtide is the first drug to block human immunodeficiency virus type 1 (HIV-1) glycoprotein 41-mediated viral fusion to host cells. This study investigated whether enfuvirtide can influence the activities of cytochrome P450 (CYP) enzymes in HIV-1-infected patients. METHODS: An open-label, 1-sequence crossover study was conducted in 12 HIV-1-infected adults, by use of a 5-drug cocktail consisting of caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin to assess the activities of CYP1A2, CYP2E1, CYP3A4, CYP2D6, and CYP2C19, respectively. Dapsone was used to assess N-acetyltransferase activity. Patients received a single dose of the cocktail alone on day -15 and another together with enfuvirtide on day 6. Enfuvirtide (90 mg subcutaneously) was administered twice daily on days 1 to 7. Phenotypic index parameters were estimated and analyzed by ANOVA with factors subject and day (-15 and 6). RESULTS: The phenotypic index parameters, with and without enfuvirtide, for CYP3A4 (0.33 versus 0.34; 90% confidence interval [CI] for ratio of least squares means, 0.88-1.09), CYP2D6 (0.72 versus 0.71; 90% CI, 0.97-1.06), and N-acetyltransferase (0.35 versus 0.39; 90% CI, 0.82-0.98) were bioequivalent. The phenotypic index parameters, with and without enfuvirtide, for CYP1A2 (0.76 versus 0.81; 90% CI, 0.71-1.17), CYP2E1 (1.3 versus 1.2; 90% CI, 0.87-1.29), and CYP2C19 (93 versus 81.8; 90% CI, 0.98-1.28) were not bioequivalent but were not substantially different. CONCLUSIONS: Enfuvirtide had no clinically important effect on the metabolism of probe drugs mediated by CYP3A4, CYP2D6, or N-acetyltransferase and had little effect on the metabolism of drugs mediated by CYP1A2, CYP2E1, or CYP2C19. The potential for interactions between enfuvirtide and concomitantly administered drugs metabolized by the CYP enzymes tested in this study is low.

Lack of interaction between enfuvirtide and ritonavir or ritonavir-boosted saquinavir in HIV-1-infected patients.

Enfuvirtide (Fuzeon) is an HIV fusion inhibitor, the first drug in a new class of antiretrovirals. The HIV protease inhibitors ritonavir and saquinavir both inhibit cytochrome P450 (CYP450) isoenzymes, and low-dose ritonavir is often used to boost pharmacokinetic exposure to full-dose protease inhibitors. These two studies were designed to assess whether ritonavir and ritonavir-boosted saquinavir influence the steady-state pharmacokinetics of enfuvirtide. Both studies were single-center, open-label, one-sequence crossover clinical pharmacology studies in 12 HIV-1-infected patients each. Patients received enfuvirtide (90 mg twice daily [bid], subcutaneous injection) for 7 days and either ritonavir (200 mg bid, ritonavir study, orally) or saquinavir/ritonavir (1000/100 mg bid, saquinavir/ritonavir study, orally) for 4 days on days 4 to 7. Serial blood samples were collected up to 24 hours after the morning dose of enfuvirtide on days 3 and 7. Plasma concentrations for enfuvirtide, enfuvirtide metabolite, saquinavir, and ritonavir were measured using validated liquid chromatography tandem mass spectrometry methods. Efficacy and safety were also monitored. Bioequivalence criteria require the 90% confidence interval (CI) for the least squares means (LSM) of C(max) and AUC(12h) to be between 80% and 125%. In the present studies, analysis of variance showed that when coadministered with ritonavir, the ratio of LSM for enfuvirtide was 124% for C(max) (90% confidence interval [CI]: 109%-141%), 122% for AUC(12h) (90% CI: 108%-137%), and 114% for C(trough) (90% CI: 102%-128%). Although the bioequivalence criteria were not met, the increase in enfuvirtide exposure was small (< 25%) and not clinically relevant. When administered with ritonavir-boosted saquinavir, the ratio of LSM for enfuvirtide was 107% for C(max) (90% CI: 94.3%-121%) and 114% for AUC(12h) (90% CI: 105%-124%), which therefore met bioequivalence criteria, and 126% for C(trough) (90% CI: 117%-135%). The pharmacokinetics of enfuvirtide are affected to a small extent when coadministered with ritonavir at a dose of 200 mg bid but not when coadministered with a saquinavir-ritonavir combination (1000/100 mg bid). However, previous clinical studies have shown that such increases in enfuvirtide exposure are not clinically relevant. Thus, no dosage adjustments are warranted when enfuvirtide is coadministered with low-dose ritonavir or saquinavir boosted with a low dose of ritonavir.

Lack of enzyme-inducing effect of rifampicin on the pharmacokinetics of enfuvirtide.

The primary objective was to determine whether rifampicin influences the pharmacokinetics of enfuvirtide in HIV-1-infected patients. In a single-center, open-label, one-sequence crossover, clinical pharmacology study, 12 HIV-1-infected adults received enfuvirtide (90 mg, twice daily) on days 1 to 3 and days 11 to 13 (morning dose only on days 3 and 13) and rifampicin (600 mg, once daily) from days 4 to 13. Plasma concentrations were measured for enfuvirtide and its metabolite (days 3 and 13) and rifampicin (day 13 only). The ratios of least squares means (LSM) and 90% confidence intervals for enfuvirtide and enfuvirtide metabolite pharmacokinetic parameters (AUC12h, Cmax, Ctrough) were estimated in the presence and absence of rifampicin. Treatments were compared using an analysis of variance for natural log-transformed variables, with factors patient and treatment. Efficacy and safety were also monitored. Steady-state rifampicin had no appreciable effect on any of the pharmacokinetic parameters assessed for either enfuvirtide or its metabolite. The ratio of LSM for AUC12h, Cmax, and Ctrough for enfuvirtide was 97.5%, 103%, and 84.9%, respectively, and 108%, 112%, and 92.9%, for the enfuvirtide metabolite. Rifampicin did not affect the t1/2 of enfuvirtide or its metabolite. There were no unexpected effects of rifampicin on the short-term antiviral effect or safety of the administered antiretroviral treatment. The pharmacokinetics of enfuvirtide are not induced by a 10-day pretreatment with rifampicin.

Injection site reactions with the HIV-1 fusion inhibitor enfuvirtide.

BACKGROUND: Enfuvirtide is the first of a new class of antiretroviral agents for the treatment of HIV-1 infection, called the fusion inhibitors. The most common type of adverse event associated with enfuvirtide treatment is injection site reactions, occurring in up to 98% of patients. Many of these lesions are symptomatic. This study investigated injection site reactions occurring in 7 patients with HIV infection who were receiving enfuvirtide. OBSERVATIONS: All biopsy specimens revealed an inflammatory response consistent with a localized hypersensitivity reaction; this was regardless of type of clinical lesion and included the patient with no clinical reaction. The pattern of inflammation resembled that of granuloma annulare and the recently described interstitial granulomatous drug reaction. Immunoperoxidase staining indicated that the inflammatory and collagen changes were greatest in areas where enfuvirtide was deposited. CONCLUSIONS: The pathologic changes and clinicopathologic correlations associated with injection site reactions in human enfuvirtide recipients have been described for the first time. This information also provides valuable insights into unusual pathogenic response to foreign antigens for patients with HIV.

BREASTAID: Clinical results from early development of a clinical decision rule for palpable solid breast masses.

OBJECTIVE: To develop a clinical decision rule (entitled BREASTAID) that will predict the probability of malignancy in women with palpable solid breast masses. SUMMARY BACKGROUND DATA: Currently, 80% of open breast biopsies are benign, resulting in excessive economic, psychologic, and physical morbidity. METHODS: A total of 452 solid breast masses were evaluated in a surgical breast clinic between November 1994 and February 1998. Breast cancer status was defined histologically as ductal carcinoma in situ or invasive cancer. Noncancer status included benign histology, mass resolution, or stability at 12-month follow-up. Data were collected on risk factors, clinical breast examination, mammography, and cytology results. Three multiple logistic regression models were used to generate the probability of cancer at 3 logical steps in the workup; Bayes' theorem was applied in a stepwise fashion to generate a final probability of cancer. RESULTS: A model incorporating only clinical breast examination and mammography resulted in an excessive number of either missed cases or biopsies compared with one that included cytology. Using a cut-point of 4%, this latter BREASTAID model had 97.6% sensitivity and 85.1% specificity. Compared with triple diagnosis, BREASTAID would have reduced the open biopsy rate from 39.8% (180 of 452) to 22.3% (101 of 452), improving the diagnostic yield from 22.7% to 40.6%. CONCLUSIONS: This study convincingly demonstrates that at minimum, clinical, radiologic, and cytologic evaluations are required to accurately evaluate a solid breast mass. BREASTAID has the potential to minimize the number of open biopsies performed while allowing safe triage to follow-up. Before widespread application, further validation studies are required.

Influence of subcutaneous injection site on the steady-state pharmacokinetics of enfuvirtide (T-20) in HIV-1-infected patients.

BACKGROUND: Enfuvirtide is the first in a new class of antiretrovirals (ARVs), the fusion inhibitors, and the first ARV to be administered by subcutaneous (s.c.) injection. OBJECTIVES: The primary objective of this study was to determine the steady-state pharmacokinetics and relative bioavailability of enfuvirtide following sc injection at three separate anatomical sites: abdomen (A), thigh (B) and arm (C). STUDY DESIGN: A single-center, open-label, multiple-dose, three-way randomized, crossover study. Twelve HIV-1-infected adults were recruited from three ongoing Phase II enfuvirtide clinical trials and randomized into three groups. Each group continued to receive s.c. injection of enfuvirtide, at a dose of 90 mg twice daily (bid), according to one of three treatment sequences: ABC, BCA or CAB; over three consecutive periods of approximately 7 days each. Plasma concentrations of enfuvirtide and its metabolite (Ro 50-6343) were measured using a validated liquid chromatography-tandem mass spectrometry method. RESULTS: The relative bioavailability of enfuvirtide, based on AUC12h and abdomen as a reference site, was 101% for thigh and 117% for arm. The AUC12h of Ro 50-6343 ranged from 14 to 16% of that for enfuvirtide. Although injection site reactions (ISRs) were common, the overall grading (based on pain or discomfort) of all reported ISRs was Grade 1 (mild). The incidence of ISRs varied according to the site of injection, as did the signs and symptoms associated with them. No patient required treatment for an ISR. CONCLUSIONS: Comparability among the three injection sites, in terms of both absorption and the ISR profile, allows HIV-1-infected patients the freedom to choose and to rotate, if necessary, the site of enfuvirtide injection among the three anatomical sites.

Guillain-Barré syndrome associated with immune reconstitution.

We report a case of acute Guillain-Barré syndrome (GBS) associated with a prompt and vigorous immune reconstitution and decrease in the virus load noted during treatment with a potent regimen of highly active antiretroviral therapy. We hypothesize that GBS may have been due to an aberrant immune response or an adverse drug reaction in association with preexisting peripheral neurologic disease.

Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition.

OBJECTIVE: Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies. METHODS: Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (+/-SD) were volume of distribution of the central compartment (3.8 +/- 0.8 L), volume of distribution of the peripheral compartment (1.7 +/- 0.6 L), total clearance (1.44 +/- 0.30 L/h), intercompartmental distribution (2.3 +/- 1.1 L/h), bioavailability (89% +/- 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the 45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35 hours for the subcutaneous dose range from 45 to 180 mg. CONCLUSIONS: An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.