Biochemical and immunological properties of cytokines conjugated to dendritic polymers.

Here we describe a post-translational modification of SC-63032, a variant of the species restricted, multi-lineage hematopoeitic factor human interleukin-3 (hIL-3). We have made two new dendritic polymer (polyamidoamine or PAMAM dendrimers, generation 5)-SC-63032 bioconjugates. Using two distinct chemistries (one of which is novel to this work), we achieved site-specific conjugation with respect to the amino acid in the proteins ligated to the dendrimers. In both bioconjugates, conjugated cytokine maintains its ability to bind the hIL-3 alpha receptor subunit, but is significantly (about 10-fold) less potent in inducing hIL-3 dependent in vitro cell proliferation than is the free cytokine. In vivo data indicates that conjugation decreases the immunogenicity of the conjugated cytokine modestly. In the absence of pharmacokinetic or biodistribution effects associated with the bioconjugates that increase their potency in vivo (which can only be tested in a higher primate, due to the species restriction of hIL-3 and its derivatives), these immune mitigation effects may be too small to be therapeutically significant. Though unmodified PAMAM dendrimers fail to elicit an antibody response in mice, protein conjugation to dendrimers haptenizes them, and a dendrimer-specific antibody response is produced. In toto, the principal limitation of the dendrimer-cytokine bioconjugates herein is in their reduced receptor affinity and potency in vitro. Were the in vivo potency of the bioconjugates to parallel the in vitro potency of the conjugates reported here, it is likely that particular dendrimer bioconjugates could not justify their higher costs of goods relative to the parent SC-63032 molecule, though retention of SC-63032 biological activities in conjugates suggests that other cytokine-dendrimer bioconjugates may be bioactive. This is good news to the nanotechnology community, in as much as PAMAM dendrimers are among the monodisperse polymeric nanomaterials available, and these results show that they can be used successfully in conjugates to bioactive proteins.

Sciatic neuropathy secondary to infiltrating intermuscular lipoma of the thigh.

Sciatic neuropathy is a rare mononeuropathy of the lower limbs that is commonly misdiagnosed as spinal stenosis or herniated nucleus pulposus. We describe an unusual case in which a patient underwent surgical excision of a large soft-tissue mass on his right side that involved the posterior and medial compartment of the thigh with displacement of the sciatic nerve posteriorly. The patient had full resolution of his pain and restoration of his neurologic function.

Complications of fluoroscopically guided caudal epidural injections.

OBJECTIVES: To assess the incidence of complications of fluoroscopically guided caudal epidural injections. DESIGN: A retrospective cohort design study in which chart review was performed on patients, who presented with radiculopathy and received fluoroscopically guided caudal epidural steroid injections. All injections were performed consecutively over a 12-mo period. An independent observer reviewed medical charts, which included a 24-hr post procedure telephone call by an ambulatory surgery center nurse, who asked a standardized questionnaire about complications after the injections. Physician follow-up office notes 1 to 3 wk after injection along with epidurograms were reviewed. RESULTS: The charts of 139 patients, who received 257 injections, were reviewed. Complications per injection included 12 episodes of insomnia the night of the injection (4.7%), 9 transient nonpositional headaches that resolved within 24 hr (3.5%), 8 increased back pain (3.1%), 6 facial flushing (2.3%), 2 vasovagal reactions (0.8%), 2 episodes of nausea (0.8%), and 1 increased leg pain (0.4%). No dural punctures occurred. CONCLUSIONS: No major complications occurred. The incidence of minor complications was 15.6% per injection. All reactions resolved without morbidity and no patient required hospitalization.

Role of weight-bearing flexion and extension myelography in evaluating the intervertebral disc.

Magnetic resonance imaging has many advantages compared with myelography and/or computed tomography in evaluating the lumbar spine for herniated nucleus pulposus. The authors have included a series of three patients whose histories and physical examinations were clinically suggestive of herniated nucleus pulposus but whose magnetic resonance imaging scans were interpreted by a radiologist as a disc bulge without nerve root compression. Because all patients had not responded to a conservative care treatment program and surgical intervention was to be considered, subsequent testing with lumbar myelography with weight-bearing flexion and extension views demonstrated more clearly the presence of herniated nucleus pulposus along with compression of the nerve root; it also revealed that a positional change in the disc occurred with flexion and extension.

Radiation exposure to the physician performing fluoroscopically guided caudal epidural steroid injections.

This study was designed to investigate radiation exposure to a physician performing fluoroscopically guided caudal epidural steroid injections. The prospective study design included 100 consecutive fluoroscopically guided caudal epidural steroid injections performed on patients with radiculitis from either herniated nucleus pulposus or lumbar spinal stenosis. Radiation exposure was monitored with the assistance of a radiological technologist (RT) who allocated four dosimetry badges to all physicians performing fluoroscopically guided caudal epidural steroid injections on consecutive patients being treated for radicular pain. The badges were placed on the ring finger, glasses and both the inside and outside of the lead apron worn by the physician. In addition, the RTs also wore a marked badge outside his/her lead apron. A control badge was placed 67 inches away from the fluoroscopy table, and a second control badge was located in a desk over 500 feet away from the procedure, to monitor ambient radiation. The average fluoroscopy time per procedure was 12.55 seconds. The average/cumulative exposure per procedure was 4.10/410 mREM at the "ring" badge, 2.47/247 mREM at the "glasses" badge, 3.98 /398 mREM at the "outside apron" badge and 0.15/15 mREM at the "inside" apron; no radiation was detectable at the "outside room" control badge. The RT's average exposure during these procedures was below the limit of detectability. Radiation exposure to the physician needs to be considered and minimized in the performance of spinal interventional procedures. Our study demonstrates that radiation exposure to the physician performing fluoroscopically guided caudal epidural steroid injections is well within safety limits when he/she adheres to proper technique.

Complications of fluoroscopically guided transforaminal lumbar epidural injections.

OBJECTIVES: To assess the incidence of complications of fluoroscopically guided lumbar transforaminal epidural injections. DESIGN: A retrospective cohort design study. Patients presenting with radiculopathy, caused by either lumbar spinal stenosis or herniated nucleus pulposus confirmed by magnetic resonance imaging or computed tomography scanning, received transforaminal epidural steroid injections as part of a conservative care treatment plan. SETTING: A multidisciplinary spine care center. INTERVENTION: All injections were performed consecutively over a 4-month period by five physiatrists. An independent observer reviewed medical charts, which included a 24-hour postprocedure telephone call by an ambulatory surgery center nurse who had asked a standardized questionnaire about complications following the injections. Physician follow-up office notes 1 to 3 weeks after the injection, along with epiduragrams, were also reviewed. RESULTS: Two hundred seven patients who received 322 injections were reviewed. Complications per injection seen included 10 transient nonpositional headaches that resolved within 24 hours (3.1%), 8 increased back pain (2.4%), 2 increased leg pain (0.6%), 4 facial flushing (1.2%), 1 vasovagal reaction (0.3%), 1 increased blood sugar (258 mg/dL) in an insulin-dependent diabetic (0.3%), and 1 intraoperative hypertension (0.3%). No dural punctures occurred. CONCLUSIONS: There were no major complications. The incidence of minor complications was 9.6% per injection. All reactions resolved without morbidity, and no patient required hospitalization.

Lumbosacral radiculopathy secondary to metastatic uterine leiomyosarcoma: a case report.

STUDY DESIGN: A retrospective case report. OBJECTIVES: To increase awareness of the fact that very serious and potentially devastating conditions can be associated with lumbosacral radiculopathy. To reinforce the need to have a definitive diagnosis before performing epidural injections in patients with radicular pain who are not responsive to conservative treatment. SUMMARY OF BACKGROUND DATA: To the authors' knowledge, this is the first reported case of uterine leiomyosarcoma presenting with a lumbosacral radiculopathy. METHODS: The authors describe the treatment and the radiologic, surgical, and pathologic findings in this patient. RESULTS: Proper diagnostic work-up led to a diagnosis of metastatic uterine leiomyosarcoma, which was managed with decompressive laminectomy, radiotherapy, and chemotherapy. CONCLUSIONS: This is the first reported case of a uterine leiomyosarcoma presenting with radicular pain. When a patient has not responded to conservative care, a definitive etiology for radiculopathy needs to be established before epidural steroid injection.

Is there a pharmacokinetic interaction between foscarnet and zalcitabine during concomitant administration?

Foscarnet, an antiviral agent used in the treatment of cytomegalovirus infection, and zalcitabine, an antiretroviral nucleoside analogue used in the treatment of human immunodeficiency virus infection, are commonly used concomitantly. Foscarnet and zalcitabine may interact pharmacokinetically, as both compounds are partially eliminated by renal tubular secretion. Owing to dose-related toxicities associated with these two drugs, it is essential that we have data regarding their pharmacokinetic disposition during concomitant therapy. Twelve patients randomly received either foscarnet (four doses) or zalcitabine (five doses) (Phase 1), followed by concomitant foscarnet (four doses) and zalcitabine (six doses) (Phase 2), followed by dosing with the drug not received in Phase 1 (Phase 3). Following the last dose in each phase of the study, serial plasma samples were collected over 8 hours for zalcitabine and over 12 hours for foscarnet to determine the pharmacokinetics of each drug using noncompartmental analysis. Foscarnet plasma and urine levels were determined using high-performance liquid chromatography, and zalcitabine levels were determined using radioimmunoassay. No clinically significant alterations in the pharmacokinetics of foscarnet or zalcitabine occurred in this study. Thus despite the potential for foscarnet and zalcitabine to compete for renal tubular secretion, no apparent pharmacokinetic interaction exists between these two drugs at the clinically relevant doses studied.