Prospective Design of Anti-Transferrin Receptor Bispecific Antibodies for Optimal Delivery into the Human Brain.

Anti-transferrin receptor (TfR)-based bispecific antibodies have shown promise for boosting antibody uptake in the brain. Nevertheless, there are limited data on the molecular properties, including affinity required for successful development of TfR-based therapeutics. A complex nonmonotonic relationship exists between affinity of the anti-TfR arm and brain uptake at therapeutically relevant doses. However, the quantitative nature of this relationship and its translatability to humans is heretofore unexplored. Therefore, we developed a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model for bispecific anti-TfR/BACE1 antibodies that accounts for antibody-TfR interactions at the blood-brain barrier (BBB) as well as the pharmacodynamic (PD) effect of anti-BACE1 arm. The calibrated model correctly predicted the optimal anti-TfR affinity required to maximize brain exposure of therapeutic antibodies in the cynomolgus monkey and was scaled to predict the optimal affinity of anti-TfR bispecifics in humans. Thus, this model provides a framework for testing critical translational predictions for anti-TfR bispecific antibodies, including choice of candidate molecule for clinical development.

Intractable pruritus during outpatient epidural hydromorphone infusion: a case report and a focused review of the literature.

BACKGROUND: Intraspinal drug delivery therapy has been increasingly used in patients with intractable, nonmalignant pain who have failed to respond to conventional treatment or cannot tolerate systemic opioid(s) due to adverse events. By infusing a small dose of an opioid analgesic directly into the cerebrospinal fluid, near opioid receptors, profound spinal analgesia can be obtained. Before the implantation of permanent intraspinal pump, a neuraxial opioid infusion trial is usually conducted to demonstrate the effectiveness of neuraxial opioid for analgesia. Patient-controlled epidural opioid infusion trial, performed in an outpatient setting, is one of the approaches used to conduct such a trial. OBJECTIVE: To report a case of severe pruritus observed during the continuous epidural hydromorphone infusion trial and to conduct a focused review of the literature. CASE REPORT: An otherwise healthy 56-year-old lady, with a 4-year history of severe low back pain and bilateral leg pain due to failed back surgery syndrome, was referred to our clinic for intraspinal drug delivery therapy. Following a preimplantation psychological evaluation confirming her candidacy, she consented to an outpatient patient-controlled continuous epidural hydromorphone trial. A tunneled lumbar epidural catheter was placed at L3-L4 with catheter tip advanced to L2 under fluoroscopic guidance. Satisfactory catheter placement was confirmed by epidurogram. The catheter was then tunneled subcutaneously and connected to a Microject™ patient-controlled epidural analgesia (PCEA) pump (Codman, Raynham, MA). The pump was programmed to deliver hydromorphone 0.3 mL/h (0.06 mg, concentration 0.2 mg/mL) at basal rate of 0.3 mL/h, with bolus dose set at 0.2 mL (0.04 mg) and 30-minute lockout interval. The patient was instructed how to operate the infusion pump prior to discharging home. During the infusion trial, she reported satisfactory analgesia (>90 percent pain reduction) and was able to reduce her oral opioid dose by more than 80 percent. However, she developed severe, persistent itching, unresponsive to meticulous epidural infusion titration or various antipruritic treatments. Her pruritus remained severe and unabated until a few hours after the termination of the epidural hydromorphone infusion. CONCLUSION: Pruritus may occur and persist during epidural hydromorphone infusion. This report describes severe pruritus in a patient on epidural hydromorphone administration, in the setting of an outpatient infusion trial.

Respiratory failure following delayed intrathecal morphine pump refill: a valuable, but costly lesson.

BACKGROUND: Spinal analgesia, mediated by opioid receptors, requires only a fraction of the opioid dose that is needed systemically. By infusing a small amount of opioid into the cerebrospinal fluid in close proximity to the receptor sites in the spinal cord, profound analgesia may be achieved while sparing some of the side effects due to systemic opioids. Intraspinal drug delivery (IDD) has been increasingly used in patients with intractable chronic pain, when these patients have developed untoward side effects with systemic opioid usage. The introduction of intrathecal opioids has been considered one of the most important breakthroughs in pain management in the past three decades. A variety of side effects associated with the long-term usage of IDD have been recognized. Among them, respiratory depression is the most feared. OBJECTIVE: To describe a severe adverse event, i.e., respiratory failure, following delayed intrathecal morphine pump refill. CASE REPORT: A 65-year-old woman with intractable chronic low back pain, due to degenerative disc disease, and was referred to our clinic for an intraspinal drug delivery evaluation, after failing to respond to multidisciplinary pain treatment. Following a psychological evaluation confirming her candidacy, she underwent an outpatient patient-controlled continuous epidural morphine infusion trial. The infusion trial lasted 12 days and was beneficial in controlling her pain. The patient reported more than 90% pain reduction with improved distance for ambulation. She subsequently consented and was scheduled for permanent intrathecal morphine pump implantation. The intrathecal catheter was inserted at right paramedian L3-L4, with catheter tip advanced to L1, confirmed under fluoroscopy. Intrathecal catheter placement was confirmed by positive CSF flow and by myelogram. A non-programmable Codman 3000 constant-flow rate infusion pump was placed in the right mid quandrant between right rib cage and right iliac crest. The intrathecal infusion consisted of preservative free morphine, delivering 1.0 mg /day. Over the following 6 months, the dosage was gradually titrated up to 4 mg/day with satisfactory pain control without significant side effects. However, the patient was not able to return to the clinic for pump refill until 12 days later than the previously scheduled pump-refill date. Her pump was accessed and was noted to be empty. Her intrathecal pump was refilled with preservative free morphine, delivering 4 mg/day (the same daily dose as her previous refill). However, on the night of pump refill, 10 hours after the pump refill, the patient was found to be unresponsive by her family members. 911 was called. Upon arriving, paramedics found her in respiratory failure, with shallow breathing at a rate of 5/min, pulse oxymetry showing oxygen saturation about 55-58%. She was emergently intubated on site and rushed to local hospital ER. The on call physician for our clinic was immediately contacted, and advised the administration of intravenous Naloxone. Her respiratory effort improved dramatically after receiving a total of 0.6 mg IV Naloxone IV over 25 minutes. Her intrathecal pump was immediately accessed by clinic on call physician and the remainder of the medication in the catheter space was aspirated. The pump infusate was immediately diluted with preservative free normal saline, to deliver preservative free morphine at 1mg/day. She was transferred to the intensive care unit and extubated the next morning. She recovered fully without any sequelae. CONCLUSION: Loss of opioid tolerance due to delayed pump refill may subject patients to the development of severe respiratory depression. Meticulous approach should be employed when refilling pumps in these patients when their pumps are completely empty. To our knowledge, this is the first reported case of this type.

Recurrent cellulitis associated with long-term intrathecal opioid infusion therapy: a case report and review of the literature.

BACKGROUND: Lower-limb edema is recognized as an untoward side effect of intrathecal opioid therapy. Cellulitis, an acute, spreading pyogenic inflammation of the dermis and subcutaneous tissue, predisposed by persistent leg edema, can become problematic in patients on intraspinal opioid infusion therapy. OBJECTIVE: To present a case of recurrent cellulitis in an elderly lady with persistent leg edema associated with intrathecal morphine/hydromorphone infusion therapy. CASE REPORT: Sixty-one-year-old woman with intractable chronic low back pain and bilateral leg pain treated with an intrathecal infusion of morphine up to 5 mg/day over 3 months with satisfactory pain control developed progressive lower extremity edema, complicated by recurrent cellulitis, requiring repeated hospitalization and intravenous antibiotic treatment. Switching to intrathecal hydromorphone helped minimally. Intrathecal baclofen and clonidine infusion resulted in complete resolution of leg edema and pain relief over the following 12 months. CONCLUSION: Intrathecal Baclofen and Clonidine may be used as alternatives to provide spinally mediated antinociception when intraspinal opioid fails due to pharmacological side effects such as persistent edema.

Multimechanistic (sumatriptan-naproxen) early intervention for the acute treatment of migraine.

BACKGROUND: Research suggests treating a migraine at the first sign of pain increases the likelihood of the best clinical outcome. OBJECTIVE: To investigate the efficacy and tolerability of a fixed-dose, single-tablet formulation of sumatriptan 85 mg, formulated with RT Technology, and naproxen sodium 500 mg (sumatriptan/naproxen) as early intervention acute therapy for migraine. METHODS: Patients (aged 18 to 65 years) with International Headache Society-defined migraine with or without aura were enrolled in one of two identically designed, randomized, double-blind, parallel group, placebo-controlled studies. Patients treated a single migraine within 1 hour of onset of migraine head pain and while the pain was mild with either sumatriptan/naproxen or placebo. The primary efficacy measure was the percentage of patients who became pain-free 2 hours postdose. RESULTS: Intent-to-treat analyses consisted of 576 and 535 migraineurs. At 2 hours, 52% and 51% of sumatriptan/naproxen-treated patients were pain free, as compared to 17% and 15% of placebo-treated patients (p < 0.001). Significant pain-free responses in favor of sumatriptan/naproxen were demonstrated as early as 30 minutes, maintained at 1 hour, and sustained from 2 to 24 hours. At 2 and 4 hours, sumatriptan/naproxen provided significantly lower rates of traditional migraine-associated symptoms (nausea, photophobia, and phonophobia) and nontraditional migraine-associated symptoms (neck pain/discomfort and sinus pain/pressure). The most commonly reported adverse events were nausea (< or =4%) and dizziness (< or =2%). CONCLUSION: The fixed-dose single-tablet formulation of sumatriptan/naproxen was effective and well tolerated in an early intervention paradigm for the acute treatment of migraine, including traditional and nontraditional symptoms.

Severe peripheral edema during an outpatient continuous epidural morphine infusion trial in a patient with failed back surgery syndrome.

BACKGROUND: Intraspinal drug delivery therapy has been increasingly used in patients with intractable, nonmalignant pain who fail to respond to conventional treatment or cannot tolerate systemic opioid therapy due to side effects. By infusing small amount of analgesics directly into the cerebrospinal fluid in close proximity to the receptor sites in the spinal cord, one is able to achieve the spinally mediated analgesia, sparing side effects due to systemic opioids. Prior to permanent intraspinal pump implantation, an intraspinal opioid screening trial is required to document the efficacy of intraspinal opioid for analgesia. Although there are a few approaches in conducting such screening trials, a patient controlled continuous epidural morphine infusion trial, performed in an outpatient setting, is widely accepted by many interventional pain specialists. The major advantage of conducting an outpatient trial is that it mimics what patients do in their daily living, therefore minimizing the false positive rate. OBJECTIVE: To report a case of severe peripheral edema observed during an outpatient continuous epidural morphine infusion trial. CASE REPORT: A 64-year-old female, with a 7-year history of severe low back pain and bilateral leg pain due to failed back surgery syndrome, was referred to our clinic for intraspinal drug delivery therapy after failing to respond to conservative treatment, including a previous history of 3 lumbosacral surgeries. Following a pre-implantation psychological evaluation confirming her candidacy, she underwent an outpatient patient-controlled continuous epidural morphine trial. A tunneled lumbar epidural catheter was placed at L2-L3 with catheter tip advanced to T12 under fluoroscopic guidance. Satisfactory catheter placement was confirmed by epidurogram. The proximal tip of the catheter was then tunneled, subcutaneously and connected to a Microject PCEA pump (Codman, Raynham, MA, USA) and reservoir bag containing preservative-free morphine 0.5 mg/mL. The pump was programmed to deliver a basal rate of 0.5 mL/hr. The bolus dose was 0.2 mL with 60 minute lock-out interval. The patient was instructed how to operate the infusion pump before discharging home. During the following 2 weeks, she reported more than 90% reduction of her low back and leg pain. She only had to use the on-demand bolus doses averaging 2 - 3 times a day. She was able to wean off her oral opioids completely. However, she developed bilateral leg edema and gained over 12 pounds during the 2-week infusion trial, despite wearing elastic stockings and keeping her legs elevated whenever possible. She did not experience any other significant side effects. Her edema finally resolved 2 days after termination of the epidural infusion. CONCLUSION: Peripheral edema may occur and persist during epidural morphine infusion. This report represents the first case report, to the best of our knowledge, describing severe peripheral edema in an otherwise healthy patient while on epidural morphine administration during an outpatient epidural morphine infusion trial. This case report shows that continuous epidural morphine infusion, even in small dose, may cause peripheral edema in some patients.

MedX3D: standards enabled desktop medical 3D.

This paper reports on the work of the Web3D Consortium's Medical Working Group to specify and implement MedX3D -- an extension to the X3D standard that will support advanced medical visualization functionality and medical data exchange. This initiative covers volume rendering, ontology support, and data import/export, for standalone applications and web-based plug-ins. It is our hypothesis that such a 3D medical standard will provide better access to data, and enable improvements in medical care.

Priapism--a rare complication following continuous epidural morphine and bupivacaine infusion.

BACKGROUND: Intraspinal drug delivery (IDD) therapy has been increasingly used in patients with intractable, nonmalignant pain who fail to respond to conventional treatment or can not tolerate systemic opioid therapy due to side effects. By infusing a small amount of analgesics directly into the cerebrospinal fluid (CSF) in close proximity to the receptor sites in the spinal cord, one is able to achieve the spinally mediated analgesia, sparing side effects ffrom systemic opioids. Prior to permanent intraspinal pump implantation, an intraspinal opioid screening trial is required to document the efficacy of intraspinal opioid for analgesia. Although there are a few approaches in conducting such screening trials, a patient-controlled continuous epidural morphine infusion trial, performed in an outpatient setting, is widely accepted by many interventional pain specialists. The major advantage of conducting an outpatient functional opioid infusion trial versus an inpatient trial is that it more closely mimics what the patient does in his or her usual activities of daily living, therefore minimizing the false positive rate of the inpatient screening trial. OBJECTIVE: To describe a rare complication, priapism, observed during an outpatient continuous epidural morphine and bupivacaine infusion trial. CASE REPORT: A 49-year-old male with intractable, chronic low back pain due to diffuse lumbar degenerative disc disease, lumbar spondylosis referred to our clinic for consideration of IDD therapy, after failing to respond to multi-modality pain management including medications, physical therapy with modality, transcutaneous nerve stimulation (TENS), and various interventional procedures. Following a pre-implant psychological evaluation, he was scheduled for the outpatient epidural morphine and bupivacaine infusion trial. A tunneled lumbar epidural a catheter was placed at L3-L4 with the catheter tip advanced to L1 under fluoroscopic guidance. The proximal tip of the catheter was then tunneled, subcutaneously, and connected to a Microject PCEA pump (Codman, Raynham, MA, USA) and reservoir bag containing preservative-free morphine 0.4 mg/mL and bupivacaine 0.016%. The pump was programmed to deliver a basal rate of 0.5 mL/h. The bolus dose was 0.2 mL with a 60-minute lock out interval. The patient was instructed how to use the pump properly before discharging home. Two hours following the initiation of infusion trial, the patient started to experience penile erection. It was initially painless, but became progressively painful and intensified. The unremitting priapism lasted 8 hours, finally resolving 2 to 3 hours after discontinuing the infusion. The patient recovered fully without any sequelae. CONCLUSION: Priapism may occur as a rare complication following epidural morphine administration. This report represents the third case report thus far in the literature revealing priapism induced by epidural morphine administration, yet, it is the only report, to our knowledge, describing priapism occurring in a patient undergoing an outpatient epidural morphine and bupivacaine infusion trial. We believe that epidural morphine, rather than bupivacaine, is responsible for causing priapism in this patient, through a yet to be defined spinal mechanism.

Medication overuse headache.

Medication overuse headache is a common feature underlying chronic headache, especially migraine. It also represents a major therapeutic challenge, especially in headache specialty clinics where it can represent the majority of patients. The syndrome remains under-diagnosed and the role of symptomatic medication overuse underestimated. Physicians should be properly educated in this area of pain, for prevention of this too often intractable syndrome could be improved. The basis of therapy is discontinuance of the abused medication. Additional treatment relies on a multifaceted approach that embraces management of psychiatric comorbidities and emphasizes patient education. Various pharmacological regimens, abortive and prophylactic, are available. Further scientific study is warranted to elucidate the ultimate mechanisms of this syndrome and define more effective treatments. This article gives detailed clinical description, tentative pathophysiologic explanation and therapeutic suggestions.

Two-year outcomes following ACL reconstruction with allograft tibialis anterior tendons: a retrospective study.

The outcomes of 18 patients (11 females, 7 males; age, 40.4+/-11 years) at 2 years after ACL reconstruction with cryopreserved tibialis anterior allografts using a double bundle technique are presented. Most subjects (72%) described themselves as being moderately active before surgery. After providing written informed consent, subjects completed the 2000 IKDC Knee Form, underwent arthrometric knee measurements, and performed one-leg hop and isokinetic quadriceps and hamstring torque tests (60 degrees /s). Ninety-four percent (17/18) of the subjects had normal or near-normal grades for manual knee ligament tests. Knee arthrometry measurements revealed a mean 1.1-mm involved side increase at 134 N (8.9+/-2 mm vs 7.8+/-3 mm) and a 2-mm involved side increase during manual maximum testing (11.3+/-2 mm vs 9.3+/-3 mm). Group means revealed active knee flexion (136+/-8 degrees vs 139+/-6 degrees ) and knee hyper-extension (3+/-2 degrees vs 5+/-2 degrees ), which were slightly reduced at the involved knee. One-leg hop testing revealed a 15% mean deficit at the involved side (0.81+/-0.3 m vs 0.95+/-0.3 m). Isokinetic testing revealed an 11% mean deficit at the involved side (143.4+/-60 Nm vs 161.8+/-54 Nm) for the quadriceps and 7% greater strength at the involved side (105.9+/-35 Nm vs 98.8+/-35 Nm) for the hamstrings. Side-to-side comparisons revealed that many patients displayed less than normal quadriceps femoris torque (72%, 13/18), hamstring torque (28%, 5/18) and hop test (28%, 5/18) performance. Moderate positive correlations existed between involved side quadriceps ( r=0.80) and hamstring ( r=0.83) torque/bodyweight and hop test performance. Scores were 77.6+/-21 (range 28.7-100) and 78.1+/-16 (range 41.7-100) for the 2000 IKDC Subjective Knee Evaluation and Health Assessment forms. Most subjects (83%, 15/18) rated their current function at >or=91% of pre-injury levels and all subjects continued to participate at their pre-injury perceived activity level. At 2 years after ACL reconstruction with tibialis anterior allografts, this subject group displayed satisfactory functional outcomes. Tibialis anterior allograft use provides an effective ACL reconstruction alternative, particularly for older individuals who want to continue recreational sports.

Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine.

In this randomized, double-blind, placebo-controlled, parallel-group study, patients received a single 50-mg oral dose of a 5-HT(1D) agonist, PNU-142633 (n = 34), or matching placebo (n = 35) during an acute migraine attack. No statistically significant treatment effects were observed at 1 and 2 h after dosing, even after stratifying by baseline headache intensity. At 1 and 2 h post-dose, 8.8% and 29.4% of the PNU-142633 group, respectively, and 8.6% and 40.0% of the placebo group, respectively, experienced headache relief; 2.9% and 8.8% of the PNU-142633 group and 0% and 5.7% of the placebo group were free of headache pain. Adverse events associated with PNU-142633 treatment included chest pain (two patients) and QTc prolongation (three patients). Results from this study suggest that anti-migraine efficacy is not mediated solely through the 5-HT(1D) receptor subtype, although this receptor may contribute, at least in part, to the adverse cardiovascular effects observed with 5-HT agonist medications.

A study to determine the accuracy of a computerized algorithm for interpretation of EEGs.

The main use of computerized EEG has been in sleep studies. A comprehensive system of interpreting routine EEGs by computers has not yet been developed and is technically difficult. We have tried to incorporate computers in the analysis and interpretation of EEGs by using information obtained from visual analysis of EEG in the present work. The purpose of this study was to determine the accuracy of such an algorithm. An electroencephalographer visually analyzed routine EEGs and the data was entered into an EEG Worksheet. The electroencephalographer then interpreted the data and a report was dictated and transcribed. Data from the EEG Worksheet was entered into a computer for interpretation, clinical correlation, and report preparation. Results indicate that the algorithm used with the EEG Worksheet can correctly interpret and clinically correlate visually-analyzed EEG data entered into a computer and reduce time for EEG report generation.

Gender perception of professional occupations.

Students (181 women and 44 men in a southern university) were asked to indicate their perception of whether each of 105 professional occupations was predominately masculine or feminine. Analysis indicated that a majority of the occupations were perceived as masculine, i.e., those predominately power- or product-oriented, while feminine occupations were predominately caregiving. Results were discussed in terms of the influence of media on the perception of gender-specific roles and the implications of these perceptions for the status of a person holding a given occupation.

Chronic daily headache in the posttrauma syndrome: relation to extent of head injury.

OBJECTIVE: To evaluate the occurrence of continued intermittent headache and chronic daily headache in patients with head injury and the relationship between severity of the headache problem and intensity of the head injury. BACKGROUND: In the majority of patients with posttraumatic headache, the condition is self-limited, but a minority of patients may develop persistent headaches. The features of posttraumatic headache may vary, but the most distressing type is the chronic daily headache. This study evaluates occurrence of chronic daily headache in relation to the intensity of head injury. METHODS: All patients with head injury who were seen by the senior author (J.R.C.) in the Southern Illinois University Medical School (SIUMS) Neurology Clinic between 1980 and 1991 were identified from the SIUMS headache registry. Data on headache status before and after head injury was obtained, and patients with more than one headache per week before head injury were excluded. Each patient's headache status at the time of the clinic visit was classified as chronic daily headache (headache occurring at least 5 of 7 days for 6 months), intermittent migraine, or no headache. Head injury severity was graded by duration of loss of consciousness or amnesia as minimal (less than 5 minutes), mild (5 to 60 minutes), moderate (1 to 24 hours), or severe (more than 24 hours). RESULTS: There was an inverse relation between extent of head injury and occurrence of chronic daily headache. For minimal head injury (n = 54), 80% had chronic daily headache, and 11% had no headache, while for moderate/severe head injury (n = 23), only 27% had chronic daily headache, and 68% had no headache (P<.001, chi2). CONCLUSION: This study suggests that the risk of developing posttraumatic chronic daily headache is greater for less severe head injury compared with moderate/severe head injury. The reason for this relation is unclear.

Treatment of severe, disabling migraine attacks in an over-the-counter population of migraine sufferers: results from three randomized, placebo-controlled studies of the combination of acetaminophen, aspirin, and caffeine.

OBJECTIVE: To examine the benefits of acetaminophen, aspirin, and caffeine (AAC) in the treatment of severe, disabling migraine attacks, in a population of migraine sufferers for whom over-the-counter (OTC) medications are appropriate. BACKGROUND: Subjects (n = 1220) who met the International Headache Society criteria for migraine with or without aura were included in three independent clinical studies. DESIGN/METHODS: Post-hoc analysis of 172 subjects who met the criteria for severe, disabling migraine reported a history of migraine attacks characterized by at least severe pain and severe disability, and treated attacks with severe pain and at least severe disability. Subjects who usually vomited with 20% or more of their migraine attacks, and those with incapacitating disability (subjects who required bed rest for more than 50% of their attacks) were not eligible for enrollment. RESULTS: From 1 h and continuing through 6 h postdose, the proportion of responders was significantly greater (p< or =0.01) for AAC than placebo. The pain intensity difference from baseline was significantly greater (p< or =0.05) for AAC than placebo from 0.5 h through 6 h. The proportion of subjects reporting improvement in functional disability, photophobia, and phonophobia was significantly greater for AAC than placebo from 2 h through 6 h postdose. CONCLUSIONS: The nonprescription combination of AAC was well tolerated and effective.