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Long-acting injectable (LAI) opioid formulations mitigate the harm profiles and management challenges associated with providing effective analgesia for animals. A single dose of a long-acting opioid analgesic can provide up to 72 h of clinically relevant pain management. Yet, few of these new drugs have been translated to products for veterinary clinics. Regulatory pathways allow accelerated drug approvals for generic and biosimilar drugs. These pathways depend on rigorous evidence for drug safety and pharmacokinetic evidence demonstrating bioequivalence between the new and the legacy drug. This report reviews the animal PK data associated with lipid and polymer-bound buprenorphine LAI formulations. Buprenorphine is a widely used veterinary opioid analgesic. Because of its safety profile and regulatory status, buprenorphine is more accessible than morphine, methadone, and fentanyl. This review of PK studies coupled with the well-established safety profile of buprenorphine suggests that the accelerated approval pathways may be available for this new family of LAI veterinary pharmaceuticals.

In 2005, Bob Adams, the Chief Veterinarian at Johns Hopkins, wondered if sustained release technology could be used to improve postsurgical analgesia for animal medicine. Henry Brem, Director of the Hunterian Laboratories, had organized an international consortium to advance therapy for brain tumors and stroke. The Hunterian had over 20 years of experience with the safety and effectiveness of neutral lipids, phospholipids, carbohydrates, gels, polymers, and assorted devices for sustained-release drug delivery. We had the technology. What was the best pharmacology? Buprenorphine was the obvious analgesic. Reports of adverse events in the veterinary literature were rare.

The respiratory rate-oxygenation (ROX) index is a fraction of oxygen saturation, Fio2, and respiratory rate that has been validated to predict receipt of invasive mechanical ventilation in patients receiving high-flow nasal cannula (HFNC). This study aimed to validate ROX in a cohort of inpatients with COVID-19-related respiratory failure.Retrospective validation of the ROX index. We calculated sensitivity, specificity, positive predictive value, negative predictive value, and 95% CIs of ROX for invasive mechanical ventilation any time during hospitalization.Twenty-one hospitals of Kaiser Permanente Northern California, an integrated healthcare delivery system.We identified adults with positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test within 3 weeks of, or during, hospitalization between February 1, 2020, and December 31, 2020. We calculated ROX at 12 hours after HFNC initiation. We grouped patients as low (≥ 4.88), intermediate (4.88 and ≥ 3.85), or high (3.85) risk using previously published thresholds.None.We identified 1,847 patients who had no limitation of life support. Of these, 525 (31.7%) received invasive mechanical ventilation any time during hospitalization and 511 died (27.7%). The sensitivity, specificity, positive predictive value, and negative predictive value of 12-hour ROX threshold (3.85) predicting invasive mechanical ventilation were 32.3% (95% CI, 28.5-36.3%), 89.8% (95% CI, 88.0-91.4%), 59.4% (95% CI, 53.8-64.9%), and 74.1% (95% CI, 71.8-76.3%), respectively.The 12-hour ROX index has a positive predictive value (59.4%) using threshold of less than 3.85 for COVID-19 patients needing invasive mechanical ventilation. Our health system has embedded ROX into the electronic health record to prioritize rounding during periods of inpatient surge.

Background Epidemiological studies of interstitial lung disease (ILD) are limited by small numbers and tertiary care bias. Investigators have leveraged the widespread use of electronic health records (EHRs) to overcome these limitations, but struggle to extract patient-level, longitudinal clinical data needed to address many important research questions. We hypothesized that we could automate longitudinal ILD cohort development using the EHR of a large, community-based healthcare system. Study design and methods We applied a previously validated algorithm to the EHR of a community-based healthcare system to identify ILD cases between 2012–2020. We then extracted disease-specific characteristics and outcomes using fully automated data-extraction algorithms and natural language processing of selected free-text. Results We identified a community cohort of 5,399 ILD patients (prevalence = 118 per 100,000). Pulmonary function tests (71%) and serologies (54%) were commonly used in the diagnostic evaluation, whereas lung biopsy was rare (5%). IPF was the most common ILD diagnosis (n = 972, 18%). Prednisone was the most commonly prescribed medication (911, 17%). Nintedanib and pirfenidone were rarely prescribed (n = 305, 5%). ILD patients were high-utilizers of inpatient (40%/year hospitalized) and outpatient care (80%/year with pulmonary visit), with sustained utilization throughout the post-diagnosis study period. Discussion We demonstrated the feasibility of robustly characterizing a variety of patient-level utilization and health services outcomes in a community-based EHR cohort. This represents a substantial methodological improvement by alleviating traditional constraints on the accuracy and clinical resolution of such ILD cohorts; we believe this approach will make community-based ILD research more efficient, effective, and scalable.

Opioids, the frontline drugs for postsurgical analgesia, have been linked to diversion and abuse with lethal consequences. The search for safe analgesics with less harm potential has been decades long. However, clinical trials for safe opioid and nonopioid analgesics have relied on subjective pain reports, which are biased by placebo effects that increase the complexity of trials to develop new therapies to manage pain.Research in opioid naïve animals and humans demonstrates that blood concentrations of opioids that effectively saturate the morphine opioid receptor are tightly linked with patient reports and quantitative sensory tests for analgesia. Opioid drug concentrations can predict clinical responses.This report reviews preclinical and clinical evidence correlating buprenorphine pharmacokinetics with analgesia. More than 30 years of data confirm buprenorphine blood concentrations can be an objective biomarker of analgesia for moderate to severe acute postoperative pain.

Regulations for new drug approvals require stringent safety testing and efficacy trial programs. The approval process for generic drugs, however, is significantly streamlined. Bioavailability data can substitute for new rounds of efficacy trials, thereby decreasing both time to approval as well as reducing the costs required for new studies. This regulatory choice has not been available when generic drugs are offered in a controlled release format such as a subcutaneous depot, transdermal patch, or implant. The purpose of this review is to suggest that the approval of generic drugs in inert controlled release envelopes should be eligible for similar regulatory relief. Proof for this concept is provided by the example of the numerous controlled release buprenorphine products. Buprenorphine is a generic opioid used since the 1980s in tablet form to treat pain and to treat opioid addiction. Long-acting, inert delivery vehicles for the drug have become available for the same indications. Safety and bioavailability profiles of the long-acting products are the same or improved over the parent product. A review of the long-acting drugs provides compelling evidence to recommend that generic drug-controlled release products may be eligible for alternative regulatory programs.

Animal models to study opiates are of growing interest. We have examined the short-term safety of buprenorphine implants in Fischer F344/NTac rats treated with excess doses of a cholesterol-triglyceride suspension of buprenorphine. A single injection of 0.65 mg/kg afforded clinically significant blood levels of analgesia for 3 days. Chemistry, hematology, coagulation, and urinalysis values with 2- to 10-fold excess doses of the drug-lipid suspension were within normal limits. Histopathology findings were unremarkable. The skin and underlying tissue surrounding the drug injection were unremarkable. Here we report the results of a long-term follow-up study of female rats injected with 0.65 and 1.3 mg/kg. The 14-month evaluation showed no abnormal findings that could be attributed to the drug or lipid suspension. These results confirm the safety of cholesterol-triglyceride carrier systems for subcutaneous drug delivery in laboratory animals and suggest that this model may be used to study long-term effects of opiate therapy.

Opioid addiction to prescription and illicit drugs is a serious and growing problem. In the US alone, >2.4 million people suffer from opioid use disorder. Government and pharmaceutical agencies have begun to address this crisis with recently released and revised task forces and medication-assisted therapies (MAT). For decades, oral or intravenous (IV) MATs have helped patients in their recovery by administration of opioid agonists (methadone, buprenorphine, oxycodone), antagonists (naltrexone, naloxone), and combinations of the two (buprenorphine/naloxone). While shown to be successful, particularly when combined with psychological counseling, oral and IV forms of treatment come with constraints and challenges. Patients can become addicted to the agonists themselves, and there is increased risk for diversion, abuse, or missed dosages. Consequently, long-acting implants have begun to be developed as a potentially preferable method of agonist delivery. To date, the newest implant approved by the US Food and Drug Administration (May 2016) is Probuphine®, which delivers steady-state levels of buprenorphine over the course of 6 months. Numerous studies have demonstrated its efficacy and safety. Yet, implants come with their own risks such as surgical site irritation, possible movement, and protrusion of implant out of skin. This review introduces the opioid abuse epidemic, examines existing medications used for therapy, and highlights Probuphine as a new treatment option. Costs associated with MATs are also discussed., Video abstract

Background COPD is the third most frequent cause of death globally, with much of this burden attributable to household biomass smoke exposure in developing countries. As biomass smoke exposure is also associated with cardiovascular disease, lower respiratory infection, lung cancer, and cataracts, it presents an important target for public health intervention. Methods Lung function in Guatemalan women exposed to wood smoke from open fires was measured throughout the Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) stove intervention trial and continued during the Chronic Respiratory Effects of Early Childhood Exposure to Respirable Particulate Matter (CRECER) cohort study. In RESPIRE, early stove households received a chimney woodstove at the beginning of the 18-month trial, and delayed stove households received a stove at trial completion. Personal exposure to wood smoke was assessed with exhaled breath carbon monoxide (CO) and personal CO tubes. Change in lung function between intervention groups and as a function of wood smoke exposure was assessed using random effects models. Results Of 306 women participating in both studies, acceptable spirometry was collected in 129 early stove and 136 delayed stove households (n = 265), with a mean follow-up of 5.6 years. Despite reduced wood smoke exposures in early stove households, there were no significant differences in any of the measured spirometric variables during the study period (FEV1, FVC, FEV1/FVC ratio, and annual change) after adjustment for confounding. Conclusions In these young Guatemalan women, there was no association between lung function and early randomization to a chimney stove or personal wood smoke exposure. Future stove intervention trials should incorporate cleaner stoves, longer follow-up, or potentially susceptible groups to identify meaningful differences in lung function.

The use of appropriate analgesia in laboratory mice may be suboptimal because of concerns about adverse events (AE). Target Animal Safety trials were conducted to determine the safety of an extended-release suspension of buprenorphine. Drug or control suspensions were injected subcutaneously in surgically-treated BALB/c mice anesthetized with ketamine–xylazine to mimic post-operative conditions in which the compound might commonly be administered. Single and repeat five-fold (5×) excesses of the 3.25 mg/kg intended dose were used to provoke potential AE. Trials included prospective measurements of weight changes, blood chemistry, hematology, and histopathology. Clinical and histopathology findings were similar in drug-treated and control mice in a four-day trial using a single 16.25 mg/kg, 5× overdose of the drug. In a 12-day trial, which used a total buprenorphine dose of 48.75 mg/kg, clinical and histopathology values were also similar in control and drug-treated female mice. In the male arm of the repeat-overdose trial, two of eight mice died on the morning of day 12, three days following the third 16.25 mg/kg overdose administration. Histopathology did not reveal a cause of death. In a 14-month trial using a single 3.25 mg/kg dose of the drug, no significant findings identified potential AE. These findings indicate a high tolerance to an extended-release buprenorphine suspension administered post-operatively in mice with appropriate husbandry.

Buprenorphine is a long-acting opiate with a high therapeutic index. The authors review the pharmacology, toxicity, analgesic effects and delivery of buprenorphine for use in laboratory mice and rats. Buprenorphine-based analgesic therapy has a substantial record of safety, and there is growing evidence of its effectiveness for treating post-operative pain. Nonetheless, more research is needed to determine optimal delivery systems and analgesic regimens for pain therapy in laboratory animals.

Technical aspects of local chemotherapy in inoperable brainstem gliomas by convection-enhanced delivery (CED) are still under experimental considerations. In this study, we characterize the feasibility of multiple cannula placements in the rat brainstem.In 38 male Fisher rats, up to three guided screws were positioned in burr holes paramedian at 2.5 mm anterior and posterior to as well as at the lambdoid suture. Using Alzettrade mark pumps (1 microl/h flow rate over 7 days) either vehicle (5% dextrose) or 0.1 mg carboplatin was delivered via one, two, or three cannulas, respectively. During cannula insertion, electrocardiogram and respiratory rate was monitored. All rats were subsequently evaluated neurologically for 8 days. For drug distribution in coronal sections, the brain tissue concentration of platinum was measured. HE staining was used to evaluate the local site of drug delivery. Heart and respiratory rate remained within normal range during surgical procedure. Neurological scoring showed only mild neurological impairment in the groups receiving two or three cannulas, which resolved after vehicle delivery. However, after carboplatin delivery, this deficit remained unchanged. Drug distribution was more homogeneous in the three cannula group. Histological slices visualized edematous changes at the sight of cannula placement.The unilateral application of up to three cannulas in the brainstem of rats for local drug delivery studies is feasible. The remaining neurological deficit in carboplatin-treated animals underlines the need of low toxicity drugs for CED in the brainstem.

BackgroundCOPD is the third most frequent cause of death globally, with much of this burden attributable to household biomass smoke exposure in developing countries. As biomass smoke exposure is also associated with cardiovascular disease, lower respiratory infection, lung cancer, and cataracts, it presents an important target for public health intervention.MethodsLung function in Guatemalan women exposed to wood smoke from open fires was measured throughout the Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) stove intervention trial and continued during the Chronic Respiratory Effects of Early Childhood Exposure to Respirable Particulate Matter (CRECER) cohort study. In RESPIRE, early stove households received a chimney woodstove at the beginning of the 18-month trial, and delayed stove households received a stove at trial completion. Personal exposure to wood smoke was assessed with exhaled breath carbon monoxide (CO) and personal CO tubes. Change in lung function between intervention groups and as a function of wood smoke exposure was assessed using random effects models.ResultsOf 306 women participating in both studies, acceptable spirometry was collected in 129 early stove and 136 delayed stove households (n = 265), with a mean follow-up of 5.6 years. Despite reduced wood smoke exposures in early stove households, there were no significant differences in any of the measured spirometric variables during the study period (FEV1, FVC, FEV1/FVC ratio, and annual change) after adjustment for confounding.ConclusionsIn these young Guatemalan women, there was no association between lung function and early randomization to a chimney stove or personal wood smoke exposure. Future stove intervention trials should incorporate cleaner stoves, longer follow-up, or potentially susceptible groups to identify meaningful differences in lung function.

Household air pollution (HAP) from solid fuel combustion is a major contributor to the global burden of disease, with considerable impact from respiratory infections in children. The impact of HAP on lung function is unknown.The Childhood Exposure to Respirable Particulate Matter (CRECER) prospective cohort study followed Guatemalan children who participated in the Randomised Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) trial of a chimney stove intervention to determine the effect of early childhood HAP exposure on growth of lung function.RESPIRE households with pregnant women or infant children were randomised to receive a chimney stove at the beginning or at the end of the 18-month trial. During CRECER, a subset of these children, as well as children from households with newly installed stoves, were followed with spirometry beginning at age 5. Biomass smoke exposure was measured using personal carbon monoxide tubes. Two-stage regression models were employed to analyse associations with lung function growth.Longitudinal peak expiratory flow (PEF) and FEV1 data were available for 443 and 437 children, respectively, aged 5-8 (mean follow-up 1.3 years). Decreases in PEF growth of 173 mL/min/year (95% CI -341 to -7) and FEV1 of 44 mL/year (95% CI -91 to 4) were observed with stove installation at 18 months compared with stove installation at birth in analyses adjusted for multiple covariates. No statistically significant associations were observed between personal HAP exposure and lung function.A significant decrease in PEF growth and a large non-significant decrease in FEV1 growth were observed with later stove installation. Additional studies including longer follow-up and cleaner stoves or fuels are needed.

OBJECT Percutaneous treatments for trigeminal neuralgia are safe, simple, and effective for achieving good pain control. Procedural risks could be minimized by using noninvasive imaging techniques to improve the placement of the radiofrequency thermocoagulation probe into the trigeminal ganglion. Positioning of a probe is crucial to maximize pain relief and to minimize unwanted side effects, such as denervation in unaffected areas. This investigation examined the use of laser speckle imaging during probe placement in an animal model. METHODS This preclinical safety study used nonhuman primates, Macaca nemestrina (pigtail monkeys), to examine whether real-time imaging of blood flow in the face during the positioning of a coagulation probe could monitor the location and guide the positioning of the probe within the trigeminal ganglion. RESULTS Data from 6 experiments in 3 pigtail monkeys support the hypothesis that laser imaging is safe and improves the accuracy of probe placement. CONCLUSIONS Noninvasive laser speckle imaging can be performed safely in nonhuman primates. Because improved probe placement may reduce morbidity associated with percutaneous rhizotomies, efficacy trials of laser speckle imaging should be conducted in humans.

Introduction: Sucrose acetate isobutyrate (SAIB) is a water insoluble, biodegradable gel used for controlled-release oral and subcutaneous drug delivery. We investigated SAIB compatibility in the rat central nervous system (CNS) by implanting solutions of SAIB in adult and in neonatal brains. Methods: 10–15 μL solutions of SAIB gels in 0–30% ethanol were injected into the cerebral cortex of adult Fischer 344 rats. Control animals were implanted with a 10 mg biodegradable poly anhydride copolymer of poly [bis (p-carboxyphenoxy) propane] anhydride and sebacic acid (PCPP:SA). Adult rats were evaluated for signs of pain and distress, including changes in posture, facial signs, and grooming behavior. 1–2 μL solutions of SAIB gels in 15% ethanol were injected into brains of 12–24 h-old rats. Neonatal rats were evaluated for survival. Adult and neonatal brains were examined by histopathology 3–48 days after implant. Results: Gel implants produced elliptical compression of cortical tissue, cell loss, and inflammation. Cell loss appeared to be confined to the implantation wound and associated neuronal fields. In adult rats, neurophil compression, inflammation, and cell loss appeared similar with the 10-mg PCPP:SA implants and the 10-mg SAIB implants. There was no clinical evidence of pain or distress from SAIB implants. 1–2 μL implants of SAIB–15% ethanol had no effect on survival of neonatal animals. Conclusion: Brain implants of SAIB induce a mild to moderate inflammatory response and associated neuronal cell damage. The implants appeared to be biocompatible in adult and neonatal animals. These results suggest that further studies of SAIB as an injectable drug-delivery scaffold for CNS therapeutic agents are warranted.

Object Survival rates for high-grade brainstem tumors are approximately 10% and optimal therapy has yet to be determined. Development of a satisfactory brainstem tumor model is necessary for testing new therapeutic paradigms that may prolong survival. The authors report the technique, functional progression, radiological appearance, and histopathological features of a novel brainstem tumor model in rats. Methods Thirty female Fischer 344 rats were randomized (10 animals/group) to receive an injection of either 3 μl of 9L gliosarcoma cells (100,000 cells), 3 μl of F98 glioma cells (100,000 cells), or 3 μl of medium (Dulbecco modified Eagle medium) into the pontine tegmentum of the brainstem. Using a cannulated guide screw system implanted in the skull of the animal, rats in each group were injected at coordinates 1.4 mm to the right of the sagittal and 1 mm anterior to the lambdoid sutures, at a depth of 7 mm from the dura mater. The angle of the syringe during injection was anteflexed 5° from the vertical. Postoperatively, the rats were evaluated for neurological deficits by using an automated rotarod test. High-resolution [18F]fluorodeoxyglucose–positron emission tomography (FDG-PET) fused with computerized tomography (CT) scans were acquired pre- and postoperatively through the onset of hemiparesis and correlated accordingly. Kaplan–Meier curves were generated for survival and disease progression, and brains were processed postmortem for histopathological investigation. The 9L and F98 tumor cells grew in 95% of the animals in which they were injected and resulted in a statistically significant mean onset of hemiparesis of 16.5 ± 0.56 days (p = 0.001, log-rank test), compared with animals in the control group, which had no neurological deficits by Day 45. The FDG-PET studies coregistered with CT scans demonstrated space-occupying brainstem lesions, and this finding was confirmed by histological studies. Animals in the control group showed no functional, radiological, or pathological signs of tumor. Conclusions Progression to hemiparesis was consistent in all tumor-injected animals, with predictable onset of symptoms occurring approximately 17 days postsurgery. The histopathological and radiological characteristics of the 9L and F98 brainstem tumors were comparable to those of aggressive primary human brainstem tumors. Establishment of this animal tumor model will facilitate the testing of new therapeutic paradigms for the treatment of these lesions.

Introduction: Neuropharmacology studies depend on consistency in drug delivery. Drug infusions into central nervous system (CNS) tissues have been described as unreliable. Speculation has focused on infusion pumps as the source of variation. This report demonstrates that the catheter may be a source of variability. The inconsistency can be significantly reduced by a change in catheter design. Methods: Normal and tumor cell-challenged (abnormal) brains of Fischer rats were infused with small and large molecular weight cytotoxic drugs via rigid and flexible catheters placed directly into the parenchyma. Coronal tissue sections rostral and caudal to the infusion point were analyzed for drug concentrations. Carboplatin, estimated through atomic absorption assays, and doxorubicin and transferrin-bound doxorubicin, measured by fluorescent spectroscopy, were mapped in serial sections at various distances from the infusion point. Results: The expected drug distribution pattern approximates a bell-shaped curve with a maximum drug concentration near the infusion point and approximately equal, declining concentrations rostral and caudal to the infusion. This expected distribution was found in only 10 of the 17 normal brains and 15 of the 28 abnormal brains infused with a rigid catheter. In contrast, 10 of the 10 normal brains and 16 of the 16 abnormal rat brains infused with a flexible catheter had the expected distribution pattern. The distribution pattern was not associated with the molecular weight of the infused drug. Conclusion: Replacement of rigid infusion tubes with flexible tubing increases the reliability of local CNS drug infusions. Rigid catheters may allow backflow of the infused drug along the path of the catheters into the subdural space.

The aim of this study was to investigate the optimal delivery rates of chemotherapy for the treatment of central nervous system tumors and to determine whether local delivery can lower toxicity profiles and increase target concentrations of chemotherapy.The authors used two brain tumor models in rats. Slow (1 microl/hour) and fast (10 microl/hour) pumps were used to deliver chemotherapy--carboplatin, doxorubicin, and a high-molecular-weight transferrin-doxorubicin conjugate to the brains of normal rats and rats previously injected with F98 or 9L rat brain tumor cells. Brains were cut in 1-mm sections rostral and caudal from the infusion point. Slices were analyzed for doxorubicin and platinum by fluorescence and atomic absorption, respectively. In the normal tissues, the volume of drug distribution is generally greater at the faster flow rate. In abnormal tissues, distribution is similar at slow and fast infusion rates for low-molecular-weight drugs and greater at slow rates for a high-molecular-weight targeted toxin.After local administration the distribution of chemotherapy appears to be significantly influenced by tumor metabolism. Additional studies are needed to determine the optimal delivery rates for the interaction of the drug with the targeted tumor.

Achondroplasia is the most common of the heritable skeletal dysplasias. Cervico-medullary compression is a frequently encountered and potentially lethal neurological complication. Cervico-medullary decompression (CMD) at the foramen magnum is often employed to relieve the pressure on the emerging cervical cord. Given the inherent risks associated with major surgery, there has been a substantial debate regarding the best criteria for CMD. Our objectives for this study are to explore the quality of life of patients who had undergone CMD, and to assess whether surgery is associated with mortality and increased long-term morbidity. A Medical Outcome Study 36-item Short Form General Health Survey designed to evaluate eight general health concepts as well as achondroplasia-related issues, was administered to patients assessed in the neurosurgery department in Johns Hopkins Hospital between 1977 and 1998. One hundred and sixty-seven patients were eligible for inclusion. Forty-three could not be contacted, and two refused consent. One hundred and twenty-two patients were assessed. Fifty-six (46%) individuals had CMD and 66 (54%) did not. There was 1 case of mortality in the CMD group and 12 cases in the non-CMD group. In the non-CMD group, all deaths, as far as we know, were unrelated to cervico-medullary compression. In this cohort of surviving patients (n = 109), the quality of life of the 55 (50.5%) who had undergone CMD is comparable to that of the 54 (49.5%) who did not have surgery, controlled for age and sex. CMD is indicated for patients with achondroplasia with significant symptomatic foramen magnum compression. It can be life saving. It can abolish profound central apnea that may cause sudden death and alleviate neurological complications associated with damage of the significantly compressed spinal cord. With regards to long-term outcome evaluation, the quality of life of individuals with achondroplasia who had CMD is similar to those age- and sex-matched patients who did not have this surgery. Moreover, CMD, with all its inherent surgical risks, does not appear to be associated with higher mortality or increased long-term morbidity. © 2004 Wiley-Liss, Inc.

OBJECTIVE We sought to develop a neurosurgical procedure to access the pons with a drug delivery device for chronic therapy and collect preliminary data on the toxicity of direct infusions of carboplatin in primates. METHODS We made midline incisions on five cynomolgus monkeys, identified the inion, made a burr hole 2.5 cm below the inion, and inserted a catheter through the cerebellum into the roof of the pons. Pumps that infused saline for 90 days or carboplatin solutions for 30 to 35 days at 10 μl/d were placed subcutaneously in the low cervical/high thoracic region. Monkeys were assessed by computed tomography and magnetic resonance imaging, laboratory studies, daily neurological observation, postmortem examinations, and histopathology. RESULTS Monkeys infused with saline and 82 μg of carboplatin remained neurologically intact throughout the infusion periods. Serial imaging showed that the catheter tip was in the pons and revealed no evidence of hemorrhage, edema, or migration. Two monkeys infused with up to 850 μg of carboplatin showed hyperintense magnetic resonance imaging signals at Days 15 and 18 and neurological deficits at approximately Week 3. Platinum levels greater than 10 ng/mg tissue were detected over a distance of 1 cm in tissue slices. Histopathology demonstrated significant tissue necrosis around the tip of the catheter. CONCLUSION The pons of monkeys is safely accessed with a catheter for drug delivery by using a posterior midline approach. Clinical observations, radiographic imaging, and laboratory tests of animals infused with saline for 3 months or 0.26 mg/ml of carboplatin for 1 month were unremarkable. Neurotoxicity was seen with dose levels of 2.6 mg/ml of drug for 1 month. This procedure offers opportunities for examining the toxicity of brainstem antitumor therapy in primates.

Because the brainstem has little functional redundancy, diffuse lesions have been regarded as inoperable. To determine whether local drug therapy can prolong survival in a rodent model of a tumor in such eloquent tissue, lethal doses of F98 and 9L tumor cells were injected into the brainstems of Fischer 344 rats. Five days after inoculations, 0.5 mg/ml solutions of carboplatin were infused at 1 μl/h for 7 days. Compared to control groups that survived 13–17 days with F98 tumors and 22–23 days with 9L tumors, animals locally infused with 0.1 mg of carboplatin survived 27–30 days (Prob > Chi Sq = 0.0003), and 32 days (Prob > Chi Sq = 0.01), respectively. Measurements of tissue platinum levels at autopsy suggested that infusions distributed pharmacologically relevant levels of carbo-platin through a volume of tissue at least 0.5 cm in diameter. The results suggest that chronic low-flow infusions provide a promising approach to therapy for CNS lesions in tissues considered to be inoperable.

An assistive device (AD) was used to treat 122 infants with moderate-to-severe positional plagiocephaly. Clinical evaluations indicate that the AD provided the most benefit when applied to 2- to 8-month-old children. Our results suggest that the AD may join molding helmets and physical therapy as a treatment for moderate-to-severe positional plagiocephaly in infants under the age of 1 year.

Introduction: A variety of surgical interventions have been recommended for patients with syringomyelia and Chiari malformation. To obtain a better understanding of currently used management strategies and surgical interventions, this study evaluates current opinions in the treatment of these entities. Methods: Members of the Pediatric Section of the American Association of Neurological Surgeons (AANS) were surveyed in July of 1998. A questionnaire was designed to assess (1) management of asymptomatic and symptomatic cases; (2) signs and symptoms that warrant surgical intervention, and (3) surgical strategies. Seventy-seven of 234 surveys (33%) were returned. Responses were entered in a Microsoft Excel spreadsheet for data analysis. Results: Each year, respondents evaluated on average 10 patients with confirmed syringomyelia and operated on 7. There was substantial agreement to operate on patients with syringomyelia who had progressive scoliosis or progressive motor/sensory loss. For isolated syringomyelia without a Chiari malformation, the majority of respondents recommended shunting of the syrinx. Opinion was mixed concerning physical restrictions for asymptomatic patients with syringomyelia and Chiari malformations. For Chiari malformations, the majority of respondents recommended a minimum cervicomedullary decompression with dural patch grafting. No consensus was obtained on whether dural patch grafting should be done alone or in combination with intradural dissection or manipulation of the tonsils. Conclusion: Although many respondents agreed on the management and surgical treatment of symptomatic patients with syringomyelia and/or Chiari malformations, there was disagreement with regard to the optimal surgical procedure. Respondents rejected prophylactic surgery for their asymptomatic patients, choosing to follow them conservatively with serial imaging and neurological examinations.

Mutations in superoxide dismutase 1 (SOD1) have been linked to familial amyotrophic lateral sclerosis, a dominantly inherited motor neuron disorder of midlife. Because SOD1 is a homodimeric enzyme, dimerization of mutant and wild-type SOD1 subunits could dominantly alter the activity, stability, or localization of wild-type SOD1 subunits. To explore these possibilities, we used transient and stable gene transfection to express high levels of either of two mutant human SOD1 subunits in the presence of limited levels of wild-type mouse and/or human SOD1 subunits. Although both mutant subunits displayed diminished half-lives and free radical scavenging activities, their presence caused no change in the half-life or activity of wild-type SOD1 subunits. Our data indicate that mutant subunits do not dominantly affect the function of wild-type SOD1 subunits. These findings, together with observations that many mutant SOD1 subunits retain significant stability and activity, suggest that motor neuron damage in familial amyotrophic lateral sclerosis is caused by the acquisition of injurious properties by mutant SOD1 subunits.

Background: More than two-fifths of the world’s population uses solid fuels, mostly biomass, for cooking. The resulting biomass smoke exposure is a major cause of chronic obstructive pulmonary disease (COPD) among women in developing countries. Objective: To assess whether lower woodsmoke exposure from use of a stove with a chimney, compared to open fires, is associated with lower markers of airway inflammation in young women. Design: We carried out a cross-sectional analysis on a sub-cohort of participants enrolled in a randomized controlled trial in rural Guatemala, RESPIRE. Participants: We recruited 45 indigenous women at the end of the 18-month trial; 19 women who had been using the chimney stove for 18–24 months and 26 women still using open fires. Measurements: We obtained spirometry and induced sputum for cell counts, gene expression of IL-8, TNF-α, MMP-9 and 12, and protein concentrations of IL-8, myeloperoxidase and fibronectin. Exhaled carbon monoxide (CO) and 48-hr personal CO tubes were measured to assess smoke exposure. Results: MMP-9 gene expression was significantly lower in women using chimney stoves. Higher exhaled CO concentrations were significantly associated with higher gene expression of IL-8, TNF-α, and MMP-9. Higher 48-hr personal CO concentrations were associated with higher gene expression of IL-8, TNF- α, MMP-9 and MMP-12; reaching statistical significance for MMP-9 and MMP-12. Conclusions: Compared to using an open wood fire for cooking, use of a chimney stove was associated with lower gene expression of MMP-9, a potential mediator of airway remodeling. Among all participants, indoor biomass smoke exposure was associated with higher gene expression of multiple mediators of airway inflammation and remodeling; these mechanisms may explain some of the observed association between prolonged biomass smoke exposure and COPD.

In prion diseases, the cellular prion protein (PrPc), abundant in neurons, is converted posttranslationally into an amyloid-forming scrapie prion protein (PrPSc), which accumulates in white matter tracts and nerve terminals. The trafficking of PrPc in neurons was investigated in vivo by injecting [35S]methionine into the L4 and L5 dorsal root ganglia and the entorhinal cortices of adult rats and by tracing the movement of radiolabeled PrPc. In both paradigms, labeled 33-35-kDa PrPc was transported, within 4 h, to distal axons and nerve terminals cofractionating with proteins in the fast component. Future studies using these methods may allow us to determine whether PrPc is converted into PrpSc during axonal transport and whether PrPSc is transported in animals with prion diseases.

In the early 1960s, J.J. Gibson and W. Haddon, Jr. published papers that had a profound effect on modern safety. The papers provided a simple formula to analyze the cause of injuries and offered a framework for medicine and engineering to systematically design preventive strategies. According to one estimate, the work has led to the prevention of approximately 5,000 traffic deaths per year since 1966. This paper traces the separate paths that led two scientists to the same remarkable conclusion.

Methods to infuse drugs into the parenchyma of the central nervous system (CNS) have been reported as inconsistent or unpredictable. The source of variability appears to be a compromised seal between the tissue and the outer surface of the cannula. Failure of the tissue to seal to the cannula creates a path of least resistance. Rather than penetrate the target area, the drug backflows along the path of the cannula. This artifact can be difficult to detect because drugs enter the systemic circulation and provide some fraction of the intended therapy. Decreasing the rate of the infusion can reduce backflow. However, this may not be an attractive option for certain therapeutic targets because decreased infusion rates decrease the volume of drug distribution in normal tissue. Cannula design plays a role. Rigid catheters that are fixed to the skull will oppose movements of the brain and break the seal between the catheter and the tissue during chronic infusions. Flexible infusion cannulas, which can be readily made by modifying commercially available brain infusion catheters with plastic tubing, appear to provide consistent infusion results because they can move with the brain and maintain their tissue seal.

Methods to infuse drugs into the parenchyma of the central nervous system (CNS) have been reported as inconsistent or unpredictable. The source of variability appears to be a compromised seal between the tissue and the outer surface of the cannula. Failure of the tissue to seal to the cannula creates a path of least resistance. Rather than penetrate the target area, the drug backflows along the path of the cannula. This artifact can be difficult to detect because drugs enter the systemic circulation and provide some fraction of the intended therapy. Decreasing the rate of the infusion can reduce backflow. However, this may not be an attractive option for certain therapeutic targets because decreased infusion rates decrease the volume of drug distribution in normal tissue. Cannula design plays a role. Rigid catheters that are fixed to the skull will oppose movements of the brain and break the seal between the catheter and the tissue during chronic infusions. Flexible infusion cannulas, which can be readily made by modifying commercially available brain infusion catheters with plastic tubing, appear to provide consistent infusion results because they can move with the brain and maintain their tissue seal.

This chapter assesses the safety of freehand placement of an infusion catheter (outer diameter, 0.3 mm) in brainstems of cynomolgus monkeys (Macaca fascicularis) for local infusion therapy. A posterior midline approach through the cerebellum and roof of the fourth ventricle was used to implant catheters into a pontine target area. Computer tomography (CT), magnetic resonance imaging (MRI), and histology were used to examine the position of the implants. The freehand placement of a catheter resulted in approximately 5-mm variations in anterior-posterior and dorsal-ventral locations of the targeted implantation site. No evidence of morbidity from the surgery, or from the infusion process was present. In conclusion, small-diameter catheters for chronic drug infusions can be implanted safely into the brainstem, an eloquent region that has been considered surgically inoperable. Infusion systems may offer a minimally invasive, generally applicable tool to provide chronic therapy for central nervous system (CNS) lesions.

Ototoxicity is a common side effect of platinum-based chemotherapy. Intratumoral drug delivery theoretically could reduce the ototoxic effects of systemic drug infusions. However, local delivery to central nervous system (CNS) tumors might promote ototoxicity through drug release into cerebrospinal fluid (CSF). This report describes an examination of the cytoarchitecture of vestibular cells of cynomolgus monkeys that had chronic brainstem infusions with the maximum tolerated dose (MTD) of carboplatin. The brainstems of adult monkeys were infused for 30 days at 0.42 μl/h with 0.025 to 0.25 mg/kg (MTD) of carboplatin. The vestibular sensory epithelia of eight drug-treated animals were isolated for microscopic examination of vestibular hair cells and support cells. Local infusions produced chronic elevated CSF levels of platinum, neurological symptoms, and radiographic evidence of pontine injury. Histology revealed significant cell damage at the infusion sites. Microscopic examinations of vestibular support cells and hair cells demonstrate a small reduction in cell counts in the drug-treated monkeys compared to a noninfused control animal. Parametric and nonparametric tests show no effect of dose in predicting the vestibular cell counts. In this single study of eight monkeys, a dose-dependent reduction of vestibular hair cells or support cells was not observed in animals infused with brainstem infusions of 0.025 to 0.25 mg/kg of carboplatin.

✓ This 9-year-old boy with a history of behavioral problems and worsening psychosis responded initially to treatment with haloperidol. However, a magnetic resonance image obtained as part of his psychiatric evaluation revealed an anterior third ventricle tumor and mild-to-moderate hydrocephalus. The resected tumor was found on pathological examination to be a choroid plexus papilloma. The patient had an uneventful postoperative course and remained free of psychosis or mood disorder at 1-year follow-up examination.

Survival rates for high-grade brainstem tumors are approximately 10% and optimal therapy has yet to be determined. Development of a satisfactory brainstem tumor model is necessary for testing new therapeutic paradigms that may prolong survival. The authors report the technique, functional progression, radiological appearance, and histopathological features of a novel brainstem tumor model in rats.Thirty female Fischer 344 rats were randomized (10 animals/group) to receive an injection of either 3 ml of 9L gliosarcoma cells (100,000 cells), 3 ml of F98 glioma cells (100,000 cells), or 3 ml of medium (Dulbecco modified Eagle medium) into the pontine tegmentum of the brainstem. Using a cannulated guide screw system implanted in the skull of the animal, rats in each group were injected at coordinates 1.4 mm to the right of the sagittal and 1 mm anterior to the lambdoid sutures, at a depth of 7 mm from the dura mater. The angle of the syringe during injection was anteflexed 5 degrees from the vertical. Postoperatively, the rats were evaluated for neurological deficits by using an automated rotarod test. High-resolution [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) fused with computerized tomography (CT) scans were acquired pre- and postoperatively through the onset of hemiparesis and correlated accordingly. Kaplan-Meier curves were generated for survival and disease progression, and brains were processed postmortem for histopathological investigation. The 9L and F98 tumor cells grew in 95% of the animals in which they were injected and resulted in a statistically significant mean onset of hemiparesis of 16.5 6 0.56 days (p = 0.001, log-rank test), compared with animals in the control group, which had no neurological deficits by Day 45. The FDG-PET studies coregistered with CT scans demonstrated space-occupying brainstem lesions, and this finding was confirmed by histological studies. Animals in the control group showed no functional, radiological, or pathological signs of tumor.Progression to hemiparesis was consistent in all tumor-injected animals, with predictable onset of symptoms occurring approximately 17 days postsurgery. The histopathological and radiological characteristics of the 9L and F98 brainstem tumors were comparable to those of aggressive primary human brainstem tumors. Establishment of this animal tumor model will facilitate the testing of new therapeutic paradigms for the treatment of these lesions.

Brainstem tumor models are required to advance the treatment for diffuse pontine gliomas in children. The feasibility of creating an experimental rodent model by inoculating newborn pups with tumor cells was examined. The study was performed to create an animal model for diffuse brainstem tumors. Eighty-two Fischer rat pups aged 12–24 h were anesthetized by hypothermia. The brainstem was injected with saline to identify anatomical coordinates for subsequent tumor cell challenges. The newborn pups were then inoculated with F98 (n=30) or 9L (n=30) glioma cells. Animals were returned to their mother for nursing. Tumor growth was assessed by survival and histopathology. Twenty-one percent of the saline-treated animals (17 out of 82) and 5% of the tumor cell-challenged pups (3 out of 60) were eliminated by their mothers. Inoculations with 9L and F98 cells produced brainstem tumors in 83% (24 out of 29) and 93% of animals (26 out of 28) respectively that were evaluated. Our results demonstrate that neonatal rat models for brainstem tumors can be prepared using known injection coordinates and orthotopic cell lines. Decreasing rates of maternal removal during the course of the work suggests that the method involves a learning curve.

Purpose: Carboplatin was infused into the brainstem of cynomolgus monkeys to investigate neurotoxicity and systemic exposures following chronic local delivery. Methods: Infusions at 0.42 ul/h were intended to deliver 0.025 (n = 2), 0.075 (n = 3), 0.25 (n = 5), and 0.75 (n = 3) mg/kg by day 30. Laboratory tests, radiographic measurements, and clinical observations were used to monitor toxicity. Blood and cerebrospinal fluid (CSF) were sampled for platinum. Results: Lethargy and ataxia were observed after week 4 in the monkeys given 0.075 mg/kg, and week 2 in the monkeys given 0.25 mg/kg when the infused doses were ∼250 and 400 ug, respectively. Rapidly progressive neurotoxicity with the 0.75 mg/kg dose required termination of the infusions at days 4–10. Hematology and chemistry values were unremarkable in all groups. Blood levels of platinum remained undetectable in 0.025 and 0.075 mg/kg dose groups. Levels in the 0.25 mg/kg group were 3.1 ± 0.6 μg/l at 2 weeks and 5.2 ± 0.8 μg/l at 1 month. The CSF platinum levels varied. Animals in the 0.25 mg/kg group had higher CSF levels at 2 weeks (avg. 65 ug/l, range 36–89) compared to their 1 month value (avg. 60 ug/l, range 7–170), despite the constant infusion. Conclusion: Carboplatin can be chronically infused into monkey brainstems. Neurotoxicity is the predominant side effect and is dose-dependent. Pharmacokinetics of local and systemic delivery are different for carboplatin. Further studies are needed to monitor toxicity at higher flow rates and to investigate drug binding to abnormal central nervous system (CNS) tissues.

Because the brainstem has little functional redundancy, diffuse lesions have been regarded as inoperable. To determine whether local drug therapy can prolong survival in a rodent model of a tumor in such eloquent tissue, lethal doses of F98 and 9L tumor cells were injected into the brainstems of Fischer 344 rats. Five days after inoculations, 0.5 mg/ml solutions of carboplatin were infused at 1 microl/h for 7 days. Compared to control groups that survived 13-17 days with F98 tumors and 22-23 days with 9L tumors, animals locally infused with 0.1 mg of carboplatin survived 27-30 days (ProbChi Sq = 0.0003), and 32 days (ProbChi Sq = 0.01), respectively. Measurements of tissue platinum levels at autopsy suggested that infusions distributed pharmacologically relevant levels of carboplatin through a volume of tissue at least 0.5 cm in diameter. The results suggest that chronic low-flow infusions provide a promising approach to therapy for CNS lesions in tissues considered to be inoperable.

Despite recent advances in surgical technology, resection is not an option for many brainstem tumors. Experimental models have played essential roles in examining new approaches to therapy. The objective of the present study was to generate models by determining coordinates for safe inoculation into the brainstem of mice and rats, and to establish whether the implantation of heterotopic cells would create reproducible survival curves. Morbidity and survival studies were used to map stereotactic coordinates allowing successful inoculation of tumor cells. Survival studies were used to investigate the time course of tumor growth. Tumor location was examined by light microscopy and magnetic resonance imaging. Mice survived injections of 2 μL of saline at interaural, lateral, and depth coordinates of −2.5, 1.0, and 3.5 mm and −1.5, 1.0, and 3.5 mm. Rats survived injections at interaural, lateral, and depth coordinates of −2.0, 2.0, and 7.0 mm and −3.0, 0, and 7.0 mm. Median survival of mice challenged with 5 × 105 EMT6 and 104 B16 tumor cells was 11 and 10 days, respectively. Median survival for rats challenged with 104 9L and F98 cells was 14 and 13 days, respectively. The present study demonstrates a feasible approach to preparing models of brainstem tumors. Limitations of these models are discussed.

Purpose. The DNA-repair protein, O6-alkylguanine-DNA alkyl transferase, may account for resistance of CNS tumors to DNA-alkylating drugs, such as bis-(2-chloroethyl)-1-nitrosourea (BCNU). The therapeutic effects of BCNU can be potentiated by inhibiting the repair protein with an alkylated guanine analog, O6-benzyl guanine (O6BG). To investigate potential toxicity of this inhibition, we examined the effects of O6BG in mice treated with intracranial (i.c.) BCNU given via a biodegradable polymer. Methods. Mice were treated with escalating doses of BCNU chronically delivered i.c., and with chronically delivered O6BG. The O6BG was delivered via a 7-day intraperitoneal (i.p.) or i.c. osmotic minipump. Toxicity of the combination therapies was measured from survival data. Bone marrow response was estimated from white blood cell counts. Results. Combining systemic (i.p.) O6BG with locally (i.c.) delivered BCNU resulted in a decrease in the maximum tolerated dose (MTD) of local BCNU. With local delivery of O6BG, the MTD of BCNU in combination with O6BG was increased. Conclusions. Based on the results of this study, a dose escalation study will be necessary when combining systemic O6BG with the higher doses of i.c. BCNU.

We sought to develop a neurosurgical procedure to access the pons with a drug delivery device for chronic therapy and collect preliminary data on the toxicity of direct infusions of carboplatin in primates.We made midline incisions on five cynomolgus monkeys, identified the inion, made a burr hole 2.5 cm below the inion, and inserted a catheter through the cerebellum into the roof of the pons. Pumps that infused saline for 90 days or carboplatin solutions for 30 to 35 days at 10 microl/d were placed subcutaneously in the low cervical/high thoracic region. Monkeys were assessed by computed tomography and magnetic resonance imaging, laboratory studies, daily neurological observation, postmortem examinations, and histopathology.Monkeys infused with saline and 82 microg of carboplatin remained neurologically intact throughout the infusion periods. Serial imaging showed that the catheter tip was in the pons and revealed no evidence of hemorrhage, edema, or migration. Two monkeys infused with up to 850 microg of carboplatin showed hyperintense magnetic resonance imaging signals at Days 15 and 18 and neurological deficits at approximately Week 3. Platinum levels greater than 10 ng/mg tissue were detected over a distance of 1 cm in tissue slices. Histopathology demonstrated significant tissue necrosis around the tip of the catheter.The pons of monkeys is safely accessed with a catheter for drug delivery by using a posterior midline approach. Clinical observations, radiographic imaging, and laboratory tests of animals infused with saline for 3 months or 0.26 mg/ml of carboplatin for 1 month were unremarkable. Neurotoxicity was seen with dose levels of 2.6 mg/ml of drug for 1 month. This procedure offers opportunities for examining the toxicity of brainstem antitumor therapy in primates.

Object. Chiari Type I malformation (CMI) is a congenital disorder recognized by caudal displacement of the cerebellar tonsils through the foramen magnum and into the cervical canal. Frequently, associated findings include abnormalities of nearby bony and neural elements as well as syringomyelia. Cerebellar tonsillar ectopia is generally considered pathological when greater than 5 mm below the foramen magnum. However, asymptomatic tonsillar ectopia is an increasingly recognized phenomenon, the significance of which is poorly understood.Methods. The authors retrospectively reviewed the records of all brain magnetic resonance (MR) images obtained at our hospital over a 43-month period in an attempt to ascertain the relative prevalence and MR imaging characteristics of asymptomatic CMIs. Of 22,591 patients who underwent MR imaging of the head and cervical spine, 175 were found to have CMIs with tonsillar herniation extending more than 5 mm below the foramen magnum. Of these, 25 (14%) were found to be clinically asymptomatic. The average extent of ectopia in this population was 11.4 ± 4.86 mm, and was significantly associated with a smaller cisterna magna. Syringomyelia and osseous anomalies were found in only one asymptomatic patient.Conclusions. The authors suggest that the isolated finding of tonsillar herniation is of limited prognostic utility and must be considered in the context of all available clinical and radiographic data. Strategies for treating patients with asymptomatic CMIs are discussed.

Object. Interleukin-12 (IL-12) has potential for the treatment of tumors because it can stimulate an antitumor immune response and possesses antiangiogenic properties. In the study reported here, the authors investigated the therapeutic role of locally delivered IL-12 in a malignant brain tumor model.Methods. After genetically engineering 9L gliosarcoma cells to express IL-12 (9L-IL12 cells), the authors used these cells as a source of locally delivered cytokine. First, they investigated the behavior of these cells, which were implanted with the aid of stereotactic guidance into the rat brain, by using serial magnetic resonance imaging and histopathological examination. Second, they assessed the antitumor efficacy of proliferating, as well as nonproliferating (irradiated), 9L-IL12 cells by implanting these cells in animals challenged by wild-type 9L gliosarcoma (9Lwt) cells. The IL-12 expression in brain regions injected with 9L-IL12 was confirmed by reverse transcription—polymerase chain reaction. Last, the authors explored whether animals treated with 9L-IL12 cells developed an antitumor immunological memory by rechallenging the survivors with a second injection of 9Lwt cells.The authors demonstrated that local delivery of IL-12 into the rat brain by genetically engineered cells significantly prolongs survival time in animals challenged intracranially with a malignant glioma.Conclusions. These findings support continued efforts to refine local delivery systems of IL-12 in an attempt to bring this therapy to clinical trials.