In-hive Pesticide Exposome: Assessing risks to migratory honey bees from in-hive pesticide contamination in the Eastern United States.

This study measured part of the in-hive pesticide exposome by analyzing residues from live in-hive bees, stored pollen, and wax in migratory colonies over time and compared exposure to colony health. We summarized the pesticide burden using three different additive methods: (1) the hazard quotient (HQ), an estimate of pesticide exposure risk, (2) the total number of pesticide residues, and (3) the number of relevant residues. Despite being simplistic, these models attempt to summarize potential risk from multiple contaminations in real-world contexts. Colonies performing pollination services were subject to increased pesticide exposure compared to honey-production and holding yards. We found clear links between an increase in the total number of products in wax and colony mortality. In particular, we found that fungicides with particular modes of action increased disproportionally in wax within colonies that died. The occurrence of queen events, a significant risk factor for colony health and productivity, was positively associated with all three proxies of pesticide exposure. While our exposome summation models do not fully capture the complexities of pesticide exposure, they nonetheless help elucidate their risks to colony health. Implementing and improving such models can help identify potential pesticide risks, permitting preventative actions to improve pollinator health.

Local delivery methods of therapeutic agents in the treatment of diffuse intrinsic brainstem gliomas.

Brainstem gliomas comprise 10-20% of all pediatric central nervous system (CNS) tumors and diffuse intrinsic pontine gliomas (DIPGs) account for the majority of these lesions. DIPG is a rapidly progressive disease with almost universally fatal outcomes and a median survival less than 12 months. Current standard-of-care treatment for DIPG includes radiation therapy, but its long-term survival effects are still under debate. Clinical trials investigating the efficacy of systemic administration of various therapeutic agents have been associated with disappointing outcomes. Recent efforts have focused on improvements in chemotherapeutic agents employed and in methods of localized and targeted drug delivery. This review provides an update on current preclinical and clinical studies investigating treatment options for brainstem gliomas.

The formulation makes the honey bee poison.

Dr. Fumio Matsumura's legacy embraced a passion for exploring environmental impacts of agrochemicals on non-target species such as bees. Why most formulations are more toxic to bees than respective active ingredients and how pesticides interact to cause pollinator decline cannot be answered without understanding the prevailing environmental chemical background to which bees are exposed. Modern pesticide formulations and seed treatments, particularly when multiple active ingredients are blended, require proprietary adjuvants and inert ingredients to achieve high efficacy for targeted pests. Although we have found over 130 different pesticides and metabolites in beehive samples, no individual pesticide or amount correlates with recent bee declines. Recently we have shown that honey bees are sensitive to organosilicone surfactants, nonylphenol polyethoxylates and the solvent N-methyl-2-pyrrolidone (NMP), widespread co-formulants used in agrochemicals and frequent pollutants within the beehive. Effects include learning impairment for adult bees and chronic toxicity in larval feeding bioassays. Multi-billion pounds of formulation ingredients like NMP are used and released into US environments. These synthetic organic chemicals are generally recognized as safe, have no mandated tolerances, and residues remain largely unmonitored. In contrast to finding about 70% of the pesticide active ingredients searched for in our pesticide analysis of beehive samples, we have found 100% of the other formulation ingredients targeted for analysis. These 'inerts' overwhelm the chemical burden from active pesticide, drug and personal care ingredients with which they are formulated. Honey bees serve as an optimal terrestrial bioindicator to determine if 'the formulation and not just the dose makes the poison'.

Genomic analysis of the interaction between pesticide exposure and nutrition in honey bees (Apis mellifera).

Populations of pollinators are in decline worldwide. These declines are best documented in honey bees and are due to a combination of stressors. In particular, pesticides have been linked to decreased longevity and performance in honey bees; however, the molecular and physiological pathways mediating sensitivity and resistance to pesticides are not well characterized. We explored the impact of coumaphos and fluvalinate, the two most abundant and frequently detected pesticides in the hive, on genome-wide gene expression patterns of honey bee workers. We found significant changes in 1118 transcripts, including genes involved in detoxification, behavioral maturation, immunity, and nutrition. Since behavioral maturation is regulated by juvenile hormone III (JH), we examined effects of these miticides on hormone titers; while JH titers were unaffected, titers of methyl farnesoate (MF), the precursor to JH, were decreased. We further explored the association between nutrition- and pesticide-regulated gene expression patterns and demonstrated that bees fed a pollen-based diet exhibit reduced sensitivity to a third pesticide, chlorpyrifos. Finally, we demonstrated that expression levels of several of the putative pesticide detoxification genes identified in our study and previous studies are also upregulated in response to pollen feeding, suggesting that these pesticides and components in pollen modulate similar molecular response pathways. Our results demonstrate that pesticide exposure can substantially impact expression of genes involved in several core physiological pathways in honey bee workers. Additionally, there is substantial overlap in responses to pesticides and pollen-containing diets at the transcriptional level, and subsequent analyses demonstrated that pollen-based diets reduce workers' pesticide sensitivity. Thus, providing honey bees and other pollinators with high quality nutrition may improve resistance to pesticides.

Four common pesticides, their mixtures and a formulation solvent in the hive environment have high oral toxicity to honey bee larvae.

Recently, the widespread distribution of pesticides detected in the hive has raised serious concerns about pesticide exposure on honey bee (Apis mellifera L.) health. A larval rearing method was adapted to assess the chronic oral toxicity to honey bee larvae of the four most common pesticides detected in pollen and wax--fluvalinate, coumaphos, chlorothalonil, and chloropyrifos--tested alone and in all combinations. All pesticides at hive-residue levels triggered a significant increase in larval mortality compared to untreated larvae by over two fold, with a strong increase after 3 days of exposure. Among these four pesticides, honey bee larvae were most sensitive to chlorothalonil compared to adults. Synergistic toxicity was observed in the binary mixture of chlorothalonil with fluvalinate at the concentrations of 34 mg/L and 3 mg/L, respectively; whereas, when diluted by 10 fold, the interaction switched to antagonism. Chlorothalonil at 34 mg/L was also found to synergize the miticide coumaphos at 8 mg/L. The addition of coumaphos significantly reduced the toxicity of the fluvalinate and chlorothalonil mixture, the only significant non-additive effect in all tested ternary mixtures. We also tested the common 'inert' ingredient N-methyl-2-pyrrolidone at seven concentrations, and documented its high toxicity to larval bees. We have shown that chronic dietary exposure to a fungicide, pesticide mixtures, and a formulation solvent have the potential to impact honey bee populations, and warrants further investigation. We suggest that pesticide mixtures in pollen be evaluated by adding their toxicities together, until complete data on interactions can be accumulated.

Learning impairment in honey bees caused by agricultural spray adjuvants.

BACKGROUND: Spray adjuvants are often applied to crops in conjunction with agricultural pesticides in order to boost the efficacy of the active ingredient(s). The adjuvants themselves are largely assumed to be biologically inert and are therefore subject to minimal scrutiny and toxicological testing by regulatory agencies. Honey bees are exposed to a wide array of pesticides as they conduct normal foraging operations, meaning that they are likely exposed to spray adjuvants as well. It was previously unknown whether these agrochemicals have any deleterious effects on honey bee behavior. METHODOLOGY/PRINCIPAL FINDINGS: An improved, automated version of the proboscis extension reflex (PER) assay with a high degree of trial-to-trial reproducibility was used to measure the olfactory learning ability of honey bees treated orally with sublethal doses of the most widely used spray adjuvants on almonds in the Central Valley of California. Three different adjuvant classes (nonionic surfactants, crop oil concentrates, and organosilicone surfactants) were investigated in this study. Learning was impaired after ingestion of 20 µg organosilicone surfactant, indicating harmful effects on honey bees caused by agrochemicals previously believed to be innocuous. Organosilicones were more active than the nonionic adjuvants, while the crop oil concentrates were inactive. Ingestion was required for the tested adjuvant to have an effect on learning, as exposure via antennal contact only induced no level of impairment. CONCLUSIONS/SIGNIFICANCE: A decrease in percent conditioned response after ingestion of organosilicone surfactants has been demonstrated here for the first time. Olfactory learning is important for foraging honey bees because it allows them to exploit the most productive floral resources in an area at any given time. Impairment of this learning ability may have serious implications for foraging efficiency at the colony level, as well as potentially many social interactions. Organosilicone spray adjuvants may therefore contribute to the ongoing global decline in honey bee health.

Treatment of pituitary adenomas using radiosurgery and radiotherapy: a single center experience and review of literature.

Fractionated radiotherapy (FRT) and gamma knife stereotactic radiosurgery (GKSRS) are used as adjuvant therapies to surgical resection for functional and non-functional pituitary adenomas, although their optimum role in the treatment algorithm, as well as long-term safety and efficacy, still awaits further study. We report a single center experience with 33 patients with non-functional (16 patients), ACTH- (five patients), GH- (four patients), or prolactin-secreting (eight patients) tumors treated with FRT or SRS. The median tumor diameter was 1.9 cm, and the median follow-up was 36 months. For GKSRS, the median dosage was 16 Gy for non-functional adenomas and 23 Gy for hormone-secreting tumors. The median total dose for FRT was 50.4 Gy over 28 fractions (median). Two patients (6%) demonstrated radiographic evidence of tumor progression, three patients (9%) demonstrated radiation-induced visual field deficits on neuro-ophthalmic evaluation, and two patients (6%) suffered from radiation-induced hypopituitarism. Biochemical control, defined as normalized hormone values in the absence of medical therapy, was achieved in five out of eight prolactinoma patients and two out of five patients with Cushing's disease, but none of the four patients with acromegaly. These results are presented with a review of the relevant literature on the differential characteristics of FRT versus SRS in the treatment of functional and non-functional pituitary adenomas and validate postoperative irradiation as a potentially safe and effective means for tumor control.

Rapid malignant transformation of low-grade astrocytomas: report of 2 cases and review of the literature.

BACKGROUND: Low-grade gliomas have been documented to undergo transformation into high-grade astrocytomas, and the time interval of this transformation has been reported to generally occur within 5 years in about 50% of patients harboring these low-grade lesions. Several studies have investigated the evolution of low-grade gliomas into malignant gliomas by CT and MRI characteristics, but many have not documented the timing of these transformation processes. CASE DESCRIPTION: The authors discuss the cases of 2 patients with histopathologically confirmed grade II astrocytomas after craniotomies that underwent rapid evolution into malignant gliomas within 13 weeks. Interestingly, both low-grade astrocytomas were positive with immunostaining for the epidermal growth factor receptor, in which its amplification has been implicated as a molecular marker of malignant gliomas. In addition, the grade II astrocytomas were negative for p53 in both patients but were found to be positive upon transformation into malignant gliomas. CONCLUSIONS: To our knowledge, this is the first report of rapid malignant transformation of low-grade gliomas, which were proven by histology, within 13 weeks. There may be patients with a subtype of low-grade astrocytomas that may warrant molecular characterization to determine if aggressive adjuvant therapy would be of benefit.

High levels of miticides and agrochemicals in North American apiaries: implications for honey bee health.

BACKGROUND: Recent declines in honey bees for crop pollination threaten fruit, nut, vegetable and seed production in the United States. A broad survey of pesticide residues was conducted on samples from migratory and other beekeepers across 23 states, one Canadian province and several agricultural cropping systems during the 2007-08 growing seasons. METHODOLOGY/PRINCIPAL FINDINGS: We have used LC/MS-MS and GC/MS to analyze bees and hive matrices for pesticide residues utilizing a modified QuEChERS method. We have found 121 different pesticides and metabolites within 887 wax, pollen, bee and associated hive samples. Almost 60% of the 259 wax and 350 pollen samples contained at least one systemic pesticide, and over 47% had both in-hive acaricides fluvalinate and coumaphos, and chlorothalonil, a widely-used fungicide. In bee pollen were found chlorothalonil at levels up to 99 ppm and the insecticides aldicarb, carbaryl, chlorpyrifos and imidacloprid, fungicides boscalid, captan and myclobutanil, and herbicide pendimethalin at 1 ppm levels. Almost all comb and foundation wax samples (98%) were contaminated with up to 204 and 94 ppm, respectively, of fluvalinate and coumaphos, and lower amounts of amitraz degradates and chlorothalonil, with an average of 6 pesticide detections per sample and a high of 39. There were fewer pesticides found in adults and brood except for those linked with bee kills by permethrin (20 ppm) and fipronil (3.1 ppm). CONCLUSIONS/SIGNIFICANCE: The 98 pesticides and metabolites detected in mixtures up to 214 ppm in bee pollen alone represents a remarkably high level for toxicants in the brood and adult food of this primary pollinator. This represents over half of the maximum individual pesticide incidences ever reported for apiaries. While exposure to many of these neurotoxicants elicits acute and sublethal reductions in honey bee fitness, the effects of these materials in combinations and their direct association with CCD or declining bee health remains to be determined.

Disseminated intravascular coagulation associated with ventriculoperitoneal shunt surgery.

Disseminated intravascular coagulation (DIC) as a complication of surgery for ventriculoperitoneal (VP) shunts is extremely rare, and only one case has been documented in the literature. The authors present the case of a 9-year-old girl with shunted hydrocephalus who presented with a 3-day history of headaches and vomiting. A head CT showed enlarged ventricles compared with baseline. An emergent VP shunt revision was performed, during which an obstructed proximal catheter was found. Immediately after extubation, the patient became apneic and progressed to cardiopulmonary arrest. A breathing tube was reinserted followed by resuscitation attempts that led to extracorporeal membrane oxygenation. Soon after reintubation, bloody drainage was noted in the endotracheal tube, and subsequent laboratory studies were consistent with DIC. The patient died on postoperative Day 1, and autopsy findings confirmed DIC. Note that DIC is a recognized complication of trauma, particularly with brain injury, but it is rare with neurosurgical procedures. Disseminated intravascular coagulation should be considered if excessive bleeding occurs after any brain insult.

Stereotactic radiosurgery in the management of brain metastases: an institutional retrospective analysis of survival.

PURPOSE: The objective of this study was to report our experience with stereotactic radiosurgery performed with the Gamma Knife (GK) in the treatment of patients with brain metastases and to compare survival for those treated with radiosurgery alone with survival for those treated with radiosurgery and whole-brain radiotherapy. METHODS AND MATERIALS: Prospectively collected demographic and clinical characteristics and treatment and survival data on 237 patients with intracranial metastases who underwent radiosurgery with the GK between 2003 and 2007 were reviewed. Kaplan-Meier and Cox proportional hazards regression analyses were used to compare survival by demographic and clinical characteristics and treatment. RESULTS: The mean age of the patient population was 56 years. The most common tumor histologies were non-small-cell lung carcinoma (34.2%) and breast cancer (13.9%). The median overall survival time was 8.5 months from the time of treatment. The median survival times for patients with one, two/three, and four or more brain metastases were 8.5, 9.4, and 6.7 months, respectively. Patients aged 65 years or greater and those aged less than 65 years had median survival times of 7.8 and 9 months, respectively (p = 0.008). The Karnofsky Performance Score (KPS) at the time of treatment was a significant predictor of survival: those patients with a KPS of 70 or less had a median survival of 2.9 months compared with 10.3 months (p = 0.034) for those with a KPS of 80 or greater. There was no statistically significant difference in survival between patients treated with radiosurgery alone and those treated with radiosurgery plus whole-brain radiotherapy. CONCLUSIONS: Radiosurgery with the GK is an efficacious treatment modality for brain metastases. A KPS greater than 70, histology of breast cancer, smaller tumor volume, and age less than 65 years were associated with a longer median survival in our study.

Immunotherapy combined with chemotherapy in the treatment of tumors.

This article provides a broad overview of the data, including laboratory and clinical studies, currently available on the combination of immunotherapy and chemotherapy for treating cancer. The various forms of immunotherapy combined with chemotherapy include monoclonal antibodies, adoptive lymphocyte transfer, or active specific immunotherapy, such as tumor proteins, irradiated tumor cells, tumor cell lysates, dendritic cells pulsed with peptides or lysates, or tumor antigens expressed in plasmids or viral vectors. This discussion is not limited to malignant brain tumors, because many of the studies have been conducted on various cancer types, thereby providing a comprehensive perspective that may encourage further studies that combine chemotherapy and immunotherapy for treating brain tumors.

Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies.

Diffuse intrinsic pontine gliomas constitute ~ 60-75% of tumors found within the pediatric brainstem. These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions. Magnetic resonance imaging is usually sufficient to establish the diagnosis and obviates the need for surgical biopsy in most cases. The prognosis of the disease is dismal, and the median survival is < 12 months. Resection is not a viable option. Standard therapy involves radiotherapy, which produces transient neurological improvement with a progression-free survival benefit, but provides no improvement in overall survival. Clinical trials have been conducted to assess the efficacy of chemotherapeutic and biological agents in the treatment of diffuse pontine gliomas. In this review, the authors discuss recent studies in which systemic therapy was administered prior to, concomitantly with, or after radiotherapy. For future perspective, the discussion includes a rationale for stereotactic biopsies as well as possible therapeutic options of local chemotherapy in these lesions.

Isolated Whipple disease of the brain resembling a tumour.

INTRODUCTION: Isolated Whipple disease of the central nervous system is a rare occurrence. Migratory arthralgias and gastrointestinal problems, including malabsorption, abdominal pain, diarrhea, and weight loss, are common presenting symptoms. DISCUSSION: For those patients with systemic signs and symptoms of Whipple disease, 6% to 43% will have clinically manifested CNS involvement that may include alterations in personality, ataxia, and dementia. We report our experience with a patient, who was successfully treated for Whipple disease 12 years prior to presentation and had a magnetic resonance image of the brain that revealed two solitary lesions resembling a tumor upon presentation.

A review on the management of epilepsy associated with hypothalamic hamartomas.

INTRODUCTION: Hypothalamic hamartomas are rare congenital malformations located in the region of the tuber cinereum and third ventricle. Patients may be asymptomatic, but the usual presentation is gelastic seizures, precocious puberty, and/or developmental delay. CLINICAL PRESENTATION: Without surgical intervention, the gelastic seizures, which are typically present in childhood, may progress to other seizure types, including generalized epilepsy, and are generally refractory to antiepileptic drugs. SUMMARY: This review will discuss the clinical and electrophysiologic aspects of these lesions, as well as treatment options, including surgery, endoscopy, and radiosurgery.

Combined endoscopic and microscopic management of pediatric pituitary region tumors through one nostril: technical note with case illustrations.

OBJECTIVE: Sellar and parasellar lesions in the pediatric population have traditionally been approached through either a transsphenoidal hypophysectomy or craniotomy or a combination of the two, with the surgical approach being dictated by the anatomical location and extent of the pathology. The introduction and evolution of the endonasal endoscopic technique has provided a minimally invasive method alone or in combination with the operative microscope for removal of these lesions in the pediatric population. The authors have implemented in their practice the use of endonasal endoscopic-assisted microsurgery in the pediatric population harboring sellar and/or lesions extending to the suprasellar space and report our experience in nine patients. MATERIALS AND METHODS: Five craniopharyngiomas, one Rathke's cleft cyst, and two pituitary tumors were treated via endonasal endoscopic-assisted microsurgery. Histopathologic examination revealed lymphocytic hypophysitis in one patient with an enhancing lesion in the pituitary stalk. The approach utilized by the authors is performed through one nostril without any resection of the nasal turbinates or nasal septum. The middle turbinate is displaced laterally, while the nasal septum is moved medially. CONCLUSION: Gross total, near-total, and subtotal resections and a diagnostic biopsy were obtained in six, one, one, and one patients, respectively. The authors were able to safely perform this procedure in nine pediatric patients, and the lack of turbinate or septum resection minimized postoperative discomfort.

Management of brain abscesses in children.

Brain abscesses occur infrequently but continue to be problematic for the pediatric neurosurgical community. The incidence of brain abscesses in children has not changed much, although individual reports may show an increase or decrease in the number of reported cases depending on the patient population studied. An increase could be attributed to earlier detection due to advancements in imaging modalities and/or to an increase in the number of children with immunodeficient states caused by AIDS, chemotherapy for malignant lesions, and immunosuppressive therapy for organ transplantation. A decrease in the incidence of brain abscesses could be attributed to practices such as antibiotic treatment for otitis media, sinusitis, and/or prophylactic antimicrobial treatment for congenital heart disease in children. The morbidity and mortality rates associated with brain abscesses have not changed dramatically in the antibiotic and imaging era, and their preferred management can vary among healthcare providers. These lesions have been successfully treated by neurosurgeons. The causes of brain abscesses are highly variable in children, which is also the case in adults, but the predisposing factors in the pediatric population differ in prevalence. Cyanotic congenital heart disease, hematogenous dissemination, contiguous infection, and penetrating traumatic injuries are the most common causes of brain abscesses in children. In this review, the authors discuss the causes and medical and surgical management of brain abscesses in children.

Inhibition of cerebral vasospasm by intracranial delivery of ibuprofen from a controlled-release polymer in a rabbit model of subarachnoid hemorrhage.

OBJECT: Leukocyte-endothelial cell interactions may play a role in the development of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) because the extravasation of circulating leukocytes into the periadventitial space within 24 hours after the hemorrhage appears to be a critical event in this process. Ibuprofen is an antiinflammatory agent that inhibits the expression of specific cell adhesion molecules and, consequently, disrupts leukocyte-endothelial cell interactions. The authors investigated the efficacy of ibuprofen delivered locally from controlled-release polymers in the rabbit basilar artery (BA) model of cerebral vasospasm. METHODS: Ibuprofen was incorporated into controlled-release ethylene-vinyl acetate copolymer (EVAc) constituting 45% of the resulting polymer by weight. Fifty-four New Zealand White rabbits were randomized to 10 groups: sham operation (seven animals); SAH only (seven animals); and SAH plus either empty EVAc or ibuprofen-EVAc polymer at 30 minutes or 6, 12, or 24 hours (five animals per group; 40 total). The rabbits were killed 72 hours after induction of SAH, at the time of maximal vasospasm. The efficacy of ibuprofen in preventing vasospasm was assessed by measuring lumen patency of the rabbit's BAs. The intracranial controlled release of ibuprofen resulted in a significant inhibition of vasospasm when treatment was initiated at 30 minutes (patency 92.3 +/- 5.1% compared with 52.1 +/- 5.1% in animals given empty EVAc; p < 0.001) and 6 hours (patency 69.5 +/- 3.5% compared with 47.2 +/- 1.5% in animals given empty EVAc; p < 0.03) after blood deposition compared with treatment with empty EVAc. No effect was observed when treatment was begun at either 12 or 24 hours. CONCLUSIONS: Local intracranial delivery of ibuprofen accomplished using controlled-release polymers prevents vasospasm in the rabbit BA model of vasospasm when administered within 6 hours after blood exposure.

Pharmacokinetics of controlled-release polymers in the subarachnoid space after subarachnoid hemorrhage in rabbits.

OBJECT: Implantation of controlled-release polymers into the subarachnoid space to deliver drugs for treatment of vasospasm after subarachnoid hemorrhage (SAH) is currently of interest. Among the issues regarding local delivery of drugs in the subarachnoid space, however, are the extent of diffusion and the rate of release of the loaded agents. In this study Evans blue dye (EBD) was loaded into controlled-release polymers and its pharmacokinetic properties were determined in vitro and in vivo by using a rabbit model of SAH. METHODS: Ethylene-vinyl acetate copolymer (EVAc) was loaded 40% (w:w) with EBD and its pharmacokinetics were spectrophotometrically determined in vitro by examining three EBD-EVAc polymers. Additional polymers were implanted either into the frontal lobe or into the cisterna magna of 16 New Zealand White rabbits. Subarachnoid hemorrhage was induced in eight of the animals by an injection of 1.5 ml of arterial blood into the cisterna magna. The animals were killed 3 or 14 days postoperatively, their brains and spinal cords were harvested, and samples of each were placed in formamide for dye extraction and quantification. Specimens were examined macroscopically and the concentrations of EBD were determined with the aid of a spectrophotometer. The EBD-EVAc polymers continuously released EBD over a 133-day period. The controlled release of the dye into the subarachnoid space in either location resulted in staining of the entire central nervous system (CNS) in rabbits when the polymers were placed either on the frontal lobe or in the cisterna magna. The EBD diffusion covered a distance of at least 40 cm. The presence of blood in the subarachnoid space did not interfere with the diffusion. CONCLUSIONS: In this study the authors define the rate and extent of diffusion of EBD from controlled-release polymers placed in the subarachnoid space under conditions of SAH. Evans blue dye diffused through the entire rabbit CNS, covering a distance greater than that of the longest dimension of the hemicircumference of the subarachnoid space around the human brain. The pharmacokinetic properties of EBD-EVAc polymers are comparable to those of antivasospasm agents that are successfully used in animal models of SAH.

Local delivery of minocycline and systemic BCNU have synergistic activity in the treatment of intracranial glioma.

Minocycline, a tetracycline derivative, has been shown to inhibit tumor angiogenesis through inhibitory effects on matrix metalloproteinases. Previous studies have shown this agent to be effective against a rodent brain tumor model when delivered intracranially and to potentiate the efficacy of standard chemotherapeutic agents. In the present study, the in vivo efficacy of intracranial minocycline delivered by a biodegradable controlled-release polymer against rat intracranial 9L gliosarcoma was investigated to determine whether it potentiates the effects of systemic 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU). Minocycline was incorporated into the biodegradable polymer polyanhydride poly[bis(p-carboxyphenoxy)propane-sebacic acid] (pCPP:SA) at a ratio of 50:50 by weight. The release kinetics of minocycline from the polymer were assessed. For the efficacy studies, female Fischer 344 rats were implanted with 9L glioma. Treatment with minocycline delivered by the pCPP:SA polymer at the time of tumor implantation resulted in 100% survival in contrast to untreated control animals that died within 21 days. Treatment with the minocycline-polymer 5 days after tumor implantation provided only modest increases in survival. The combination of intracranial minocycline and systemic BCNU extended median survival by 82% compared to BCNU alone (p < 0.0001) and 200% compared to no treatment (p < 0.004). We conclude that local intracranial delivery of minocycline from biodegradable controlled-release polymers inhibits tumor growth and may have clinical utility when combined with a chemotherapeutic agent.