Stability, compatibility, and safety of intrathecal bupivacaine administered chronically via an implantable delivery system.

OBJECTIVE: The only agent approved by the U.S. Food and Drug Administration for chronic intrathecal infusion for the treatment of chronic pain is morphine sulfate. In patients who do not experience adequate relief from intrathecal opioids, bupivacaine is frequently added to increase efficacy. The studies reported here were conducted to demonstrate the stability and compatibility of bupivacaine in a commonly used implantable infusion system and the long-term clinical safety of this therapy. METHODS: A commercially available bupivacaine solution (7.5 mg/ml) was incubated at 37 degrees C for 12 weeks with intact delivery systems and with the individual materials that comprise the fluid pathway. Intermittent samples were collected and analyzed using liquid chromatography. Materials chronically exposed to bupivacaine were analyzed for mechanical integrity. One hundred eight patients treated with intrathecal bupivacaine (average dose: 10 mg/d, range: 2-25 mg/d) and opioids for an average duration of 86 weeks were monitored clinically (patient interviews and neurologic examinations) approximately every 4 weeks. RESULTS: Bupivacaine concentrations remained greater than 96% of the starting material after chronic exposure to the delivery system materials or the intact pump-catheter systems. and the mechanical integrity of the delivery system and materials remained intact. When combined with intrathecal morphine or hydromorphone, no clinical evidence of drug-induced toxicity or complications was observed in any patient. Supplementing opioid therapy with bupivacaine allowed the pain patient to continue to be effectively managed using an implantable intrathecal delivery system. CONCLUSIONS: Bupivacaine is stable and compatible with a commonly used implantable drug infusion system. In this study, chronic supplementation of intrathecal opioids with bupivacaine was a safe method for providing continued management of chronic pain of cancer or noncancer origin.

Chronic Intracerebral Delivery of Trophic Factors via a Programmable Pump as a Treatment for Parkinsonism.

The most common treatment for Parkinson's disease (PD) aims at pharmacologically augmenting striatal dopamine (DA) using the DA precursor levodopa. Such treatment provides symptomatic relief, but does not slow or halt continued degeneration of nigral dopaminergic neurons. Considerable effort has been devoted to the search for neurotrophic factors with survival-promoting activities on dopaminergic neurons that could potentially be of therapeutic value in the treatment of PD. One such candidate is glial cell line-derived neurotrophic factor (GDNF).

Long-term infusion of nonphysiologic solutions into brain parenchyma: effects of pH, osmolarity, and flow rate.

The effects of long-term (3-day) infusion of nonphysiologic solutions into brain parenchyma were investigated in male Fischer (F344) 344 rats. Two weeks prior to infusion, a guide cannula was placed into the striatum, substantia nigra, or hippocampus. Solutions were infused continually for 3 days at flow rates of 0.03 (129.6 microl total) or 0.10 (432 microl total) microl/min. Four days after infusion, rats were euthanized and the brain was removed and processed for histologic evaluation. Rats that received cannula implants alone had the usual mechanical damage induced by implantation of the cannula. The brain regions that received 0.9% saline, pH 5.0 or pH 9.0 buffer at the two aforementioned flow rates had only minor evidence of tissue damage adjacent to the infusion site that was similar to that attributable to mechanical damage from the cannula implants. Brain tissue infused with distilled water or 1.8% saline also had modest effects of the solutions similar to the usual mechanical damage induced by the infusion cannulae. In contrast, contamination of the infusion sites was seen to induce inflammation. Data from these studies support the hypothesis that nonphysiologic solutions can be used to deliver compounds into brain parenchyma, without the infusion solutions themselves causing excess damage to brain tissue.

Pharmacokinetics and tolerability of ventricularly administered superoxide dismutase in monkeys and preliminary clinical observations in familial ALS.

The discovery of mutations in the gene for Cu/Zn superoxide dismutase (SOD) in some cases of familial amyotrophic lateral sclerosis (FALS) provides a rationale for enzyme replacement therapy. The inability of SOD to cross the blood-brain barrier motivated this study of the safety, tolerability and pharmacokinetics of bovine SOD (bSOD) administered into the CSF of rhesus monkeys and one late-stage, SOD-deficient FALS patient. Kinetic analyses in the patient indicated that intracerebroventricular (i.c.v.) administration, but not lumbar administration, delivered bSOD to the entire CSF pathway. Daily bolus i.c.v. injections (32 mg/day) and continuous i.c.v. infusion (30 mg/day) were well tolerated by the patient. During the period of daily bolus injections, the patient's performance on manual muscle tests was nearly stable, in contrast with the rapid decline before and after that period. These results justify further investigation of bSOD therapy in SOD-deficient FALS patients.

Effect of staphylococcal enterotoxin B on the electroencephalogram of monkeys.

A highly purified preparation of staphylococcal enterotoxin B was administered intravenously, 1 mg/kg, to rhesus monkeys. Electroencephalograms (EEG) were recorded from electrodes attached to the skin or implanted on the dura. The dose of toxin employed consistently produced a sequence of vascular collapse followed by death; in control studies, animals were bled periodically to produce a similar pattern of shock. Regardless of the time to death following administration of the enterotoxin, there were essentially no changes from base line EEG patterns until shortly before death. With the development of preterminal severe shock, there was a marked decrease in EEG wave frequency and an initial increase in amplitude. The latter diminished progressively to produce an isoelectric tracing immediately prior to death. This could be reversed for a brief period by epinephrine. An identical sequence of EEG changes was observed during the terminal period of hemorrhagic shock. It is postulated that cerebral anoxia, caused by inadequate blood flow, is the primary cause of the altered EEG patterns that accompany enterotoxin toxicity. In this respect, staphylococcal enterotoxin B produces changes apparently similar to bacterial endotoxin but distinctly different from the EEG effects reported after botulinum toxin, anthrax toxin, or rattlesnake and cobra venom.