Stability and compatibility of hydromorphone hydrochloride in an implantable infusion system.

With the exception of morphine, hydromorphone is the most commonly used intrathecal opioid for the treatment of intractable pain. The purpose of this study was to evaluate the stability and compatibility of hydromorphone in the implantable infusion system that is most commonly used in these patients. Hydromorphone solution was incubated at 37 degrees C in infusion system reservoirs and with individual materials which comprise the fluid pathway of the infusion system. Stability was analyzed using high performance liquid chromatography; mechanical integrity of device materials was evaluated after drug exposure. After 4 months of exposure to device materials or intact devices, hydromorphone concentration remained greater than 95% of starting material. All device materials retained acceptable mechanical performance. These results demonstrate that hydromorphone is stable at physiological temperatures for at least 4 months in an implantable infusion system and that current clinical practice of refilling the pump every 3 months is appropriate.

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.

Electrophysiologic characteristics of a pulsed iontophoretic drug-delivery system in coronary arteries.

This study evaluated the electrophysiologic effects of a pulsed iontophoretic drug-delivery system when used in the coronary arteries. Prevention of acute thrombosis and restenosis after intravascular procedures may be enhanced by high concentrations of therapeutic agents within the vessel wall. A new intravascular drug-delivery system uses iontophoresis to maximize local tissue concentrations of drug. However, the electrophysiologic effects of such a system in coronary arteries are unknown. An iontophoretic membrane balloon-tipped catheter was placed fluoroscopically in the mid left anterior descending coronary artery of 10 anesthetized dogs. Strength-duration curves and effective refractory period (ERP) were initially determined. Threshold for capture was assessed at pulse widths of 0.5, 1.0, 2.0, 4.0, and 8.0 ms. Capture occurred at 4.9 +/- 0.9, 3.4 +/- 0.5, 2.6 +/- 0.5, 1.6 +/- 0.2, and 1.2 +/- 0.2 mA, respectively. The ERP was 169 +/- 6 ms (4.0-ms pulses at twice threshold). Then square-wave pulses for iontophoresis were R-wave synchronized and delivered at 50 and 75% of the ERP with the balloon inflated to 1 atm. Output was increased until significant arrhythmias occurred [premature beats > 10/min, supraventricular tachycardia (SVT), ventricular tachycardia (VT), ventricular fibrillation (VF)], by using sequential steps of 1, 5, 10, 15, and 20 mA. Highest average outputs achieved without an arrhythmia were 14.1 +/- 2.5 and 4.9 +/- 2.0 mA at 50 and 75% of ERP, respectively (p < 0.05). High-grade arrhythmias (pulseless VT or VF) occurred in three of four animals studied before use of a frequency limiter, which allowed current delivery only at intervals > 400 ms (thus inhibiting current activation during premature beats). No further VT or VF occurred in the remaining six animals, except for one episode of nonsustained VT (11 beats). An R-wave synchronized iontophoretic field with a response-frequency limiter can be safely used within the canine coronary arterial system at 50% of ERP with moderate outputs (5-10 mA). Increasing the stimulus duration to 75% of ERP increases arrhythmogenesis but is tolerated at lower output levels (< 5 mA).

Molecular characterization of alpha 2-adrenergic receptors regulating intestinal electrolyte transport.

Norepinephrine (NE) is an important neuromodulator of active Na+ and Cl- transport by the small intestine; however, the cellular targets and the adrenergic receptor (AR) subtype mediating its effects on ion transport have not been clearly defined. NE inhibited short-circuit current in submucosal-mucosal sheets of porcine distal jejunum under basal conditions and after electrical transmural stimulation of intrinsic neurons. A membrane fraction (P2) prepared from the submucosa of porcine jejunum was enriched in specific [3H]saxitoxin binding sites, relative to other submucosal fractions. This fraction contained homogeneous and high affinity sites binding the alpha 2-AR antagonist [3H]yohimbine (Kd = 0.39 +/- 0.03 nM). A prazosin versus oxymetazoline Ki ratio of 218 was obtained for the submucosal AR binding site, suggesting that it represents a neuronal alpha 2A-AR. A cell membrane fraction prepared from the mucosa exhibited specific and saturable high affinity binding of the muscarinic cholinergic antagonist [3H] quinuclidinyl benzilate (Kd = 77 +/- 9 pM) but displayed minimal specific binding of [3H]saxitoxin or [3H]yohimbine. A [32P]cDNA probe derived from the human alpha 2-C10 gene encoding the alpha 2A-AR hybridized to a 3.8-kilobase message that was prevalent in poly(A)+ RNA isolated from the jejuno-ileal submucosa and was also detected in porcine cerebral cortex and kidney; no message was detected in RNA isolated from the jejunal mucosa. These results suggest that NE modulates active ion transport in the small intestine through interactions with a submucosal alpha 2A-AR probably associated with enteric neurons.

Norepinephrine and alpha-2 adrenoceptors modulate active ion transport in porcine small intestine.

The effects of norepinephrine (NE) were examined on active ion transport in the porcine distal jejunum under base-line conditions and after electrical transmural stimulation (ETS). Serosal administration of NE decreased basal short-circuit current across sheets of muscle-stripped jejunal submucosa-mucosa in vitro. These effects were absent in tissues pretreated with the neuronal conduction blocker, tetrodotoxin. NE stimulated net Na secretion in tissues which displayed basal net Na and Cl absorption and increased net Cl absorption in tissues which displayed net Na absorption and Cl secretion under base-line conditions. Moreover, NE inhibited short-circuit current elevations produced by ETS (300 pulses at 10 Hz, 0.5 msec pulse duration, 2.8 mA cm-2), the ganglionic stimulant dimethylphenyl-piperazinium or the gut peptide neurotensin. In contrast, NE did not alter mucosal responses to the directly acting secretagogues forskolin and carbachol. The inhibitory action of NE on mucosal responses evoked by ETS were selectively antagonized by the alpha adrenoceptor blockers phentolamine and yohimbine. Moreover, the selective alpha-2 adrenoceptor agonists p-aminoclonidine, UK-14,304 and oxymetazoline and the NE releasing agent tyramine mimicked the inhibitory effects of NE on ETS-evoked mucosal responses. Desipramine, a blocker of neuronal NE uptake, produced a 1000-fold increase in the potency of NE at concentrations less than 1 nM. These results suggest that NE modulates active ion transport by interacting with alpha-2 adrenoceptors located on submucosal neurons of the porcine small intestine.

Cholinergic neurons and muscarinic receptors regulate anion secretion in pig distal jejunum.

The neurotransmitter acetylcholine is thought to modulate epithelial ion transport in the mammalian small intestine. In this study, the non-selective acetylcholine agonist, carbachol, produced rapid changes in short-circuit current (Isc), an electrical measure of active anion secretion, across isolated sheets of the distal jejunal mucosa-submucosa from swine. The potency of carbachol in elevating Isc was decreased 26-fold in the presence of 10 nM atropine, but remained unchanged by 1-100 microM hexamethonium or 0.1 microM tetrodotoxin. The acetylcholine antagonists produced little or no decrease in spontaneous Isc, whereas tetrodotoxin decreased Isc by 54 microA/cm2. [3H]Quinuclidinyl benzilate (QNB), a muscarinic acetylcholine receptor blocker, bound to a single species of sites within the mucosa-submucosa with a KD = 38 pM and Bmax = 94 fmol/mg protein. Selective muscarinic acetylcholine receptor blockers competed with [3H]QNB for this site with a rank order of affinity indicative of an interaction with a M3-muscarinic acetylcholine receptor. Specific [3H]QNB binding sites were autoradiographically localized in the jejunal wall to the epithelium, submucosa and muscularis propria. Transmural electrical stimulation (3-600 pulses/10 s, 0.5 ms, 60 V) of the mucosa-submucosa produced increases in Isc which were dependent upon the number of impulses delivered and did not undergo tachyphylaxis upon repeated stimulation. Responses to electrical transmural stimulation were inhibited by atropine and hexamethonium, as well as the respective neuronal Na+ and Ca2+ channel blockers tetrodotoxin and omega-conotoxin GVIA, suggesting that electrical transmural stimulation depolarizes submucosal cholinergic neurons which terminate on ion-transporting epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrinsic neuroregulation of ion transport in porcine distal jejunum.

The roles of spontaneous and electrically stimulated neural activity on mucosal ion transport were examined in the distal jejunum of the pig, an omnivorous species whose digestive function bears similarities to that of humans. Serosal administration of the neuronal conduction blocker tetrodotoxin (TTX; 0.1 mumol/l), the presynaptic Ca channel blocker omega-conotoxin GVIA (0.1 mumol/l) and the ganglionic-blocking agent hexamethonium (0.1 mmol/l) decreased basal short-circuit current (Isc) across sheets of jejunal mucosa-submusa in vitro. The TTX-induced change in Isc was attributable to an increase in net Cl absorption. Electrical transmural stimulation (ETS; 300 pulses at 0.5, 3 or 10 Hz, 0.5-msec pulse width, 2.8 mA cm-2) of the mucosa-submucosa produced a frequency-dependent increase in Isc and an increase in net anion secretion. TTX, conotoxin and hexamethonium produced concentration-dependent decreases of the ETS-evoked increase in Isc, indicating that ETS depolarizes enteric neurons and suggesting that cholinergic neurons synapsing with submucosal neurons play a significant role in mediating ETS-evoked ion transport. The ETS-induced Isc appears to be mediated by neurons containing acetylcholine but not substance P or vasoactive intestinal polypeptide. These results suggest that submucosal noncholinergic neurons tonically limit Cl but not Na absorption. Electrical depolarization of submucosal neurons evokes anion secretion which appears to be mediated by cholinergic neurons as well as neurons of unknown chemical identity.

Effects of galanin on smooth muscle and mucosa of porcine jejunum.

The enteric neuropeptide galanin (GAL) increased the amplitude of spontaneous contractions in longitudinally oriented muscle strips and inhibited short-circuit current (Isc) elevations induced by transmural electrical stimulation (ES) of mucosal sheets from porcine jejunum in vitro. GAL-induced contractions (GAL EC50 = 9 nmol/l) were maximally 25% of those elicited by 10 mumol/l carbamylcholine and remained unaffected by atropine, tetrodotoxin, or tachyphylaxis to substance P. The presynaptic Ca2+ channel blocker, omega-conotoxin (0.1 mumol/l), inhibited GAL-induced contractions by 66%. GAL attenuated mucosal Isc elevations induced by ES with an IC50 = 13 nmol/l and at 0.1 mumol/l produced rapid decreases in basal Isc averaging 8 +/- 2 microA cm-1 in 77% of tissues examined. The alpha-adrenoceptor blocker phentolamine or the opiate antagonist naloxone did not alter tissue Isc responses to GAL. These results suggest that GAL modulates neuronal activity linked to secretomotor function in the porcine small intestine.