Implantable Infusion Pump Research Articles

In vivo enhancement of murine natural killer cell activity by 7-allyl-8-oxoguanosine (loxoribine)

7-Allyl-8-oxoguanosine (loxoribine) is a novel immunostimulatory compound which has been shown previously to enhance the antibody synthesis of antigen-stimulated B-lymphocytes. In this report, loxoribine was tested for the ability to activate murine natural killer (NK) cells. In studies in which mice were given a single subcutaneous (s.c.) or intravenous (i.v.) injection of loxoribine, splenic NK cell activity was increased in a dose-related manner with clear enhancement seen within 2 h of drug administration. The enhancement was optimal at 48 h but persisted for a minimum of 4 days. Slow and continuous administration of loxoribine via subcutaneously implanted infusion pumps successfully enhanced the NK activity for several days after all of the pump contents had been delivered. Peak NK responses were seen following s.c. or i.v. administration of 2–3 mg loxoribine per mouse in sesame oil, intralipid, or saline vehicles. Significant oral activity was seen after the administration of 8–10 mg/mouse in sesame oil or intralipid. The in vivo enhancement of NK activity was observed in spleen, blood, and bone marrow but was negligible in lymph nodes and thymus. Multiple injections of optimal concentrations of loxoribine did not tend to enhance the NK activity above that seen with a single injection, suggesting that the timing of injections was critical for optimal responsiveness.

The spring-driven implantable pump. A low-cost alternative.

In the current era of cost containment in medicine, manufacturing economics have become increasingly important. The authors devised an implantable pump powered by spring force from an elastomeric Belleville washer, which is also the outer flexible wall of the drug reservoir. Use of formed and injection molded parts provides for low-cost manufacturing, in contrast to the precision welded alternative designs. Additional advantages include insensitivity to changes in ambient temperature and pressure. Finite element modeling of the elastomer spring allows prediction of the effects of parameter changes on performance, so that expansions and reductions of scale can be made without compromising the uniform spring rate of the device. A concern that subcutaneous fibrous encapsulation might markedly alter reservoir pressure was not supported by experimental data. In a unit implanted subcutaneously in a dog, reservoir pressures measured over a 4 year period were stable. This new, simple, implantable infusion pump can serve as an economical vehicle for prolonged parenteral drug treatment of ambulatory subjects in circumstances where continuous single-rate infusion is appropriate.

Cholesterol inhibition, cancer, and chemotherapy

An important feature of malignant transformation is loss of the cholesterol feedback inhibition mechanism that regulates cholesterol synthesis. Cancer cells seem to require an increase in the concentrations of cholesterol and of cholesterol precursors. Therefore, a reasonable assumption is that prevention of tumour-cell growth can be achieved by restricting either cholesterol availability or cholesterol synthesis. In-vivo and cell-culture experiments have shown that lowering the plasma cholesterol concentration or intervening in the mevalonate pathway with 3-hydroxy-3-methylglutaryl (HMG) CoA reductase inhibitors decreases tumour growth. Currently prescribed doses of H MG-CoA reductase inhibitors given orally or continuously by an implantable infusion pump could achieve tumour therapeutic tissue concentrations of these agents. My hypothesis is that cholesterol inhibition can inhibit tumour cell growth, can act as an adjuvant to cancer chemotherapy, and, possibly, can prevent carcinogenesis.

Hepatobiliary Toxicity of 5-Fluoro-2??-Deoxyuridine

Biliary sclerosis remains the dose-limiting toxicity in a subset of patients receiving hepatic arterial (HA) floxuridine (FUDR) for the treatment of hepatic malignancy. To investigate the etiology of FUDR-associated sclerosing cholangitis, portal vein catheters were placed in mixed-breed hounds (N = 4) and connected to an implanted infusion pump system. Floxuridine 0.3 mg/kg/day was infused for 49 to 77 days each, as a continuous infusion. Cholangiograms were performed before and after infusion, and weekly liver function tests were obtained. The results were compared to dogs (N = 6) that received HA FUDR 0.3 mg/kg/d x 30 days, and dogs (N = 5) that received HA saline for 100 days. Elevation in the serum glutamic pyruvic transaminase and alkaline phosphatase, indistinguishable from the HA group, was seen in all four dogs with portal vein infusion. Maximum bilirubin levels ranged from 0.6 to 3.0 (mean 1.7), compared to a range of 6.4 to 28 (mean 13.4) for the HA dogs. Cholangiograms demonstrated hepatic volume loss consistent with hepatocellular injury, but no biliary sclerosis. These data suggest that sclerosing cholangitis resulting from intra-arterial infusion of FUDR is unlikely to be due to metabolites of the drug excreted in the bile, but due to direct toxicity to the biliary tree.

Intra-arterial Floxuridine vs Systemic Fluorouracil for Hepatic Metastases From Colorectal Cancer

Seventy-four patients with liver metastasis from proved colorectal primary adenocarcinoma were entered into a prospective, randomized clinical trial to evaluate treatment with intra-arterial floxuridine compared with standard outpatient therapy with fluorouracil delivered by intravenous bolus injection. Eligible patients were randomized to hepatic arterial chemotherapy with an implanted infusion pump or systemic chemotherapy. No crossover between treatment arms was permitted, and patients were followed up to progression and death. Objective tumor response was observed in 48% of patients receiving intra-arterial floxuridine and in 21% of patients receiving intravenous fluorouracil. Time to hepatic progression was significantly longer in the group given intra-arterial therapy: 15.7 vs 6.0 months. However, time to overall progression (6.0 vs 5.0 months) and survival (12.6 vs 10.5 months) were not statistically different. Based on these data, we cannot recommend treatment with intra-arterial floxuridine as given in this study for metastatic colorectal cancer to the liver.

Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas

In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR ( 400−600 mg/m 2/day × 8 1 2 weeks) and focal external beam radiotherapy (59.4Gy at 1.8 Gy/day in 6 1 2 weeks ). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1 2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas.

Insulin Therapy of Diabetes with Implantable Infusion Pumps: Clinical Aspects

Insulin Therapy of Diabetes with Implantable Infusion Pumps: Clinical Aspects

A Stability Indicating HPLC Assay for Prednisolone Sodium Phosphate in Implantable Infusion Pumps

Abstract A stability indicting assay for prednisolone sodium phosphate (PSP) in solutions for implantable infusion pumps was developed. PSP and its major breakdown product, prednisolone, were separated from formulation excipients by reverse phase chromatography on a phenyl-bonded phase column using an acetonitrile-phosphate buffer mobile phase. Detection was by ultraviolet absorbance at 243 mm. Recovery from a synthetic formulation was 101.0 ± 0.4% (n=6). The method was used to monitor the stability of PSP solutions in implantable infusion pumps maintained at 37°C over a 21 day period.

Fatty Liver Change as a Result of Hepatic Artery Infusion Chemotherapy

Direct hepatic arterial infusion of floxuridine (FUDR) (Roche Laboratories, Division of Hoffman-LaRoche Inc., Nutley, NJ, U.S.A.) has been used extensively in the treatment of metastases of colorectal tumors to the liver. The effectiveness of infusion and tolerance of the chemotherapy has been improved utilizing a totally implantable infusion pump delivery system. However, unequal distribution of drug infusion may occur to different parts of the liver parenchyma as demonstrated by hepatic arterial infusion scintigraphy (HAPS). We present a case of such unequal perfusion in which fatty metamorphosis of the liver occurred in the overperfused liver segment after FUDR therapy. The liver parenchymal changes were followed by serial computerized tomography scans and proven by biopsy during a minilaparotomy. Serial HAPS examinations show redirection of subsequent infusion to the opposite liver lobe due to parenchymal damage and vascular sclerosis. The importance of uniform liver perfusion and a rare dose-related effect of FUDR on liver parenchyma are thereby demonstrated.

Neck and Shoulder Pain Associated with Hepatic Arterial Chemotherapy Using an Implantable Infusion Pump

Neck and Shoulder Pain Associated with Hepatic Arterial Chemotherapy Using an Implantable Infusion Pump

Neck and shoulder pain associated with hepatic arterial chemotherapy using an implantable infusion pump

Neck and shoulder pain associated with hepatic arterial chemotherapy using an implantable infusion pump

An implantable pump for intrarenal infusion of immunosuppressants in a canine autotransplant model.

We developed a canine renal allograft model utilizing implantable infusion pumps and biocompatible catheters to investigate the pharmacokinetics of local immunosuppressive drug administration. Seven mongrel dogs underwent bilateral nephrectomy and autotransplantation of one kidney to the iliac vessels. The proximal end of an infusion catheter directed into the iliac artery was tunneled to a subcutaneously placed programmable pump. A second, sampling catheter was placed with its tip in the iliac vein. Simultaneous regional (iliac vein) and systemic (jugular vein) venous concentrations of 6-mercaptopurine (6-MP), the immunosuppressive metabolite of azathioprine, were determined during a continuous 24-h intraarterial infusion (10 mg/kg/24 hr). The gradient between regional and systemic 6-MP concentrations was maximal initially when the pump was turned on, continuously decreased until steady state was reached, and disappeared immediately after the pump was turned off. The mean ratio of steady-state iliac vein to systemic 6-MP concentrations was 5.0 +/- 1.4, demonstrating a pharmacokinetic advantage of continuous intraarterial 6-MP infusion to the autotransplanted kidney. The novel canine renal allograft model described herein overcomes the technical limitations of earlier models and represents a foundational step in the design of intrarenal infusion patterns of immunosuppressive agents which we expect to prolong survival of the allotransplanted kidney with minimal systemic drug exposure and side effects.

Magnetically enhanced insulin release in diabetic rats.

Polymer matrices containing insulin and embedded magnets were implanted subcutaneously in diabetic rats for 51 days. Passive release of insulin from the polymer resulted in a decrease in the blood glucose level. When the diabetic rats were exposed to an oscillating magnetic field, the blood glucose levels were additionally lowered by nearly 30%. No statistically significant effect in blood glucose decrease was observed in four different sets of control animals subjected to the magnetic field. Because of the very small size of the implants, they may, with additional study, provide an alternative to current modes of therapy using programmable implantable infusion pumps.

A complication of the infusaid pump: Duodenal atony reversed by urecholine

The totally implantable infusion pump (Infusaid pump) for treating metastatic disease to the liver is a new treatment that is gaining widespread acceptance. However, as might be expected for any new major surgical procedure, there are increasing reports of complications. We report a complication in which duodenal atony was caused by the infusion of the chemotherapeutic agent (FUDR) into the stomach and duodenum. The atony was totally reversed by the subcutaneous administration of urecholine.

Intra-arterial chemotherapy for head and neck cancer. An update on the totally implantable infusion pump.

Intra-arterial chemotherapy for the treatment of localized malignant neoplasms in the head and neck is an appealing approach for several reasons. Perhaps the most important is the possibility of obtaining a regional advantage such that an increased drug concentration is delivered systemically. The patient may, therefore, be spared systemic toxicity. We report our accumulated experience using a totally implantable infusion pump in 37 patients. A total of 42 pumps were implanted: 28 single-catheter pumps and 14 dual-catheter pumps. Radionuclide imaging demonstrated total perfusion of the tumor in all patients. A combination of cisplatin (50 to 100 mg/m2) and floxuridine (0.01 to 0.045 mg/kg/d) was used to treat 26 patients. For these heavily pretreated patients, we observed a 43% complete and partial response rate in the subgroup of patients with squamous cell carcinoma. These results are comparable with those reported for these drugs administered systemically and for other drug combinations tested in the treatment of recurrence disease.

Long term intrathecal administration of morphine: a comparison of bolus injection via reservoir with continuous infusion by implanted pump.

Twenty-six cases of chronic intrathecal morphine administration are described: 19 cases utilizing the Spinalgesic injectable subcutaneous reservoir and 7 cases utilizing the Infusaid implanted infusion pump. In 25 cases, the morphine was delivered into the spinal subarachnoid space, and in 1 case of thalamic pain it was delivered into the temporal horn of the ipsilateral cerebral ventricle. The average duration of usage of the system was 132 days. The efficacy of the method was excellent: 23 of 26 patients used no other analgesics or only minor ones such as aspirin, paracetamol, or dextropropoxyphene. The complication rate was low, with no infections under the author's care, and only 4 catheter blockages (1 by tumor). There have been no complications in the 7 patients with implanted pumps. From this experience, the author concludes that the implanted pump is now the method of choice in all patients who can afford it and for whom the life expectancy outside an institution is in excess of 60 days. A special and relatively absolute indication for the pump is the situation of pain in the arm, head, or neck areas, in which case the constant morphine levels likely to be achieved with the pump may prevent failure of the method due to intractable nausea or emesis. The subcutaneous reservoir is otherwise to be preferred if the patient's disease is progressing rapidly, if the patient is already institutionalized and likely to remain so, or where the cost of the implanted pump would cause hardship. Either method of delivery of morphine to the subarachnoid space can provide incomparable analgesia without clouding of consciousness, with a very low complication rate.

Treatment of Liver Metastases with a Combination of Chemotherapy and Hyperfractionated External Radiation Therapy

Twelve patients with liver metastases from colorectal cancer were treated with 5-FUdR hepatic artery, or 5-FU i.v. infusion therapy and hyperfractionated whole liver irradiation (2,100 rad in 14 fractions, two fractions/day over a period of 9 days). All 12 patients tolerated treatments well and no unusual toxicity was noted from this therapy. Response was assessed on completion of treatment and on follow-up examinations by physical examination, repeat liver function tests (LFTS), and CT scans. Symptomatic relief was achieved in all patients. Decreased liver size and improved LFTS were noted in 10/12 (83%) of patients. CT scans showed decrease in size of metastases. Survivals ranged from 16 to 120 weeks. Infusion therapy was given either by implanted infusion pump or continuous i.v. infusion therapy, 5-FUdR 0.3 mg/kg of body weight/day or 5-FU 1,000 mg/m2/day. Hyperfractionated external radiotherapy with concomitant 5-FUdR hepatic artery of 5-FU i.v. infusion therapy for liver metastases was well-tolerated, and both subjective and objective response and quality of survival were noted. Hyperfractionated external beam irradiation with concurrent chemotherapy can be effective in palliating patients with liver metastases.

A dog model using an implanted system for protracted hepatic arterial chemotherapy

A model for hepatic arterial chemotherapy studies using large dogs and an implantable infusion pump has been developed. Using this technique near complete perfusion (>90%) of the liver can be achieved in vivo as determined by hepatic arterial perfusion scintigraphy with technitium 99m macroaggregated albumin. The system is reliable and has been in use for a total of 1353 days (mean of 104 days, range 52–239) in 13 dogs. Pump implantation causes no apparent acute liver damage based on pre- and post-operative alkaline phosphatase and serum glutamic-pyruvic transaminase determinations and does not affect the general mobility or behavior of the animals. Careful placement of the catheter and attention to the physicochemical properties of the solutions loaded are factors contributing to the success of the model. The model permits comprehensive preclinical pharmacokinetic and toxicologic studies of new or preexistent chemotherapeutic agents in the same device that will be used for later administration in human subjects. By providing the means to examine and develop new treatment modalities, it enables the design of even more potent cytotoxic therapy directed into the tumor vascular bed.

Developing and assessing an implantable insulin infusion pump. Interactions of university, industry, and government.

The validity of technology assessment may depend largely upon who performs the job, and when they get involved. The options are many. Industry may hire a small private laboratory to perform animal trials on a completed device or drug; manufacturers may support their own in-house laboratories or even study beds; industry may contract with hospitals or private medical groups to evaluate a potential product. It is the thesis of this discussion that there is a different option which brings together the strengths of three often stubbornly independent institutions: industry, university-based investigators, and federal science granting agencies.

Effect of prolonged intra-arterial prostaglandin E1 infusion on canine arterial graft patency.

This study examined the effect of long-term intra-arterial prostaglandin (PG) E1 infusion on the patency of canine femoral-artery grafts made of polytetrafluoroethylene and measuring 4 X 90 mm (diameter X length). An infusion catheter was placed proximal to one of the bilateral femoral-artery grafts and connected to a subcutaneously implanted infusion pump to continuously infuse PGE1 (1 ng/kg/min) in seven experimental dogs and vehicle alone in seven control dogs. Two-week graft patency was significantly higher in both infused (86%) and noninfused (100%) limbs of PGE1-treated dogs than in control dogs (29%). Although hind-limb blood flow was increased twofold to threefold by PGE1 infusion, graft patency did not improve. Prostaglandin E1 infusion did not significantly alter systemic platelet aggregation but did cause considerable hind-limb edema. Improved early graft patency, which did not persist beyond four weeks, was apparently related to systemic effects of local PGE1 infusion.