Selective activation of the human tibial and common peroneal nerves with a flat interface nerve electrode.

OBJECTIVE: Electrical stimulation has been shown effective in restoring basic lower extremity motor function in individuals with paralysis. We tested the hypothesis that a flat interface nerve electrode (FINE) placed around the human tibial or common peroneal nerve above the knee can selectively activate each of the most important muscles these nerves innervate for use in a neuroprosthesis to control ankle motion. APPROACH: During intraoperative trials involving three subjects, an eight-contact FINE was placed around the tibial and/or common peroneal nerve, proximal to the popliteal fossa. The FINE's ability to selectively recruit muscles innervated by these nerves was assessed. Data were used to estimate the potential to restore active plantarflexion or dorsiflexion while balancing inversion and eversion using a biomechanical simulation. MAIN RESULTS: With minimal spillover to non-targets, at least three of the four targets in the tibial nerve, including two of the three muscles constituting the triceps surae, were independently and selectively recruited in all subjects. As acceptable levels of spillover increased, recruitment of the target muscles increased. Selective activation of muscles innervated by the peroneal nerve was more challenging. SIGNIFICANCE: Estimated joint moments suggest that plantarflexion sufficient for propulsion during stance phase of gait and dorsiflexion sufficient to prevent foot drop during swing can be achieved, accompanied by a small but tolerable inversion or eversion moment.

Selective stimulation of the human femoral nerve with a flat interface nerve electrode.

In humans, we tested the hypothesis that a flat interface nerve electrode (FINE) placed around the femoral nerve trunk can selectively stimulate each muscle the nerve innervates. In a series of intraoperative trials during routine vascular surgeries, an eight-contact FINE was placed around the femoral nerve between the inguinal ligament and the first nerve branching point. The capability of the FINE to selectively recruit muscles innervated by the femoral nerve was assessed with electromyograms (EMGs) of the twitch responses to electrical stimulation. At least four of the six muscles innervated by the femoral nerve were independently and selectively recruited in all subjects. Of these, at least one muscle was a hip flexor and at least two were knee extensors. Results from the intraoperative experiments were used to estimate the potential for the electrode to restore knee extension and hip flexion through functional electrical stimulation. Normalized EMGs and biomechanical simulations were used to estimate joint moments and functional efficacy. Estimated knee extension moments exceed the threshold required for the sit-to-stand transition.

Intraoperative evaluation of the spiral nerve cuff electrode on the femoral nerve trunk.

Evaluation of the Case Western Reserve University spiral nerve cuff electrode on the femoral nerve trunk was performed intraoperatively in four subjects undergoing femoral-popliteal bypass surgery. The threshold, nerve size and selective activation capabilities of the electrode were examined. The activation thresholds for the first muscle to be recruited were 6.3, 9, 10.6, and 37.4 nC with pulse amplitudes ranging from 0.3 to 1 mA. The femoral nerve was found to have an elliptical cross-section with a major axis average length of 9 mm (8-12 mm) and a minor axis length of 1.5 mm. In all four subjects selective activation of the sartorius was obtained. In two subjects, the rectus femoris could also be selectively activated and in one subject the vastus medialis was selectively activated. Each electrode had four independent contacts that were evaluated separately. Small air bubbles were formed in the space over some contacts, preventing stimulation. This occurred in one contact in each electrode, leaving three effective stimulation channels. This issue has been corrected for future studies.

Enhanced potentiation of cisplatin cytotoxicity in human ovarian carcinoma cells by prolonged glutathione depletion.

We have determined the effect of extended glutathione (GSH) depletion on cis-diamminedichloroplatinum(II) (DDP) cytotoxicity in parent and DDP-resistant human ovarian carcinoma cells. Cells were exposed to 50 microM buthionine sulfoximine (BSO) for 48 h and exposed to DDP for the last 24 h of this time. This treatment protocol sensitized 2008 cells to DDP. The dose modification factor (DMF) defined as IC50 control cells/IC50 GSH depleted cells was 1.6 +/- 0.5 (N = 9). DDP-resistant cells selected by acute, high dose DDP exposure were also sensitized by this treatment; the DMF in the 3-6-fold resistant 2008/DDP cells was 2.4 +/- 1.2 (N = 9). The sensitization was not significantly greater in the resistant cells than in the parent cells (P greater than 0.05). When the rebound of GSH following BSO exposure was reexamined, the GSH levels were found to rise rapidly following trypsinizing and plating. BSO treatment following DDP exposure had no effect on DDP cytotoxicity in 2008 and 2008/DDP cells. These results indicate that simply depleting GSH prior to DDP exposure is not sufficient for sensitizing these cells to DDP. In contrast to the potentiation of nitrogen mustard cytotoxicity, exposure to GSH depletion must be maintained during DDP treatment for enhancement of DDP cytotoxicity to occur.

Antagonism of cocaine-induced hepatotoxicity by the alpha adrenergic antagonists phentolamine and yohimbine.

The ability of the alpha adrenoreceptor antagonists phentolamine and yohimbine to antagonize cocaine-induced hepatotoxicity was determined in phenobarbital-induced B6C3/F1 mice. Hepatotoxicity was assessed by the histologic extent of necrosis, incidence of latent lethality and increases in serum alanine aminotransferase activity. The depression of hepatic glutathione levels also were measured. The administration of a single 5-mg/kg dose of phentolamine antagonized the decrease in glutathione levels and the elevation of aminotransferase activity caused by a 60-mg/kg dose of cocaine. Similar results were obtained in mice pretreated with the alpha-2 antagonist yohimbine. Whereas the duration of antagonism could be extended by administering a 30-mg/kg dose of yohimbine, the magnitude of the antagonism was not increased. In contrast to the experiments with the larger dose, multiple hourly doses of 2.5 mg/kg of yohimbine increased both the duration of antagonism and the magnitude of protection against the hepatotoxicity produced by cocaine. Yohimbine pretreatment reduced cocaine-induced latent lethality by 50%, but did not alter the time to lethality. The results of these experiments indicate that the alpha adrenoreceptor antagonist reduces the toxicity of cocaine rather than merely delaying its time of onset. This effect does not appear to result from an inhibition of the toxic metabolite(s) of cocaine, as a 10-fold molar excess of yohimbine failed to antagonize lipid peroxidation caused by in vitro incubation of cocaine with hepatic microsomes. Additional experiments in mice whose liver metabolism had not been induced by prior pretreatment with phenobarbital revealed that 60 mg/kg of cocaine lowered glutathione but was not hepatotoxic.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I/pharmacokinetic study of intraperitoneal cisplatin and etoposide.

We administered cisplatin and etoposide by peritoneal dialysis to 39 patients with i.p. malignancies in order to investigate the toxicity, pharmacokinetics, and clinical activity of this 2-drug combination. All patients received i.v. sodium thiosulfate concurrently with the i.p. chemotherapy. Myelosuppression, nausea, vomiting, and malaise were the primary toxicities encountered. The maximum tolerated dose of etoposide was 350 mg/m2, when administered with a fixed dose of cisplatin, 200 mg/m2. Although the total (free and protein-bound) etoposide exposure for the peritoneal cavity was only 1.5-fold greater than that for the plasma, the free (non-protein bound) etoposide peritoneal exposure was 65-fold greater than the plasma. Tumor regressions were noted in patients with ovarian and pancreatic carcinomas. This study is the first demonstration of the large pharmacokinetic advantage that exists for the i.p. administration of highly protein-bound drugs, and it also documents the clinical activity of i.p. cisplatin and etoposide.