Proposal for translational analysis and development of clinical radiolabeled immunoglobulin therapy.

BACKGROUND AND PURPOSE: Radiolabeled immunoglobulin therapy (RIT) can be a selective, effective, low-toxicity outpatient cancer therapy. A consensus on the best approach for the preclinical and clinical development of RIT reagents needs to be developed. We report the M.D. Anderson Cancer Center prior experience in translating RIT from laboratory to clinic for the treatment of Hodgkin's disease and propose a flow diagram for the development of RIT for other malignancies. MATERIAL AND METHODS: Three different animal models are described: nude mice bearing human tumor xenografts, normal beagle dogs, and normal rhesus monkeys. We produced and purified antibodies and prepared chelate-immunoconjugates reactive with six different human tumor-associated antigens. The Igs used were derived from rabbits, mice, and humans (human-derived RIT reagents being less immunogenic in human patients). Eighty patients with refractory Hodgkin's disease were treated with radiolabeled antiferritin. RESULTS: We recommend a two-injection scheme using, (1) an indium-111-labeled radioimmunoconjugate for diagnosis, pharmacokinetic studies, and dosimetry, and (2) a yttrium-90-labeled radioimmunoconjugate for therapy. The animal models provide useful data on tumor targeting, radiotoxicology, and undesirable biodistributions. A 70% response rate is obtained in patients with advanced recurrent Hodgkin's disease. More extensive preclinical testing allows for safer and more effective clinical RIT studies. CONCLUSIONS: We recommend, (1) preclinical optimization of chelation chemistry, Ig size, Ig origin, route of administration, and fractionation, (2) new clinical Phase I-III studies more appropriate for RIT development than the classical Phase I-III studies used for the development of chemotherapeutic agents, and (3) more extensive preclinical testing of RIT reagents.

NG-methyl-L-arginine, an inhibitor of nitric oxide formation, reverses IL-2-mediated hypotension in dogs.

The effects of NG-methyl-L-arginine (L-NMA), an inhibitor of nitric oxide formation, were studied in dogs treated with interleukin-2 (IL-2). The administration of IL-2 to dogs resulted in hypotension within 3 days of treatment. The development of hypotension correlated with accumulation in the serum of nitrate, which is a stable breakdown product of nitric oxide. Administration of L-NMA decreased serum nitrate levels and increased the mean arterial pressure. The antihypotensive effect was dose dependent with a maximum effect observed at a dose of 20 mg/kg. Administration of a continuous infusion of L-NMA (5 mg.kg-1.h-1) maintained the mean arterial pressure for 48 h with concurrent administration of IL-2. Evaluation of IL-2-induced lymphokine-activated killer cell proliferation and tumoricidal activity toward a canine glioblastoma target cell line was unaffected by L-NMA. These studies imply that L-NMA may effectively ameliorate the dose-limiting hypotension associated with administration of IL-2 without adversely affecting the antitumor effects.

Hepatic arterial infusion of verapamil and doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration: pharmacological evaluation of reduction in systemic drug exposure and assessment of hepatic toxicity.

Tumour resistance to chemotherapeutic drugs through expression of the multidrug resistance phenotype is a major impediment in the treatment of hepatic malignancies. We performed hepatic arterial infusion of verapamil (at a dose known to block P-glycoprotein activity) and doxorubicin combined with complete hepatic venous isolation and extracorporeal chemofiltration in non-tumour-bearing pigs with normal livers to evaluate the pharmacology and toxicology of this drug combination. The complete hepatic venous isolation-chemofiltration system significantly reduced system exposure to both verapamil and doxorubicin (P < 0.01). Hepatic arterial infusion of verapamil (2 mg/kg) alone did not result in hepatocellular toxicity. However, the combination of verapamil and doxorubicin (3 mg/kg or 5 mg/kg) produced significant elevations in liver enzymes (P < 0.01), and gross histological evidence of liver damage in 90% of the treated animals. The results of this study indicate that hepatic arterial infusion of verapamil and doxorubicin, in an attempt to improve treatment response in unresectable liver tumours expressing the multidrug resistance phenotype, may not be tolerated by patients with limited hepatic reserve.

Amiprilose in the prevention of restenosis after coronary intervention in a swine model.

BACKGROUND: Amiprilose hydrochloride is a synthetic carbohydrate with anti-inflammatory and antiproliferative properties. This study tested the potential benefit of amiprilose in preventing coronary artery restenosis in a swine model. METHODS: The swine restenosis model was prepared using Hanford miniature swine made atherosclerotic with coronary abrasion, high-fat and high-cholesterol feeding, and intracoronary stenting. Eighteen animals were randomized to receive amiprilose, 100 mg/kg body weight orally twice per day (n = 9), or no amiprilose (n = 9) beginning 5 days before stenting and continuing through 4 weeks until sacrifice. Presacrifice quantitative coronary angiography and postsacrifice histologic examination revealed the degree of intimal proliferation. RESULTS: Coronary angiography revealed no difference in percentage-diameter stenosis between the amiprilose and control groups (left anterior descending artery [LAD], 46% +/- 10% vs 44% +/- 17%; circumflex artery [CFX], 43% +/- 21% vs 42% +/- 15%; right coronary artery [RCA], 37% +/- 11% vs 34% +/- 9%; P = not significant [NS]), respectively, or in change in lumen diameter from poststenting to presacrifice (LAD, -1.0 +/- 0.4 mm vs -1.1 +/- 0.7 mm; CFX, -1.2 +/- 0.8 mm vs -1.0 +/- 0.7 mm; RCA, -1.1 +/- 0.4 mm vs -1.0 +/- 0.4 mm; P = NS). Morphometric histologic analysis likewise showed no difference in percentage-area stenosis (LAD, 55% +/- 14% vs 55% +/- 15%; CFX, 53% +/- 15% vs 54% +/- 12%; RCA, 39% +/- 17% vs 39% +/- 20%; P = NS) or in maximal intimal thickness. CONCLUSION: Amiprilose hydrochloride did not prevent coronary intimal proliferation in this swine model of restenosis.

Elastographic imaging of thermal lesions in soft tissue: a preliminary study in vitro.

The use of elastography for the visualization of thermal lesions in biological soft tissue in vitro was investigated. Thermal lesions were created in samples of postmortem ovine kidney using a surgical neodymium: YAG (Nd:YAG) laser. The kidney samples were cast in gel, and elastographic images of the lesions were constructed using sonographic information and external markers to locate the region of interest. Gross pathology of the kidney samples confirmed the dimensions of the lesions. Good correlation between the lesion length along the laser fiber axis and maximum diameter measured off of the fiber axis determined from elastographic images and gross pathology photographs was found.

Transurethral canine prostatectomy with the Nd:YAG laser.

Although laser energy in combination with conventional techniques has been used to ablate prostatic tissue in the dog, the use of the Nd:YAG laser alone to perform transurethral prostatectomies has not been feasible because of the difficulty of directing the laser energy into the prostate. In this study, a 600-microns quartz laser fiber with an attached gold-plated metal alloy reflector and a 1.06-microns Nd:YAG laser were used to perform transurethral laser prostatectomies in 10 mongrel dogs. Each dog received approximately 3600 J to each quadrant of the prostate. No signs of urinary incontinence were noted in any of the dogs postoperatively. Transurethral laser prostatectomies can be performed safely and effectively in the dog and can significantly decrease the incidence of postoperative urinary incontinence.

Warfarin sodium for anticoagulation of atherosclerotic miniature swine.

Warfarin sodium (Coumadin) has been used as an effective anticoagulating agent in human medicine for many years, although careful monitoring of its effects are necessary to avoid excessive anticoagulation. Previous experience with this drug for chronic anticoagulation therapy in miniature swine has been limited. The effect of warfarin sodium was studied by measuring prothrombin time in twelve 8-month-old Hanford miniature swine. The pigs had been fed a high-cholesterol diet and had undergone a prior coronary artery abrasion procedure for development of an atherosclerotic coronary disease model. Atherosclerosis was induced by feeding a high-cholesterol diet. Baseline prothrombin time ranged from 12.8 to 15.0 s (13.7 s mean). Prothrombin time was determined daily for the first 5 days of treatment and at least twice weekly thereafter until the animals were sacrificed. Animals received warfarin for 37-41 days. Prothrombin time could be increased 33-50% by once daily oral administration of warfarin 0.04-0.08 mg/kg. Oral administration of more than 0.08 mg/kg as a maintenance dose resulted in the death of two pigs. Most animals responded well to 0.08 mg/kg for the first 3 days of treatment followed by a maintenance dose of 0.06 mg/kg. Dosage was adjusted periodically when prothrombin times exceeded 50% above baseline. It is our experience that monitoring prothrombin time at least twice weekly and adjusting the maintenance dose can eliminate death losses due to warfarin intoxication.

Bretylium and diltiazem in porcine cardiac procedures.

The use of miniature swine as a model for cardiovascular diseases of humans is becoming more popular for many reasons. One of the problems involved in using swine is their propensity for fatal cardiac arrhythmias during surgical procedures requiring general anesthetics, especially cardiac procedures. In preparation for use as a model of human atherosclerotic coronary artery disease, 30 three-month-old (15 kg) Hanford miniature swine underwent left heart catheterization, coronary angiography, and abrasion of the left anterior descending coronary artery. All pigs were treated with diltiazem HCl 30-60 mg (2-4 mg/kg) three times daily and aspirin 25 mg once daily, both given orally for three days before surgery. General anesthesia was induced with a combination of ketamine HCl 25 mg/kg, atropine sulfate 0.1 mg/kg, and acepromazine 0.22 mg/kg, all given intramuscularly. Halothane 1-2% and nitrous oxide 30% were used to maintain general anesthesia after endotracheal intubation. After successful cannulation of the femoral artery, all animals were given 200 units/kg heparin and 5 mg/kg bretylium tosylate intravenously. The electrocardiogram and mean blood pressure were monitored throughout the procedure. No significant change in blood pressure was noted during the procedure. Intracoronary nitroglycerin 200 micrograms was administered prior to abrasion of the left anterior descending with a 2.0-mm angioplasty balloon. The pigs were allowed to recover after routine closure of the incision. One pig (1/30) died during the abrasion procedure as a result of ventricular fibrillation. This represents a low, acceptable mortality using the present regimen compared with other regimens.

Drug-induced vasodilation in an in vitro and in vivo study: the effects of nicardipine, papaverine, and lidocaine on the rabbit carotid artery.

Extreme arterial vasoconstriction (vasospasm) is a common problem encountered in microvascular surgery. An ideal pharmacologic tool able to counteract ischemia during microsurgery should be easy to apply and exert its action both locally and distally in the microcirculation of the flap. We have compared in vitro and in vivo vascular properties of nicardipine, papaverine, and lidocaine in the rabbit carotid artery. In vitro, rings from the rabbit carotid artery (n = 7) were bathed in Krebs-Ringers solution and stretched progressively to an optimal tension of 3.7 to 4.2 g. The specimens were contracted with norepinephrine (1 microM), and a cumulative dose response curve was established. In vivo, microvascular anastomoses were performed bilaterally in the rabbit carotid artery in 35 animals using 9-0 nylon suture and standard microsurgical techniques. During and after the anastomoses, nicardipine (0.1, 0.01 mg topical, or 0.1 mg/hour IV), papaverine (30 mg/cc topical), and lidocaine (2% with and without epinephrine) were applied (blinded) at the anastomotic site in five rabbits each. Heparinized sodium chloride was used as topical irrigation for control and to clean the anastomosis. Blood flow changes were monitored continuously with the transonic Doppler for 30 minutes after the procedure. The systemic blood pressure was also monitored in a group of pilot experiments. A documented decrease in blood flow was noted in all animals after the microvascular anastomosis. Nicardipine and papaverine evoked a concentration-dependent relaxation to precontracted rings to norepinephrine. Nicardipine was greater than papaverine in inducing relaxation. Lidocaine demonstrated a biphasic response with low concentrations potentiating contraction. Systemic nicardipine and papaverine significantly increased the blood flow in the rabbit carotid artery. Topical application of nicardipine and lidocaine did not significantly alter the blood flow; however, the application of nicardipine demonstrates a trend toward increased flow. Lidocaine with epinephrine significantly decreased the blood flow. No drug was found to alter the blood pressure of the animals. Our results demonstrate that nicardipine and papaverine seem to be pharmacologic tools able to increase the blood flow in anastomotic arteries. In contrast, the use of 2% lidocaine as a spasmolytic agent should be re-evaluated, since this substance may act as a partial agonist.

Iatrogenic Horner's syndrome in an experimental pig.

An adult domestic female pig (Sus scrofa) exhibited clinical signs of right-sided Horner's syndrome after experimental placement of a woven aortic stent followed by aortic catheterization. The clinical signs included a miotic pupil, ptosis of the upper eyelid, prolapse of the nictitating membrane, and enophthalmos. Necropsy revealed a large mass in the right midcervical region that encased or was in contact with the carotid artery, internal jugular vein, and vagus nerve. Closer evaluation of the mass revealed that it was a small piece of surgical suture material that was embedded within the lumen of the carotid artery. This extrinsic material served as a nidus for an inflammatory reaction involving the vagus nerve.

Insular amyloidosis and diabetes mellitus in a crab-eating macaque (Macaca fascicularis).

Clinicopathologic examination of a crab-eating macaque (Macaca fascicularis) with chronic weight loss and bilateral cataracts revealed high fasting serum glucose, glucosuria and hypercholesterolemia. Clinical signs were eliminated by treatment once a day with isophane insulin suspension. Extensive insular amyloidosis was found microscopically sixty days later.

Interstitial laser prostatectomy.

Serial gross and histopathologic examinations of the prostate following interstitial laser prostatectomy in the canine model demonstrated distinct zonal thermal changes around the entire active area of the interstitial thermal therapy (ITT) fiber. A large, well-demarcated area of acute coagulative necrosis immediately surrounded each fiber tract; beyond that were a prominent narrow peripheral zone of marked tissue disruption and an outer zone of hemorrhage. Liquefaction within these coagulative areas was evident within 24 hours, and by 4 days, each lobe of the prostate contained an irregular cavity that became lined by normal-appearing transitional epithelium and that, by 5 weeks, communicated with the prostatic urethra. These postmortem pathologic observations, similar to findings previously reported following transurethral laser prostatectomy, suggest that interstitial laser thermal therapy may provide an additional means for treating benign prostatic hyperplasia in men.

Pathologic changes following transurethral canine prostatectomy with a cylindrically diffusing fiber.

Transurethral laser prostatectomy was performed on eight mongrel dogs employing a cylindrically diffusing fiber delivery system and a 1.06 mu Nd:YAG laser. Each dog received 15,000 joules of laser energy delivered to the prostate in one continuous dose of 25 watts for 10 minutes. Gross and histopathologic examinations of serial sections of the prostate were performed postoperatively after intervals of 2 hours to 7 weeks. Grossly, a spherical zone of destruction averaging 2.8 cm in diameter was present in dogs except one. Histopathologic changes in the prostate consisted of acute coagulative necrosis with interstitial edema at 2 hours, becoming hemorrhagic by 24 hours. A prominent circular area of acute coagulative necrosis with progressively larger areas of liquefaction and hemorrhage was present in prostates harvested from 4 days to 1 week after lasing. Initial re-epithelization of the resulting cavity was observed at 3 weeks with nearly complete epithelialization 7 weeks after laser treatment. The simplified fiber placement and lack of postoperative complications in this small group of dogs suggest that the cylindrically diffusing fiber could offer significant advantages over laterally deflecting fibers for transurethral prostatectomies in the dog model.

Transurethral incision of the prostate using the holmium:YAG laser.

Transurethral incisions of the prostate were made endoscopically in 5 dogs under a fluid medium using a holmium:YAG (Ho:YAG) laser operating at a wavelength of 2.1 microns and with delivery of 1.0 J/pulse in 15 Hz (15 W). Histopathologic examination of tissues collected immediately after surgery revealed irregular crevices outlined by a narrow zone of coagulative necrosis. Ulcerated fissures persisted at 5 and 7 days with the initial stages of epithelial regeneration partially re-epithelializing the ulcerated surfaces. A modest inflammatory response characterized by edema, hemorrhage, and a mixed inflammatory cell infiltrate was also associated with the laser incision sites at 5 and 7 days. Three weeks postlasing, the ulcerated surfaces of the fissures were completely re-epithelialized. At 5 weeks only a slight indentation persisted at the incision sites with minimal changes in the subjacent submucosa and prostatic glandular architecture. Although the results of these investigations are preliminary, we believe that the Ho:YAG laser warrants further clinical evaluation for treating patients with benign prostatic hyperplasia (BPH), urethral strictures, bladder neck contractures, and constrictions of the upper urinary tracts.

Pathologic changes occurring in the prostate following transurethral laser prostatectomy.

Serial gross and histopathologic examinations of the prostate following transurethral laser prostatectomy in the canine model demonstrated an immediate well-demarcated sphere of thermal necrosis measuring 2.7 cm in diameter, which, within 24 hours, had begun liquefaction and was showing multiple areas of cavitation. By the end of the 1st week, the areas of cavitation had coalesced to form a central cavity lined by a narrow layer of necrotic tissue clinging to the thin surviving peripheral belt of prostatic glandular parenchyma. At 3 weeks, the bluish-black discoloration resulting from breakdown of blood in the necrotic tissue had subsided, leaving masses of coagulonecrotic tissue within the central cavity. Within 5 weeks, the ectatic central cavity was lined by transitional epithelium. These postmortem pathologic observations confirm our surgical and clinical impressions of being able to satisfactorily perform an effective transurethral prostatectomy using neodymium:YAG (Nd:YAG) laser photoirradiation.

Use of the holmium:YAG laser in urology.

The tissue effects of a holmium:YAG (Ho:YAG) laser operating at a wavelength of 2.1 mu with a maximum power of 15 watts (W) and 10 different energy-pulse settings was systematically evaluated on kidney, bladder, prostate, ureteral, and vasal tissue in the dog. In addition, various urologic surgical procedures (partial nephrectomy, transurethral laser incision of the prostate, and laser-assisted vasovasostomy) were performed in the dog, and a laparoscopic pelvic lymph node dissection was carried out in a pig. Although the Ho:YAG laser has a strong affinity for water, precise tissue ablation was achieved in both the contact and non-contact mode when used endoscopically in a fluid medium to ablate prostatic and vesical tissue. Using the usual parameters for tissue destruction (blanching without charring), the depth of thermal injury in the bladder and ureter was kept superficial. In performing partial nephrectomies, a 2-fold reduction in the zone of coagulative necrosis was demonstrated compared to the use of the continuous wave Neodymium:YAG laser (Nd:YAG). When used through the laparoscope, the Ho:YAG laser provided precise cutting and, combined with electrocautery, allowed the dissection to proceed quickly and smoothly. Hemostatic control was adequate in all surgical procedures. Although the results of these investigations are preliminary, our initial experience with the Ho:YAG laser has been favorable and warrants further investigations.

Alternative methods of exposure minimize cardiopulmonary risk in experimental animals during minimally invasive surgery.

BACKGROUND: Alternative methods of exposure are needed for minimally invasive surgery to avoid hypercarbia and acidosis associated with carbon dioxide (CO2) abdominal insufflation. The goals of this study were to determine the pulmonary and hemodynamic effects of both helium (HE) abdominal insufflation and placement of a mechanical abdominal wall-lifting device (lifter) during laparoscopy. METHODS: Sixteen adult domestic pigs under general endotracheal anesthesia underwent baseline measurements of pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and arterial blood gas. Six pigs underwent standard CO2 abdominal insufflation, five pigs underwent abdominal insufflation with HE, and a lifter was used for exposure in five other animals. Sequential readings of PCWP, CO, and arterial blood gas were recorded at 20-min intervals for 60 min in all 16 animals. RESULTS: No significant changes from baseline values were noted in arterial pCO2 or pH in animals who underwent placement of the lifter at any time point. After undergoing HE insufflation, animals experienced modest but significant acidosis and little change in pCO2. There was a significant rise in arterial pCO2 and decrease in pH from baseline values at all time points in animals undergoing CO2 insufflation. CONCLUSIONS: This study shows that neither HE abdominal insufflation or the lifter have significant deleterious pulmonary or hemodynamic effects on experimental animals during laparoscopy. Gasless laparoscopy or HE insufflation may provide a safer alternative method of exposure for minimally invasive surgery in patients with pre-existing pulmonary or cardiac dysfunction. By minimizing risk in these patients, costly invasive monitoring may be avoided.

Thrombosis in an ischemia-reperfusion injury flap model: is vessel anastomosis a factor?

This study was undertaken to elucidate the possible contribution of vessel anastomosis to the incidence of vessel thrombosis in an ischemia- reperfusion injury flap model in rabbits. Bilateral groin flaps were elevated on isolated vascular pedicles and rendered ischemic for 6 (n = 11), 8 (n = 5), 15.5 (n = 5), or 24 hr (n = 8). After the ischemic episode, an arterial anastomosis was performed on one side, and then perfusion was reestablished on both sides. Although the incidence of thrombosis increased with the interval of ischemia, there was no statistically significant difference in thrombosis rate between the two sides for any of the ischemia intervals studied. The authors conclude that the presence of an arterial anastomosis does not increase the rate of vessel thrombosis in flaps after primary ischemia-reperfusion injury in the rabbit model.

Visual laser ablation of the canine prostate with a diffusing fiber and an 805-nanometer diode laser.

BACKGROUND AND OBJECTIVE: Although the popularity of visual laser ablation of the prostate (VLAP) as a treatment for symptomatic, benign prostatic hyperplasia (BPH) is increasing, the perceived advantages of VLAP over conventional transurethral electroresection of the prostate (TURP) is being debated because optimal technique and dosimetry for surgical lasers are still being refined. At this time, the 1.06 neodymium:yttrium-aluminum-garnet (Nd:YAG) laser and a laterally deflecting delivery system is the hardware combination most widely used for VLAP. STUDY DESIGN/MATERIALS AND METHODS: Reported here is a study of an alternate system, a 805-nm diode laser (Diomed 25 Diomedics, The Woodlands, TX) with a cylindrically diffusing fiber (Surgimedics Inc., The Woodlands, TX). Eight mongrel dogs were prostatectomized by transurethral irradiation of the prostate with 15,000 J of diode laser energy delivered via a fiber that diffuses the energy in a 1.5-cm-long cylindrical pattern. The dogs were sacrificed and prostates harvested at 3 hours and 1,4,7,14,21,35, and 49 days after the procedure, fixed with 10% buffered formalin, and examined histologically. RESULTS/CONCLUSIONS: It was found that this laser/fiber combination created volumes of tissue coagulation similar to those encountered in our previous work with the Nd:YAG laser in combination with both laterally deflecting and diffuser fibers, while offering the distinct advantages of simplified technique, lower cost hardware, and fewer postoperative complications in the dog model.

NG-methyl-L-arginine, an inhibitor of nitric oxide formation, acts synergistically with dobutamine to improve cardiovascular performance in endotoxemic dogs.

OBJECTIVE: To evaluate the hemodynamic effects of the nitric oxide inhibitor, NG-methyl-L-arginine, and dobutamine during experimental endotoxemia. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Adult, male mongrel dogs. INTERVENTIONS: After catheterization with a flow-directed, thermal-dilution pulmonary artery flotation catheter and arterial catheter, awake dogs received either NG-methyl-L-arginine or dobutamine alone or in combination (controls; n = 5). Other animals were administered endotoxin (50 micrograms/kg), then received either NG-methyl-L-arginine alone or in combination with dobutamine after the onset of hypotension (endotoxin-treated; n = 5). MEASUREMENTS AND MAIN RESULTS: Both dobutamine and NG-methyl-L-arginine alone had a small, but significant vasopressor effect on control animals. In contrast, administration of the combination of NG-methyl-L-arginine and dobutamine resulted in a 48.6% increase in mean arterial pressure, an effect which was dose-dependent with respect to NG-methyl-L-arginine. In dogs treated with 50 micrograms/kg of endotoxin, hypotension could be only partially reversed by NG-methyl-L-arginine, mainly due to a decline in cardiac output. Co-infusion of dobutamine reversed this depression of cardiac output and resulted in a complete restoration of blood pressure. CONCLUSIONS: Later stages of septic shock are characterized by hypotension and decreased myocardial performance. A major mediator of hypotension is nitric oxide, a vasodilatory agent derived from L-arginine. Administration of the arginine derivative, NG-methyl-L-arginine, improved systemic vascular resistance but not myocardial performance. The addition of an inotropic agent to NG-methyl-L-arginine, a nitric oxide synthase inhibitor, resulted in an enhancement of the antihypotensive action of NG-methyl-L-arginine through the restoration of cardiac output. The synergistic action between dobutamine and NG-methyl-L-arginine may be of therapeutic value in the treatment of septic shock.