Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study

Antagonizing the effect of interleukin (IL)-5 is a potential new treatment strategy in allergic disorders. We evaluated the safety, biological activity, and pharmacokinetics of SCH55700, a humanized anti-human IL-5 antibody, in subjects with severe persistent asthma treated with oral or high doses of inhaled steroids. In a double-blind, randomized, multicenter trial, a rising single dose of SCH55700 (0.03 mg/kg [n = 2], 0.1 mg/kg [n = 4], 0.3 mg/kg [n = 6], or 1.0 mg/kg [n = 12]) or placebo (n = 8) was administered intravenously. SCH55700 dose dependently reduced circulating eosinophil counts. At a dose of 1.0 mg/kg, the decrease remained significant up to Day 30 [(0.07 +/- 0.01) x 10(9)/L versus (0.23 +/- 0.04) x 10(9)/L at baseline] (mean +/- SEM) (p = 0.05). After administration of SCH55700 at 0.3 and 1.0 mg/kg, a trend toward improvement in baseline FEV1 was observed, which reached significance 24 hours after the 0.3-mg/kg dose (p = 0.019 versus placebo). No significant changes occurred in other clinical indices of disease activity. Adverse events were not different between active treatment and placebo. We conclude that SCH55700 is a biologically active anti-human IL-5 antibody that can be safely used in severe steroid-treated asthma. Its therapeutic potential needs to be addressed in specifically designed efficacy trials.     

Interaction between vasodilators and vasopressin in internal mammary artery and clinical significance

BACKGROUND: Arginine vasopressin (AVP) has recently been demonstrated as an alternative in the treatment of severe refractory vasodilatation in coronary artery bypass grafting. However, AVP may be a spasmogen for graft spasm. We compared the in vitro antispastic effect among calcium-channel antagonists (nifedipine, diltiazem, and verapamil), nitroglycerin, and the highly selective AVP (V1) receptor antagonist [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin. METHODS: Human internal mammary artery segments (n = 218) were studied in organ baths. The inhibitory effects of the above vasodilators on AVP-mediated contraction were studied in two ways: relaxation with AVP precontraction and depression of the AVP-induced contraction after pretreatment with vasodilators. RESULTS: All three calcium-channel antagonists caused limited relaxation (18.3%+/-5.4% for nifedipine, n = 11; 22.2%+/-3.8% for verapamil, n = 10; and 26.2%+/-7.5% for diltiazem, n = 9). The plasma concentration of calcium-channel antagonists had no significant depression effect on the AVP-induced contraction. In contrast, [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin caused full (100%, n = 11) and nitroglycerin caused nearly full (93%+/-3%, n = 10) relaxation. Pretreatment with [1-deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin (10(-8), 10(-7), or 10(-6) mol/L, respectively) significantly increased the effective concentration for 50% of the AVP-induced contraction (10(-8.6)+/-10(0.1) mol/L, p = 0.009; 10(-7.8)+/-10(0.07) mol/L, p = 0.000; or 10(-6.9)+/-10(0.11) mol/L, p = 0.000 versus the control, 10(-9.24)+/-10(0.16) mol/L). However, nitroglycerin only slightly depressed the AVP-induced contraction. CONCLUSIONS: [1-Deaminopenicillamine, 4-valine, 8-D-arginine] vasopressin may provide specific antispastic effect in either prophylaxis or treatment of the AVP-related vasospasm in the internal mammary artery. Nitroglycerin may be effective in treatment but has little effect on prophylaxis. Use of calcium-channel antagonists may have little benefit in AVP-related vasospasm.     

Polymer Delivery of Camptothecin against 9L Gliosarcoma: Release,Distribution, and Efficacy

Camptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro; unfortunately, systemic toxicity has limited its in vivo efficacy. This is the first study to investigate the release, biodistribution, and efficacy of camptothecin from a biodegradable polyanhydride polymer. Tritiated camptothecin was incorporated into biodegradable polymers that were implanted intracranially in 16 male Fischer 344 rats and the animals were followed up to 21 days post-implant. A concentration of 11–45g of camptothecin-sodium/mg brain tissue was within a 3mm radius of the polymer disc, with levels of 0.1g at the outermost margin of the rat brain, 7mm from the site of implantation. These tissue concentrations are within the therapeutic ranges for human and rat glioma lines tested against camptothecin-sodium in vitro. The in vivo efficacy of camptothecin-sodium was evaluated with male Fischer 344 rats implanted intracranially with 9L gliosarcoma and compared with the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The animals were divided into four groups. Group 1 (control) had a median survival of 17 days. Group 2 (3.8% BCNU polymer) had a median survival of 23 days (P=0.006). Group 3 (20% camptothecin polymer) had a median survival of 25 days (P=0.023). Group 4 (50% camptothecin polymer) had a median survival of 69 days (P<0.001). Drug loadings of 20% and 50% camptothecin released intact camptothecin for up to 1000h in vitro. We conclude that the biodegradable polymer p(CPP:SA) releases camptothecin-sodium, produces tumoricidal tissue levels, results in little or no systemic toxicity, and prolongs survival in a rat glioma model.     

Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease

BACKGROUND: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use. METHODS: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided. RESULTS: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment. CONCLUSIONS: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco.     

Epidermal langerhans cell depletion after artificial ultraviolet B irradiation of human skin in vivo: apoptosis versus migration

Ultraviolet B radiation can suppress cellular immunity. One of the mechanisms related to this immunosuppression is the disappearance of Langerhans cells from the epidermis. The aim of this study was to establish the mechanism of ultraviolet B-induced Langerhans cell disappearance in healthy individuals. The two most likely mechanisms for Langerhans cell disappearance are apoptosis and migration. Apoptosis was assessed in vivo by exposing buttock skin of 10 healthy volunteers to six minimal erythema doses of ultraviolet B. Only very few apoptotic Langerhans cells could be observed in sections from the ultraviolet B-exposed skin. Migration of Langerhans cells cannot be established in skin sections and suction blisters were therefore raised in an attempt to trap migrating Langerhans cells in the sub-basal membrane blister fluid. Blisters were raised on the flexor side of the lower arm of 30 healthy volunteers at several time points after exposure of the skin to six minimal erythema doses of ultraviolet B. Blister fluid was collected and blister roofs were removed to check for Langerhans cell disappearance. Langerhans cells were detected in the blister fluid of the ultraviolet B-exposed skin and not of the unexposed skin. The number of Langerhans cells in the blister fluid peaked at about 18 h after ultraviolet exposure, which coincided with the largest depletion of Langerhans cells in the blister roof. A fraction (20-30%) of the Langerhans cells in the blister fluid stained positive for DNA damage (cyclobutyl pyrimidine dimers), showing that they originated from the epidermis. Ultraviolet B-induced Langerhans cell disappearance appears to be mainly attributable to migration.     

Human "memories" can be evoked by stimulation of the lateral temporal cortex after ipsilateral medial temporal lobe resection

A patient with medically intractable seizures and mesial temporal sclerosis underwent a left anterior temporal lobectomy and amygdalohippocampectomy. After 4 months, his seizures recurred and a left temporal, subdural grid of electrodes was placed to localise his seizure focus. Stimulation through the grid evoked four distinct "memories", or experiential phenomena, despite absence of the ipsilateral medial temporal lobe. To our knowledge, this is the first documented case of experiential phenomena evoked by cortical stimulation in the absence of the ipsilateral medial temporal lobe.     

Value of therapeutic hyperthermic limb perfusion in advanced recurrent melanoma of the lower extremity

Twenty-six patients with advanced melanoma metastases confined to the lower extremity underwent 28 therapeutic limb perfusions without a major complication or treatment-related death. A complete response to treatment occurred in 21 patients (81 percent). Of 16 patients, response persisted until death in 13 and was noted at 75, 87, and 96 months follow-up in 3. In five patients, response lasted a median of 5 months (range 3 to 14 months), and repeat perfusion in two of these patients was not beneficial. Unfortunately, despite locoregional disease control, most patients died from distant metastases at a median of 15 months after treatment. In fact, regardless of response to perfusion, the 3 year survival rate of patients with advanced metastatic melanoma of the extremity was only 25 percent or less. Thus, although limb perfusion can be a safe and highly effective means of achieving locoregional disease control, there appears to be little survival benefit. Therefore, perfusion should be reserved for palliative treatment of selected patients with locally advanced melanoma.