A phase II trial with RFS2000 (rubitecan) in patients with advanced non-small cell lung cancer.

Rubitecan (RFS2000, 9 nitrocamptothecin,) is a new oral topoisomerase I inhibitor. We report a phase II, single-arm, open-label study of RFS2000 as first line treatment for non-small cell lung cancer (NSCLC). Seventeen treatment-naïve patients with stage IIIB (9/17) and IV (8/17) NSCLC (11 male and 6 female) were treated, the median age was 62 years (range 52-86), and the majority of patients (14/17) were of performance status 1. RFS2000 was given orally, daily for 5 days, repeated every week. The starting dose was 1.5 mg/m(2)/day, and dose adjustment was permitted based upon toxicity. Fifteen patients had a dose escalation to 1.75 mg/m(2)/day and 7 had a second dose escalation to the protocol maximum level of 2.0 mg/m(2)/day. RFS2000 was tolerated well. Almost all adverse events were grade 1 and 2. The most frequently encountered adverse events were diarrhoea, nausea, anorexia, and lethargy. Neutropenia and thrombocytopenia were not observed in any patient. There were no responders to RFS2000 treatment, 10 patients had stable disease as their best response, whilst five had tumour progression. Two patients were not assessable for tumour response. The median survival time was 257 days (95% CI = 222-352). RFS2000 appears to be inactive at dose levels of 1.5-2.0 mg/m(2)/day in advanced NSCLC patients. Since only mild toxicity and no myelosuppression were encountered, these dose level are too low for this treatment-naïve patient population with NSCLC. Further studies at an increased dose would be required to identify whether this agent has merit in the treatment of NSCLC.

Phase II study on 9-nitrocamptothecin (RFS 2000) in patients with advanced or metastatic urothelial tract tumors.

OBJECTIVE: To investigate the antitumor activity and the safety of RFS2000, an oral topoisomerase I inhibitor, in patients with advanced or metastatic urothelial tract tumors refractory to one prior chemotherapy regimen. PATIENTS AND METHODS: Eligible patients were to have failed first line treatment for advanced or metastatic disease. Patients received RFS2000 as one daily oral intake at the dose of 1.5 mg/m(2)/day according to a "5 days on/2 days" off schedule continuously. One cycle was arbitrarily defined as a 3 week period. Sufficient oral fluid intake to prevent cystitis previously described in phase I trials with RFS2000 was recommended. Gehan design was used for sample size determination. Anti-tumor activity was evaluated according to the RECIST criteria and toxicity according to CTC version 2. RESULTS: Twenty patients received a total of 57 cycles (range 1-8). Grade 3-4 toxicity was observed in 10 patients requiring dose or schedule modifications. Hematological grade 3-4 toxicity was observed in 16% of the cycles. Only one patient experienced a partial response. CONCLUSIONS: RFS2000 could be administered orally as a "5 days on/2 days off" schedule continuously with a median dose intensity of 90.6% with an acceptable toxicity profile. However, RFS2000 did not exert significant activity in patients with advanced/metastatic urothelial tract tumors failing prior chemotherapy. The results of this study do not suggest further investigation of RFS2000 at the present dose and schedule for the treatment of urothelial tract tumors in this refractory population.

Randomized trial of Cervene, a kappa receptor-selective opioid antagonist, in acute ischemic stroke.

The purpose of this randomized trial was to confirm drug safety and to obtain preliminary efficacy data on Cervene (nalmefene), an opioid antagonist with relative kappa receptor selectivity, for the treatment of acute ischemic stroke. Patients were treated for 24 hours with either intravenous Cervene (0.05 mg/kg as an initial infusion over 15 minutes and 0.01 mg/kg/h maintenance) or placebo within 6 hours of an ischemic stroke. Efficacy was assessed by comparing the change from baseline to day 7 in the National Institutes of Health stroke scale score (NIHSSS) and the Glasgow Outcome Scale and Barthel Index at 3 months. Forty-four evaluable patients were randomized (3:1) to Cervene (n = 34; treated at 5.0 +/- 0.9 hours after onset) and placebo (n = 10; treated at 4.6 +/- 1.5 hours). No deaths or serious adverse events reasonably attributable to Cervene have been reported. A "major improvement" (NHSSS > 4) was seen at day 7: placebo, 33% (three of nine patients) and Cervene, 66% (19 of 29 patients). Only patients with initial NIHSSS >/= 4 were considered evaluable for this primary endpoint. "Good recovery" at 3 months (Glasgow = 5) was as follows: placebo, 50% (5 of 10 patients) and Cervene, 73% (24 of 33 patients). The death rate at 3 months was placebo, 20% (2 of 10 patients) and Cervene, 9.1% (3 of 33 patients). One patient was lost to follow-up. In conclusion, results from this randomized trial suggest that Cervene is safe, tolerable, and may be beneficial in the treatment of acute stroke patients.

Effects of Alzene and tacrine on water maze reference and working memory function in medial septal-lesioned rats.

The present study investigated the effects of repeated daily administration of a mixture containing free fatty acids (alpha-linolenic/linoleic acid in a 1:4 ratio at 25 mg/kg i.p., Alzene) on medial septal (MS) lesion-induced impairment of water maze (WM) spatial reference and working memory or passive avoidance (PA) behavior in adult rats (250-275 g at the beginning of the study). Alzene treatment was started 7 days before initiation of behavioral testing (WM reference memory testing on treatment days: 7-9 and 28-30 + passive avoidance on treatment days 31-32; WM working memory testing on treatment days: 7-10 and 38-31 + passive avoidance testing on treatment days 32-33) and continued until the end of the study. Alzene improved WM reference memory (treatment days 7-9 and 28-30) and PA behavior (treatment days 31-32) as effectively as an anti-cholinesterase drug, tacrine 3 mg/kg (i.p.). However, in a separate group of MS-lesioned rats we observed that working memory (treatment days 7-10 and 28-31) was not improved by either Alzene or tacrine treatment. The present results suggest that Alzene treatment improves spatial reference memory and inhibitory avoidance in MS-lesioned rats.

The antitumoral effect of the immunomodulator AS101 and paclitaxel (Taxol) in a murine model of lung adenocarcinoma.

The immunomodulator ammonium trichloro(dioxyethylene-0-0')tellurate (AS101) has been shown to possess antitumoral properties in several murine models. In the present study, we demonstrate a synergistic in vivo antitumor effect of AS101 and Taxol against early stage Madison 109 lung adenocarcinoma. Treatment with optimal doses of Taxol (25 and 17 mg/kg) and AS101 (0.5 mg/kg) resulted in 66.6 and 43.3% cures. We propose that the antitumor effect is the result of both a direct and indirect effect of the drugs on tumor cells. AS101 and Taxol directly inhibited clonogenicity of M109 cells in a synergistic dose-dependent manner. Exposure of M109 cells to clinically achievable concentrations of Taxol and AS101 produced a synergistic internucleosomal DNA fragmentation associated with programmed cell death. We suggest that AS101 renders tumor cells more susceptible to chemotherapy in general and to Taxol in particular, partly by increasing the wild-type p53 protein expression that is required for efficient execution of the death program. Moreover, we demonstrate a synergistic effect of AS101 and Taxol in increasing the tumoricidal activity of macrophages. This activity is produced by nitric oxide secretion. The synergistic antitumoral effects of AS101 and Taxol were partly ablated both in vitro and in vivo by inhibition of nitric oxide synthase. These findings indicate that AS101 in combination with Taxol may be a promising antitumor drug, and illustrate the mechanism of action of both drugs when acting synergistically. Phase II clinical trials have been initiated using AS101 in combination with Taxol.

The protective role of the immunomodulator AS101 against chemotherapy-induced alopecia studies on human and animal models.

The immunomodulator AS101 has been demonstrated to exhibit radioprotective and chemoprotective effects in mice. Following phase-I studies, preliminary results from phase-II clinical trials on non-small-cell-lung-cancer patients showed a reduction in the severity of alopecia in patients treated with AS101 in combination with chemotherapy. To further substantiate these findings, the present study was extended to include 58 patients treated either with the optimal dose of 3 mg/m2 AS101 combined with carboplatin and VP-16, or with chemotherapy alone. As compared with patients treated with chemotherapy alone, there was a significant decrease in the level of alopecia in patients receiving the combined therapy. The newly developed rat model was used to elucidate the protective mechanism involved in this effect. We show that significant prevention of chemotherapy-induced alopecia is obtained in rats treated with Ara-C combined with AS101, administered i.p. or s.c. or applied topically to the dorsal skin. We show that this protection by AS101 is mediated by macrophage-derived factors induced by AS101. Protection by AS101 can be ascribed, at least in part, to IL-1, since treatment of rats with IL-1 RA largely abrogated the protective effect of AS101. Moreover, we demonstrate that in humans there is an inverse correlation between the grade of alopecia and the increase in IL-1 alpha. In addition, protection by AS101 could be related to PGE2 secretion, since injection of indomethacin before treatment with AS101 and Ara-C partly abrogated the protective effect of AS101. To assess the ability of AS101 to protect against chemotherapy-induced alopecia, phase-II clinical trials have been initiated with cancer patients suffering from various malignancies.

Stroke before 55 years of age at Karolinska Hospital 1973-77. A study of 399 well-defined cases. Risk indicators and etiological considerations.

The etiological characteristics of cerebrovascular disease (CVD) before the age of 55 are reviewed in 399 patients admitted to the Department of Neurology, Karolinska Hospital, Stockholm, from 1973-77. The material was well-defined with regard to subtypes of stroke as well as to the diseased population. The control material consists of 829 males and females of corresponding age randomly selected from the Stockholm population. In the ischemic group, 61% had angiographic evidence of atherosclerosis and, compared to controls, in most patient groups a significant (P less than 0.05-0.001) association with hypertension, diabetes, heart disease and smoking was found as well as for female patients under age 40 the use of oral contraceptives (P less than 0.001). In the hemorrhagic group, angiography demonstrated aneurysms in 76% of the patients with subarachnoidal bleeding but also atherosclerotic lesions in about 12% of the whole group. This would imply that atherosclerosis is an important precursor also for hemorrhagic lesions, further supported by a significant (P less than 0.01-0.001) association of hypertension, diabetes and smoking with this group.

PIP: This study investigated the etiologic characteristics of cerebrovascular disease (CVD) before the age of 55 years in 399 patients admitted to Karolinska Hospital, Stockholm, in 1973-77. 829 age-matched controls were randomly selected. Cases were further classified by subtype of CVD: subarachnoid, intracerebral, ischemic, and unclassified lesions. A family history of cerebrovascular incidents, heart disease, other vascular diseases, diabetes, and hypertension was reported in 10-30% of the cases. Among male cases with ischemic lesions before age 40, a history of treated diabetes, heart disease, and smoking was reported significantly more often than by controls. Among comparable female cases, a history of treated hypertension and oral contraceptive (OC) use at the onset of the disease was found significantly more often than in controls. In terms of ischemic lesions after the age of 40, a history of treated hypertension and smoking was significantly more frequent in male and female cases than in corresponding controls; treated diabetes and heart disease were reported more often in male cases only. No differences between cases and controls were found in the use of OCs. 61% of cases in the ischemic group had angiographic evidence of atherosclerosis. In the hemorrhagic group, angiography demonstrated aneyrysms in 76% of patients with subarachnoid bleeding but also atherosclerotic lesions in 12% of the whole group, implying that atherosclerosis is an important precursor for hemorrhagic lesions as well. The results from this study seem to support an association between OC use and circulatory complications; however, since mortality rates from circulatory disease are declining in countries where OC use is widespread, conclusions about a casual relationship may be unwarranted.

Epidemiology of acute cerebrovascular disease before the age of 55 in the Stockholm County 1973-77: I. Incidence and mortality rates.

The incidence and mortality rates of cerebrovascular disease (CVD) before age 55 were estimated for the Stockholm county between 1973 and 1977 using community based diagnosis and death statistics registers. Annual validation procedures concluded that less than 5% of hospitalized patients may have escaped registration. During the study period a diagnosis of CVD (initial stroke or TIA) was reported in 2,103 individuals, giving annual average crude incidence rates for stroke and TIA of 34 and 4 respectively per 100,000 inhabitants under age 55. Hemorrhagic lesions were reported in 45.4% of the cases, ischemic lesions in 33.1% and unclassified lesions in 21.5%. For all diagnostic categories a strong correlation to age is found, and for most categories the male:female ratio is high. The mortality rates are high for hemorrhagic lesions and low for ischemic and unclassified lesions. Incidence rates are higher than in Uppsala and Gothenburg, Sweden, but lower than in North Karelia, Finland. Mortality rates are similar to those reported by most other investigators.

A study of hemostasis in ischemic cerebrovascular disease. V. A multivariate evaluation of risk indicators and predictors. Early results of a longitudinal study.

The study includes 119 patients with minor ischemic cerebrovascular lesions before the age of 55 during 1976-78. Atherosclerotic signs were found in 65% at aortocranial angiography and/or exercise test (ST depression). Abnormalities in hemostasis (defective fibrinolytic response in 50%, high Factor VIII activity in 45% of those investigated, and high Factor VIII related antigen (VIII R:Ag) in 20%) could not be explained by accumulation of atherosclerotic risk factors as most often no significant independent correlations were found at stepwise multiple regression. Significant correlations with aortocranial atherosclerosis was found for age, VIII R:Ag and blood pressure reaction at exercise test. Only E-SR showed significant correlation to ST depression at exercise test. These results indicate different determinants and risk indicators for atherosclerosis with different locations. An early evaluation of the longitudinal study (mean 42 months' follow up) showed that 16 patients had suffered new occlusive vascular incidents. The malign prognostic subgroup (cerebral or myocardial infarction or death; n = 10) showed significantly higher levels of VIII R:Ag (p less than 0.005) and triglycerides (p less than 0.05) than the benign group (new TIA, n = 6). This indicates that VIII R:Ag may be a useful marker for development of atherosclerosis and predictor for the outcome of ICD.

A study of hemostasis in ischemic cerebrovascular disease: IV. A five year follow-up of some blood coagulation parameters also including fibrinopeptide A, factor XII and prekallikrein.

Twenty-seven young adults (mean age 46) with ischemic cerebrovascular disease (ICD) were reinvestigated about 5 years after discharge and compared to 67 healthy controls. Factor VIII related antigen was again found significantly (p less than 0.005 and p less than 0.001) increased in male as well as female patients and a significant (r = 0.66, p less than 0.001) correlation was found with earlier data. Factor VIII biological activity was again found increased, significantly (p less than 0.001) in males. In contrast to earlier results antithrombin antigen and activity were significantly (p less than 0.001) decreased in males. This finding and decreased levels of factor XII in female patients (p less than 0.001) and of prekallikrein in male patients (p less than 0.01) could reflect disturbed regulatory functions or possibly constitutional differences. As in most subjects no increase of fibrinopeptide A was found, there was no sign of continuous activation of the whole coagulation sequence. Since hemostatic abnormalities were unrelated to acute phase reacting proteins they were obviously of a different nature than unspecific response to tissue damage and acute stress. High levels of factor VIII and low levels of antithrombin imply that the coagulation system could be more easily activated when other factors coincide, e.g. intimal lesions in carotide arteries.

A study of hemostasis in ischemic cerebrovascular disease. I. Abnormalities in factor VIII and antithrombin.

A sample of in all 119 young adults below the age of 55, with ischemic cerebrovascular disease (TIA and minor stroke), was investigated later than three months after acute disease. Factor VIII biological activity and antithrombin antigen were significantly (p less than 0.001) increased as compared to 80 healthy controls. In combination, these two variables correctly classified 85 percent of patients and controls at a stepwise discriminant analysis. Factor VIII related antigen was increased (p less than 0.02) in patients with atherosclerotic signs at cerebral angiography and in postmenopausal female patients (p less than 0.001). It is suggested that high levels of factor VIII might predispose for thrombosis/atherosclerosis. Antithrombin biological activity was normal in spite of high antithrombin antigen levels, possibly indicating a relative insufficiency in the antithrombin defense line. It is concluded that young stroke patients provide good opportunities to look for early operating factors and predictors in human atherosclerosis and arterial thromboembolism.

A study of hemostasis in ischemic cerebrovascular disease. II. Abnormalities in platelet ADP release, platelet cyclooxygenase regeneration time and platelet factor 3 availability.

Most earlier studies of platelet function in stroke patients have been performed in the acute phase and are hampered by diagnostic insecurity. A sample of totally 67 young adults below the age of 55, with ischemic cerebrovascular disease (TIA and minor stroke) were investigated at a late stage after acute disease and compared to 20 healthy controls. Patients with atherosclerotic signs at cerebral angiography had significantly (p less than 0.05) higher platelet factor 3 availability than angionegative patients. Unexpectedly, female patients compared to male patients had significantly (p less than 0.05) larger ADP-release after stimulation with collagen in vitro. Furthermore, when female patients were compared to female controls a significantly (p less than 0.05) increased platelet factor 3 availability was found. The results indicate that platelets in female patients may have an increased tendency to aggregate in vivo. Patients had significantly (p less than 0.01) shortened platelet cyclooxygenase regeneration half times (PRT). This was correlated to high levels of factor VIII related antigen (r=0.59) and high levels of factor VIII biological activity (r=0.67), indicating that platelets may be consumed by platelet adhesion and mural thrombi formation in abnormal vessel walls. PRT appears to be a reliable method to assess platelet function in vivo and to optimize aspirin dose and dose intervals in the individual.

A study of hemostasis in ischemic cerebrovascular disease. III. Abnormalities in vascular plasminogen activators, antiactivators and alpha 2-antiplasmin.

A sample of in all 119 patients with ischemic cerebrovascular disease (TIA and minor stroke) below the age of 55 years, were submitted for testing of fibrinolysis in the late recovery phase after acute disease. Defective fibrinolysis, as tested after venous stasis, was found in patients (p less than 0.01) as compared to controls using a conventional fibrin plate method. A new chromogenic peptide substrate method showed a similar tendency. Antiactivator activity, measured as antiurokinase, using a peptide substrate, was significantly higher (p less than 0.01) in young female patients than in female controls. Alpha 2-antiplasmin (peptide substrate method) was significantly (p less than 0.001) higher in female than male patients. However, no correlation was found between inhibitors of fibrinolysis and defective fibrinolysis after venous occlusion. Furthermore, in a pilot study of vein biopsies, normal content of vascular plasminogen activators was found in the majority of cases. Thus, it is suggested that defective fibrinolysis in most cases reflects a disturbed release function.

Fibromuscular dysplasia and the brain. II. Current concept of the disease.

Eleven hundred cases from the literature of fibromuscular dysplasia (FMD) are reviewed including 300 cases with aortocranial lesions. The male-female ratio is 1:2, and the prevalence seems increased among Caucasians. The clinical diagnosis of FMD is made by angiography, ten years earlier in patients with hypertension (mean age 39 years) than in those with cerebrovascular symptoms (mean age 50 years). Segmental dysplastic lesions are found mainly in primary aortic branches. All age groups may be affected and follow-up studies give evidence for stationary as well as slowly progressive lesions. A multifactorial hypothesis of etiology is presented: congenital minor lesions of tunica medial might predispose to aneurysms and to an abnormal fibroproliferative response to mechanical or circulatory stimuli. The association of FMD and intracranial aneurysmal disease in females is discussed. Inheritance as a dominant trait with reduced penetrance in males is suspected. Current aspects on morphology, symptomatology and clinical management are presented.

Fibromuscular dysplasia and the brain. I. Observations on angiographic, clinical and genetic characteristics.

The angiographic, clinical, and genetic characteristics of fibromuscular dysplasia (FMD) are reviewed in 37 patients (mean age 48 years) selected from a pool of 4000 angiograms of carotid or vertebral arteries. FMD was a neglected pathogenic factor in 28 patients with hemorrhagic or ischemic cerebral lesions. The aneurysms found in 19 patients had conventional appearance and were mainly located in the internal carotid or middle cerebral arteries and on the same side as the most affected cervical artery, which suggests that aneurysms and FMD are pathogenically related. A clinical syndrome is presented where headache, ECG-abnormalities, hypertension, mental distress, tinnitus, vertigo, arrhythmia, TIA, and syncope are frequent components. Hemicrania, sometimes combined with ipsilateral Horner's Syndrome, was found in patients with advanced lesions in the carotid artery of the same side. An associated occurrence of stroke in pedigrees, especially among young and middle aged females, indicates that FMD in the majority of cases in inherited as an autosomal dominant trait with reduced penetrance in males.

Computed tomography and CSF spectrophotometry. Diagnosis and prognosis in 300 patients with cerebrovascular disease.

Computed tomography (CT) has been reported to show normal findings in 13-52% of patients with cerebrovascular diseases. Among factors deciding the diagnostic accuracy are the size and location of the lesion, the time elapsed from onset to examination, the use of contrast enhancement and the type of CT scanner used. To further elucidate these aspects, we designed the present study including 300 consecutive patients, all investigated by CT with a 160 x 160 matrix and cerebrospinal fluid spectrophotometry (CSF-SPE). CT indicated a specific diagnosis in 52.7%. In the majority of the remaining cases, additional subclassification was possible by CSF-SPE, emphasizing the complementary information obtained by combined examinations. CT was also found to be a useful tool for reliable prognostic prediction, irrespective of the initial clinical course.