Single agent docetaxel plus granulocyte-colony stimulating factor (G-CSF) in previously treated patients with advanced non small cell lung cancer. A phase II study and review of the literature.

The use of salvage chemotherapy in advanced non small cell lung cancer (NSCLC) is controversial. However, many patients need to be treated in order to achieve relief of their symptoms. Docetaxel (taxotere) is one of the most active drugs for the treatment of advanced NSCLC and several studies have also shown its effectiveness in pretreated patients. In the present study, 23 patients were treated in order to evaluate both the effectiveness and toxicity of the single agent docetaxel. Furthermore, granulocyte-colony stimulating (G-CSF) factor was administered in order to reduce neutropenia related to docetaxel. Docetaxel was administered intravenously at a dose of 100 mg/m2, on day 1, and it was repeated every 3 weeks. G-CSF was administered for primary prophylaxis of neutropenia at the standard dose of 30 mg/day from day 4 to day 10 of each cycle. The treatment was tolerated well and 5 (21.7%) partial responses were obtained. The median time to progression and the median survival time were 3 and 5 months, respectively. The main side effect noted was fatigue, the intensity of which was grade 2 in 43.4% of cases and grade 3 in 8.7% of patients, respectively. One patient (4.3%) had grade 4 cutaneous toxicity. No cases of grade 4 neutropenia were reported. In conclusion, docetaxel is active when used for salvage chemotherapy in advanced NSCLC whilst concurrent primary prophylactic administration of granulocyte-colony stimulating factor seems to decrease severe neutropenia.

Urinary neopterin and kynurenine in patients submitted to surgical stress with different inhalational anesthetics (halothane or isoflurane).

Measurements were taken of urinary levels of neopterin (NPT) and kynurenine (KYN), using an HPLC method for their simultaneous analysis in patients submitted to anesthetical surgical stress with two different inhalational anesthetics (halothane and isoflurane). We studied twenty-one women affected by uterine fibromyomatosis and submitted to total hysterectomy (mean age of 42.7+/-5.4 years). They showed the same pre-operative evaluation (ASA-1), and underwent the same i.v. anesthetic treatment. Our patients were randomized in two groups: Group A: 11 patients had halothane as an inhalational anesthetic drug for the maintenance of the anesthetic induction (mean time= 1 h). Group B: 10 patients had isoflurane. A significant decrease in urinary NPT and KYN, parallel to serum-NPT, was found 4 h after anesthetic induction. Raised NPT levels appeared 24 h after A.I. with significant increased levels after 7 days. A strong correlation between urinary and serum NPT levels was seen (Rs= 0.74; p < 0.001). Significantly low KYN levels were observed both 4 h and 24 h after A.I.. In addition to the delayed increase of the excretory KYN levels, significantly raised KYN levels in Group B (isoflurane) 48 h after A.I. (10.59+/-14.31 vs 5.99+/-7.17 micromol/mol creat.; p < 0.01) were shown, whereas in Group A (halothane) we observed a progressive increase as compared to the pre-surgery values starting from 72 h after surgery. Our data seem to show that: (a) it is possible to have a biochemical and non invasive monitoring of the anesthetical-surgical stress on MM "priming" activity; (b) the activation of the phagocyte compartment is one of the earlier immunological events after surgery (NPT), but the efficiency of this "priming" appears to be delayed (KYN); (c) isoflurane appears to induce an earlier recovery in MM activation.

Time trends of consumption and costs of drugs in a cancer referral centre.

This study is a descriptive analysis of the consumption and the costs of antineoplastic chemotherapeutic agents and of the major groups of drugs used for supportive therapy during the 1990-1995 period, at the National Cancer Institute of Naples, Italy. Increasing consumption trends were observed for methotrexate, vinorelbine, oxazophorines (cyclophosphamide + ifosfamide), epirubicin, dacarbazine and 5-fluorouracil; stable trends for etoposide, mitomycin C, bleomycin, vincristine + vindesine, and platinum compounds (cisplatin + carboplatin); decreasing trends in procarbazine, nitrosoureas, mitozantrone and vinblastine consumption. Among BRM's, since 1992-1993, a decrease in consumption was observed both for immunomodulators and interferons; Cr-CSF consumption has increased during the last 3 years. Starting in 1992, among antiemetic drugs there was a decrease in alizapride and methoclopramide consumption contemporarily with the launch on the market of 5-HT3 antagonists; for the tatter drugs, a plateau seemed to have been reached in 1995. In 1992 the highest value of costs was reached (almost 2 billion Italian lire). Since 1993 the reduction in interferons and immunomodulator agents has paralleled the reduction in total costs, reaching about 1.5 billion in 1994. In 1995 the increasing consumption of G-CSF and taxol induced an increase in total costs. Reported data could reliably reflect the reality of Italian cancer referral centres; further reports from other European institutions could be beneficial to a more extensive debate.

Neopterin and alpha-interferon in patients affected by Kaposi's sarcoma from Africa.

The presence of circulating alpha-interferon and neopterin was investigated in sera of 47 patients affected by African Kaposi's sarcoma, both HIV-seropositive (13 patients) and HIV-seronegative (34 patients). For comparison, analyses were also performed in 20 HIV-seropositive symptomatic African subjects as well as in 20 African and 20 Italian healthy individuals. Alpha-interferon and neopterin levels appeared significantly higher in comparison with healthy control groups (P less than 0.001) but not with HIV-seropositve African individuals without Kaposi's sarcoma. Moreover, alpha-interferon and neopterin levels were significantly higher in progressive Kaposi's sarcoma (27 patients) than in regressive Kaposi's sarcoma (20 patients) (P less than 0.001). A significant correlation between alpha-interferon and neopterin was observed (r = 0.57; P less than 0.01). Furthermore, alpha-interferon levels of HIV-seropositive Kaposi's sarcoma patients resulted significantly higher in comparison with the seronegative ones (P less than 0.05). It is concluded that alpha-interferon and neopterin may be reliable prognostic markers in Kaposi's sarcoma patients.

Prognostic relevance of urinary neopterin in non-Hodgkin's lymphomas.

Neopterin excretion levels were assessed in 66 consecutive patients affected by non-Hodgkin's lymphomas (NHL). The logarithm of the mean value of the whole series was 2.71 (log [mumol neopterin/mol creatinine]), significantly higher (P less than 0.001) than the control value (2.12). Fifty-six of 66 patients had a raised excretion of neopterin in amounts statistically related to the stage of disease. The mean value (2.51) of patients in Stages I-II was lower than the mean value (2.86) of patients in Stage III-IV (P less than 0.001). The 2-year probability of survival was 64% for patients in Stages I-II and 34% for patients in Stages III-IV. However, patients with lower neopterin excretion (less than 2.65) fared better than patients with higher neopterin excretion, regardless of the stage. Longitudinal analysis showed a trend toward a correlation between response to therapy and neopterin excretion. In NHL, the raised neopterin excretion appears to be a consequence of activation of the host immune system rather than a product of the malignant cells. But this excessive activation of the monocytes-macrophages, as reflected by urinary neopterin levels, is not accompanied by a better outcome. In conclusion, although neopterin cannot be considered a typical tumor marker, nevertheless it is an useful prognostic marker in NHL.

Urinary neopterin and immunological features in patients with Kaposi's sarcoma.

We studied neopterin excretion levels and immunological features of 20 patients affected by Kaposi's sarcoma (KS), compared to 30 normal controls. Eighteen patients had the classic form of Kaposi's sarcoma (CKS), while two patients were anti-human immunodeficiency virus (HIV) seropositive and affected by the epidemic form associated with the acquired immunodeficiency syndrome (AIDS). In CKS patients, a trend of an increase of neopterin levels with more advanced stages appeared from our data whereas a significant reduction in CD3+ and CD4+ lymphocytes subsets was observed already at early stages (P less than 0.01). CD8+ cells did not show significant variations. A significant increase in serum IgA immunoglobulins (P less than 0.05) was also observed. Comparative analysis of the two patients affected by AIDS/KS showed the profound deficit in T-cell immunity but also the prognostic value of neopterin monitoring. Furthermore these findings seem to confirm Kaposi's sarcoma as an 'opportunistic neoplasia' and indicate neopterin as a useful prognostic marker.

Urinary neopterin levels in hematologic malignancies.

We studied urinary excretion levels of neopterin in 30 cancer patients affected by non-Hodgkin's lymphomas, Hodgkin's disease and multiple myeloma compared to 30 healthy subjects. Mean value of neopterin excretion in cancer patients (576.01 +/- 620.37) appeared significantly increased (p less than 0.001) compared to normal controls (134.40 +/- 41.65). A neopterin excretion above the upper normal limit was observed in 23/28 (82%) patients with active disease. A trend to an increased urinary level of neopterin with more advanced stage was observed, namely in patients with bone marrow involvement and constitutional symptoms. We suggest that the evaluation of urinary neopterin levels may be of value in the diagnosis and follow-up of hematologic malignancies.

Synthesis and pharmacological activity of some 1-alkylamino-3-(2'-methoxy-4'-diethylcarbamoyl-phenoxy)propan-2-ols.

The synthesis and pharmacological properties of some 1-alkylamino-3-(2'-methoxy-4'-diethylcarbamoylphenoxy)propan-2-ols, related to beta-adrenergic drugs, are described. The above compounds were found to possess beta 1 and beta 2-adrenolytic activity associated with local anesthetic and antiarrhythmic activities, which are clearly inferior to those of propranolol.

Derivatives of 4,5,6,7-tetrahydro-7,8,8-trimethyl-3-phenylamino-4,7-methano-2H-indazole with hypoglycemic and hypotensive activities.

By reaction of camphor enamine (I) with phenyl isothiocyanate, the N-phenyl thiocarboxamide (II) was obtained in excellent yield, and in turn gave 4,5,6,7-tetrahydro-7,8,8-trimethyl-3-phenylamino-4,7-methano-2H-indazole (III) in very good yield by reaction with hydrazine hydrate. A series of N-substituted ureas (IV) were synthesized in satisfactory yield by reaction of (III) with alkyl and aryl isocyanates. Ureas (IV) showed in general hypoglycemic and in some cases hypotensive activity in rats, whereas only hypotensive activity was present in the thiocarboxamide (II). Effects on heart rate, antiinflammatory and antipyretic activities in rats, infiltration anesthesia and antiarrhythmic activity in mice, as well as antiacetylcholine activity in vitro, are also reported.

N-Phenyl-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-cis-amine derivatives with hypotensive and other activities.

The synthesis of N-phenyl-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-6-cis-amine (III) starting from 6-nitrimino-1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane, as well as of a series of amides (IV) and ureas (VI) derived from (III), is described. A number of compounds (IV) showed strong hypotensive and bradycardic activity in rats, whereas the urea (IVb) showed infiltration anesthesia in mice similar to that of lidocaine. Antiarrhythmic activity in mice and antiacetylcholine activity in vitro are also reported.

Interactions between inosine and adenosine: experimental researches.

Experimental investigations have shown that inosine enhances purinergic reactivity. This was examined with adenosine at the level of the cardiovascular, intestinal and uterine musculature. The mechanism of this activity may probably be inhibition of uptake without significantly altering serum adenosinase.

In vitro effects of reproterol upon tracheo- bronchial, cardiac and cerebral adenylcyclase.

In vitro researches documented that reproterol, as well as salbutamol, is a powerful stimulant of adenyl cyclase activity in the trachea and bronchi but less potent than isoprenaline. The stimulation was antagonized by beta-blockers.

Fructose-1,6-diphosphate (FDP), hemodynamics and heart metabolism: preliminary experimental studies.

Fructose-1,6-diphosphate (FDP) has been reported to exert beneficial effects on several cardiac functions. We studied the effects of FDP on the biochemical and dynamic functions of the heart in anesthetized dogs. Significant effects of FDP were noted mostly as related to pyruvate and lactate metabolism. The results seem to indicate that FDP may improve heart metabolism, and coronary function in restricted animals.

Derivatives of 5,7,7-trimethyl-6-oxa-3-azabicyclo[3.2.2.] nonane with antiarrhythmic, local anesthetic and hypotensive activities. III.

The synthesis of alkyl and aryl ureas (II) derived from 5,7,7-trimethyl-6-oxa-3-azabicyclo[3.2.2.]nonane (I), as well as hydrazides (V), (VI) and (VII) derived from 5,7,7-trimethyl-6-oxa-3-azabicyclo[3.2.2]-nonan-3-amine (IV), is described. A number of theses compounds showed strong hypotensive and bradycardic activities in rats, as well as weak infiltration anesthesia and antiarrhythmic activity in mice. Antiacetylcholine activity in vitro is also reported.