In some cell systems muscarinic receptor stimulation can induce proliferation or transformation. This phenomenon is subtype-specific (only m1 and m3 receptors are effective) and cell type dependent. In 1321N1 astrocytoma cells activation of m3 receptors stimulates phospholipase C, but does not induce DNA synthesis. In contrast the thrombin receptor, which also couples to phospholipase C, is strongly mitogenic and induces AP-1-dependent gene expression. Various experimental findings indicate that this discrepancy is not due to muscarinic receptor desensitization or blockade of growth stimulatory pathways. Muscarinic receptor number may be limiting, in particular for receptor coupling to the pertussis toxin-insensitive G-protein G12. This G-protein is required for thrombin-induced mitogenesis in 1321N1 cells and may couple selectively to the thrombin versus muscarinic receptor. In cardiomyocytes hypertrophic cell growth is induced by heterologously expressed m1 or m3 receptors but not by the endogenous m2 receptors. Studies using chimeric receptors confirm that induction of hypertrophy requires signalling through phospholipase C, but indicate that additional signals are needed to induce the morphological features of this response. We suggest that small G-proteins of the Rho subfamily, in addition to G12, mediate growth responses to G-protein-coupled receptors.

Animals↗

PubMed1997

Paclitaxel as first-line treatment for metastatic breast cancer. The Taxol Investigational Trials Group, Australia and New Zealand.

When administered as a single agent in pretreated patients with advanced breast cancer, paclitaxel (Taxol) exhibits remarkable antitumor activity. This trial was undertaken to compare paclitaxel with standard chemotherapy as front-line therapy for this disease. Patients with measurable or evaluable metastatic breast cancer, no prior chemotherapy for metastatic disease, and an Eastern Cooperative Oncology Group performance status of 0 to 2 were randomized to receive paclitaxel 200 mg/m2 intravenously over 3 hours for eight cycles (6 months) or standard treatment with oral cyclophosphamide (Cytoxan) 100 mg/m2/d days 1 through 14, intravenous methotrexate 40 mg/ m2 days 1 and 8, intravenous 5-fluorouracil 600 mg/m2 days 1 and 8, and oral prednisolone 40 mg/m2/d (CMFP) days 1 through 14 for six cycles (6 months). Patients whose disease progressed or relapsed were recommended to receive second-line epirubicin. Accrual has been completed with 208 patients randomized, but a preplanned interim analysis of the first 100 patients is reported here. Analysis of quality of life, assessed by a linear analogue scale and overall quality of life indices, is ongoing. Objective response occurred in 31% (confidence interval, 19% to 45%) with paclitaxel and 35% (confidence interval, 22% to 51%) with CMFP with stable disease in an additional 33% and 29%, respectively. Median time to progression was 5.5 months for paclitaxel-treated patients and 6.4 months for those given CMFP, with median survival durations of 17.3 and 11.3 months, respectively. Grades 3 and 4 neutropenia occurred in 64% of patients treated with paclitaxel and in 63% treated with CMFP. However, febrile neutropenia was the primary reason for hospitalization in 1% of paclitaxel courses, compared with 8% of CMFP courses. Nine percent of the patients had major infections with CMFP, but none were seen with paclitaxel. Moderate or severe mucositis occurred in 13% of paclitaxel-treated and 27% of CMFP-treated patients. Alopecia and peripheral neuropathy were more common with paclitaxel. Quality of life assessments in the first 100 patients suggest better overall results on paclitaxel treatment as compared with CMFP. Preliminary analyses suggest that single-agent paclitaxel is well tolerated and provides comparable control of metastatic cancer to CMFP combination therapy when used as front-line treatment.

Antineoplastic Agents↗

PubMed1997

[A longitudinal study on left atrial thrombosis in patients with non-rheumatic atrial fibrillation treated with anticoagulants].

BACKGROUND: Although atrial thrombosis is common in patients with non-rheumatic atrial fibrillation (NRAF) (6-27%), there are no studies about the effect that anticoagulant or antiplatelet drugs have on it. AIM OF THE STUDY: We have investigated the role of anticoagulant therapy, followed by family physicians, on left atrial thrombosis detected via transesophageal echocardiography (TEE) in patients with NRAF. METHODS: Sixty patients enrolled in the TASAF (Trieste Area Study on non-rheumatic Atrial Fibrillation) (60% males, mean age 72 +/- 7 years, 17% with lone atrial fibrillation, duration of arrhythmia 111 +/- 79 months), in whom we found a left atrial and/or left atrial appendage thrombus via TEE, were anticoagulated. The thrombus was in the left atrial appendage in 57 patients and in the left atrium in the others. In 28 of them it was mobile and in 50, the left atrial appendage flow was low or absent. Lastly, in 46 patients we found spontaneous echocontrast and a bilobate appendage was present in 8 of them. At follow-up, we repeated the TEE to evaluate the effect of the therapy on the atrial thrombosis. RESULTS: Only 53 patients received anticoagulant therapy (45 correctly), while 7 were treated with antiplatelet drugs by their family physicians. After a mean follow-up of 16 months, all patients underwent a repeat TEE and the thrombus was no longer evident in 35 cases (58%). The thrombosis disappeared in 26 (58%) of the 45 patients who correctly took anticoagulant therapy and in 5 of the 8 who were not adequately anticoagulated. Moreover, we didn't observe the thrombus in 4 of the 7 patients who were treated with antiplatelet drugs. There was no significant statistical difference between the benefits of anticoagulants and antiplatelet therapy in dissolving left atrial thrombosis. During follow-up, we recorded only one embolic event in the retina. None of the patients on antiplatelet drugs complained of any side effects, whereas in 5 of the 53 on anticoagulant therapy, we recorded one fatal intracranial hemorrhage, one gastric hemorrhage and three minor complications. CONCLUSIONS: Left atrial thrombosis in NRAF disappears in anticoagulated patients in an high percentage of cases (the therapy probably acts on more recent thrombi). Moreover, this therapy decreases the incidence of embolic events, although it increases the risk of hemorrages. Since the management of this preventive treatment in general medicine is very difficult, we hope that our health organization will establish Anticoagulation Clinics for the centralized management of this therapy.

Aged↗

PubMed1997

A randomized study of paclitaxel versus cyclophosphamide/methotrexate/5-fluorouracil/prednisone in previously untreated patients with advanced breast cancer: preliminary results. Taxol Investigational Trials Group, Australia/New Zealand.

When administered as a single agent to previously treated patients with advanced breast cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has good activity. This trial was undertaken to compare paclitaxel with standard chemotherapy as front-line treatment for this disease. Patients with measurable or evaluable metastatic breast cancer, no prior chemotherapy for metastatic disease, and Eastern Cooperative Oncology Group performance status of 0 to 2 were randomized to receive either paclitaxel 200 mg/m2 intravenously over 3 hours for eight cycles over 24 weeks or standard treatment with oral cyclophosphamide 100 mg/m2/d days 1 to 14, intravenous methotrexate 40 mg/m2 days 1 and 8, intravenous 5-fluorouracil 600 mg/m2 days 1 and 8, and oral prednisone 40 mg/m2 daily days 1 to 14 (CMFP) for six cycles over 24 weeks. Patients whose disease progressed or relapsed were recommended for second-line therapy with epirubicin. Accrual has been completed with 209 patients randomized, and an interim analysis of the first 100 patients is reported here. Analysis of quality of life, assessed by the linear analogue scale and overall quality of life indices, is ongoing. Objective response occurred in 31% (confidence interval, 19% to 45%) with paclitaxel and 35% (confidence interval, 22% to 51%) with CMFP, with stable disease in an additional 33% and 29%, respectively. Median time to progression was 5.5 months with paclitaxel and 6.4 months with CMFP, with a median survival of 17.3 months for patients treated with paclitaxel and 11.3 months for those given CMFP. Grades 3 and 4 neutropenia occurred in 64% of patients with paclitaxel and 63% with CMFP. However, febrile neutropenia was the primary reason for hospitalization in 1% of paclitaxel courses, compared with 8% with CMFP. Major infections (World Health Organization grade 4) were seen in 7% of patients treated with CMFP, but in none of those given paclitaxel. Moderate or severe mucositis occurred in 13% of paclitaxel and 27% of CMFP patients. Alopecia and peripheral neuropathy were more common with paclitaxel. Quality of life assessments in the first 100 patients suggest better overall results for those treated with paclitaxel compared with CMFP. Preliminary analyses suggest that single-agent paclitaxel is well tolerated and provides control of metastatic cancer comparable to that of CMFP combination therapy when used as front-line therapy in an outpatient setting.

Antineoplastic Agents, Phytogenic↗

PubMed1996

Ownership of human genes.

Explore the source record for details and available documents.

Economics↗

PubMed1996

Managing HIV. Part 5: Treating secondary outcomes. 5.14 HIV and Kaposi's sarcoma.

The usual occurrence of Kaposi's sarcoma in otherwise healthy gay men in North America in the early 1980s was one of the first hints of the HIV epidemic. Kaposi's sarcoma remains a vexing problem. Existing treatments are not wholly satisfactory, but they can control the disease's unsightly appearance and the complications of visceral involvement.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Dissociation of p44 and p42 mitogen-activated protein kinase activation from receptor-induced hypertrophy in neonatal rat ventricular myocytes.

In response to hormones and mechanical stretch, neonatal rat ventricular myocytes exhibit a hypertrophic response that is characterized by induction of cardiac-specific genes and increased myocardial cell size. Hypertrophic stimuli also activate mitogen-activated protein kinase (MAPK), an enzyme thought to play a central role in the regulation of cell growth and differentiation. To determine if MAPK activation is sufficient for acquisition of the molecular and morphological features of cardiac hypertrophy we compared four agonists that stimulate G protein-coupled receptors. Whereas phenylephrine and endothelin transactivate cardiac-specific promoter/luciferase reporter genes, increase atrial natriuretic factor (ANF) expression, and promote myofilament organization, neither carbachol nor ATP induces these responses. Interestingly, all four agonists activate both the p42 and the p44 isoforms of MAPK. Furthermore, the kinetics of MAPK activation are not different for the hypertrophic agonist phenylephrine and the nonhypertrophic agonist carbachol. Transient transfection of myocytes with dominant-interfering mutants of p42 and p44 MAPK failed to block phenylephrine-induced ANF expression, although Ras-induced gene expression was inhibited by expression of the mutant MAPK constructs. Moreover, PD 098059, an inhibitor of MAPK kinase, blocked phenylephrine-stimulated MAPK activity but not ANF reporter gene expression. Thus, MAPK activation is not sufficient for G protein receptor-mediated induction of cardiac cell growth and gene expression and is apparently not required for transcriptional activation of the ANF gene.

Actin Cytoskeleton↗

PubMed1996

Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine.

The pharmacokinetic interaction between atovaquone, a 1,4-hydroxynaphthoquinone, and zidovudine was examined in an open, randomized, three-phase crossover study in 14 patients infected with human immunodeficiency virus. Atovaquone (750 mg every 12 hours) and zidovudine (200 mg every 8 hours) were given orally alone and in combination. Atovaquone significantly increased the area under the zidovudine concentration-time curve (AUC) (1.82 +/- 0.62 micrograms.hr/ml versus 2.39 +/- 0.68 micrograms.hr/ml; p < 0.05) and decreased the oral clearance of zidovudine (2029 +/- 666 ml/min versus 1512 +/- 464 ml/min; p < 0.05). In contrast, atovaquone tended to decrease the AUC of zidovudine-glucuronide (7.31 +/- 1.51 micrograms.hr/ml versus 6.89 +/- 1.42 micrograms.hr/ml; p < 0.1) and significantly decreased the ratio of AUC zidovudine-glucuronide/AUC zidovudine (4.48 +/- 1.94 versus 3.12 +/- 1.1; p < 0.05). The maximum concentration of zidovudine-glucuronide was significantly lowered by atovaquone (5.7 +/- 1.5 versus 4.57 +/- 0.97 micrograms/ml; p < 0.05). Zidovudine had no effect on the pharmacokinetic disposition of atovaquone. Atovaquone appears to increase the AUC of zidovudine by inhibiting the glucuronidation of zidovudine.

Adult↗

PubMed1996

Bacillus Calmette-Guérin plus intravesical interferon alpha-2b in patients with superficial bladder cancer.

OBJECTIVES: Bacillus Calmette-Guérin (BCG) and interferon alpha-2b (IFN alpha 2b) have been used individually for the treatment of bladder cancer. We used a low dose of BCG combined with IFN alpha 2b to determine the safety and to assess the efficacy of this combination therapy. METHODS: A study of 12 patients with superficial bladder cancer evaluated the safety and efficacy of a combination of low-dose BCG and IFN alpha 2b, given weekly for 6 weeks. Three patients were assigned to each of four groups in which 60 mg of BCG was combined with 10, 30, 60, or 100 x 10(6) IU of IFN alpha 2b. RESULTS: The combination BCG/IFN alpha 2b therapy was well tolerated, with adverse effects being mild to moderate and resolved at the end of treatment. At 12 months post-treatment there has been no tumor progression. Two patients with previous multifocal transitional cell carcinoma have had solitary recurrences. One patient has had recurrent carcinoma in situ. CONCLUSIONS: This preliminary study found combination BCG/IFN alpha 2b induction therapy to be safe and well tolerated. These early results show a high response rate, but efficacy can only be determined with Phase II and III studies.

Adjuvants, Immunologic↗

PubMed1996

Efficacy and safety of Stealth liposomal doxorubicin in AIDS-related Kaposi's sarcoma. The International SL-DOX Study Group.

The utility of current chemotherapeutic regimens in the treatment of AIDS-related Kaposi's sarcoma (AIDS-KS) is often compromised by both limited efficacy and substantial toxicity. Pegylated (Stealth) liposomal doxorubicin hydrochloride (SL-DOX) has been demonstrated specifically to deliver high concentrations of doxorubicin to Kaposi's sarcoma (KS) lesions. This phase II study was performed to evaluate the efficacy and safety of SL-DOX in the treatment of moderate to severe AIDS-KS. Patients were treated biweekly with 10, 20, or 40 mg m-2 SL-DOX. Tumour response was assessed according to AIDS Clinical Trials Groups (ACTG) criteria before each cycle. Best response was determined for 238 patients and was achieved after a mean of 2.3 cycles (range 1-20). Fifteen patients (6.3%) had a complete response to SL-DOX, 177 (74.4%) had a partial response, 44 (18.5%) had stable disease and two (0.8%) had disease progression. SL-DOX was well tolerated: ten patients discontinued therapy because of adverse events, in four cases because of neutropenia. Grade 3 or 4 neutropenia occurred after 281 of 2023 cycles (13.9%) but involved 137 of 240 patients (57.1%) for whom data were available. SL-DOX has substantial activity in AIDS-KS. Best response is typically seen after fewer than three cycles of chemotherapy and in some cases may be prolonged. The most important adverse event is neutropenia, which occurs after a minority of cycles but which may occur in over half of all patients.

Acquired Immunodeficiency Syndrome↗

PubMed1996

Experimental iron deficiency in rats: mechanical and electrophysiological alterations in the cardiac muscle.

1. Our aim was to investigate the effect of experimental iron deficiency on cardiac functional properties. We recorded ventricular isometric twitch, action potentials and the L-type Ca2+ current in isolate ventricular myocytes from iron-deficient rats and control rats. 2. Twitch tension and maximal rates of tension activation and relaxation were reduced in iron-deficient compared with control rats, whereas twitch duration was prolonged. Isoproterenol (10-(6) mol/l) augmented tension in iron-deficient rats (P < 0.05), but only moderately affected control rats. In contrast, maximal rates of tension activation and relaxation were increased equally by isoproterenol in the two groups. 3. To determine the mechanism(s) responsible for the reduced mechanical function in iron-deficient rats, action potentials and the L-type Ca2+ current (with or without isoproterenol) were recorded in both groups. 4. The L-type Ca2+ current was smaller in ventricular myocytes from control rats than in those from iron-deficient rats; at a membrane potential of 0 mV, L-type Ca2+ current amplitudes were -1.44 +/- 0.18 and -0.97 +/- 0.07 nA in myocytes from control and iron-deficient rats respectively (P < 0.05). 5. Action potential duration was markedly shortened in myocytes from iron-deficient compared with control rats; action potential duration at 50% repolarization was 12.0 +/- 1.6 and 7.2 +/- 1.4 ms in myocytes from control and iron-deficient rats respectively (P < 0.01). These iron deficiency-induced electrophysiological alterations most probably contribute to the depressed mechanical function in iron-deficient rats. 6. The L-type Ca2+ current was augmented equally by isoproterenol in the two groups, suggesting that the enhanced inotropic responsiveness in iron-deficient rats was not due to an increased response of the L-type Ca2+ current. 7. These results may have an important implication for anaemic (iron-deficient) patients; the attenuation of their cardiac mechanical performance may be compensated by an increased reactivity to beta-adrenergic stimulation.

Action Potentials↗

PubMed1996

High response rates with short infusional 2-chlorodeoxyadenosine in de novo and relapsed low-grade lymphoma. Australian and New Zealand Lymphoma Study Group.

Thirty-five patients (eight de novo, 27 relapsed disease) with low-grade non-Hodgkin's lymphoma (diffuse small lymphocytic, follicular small cleaved cell, follicular mixed cell, and lymphoplasmacytoid) were treated with 2-chlorodeoxyadenosine (2CdA) at a daily dose of 0.14 mg/kg for 5d (2 h infusion) for an average of three cycles. Minor treatment delays, generally due to haematological toxicities, occurred in nine of 105 cycles. Major toxicities were lymphopenia, neutropenia and thrombocytopenia. Opportunistic infections occurred in seven patients. Overall response rate was 69% (five complete, 19 partial) reaching 88% for de novo patients (two complete, five partial). Elevated beta 2-microglobulin level was negatively predictive of response (P = 0.0014). Eight of 24 responders relapsed, with a median follow-up of 13 months. 2CdA administered as an intermittent infusion shows considerable single-agent activity in low-grade lymphomas achieving high response rates of prolonged duration. Consideration of schedules where 2CdA is alternatively administered with combination chemotherapy appears warranted.

Adult↗

PubMed1996

Malignant pulmonary lymphoid disease: case reports illustrating anatomical pattern of disease as a prognostic marker.

Although a well documented phenomenon in Hodgkin's disease, malignant pulmonary lymphoid disease in other lymphoproliferative diseases, such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), is less frequently described. We present 3 patients, 2 with NHL and one with CLL, all demonstrating pulmonary malignant lymphoid involvement. We briefly review the probable mechanism underlying the development of this disease process and identify anatomical distribution of malignant pulmonary lymphoid disease as a prognostic marker in this condition.

Aged↗