Simultaneous Combinations Research Articles

Activities of beta-lactams, fluoroquinolones, amikacin and fosfomycin alone and in combination against Pseudomonas aeruginosa isolated from complicated urinary tract infections.

Using the checkerboard titration method as well as the time-kill curve technique, we investigated the activities of beta-lactams, fluoroquinolones, amikacin, and fosfomycin alone and in combination against Pseudomonas aeruginosa isolated from patients with complicated urinary tract infections. In the checkerboard titration studies, none of 21 combinations demonstrated antagonism against 26 strains tested, and the mean fractional inhibitory concentration (FIC) indices for these combinations ranged between 0.4694 and 0.9828. Corresponding to the respective FIC indices, the bactericidal activity determined in combinations of meropenem with ciprofloxacin or amikacin and ceftazidime with ciprofloxacin at sub-minimum inhibitory concentrations (MICs) produced a great reduction in bacterial counts (>/=2 log10 CFU/ml) within 6 h of administration against most of the strains, including strains resistant to one or both drugs, and these synergistic effects were confirmed morphologically by scanning electron microscopy. In time-lag combinations, the first administration of ciprofloxacin or amikacin supplemented by meropenem with 1-h lag diminished bactericidal activity, in comparison with the simultaneous administration of the drugs. These results suggest that simultaneous combinations of beta-lactams with fluoroquinolones or amikacin may be useful alternatives for the treatment of serious infections due to P. aeruginosa.

Bump hunting in high-dimensional data

Many data analytic questions can be formulated as (noisy) optimization problems. They explicitly or implicitly involve finding simultaneous combinations of values for a set of (’’input‘‘) variables that imply unusually large (or small) values of another designated (’’output‘‘) variable. Specifically, one seeks a set of subregions of the input variable space within which the value of the output variable is considerably larger (or smaller) than its average value over the entire input domain. In addition it is usually desired that these regions be describable in an interpretable form involving simple statements (’’rules‘‘) concerning the input values. This paper presents a procedure directed towards this goal based on the notion of ’’patient‘‘ rule induction. This patient strategy is contrasted with the greedy ones used by most rule induction methods, and semi-greedy ones used by some partitioning tree techniques such as CART. Applications involving scientific and commercial data bases are presented.

DYSSYNCHRONOUS APRAXIA: FAILURE TO COMBINE SIMULTANEOUS PREPROGRAMMED MOVEMENTS

Limb apraxia, a defect in skilled, learned purposive movement, may be related to impairment of either representational or innervatory components of praxis processing. Innervatory motor patterns, in turn, may involve on-line motor programs (visual feedback-controlled) or prepared movement programs (independent of continuous visual feedback). We evaluated movement abilities ofthe innervatory pattern system in TB,a 26-year-old patient with apraxia from a left dorsolateral frontal stroke. TB and four controls performed nonmeaningful single and multi-joint movements to command, with multi-joint movements combined sequentially (e.g. "open and close your hand and then bend your elbow") or simultaneously (e.g. "open and close your hand; keep doing that while bending your elbow"). TB showed no difference between single-joint (71.5% correct) and multi-joint movements in sequential combinations (68% correct), but she was significantly worse at simultaneous movement combinations (28.6% correct; P < .02). Controls performed consistently at > 90% mean accuracy. TB and four normals also performed the Fitts (1954) task, in which they alternately tapped with a pen between two target circles of varying size. TB was proportionately slower than controls on the larger Fitts circles, which call predominantly on prepared movement programs; her performance on the smaller circles (involving more on-line programs) was comparable to normals. We conclude that functional synchrony of one innervatory pattern subtype, prepared movement programs, may require late-level frontal processing, and that failure at this level can result in both apraxia and defective programming of nonmeaningful movements.

Chemical Library Purification Strategies Based on Principles of Complementary Molecular Reactivity and Molecular Recognition

A new methodology for solution-phase chemical library synthesis and purification is described. This approach applies fundamental properties of complementary molecular reactivity and recognition (CMR/R) as the basis for a general purification strategy. Specifically, parallel solution-phase reactions are purified by resins containing molecular recognition or molecular reactivity functionalities complementary to those of solution-phase reactants, reagents, and byproducts. When used in sequential or simultaneous combinations, various CMR/R resins remove excess reactants, reagents, and byproducts from solution-phase reaction products, which are isolated in purified form by filtration. Where reactions involve the need to remove byproducts or reagents that do not inherently contain sequestrable functionality, sequestration can be effected by the design and use of tagged reactants or reagents containing artificially-imparted molecular recognition functionality. An extension of this methodology utilizes CMR/R resi...

Treatment of HIV infection. Tolerability of commonly used antiretroviral agents.

There are a number of agents available that are active against HIV. Eight drugs are already licensed in the US: the nucleoside analogue reverse transcriptase inhibitors--zidovudine, didanosine, zalcitabine, stavudine and lamivudine--and the HIV protease inhibitors--saquinavir, indinavir and ritonavir. Antiretroviral drugs have been given as monotherapy, often as sequential monotherapy, and in alternating or simultaneous combinations. Since combination therapy has recently been shown to be superior to monotherapy, antiretrovirals will increasingly be given in combination. All available antiretroviral drugs show considerable toxicity complicating their use. In this article we describe the adverse effects of the above mentioned nucleoside analogues used in monotherapy and of several combinations of antiretroviral drugs. No unexpected toxicities were found in several different combinations tested to date and, for most combinations, no synergistic toxic effects have been reported.

A combination of recombinant single-chain urokinase-type plasminogen activator and streptokinase has a synergistic non-fibrin specific action on in vitro clot lysis

Thrombolytic effects of streptokinase (SK), a recombinant single-chain urokinase-type plasminogen activator (rscu-PA), and their combinations were measured in an in vitro system composed of 125I-fibrin labelled human plasma clot immersed in a citrated human plasma at 37°C. Clot lysis was monitored by release of 125I-fibrin degradation products and an activation of the fibrinolytic system in the surrounding plasma was measured by fibrinogen, plasminogen and α2-antiplasmin levels. SK and rscu-PA induced dose- and time-dependent clot lysis: 50% lysis in 4h was obtained with 75 nM SK and 38nM rscu-PA, respectively. At these concentrations, no significant activation of the fibrinolytic system in plasma was observed with rscu-PA, whereas SK produced fibrinogen breakdown. As was judged by a mathematical analysis of dose-response curves by the isobole method, simultaneous and sequential equimolar combinations of SK and rscu-PA caused a significant non-fibrin specific synergistic thrombolytic effect. The synergy of thrombolytic action of these combinations persisted for 24h and was more pronounced at the subsequent addition of SK followed by rscu-PA (in 1h). 4h after the addition of 25 nM of SK or rscu-PA, they had induced 6% and 25% lysis respectively, while simultaneous or sequential addition of both plasminogen activators at the same concentrations induced 55% and 80% clot lysis. The maximal achievable 5-fold increase in the thrombolytic action of sequential combinations was observed in the molar ratio of plasminogen activators 1:1, as compared with the total effect of the agents at the same concentrations as used in simultaneous combinations. The synergistic thrombolytic effect of the sequential equimolar combinations was more fibrin-specific than that of the simultaneous combinations. It is concluded that the simultaneous and sequential equimolar combinations of SK and rscu-PA possessed synergistic thrombolytic action on clot lysis in vitro. The sequential combination of equimolar concentrations of these plasminogen activators induced a moderate activation of the fibrinolytic system while the simultaneous combination produced a significant exhaustion of the fibrinolytic system.

5-Fluorouracil causes alterations in the pharmacokinetic profile of tauromustine in NMRI mice.

The pharmacokinetic profiles of 5-fluorouracil (5-FU) and tauromustine (TCNU) were investigated in NMRI mice following their administration either alone or as part of simultaneous or sequential combinations. The profile of 5-FU remained unaltered irrespective of the sequence of administration. However, following simultaneous administration of 5-FU and TCNU or pretreatment with 5-FU, plasma levels of TCNU were decreased by a factor of 2.5-3 as compared with those seen when TCNU was given alone. These decreased plasma levels were explained by an increase in the TCNU volume of distribution, although this was not due to alterations in TCNU plasma protein binding. These sequence-dependent alterations in the pharmacokinetic profile of TCNU correlate with and may explain previously reported differences in the anti-tumour activity and toxicity profile of this combination.

Current Use of Nucleoside Analogues in the Treatment of HIV Infection

Nucleoside analogues continue to play a central role in the treatment of HIV infection. The recently published Concorde I.rial has been misinterpreted as demonstrating a Jack of efficacy of zidovudine in the treatment of HIV disease. This is clearly not the case because zidovudine was prescribed to patients in both arms of the study. The Concorde study did confirm, however, the limitations of monotherapy in the treatment of this disease. Increased availability of other nucleoside analogues has allowed the development of newer therapeutic strategies. In this context, sequential use of zidovudine, followed by didanosine, has proved to be safe and effective in patients in varying stages of HIV disease. Preliminary results suggest that this strategy could be improved upon by using simultaneous combinations of zidovudine with didanosine or zalcitabine in full closes. The relative efficacy of these combinations remains to be established by phase III clinical trials, currently underway, Several new agents, including d4T, 3TC, nevirapine, other non‐nucleoside reverse transcriptase inhibitors and the more recent protein inhibitors. are being tested either a lone or in combination therapy regimens. It is anticipated that one or more of these agents will be clinically available soon. At present. the British Columbia Centre for Excellence in HIV/AIDS continues to recommend initiation of antiretroviral therapy with zidovudine in doses of 500 mg/day for all HIV‐infected individuals who are symptomatic (ie. who have AIDS or AIDS‐related complex) and for those who are asymptomatic with a CD4 count consistently below 500/mm3. If the CD4 count is lower than 350/mm3, it is recommended that combination antiretroviral therapy be considered. namely zidovudine plus didanosine or zalcitabine in full doses. Obviously, the available evidence should be thoroughly discussed with eligible individuals to ensure that they have a full understanding of the potential benefits, adverse effects and limitations of currently available therapy.

Therapy of mouse mammary carcinomas with vincristine and doxorubicin encapsulated in sterically stabilized liposomes

This study tested the therapeutic effects of vincristine sulfate and doxorubicin hydrochloride, each drug in 2 different formulations: (i) as a solution in saline, and (ii) encapsulated in sterically stabilized, long-circulating liposomes composed of hydrogenated soy-phosphatidylcholine/cholesterol/polyethylene-glycerol-disteroyl++ +- phosphatidylethanolamine. The 4 drug preparations were used to treat s.c. implants of the mouse mammary carcinoma MC2. The drugs were given by i.v. injection over 15 to 18 days, starting 3 days after tumor implantation. The single-drug therapeutic effects of vincristine (S-VCR) and doxorubicin (Doxil) in liposomes were compared, and the 2 preparations were also tested in alternate and in simultaneous combinations. These new liposome formulations of vincristine and doxorubicin were significantly more effective than the free drugs in curing the mice. Alternate, semi-weekly injection of both drugs gave the best therapeutic effect. Prolonged circulation time with increased accumulation in tumors are considered likely reasons for the improved therapeutic efficacy of both drugs when encapsulated in these liposomes.

The role of music and song in human communication.

It is only on the higher level of abstraction and generalization that the two human branches of acoustic communication, speech and music are separated from each other. Speech is primarily adjusted to the conceptual-verbal symbols and representation of an objectified, static world. In the linguistic communication the main role is played by the elements of noise, the consonants. It has never been doubted that music is a kind of communication, the mediator of human relationships, but it has been a question what music wants to express. Since the Pythagoreans, some believe to find the key to interpreting its message in the commun quantifiable nature of the musical medium and the cosmos. Another historical tradition considered music as the direct expression of human emotions. Representants of the doctrine of imitation derived music from the intonation of speech and the text seems for many to be a support to "understand" music. Music separated from the primary source of sound phenomena and their direct sensual effect constructed a specific communication system. It possesses an inestimable potential richness of discrete pitches and times, colours and sound intensity. The infinite potentials of successive and simultaneous combinations are suitable for erecting the audible, dynamic models of human relations and types of behaviour, internal events and interactions, different situations. European polyphony established a strictly regulated, closed syntax of musical communication which comes close to conceptual precision. Its logic is based upon the natural potentials of the kinship of pitches and the human organ of hearing. The live, mobile network of the relations thus created is regulated by a further developed quasi-binary logic.(ABSTRACT TRUNCATED AT 250 WORDS)

Binary effects of carcinogens and tumor promoters—a preliminary chemical structural analysis of BCIDB and PCIDB

Identification of potential interactions in exposures, either to simultaneous or sequential combinations of carcinogenic chemicals and mixtures of carcinogen and carcinogenesis-modifying chemical agents, pose formidable difficulties in human health risk assessments. Studies over the past four decades have revealed synergistic interactions among various classes of carcinogenic chemicals. An earlier effort to identify a possible chemical structural basis of interaction of binary combinations of carcinogens led to the development of Binary Carcinogen Interaction Data Base (BCIDB). A recent endeavor to identify a structural basis of interactions of carcinogens and carcinogenesis modifying chemical agents resulted in Promoter-Carcinogen Interaction Data Base (PCIDB). An attempt will be made in this report to briefly discuss chemical class-class interaction and initiator-target organ orientation as recorded in BCIDB and PCIDB.

A wind tunnel metabolism chamber with small volume and good air flow characteristics

A wind tunnel metabolism chamber is described which has a low (4.2 to 1) ratio of total to working volume to facilitate respiratory gas exchange measurements on unrestrained animals. Fine mesh screens smooth air flow to obtain 2% RMS turbulence and +or-5% uniformity. Simultaneous combinations of air temperature from -10 to 50 degrees C and wind from 0 to 3.6 m s-1can be maintained indefinitely. A window admits simulated solar radiation to the working section.

In vitro and in vivo chemosensitivity of the YTS-1 human bladder carcinoma cell line

In vitro and in vivo cytotoxicity tests were carried out using the YTS-1 human bladder carcinoma cell line. The lethal effects of a 1-hour treatment with 5 anti-cancer agents (Cisplatin [CDDP], Cytosine arabinoside [ara-C], Adriamycin [ADM], Etoposide [VP-16] and Carboplatin [CBDCA]) on the YTS-1 cells grown as monolayer were examined quantitatively by the regrowth assay methods. In addition, the lethal effects of 3 anti-cancer agents (CDDP, ADM, ara-C) were also examined in vivo. Moreover the effects of simultaneous combinations of CDDP and ara-C, and ADM and ara-C were assessed in vitro and in vivo. In vitro studies showed that, of these single agents, ADM and ara-C were cytotoxic judging from the human maximal plasma concentration of drugs, whereas CDDP, VP-16 and CBDCA were not. Combinations of CDDP and ara-C, and ADM and ara-C showed more than additive effect. In vivo studies on YTS-1 tumors implanted to athymic nude mice (BALB/c) showed that ADM was the cytotoxic agent. Although CDDP alone or ara-C alone was not cytotoxic to YTS-1 tumors, combination of CDDP and ara-C showed antitumor activity. These results show that combination of CDDP and ara-C is synergistic. The most effective combination was observed to be ADM and ara-C, but severe loss of body weight was also observed.

Psychophysiological response patterns to single, double, and triple stressors.

ABSTRACTSynergistic activation elicited by multiple stressors as compared to single stressors has received little attention in the literature. In the present study, mental arithmetic, cold pressor, and physical exercise tasks were administered to 54 male subjects alone and in all possible simultaneous combinations. The dependent variables measured were heart rate, cardiac output, RZ‐time, blood pressure, respiration rate, tidal volume, respiratory minute volume, oxygen uptake, oxygen equivalent, self‐report data of psychological and somatic tension, pain ratings during the cold pressor test, and performance on mental arithmetic. Results for physiological variables indicate synergistic effects for stressor combinations as compared to single stressors, depending on the respective combination or variable. Contrary to this finding, psychological variables revealed ceiling and depressor effects. Response patterns to the different stressors showed only moderate similarity and exhibited stimulus‐specific effects. Heart rate, diastolic blood pressure, and respiration rate were most appropriate in describing various response patterns.

Joint Action of O3 and SO2 in Modifying Plant Gas Exchange

The joint action of O(3) and SO(2) stress on plants was investigated by determining the quantitative relationship between air pollutant fluxes and effects on stomatal conductance. Gas exchange measurements of O(3), SO(2), and H(2)O vapor were made for Pisum sativum L. (garden pea). Plants were grown under controlled environments, and O(3), SO(2), and H(2)O vapor fluxes were evaluated with a whole-plant gas exchange chamber using the mass-balance approach. Maximum O(3) and SO(2) fluxes per unit area (2 sided) into leaves averaged 8 nanomoles per square meter per second with exposure to either O(3) or SO(2) at 0.1 microliters per liter. Internal fluxes of either O(3) or SO(2) were reduced by up to 50% during exposure to combined versus individual pollutants; the greatest reduction occurred with simultaneous versus sequential combinations of the pollutants. Stomatal conductance to H(2)O was substantially altered by the pollutant exposures, with O(3) molecules twice as effective as SO(2) molecules in inducing stomatal closure. Stomatal conductance was related to the integrated dose of pollutants. The regression equations relating integrated dose to stomatal conductance were similar with O(3) alone, O(3) plus added SO(2), and O(3) plus SO(2) simultaneously; i.e. a dose of 100 micromoles per square meter produced a 39 to 45% reduction in conductance over nonexposed plants. With SO(2) alone, or SO(2) plus added O(3), a dose of 100 micromoles per square meter produced a 20 to 25% reduction in conductance. When O(3) was present at the start of the exposure, then stomatal response resembled that for O(3) more than the response for SO(2). This study indicated that stomatal responses with combinations of O(3) and SO(2) are not dependent solely on the integrated dose of pollutants, but suggests that a metabolic synergistic effect exists.

Application of response-surface methodology to detect interactions of genotoxic agents in cultured mammalian cells.

Response-surface methodology (RSM) techniques provide a useful statistical approach for the design and analysis of experiments involving multiple variables. Although it has been used for some time in the areas of chemical engineering and agriculture, RSM has only recently been applied to the solution of biological problems. Here we have utilized RSM to investigate the interaction of two direct-acting, monofunctional alkylating agents [ethyl methanesulfonate (EMS) and ethylnitrosourea (ENU)] in Chinese hamster V79 cells with respect to the in vitro induction of sister chromatid exchanges (SCEs). A factorial design was employed in which the cells were exposed to the agents singly and in simultaneous combinations for 4 h. The cells were collected for SCE determination 30 h after treatment. The analysis revealed concentration-dependent increases in SCEs for both of the agents, with ENU being the more effective on an equimolar basis. In addition, single- and multiple-agent interactions were detected. The most important finding was that over the treatment range studied, a significant negative interaction occurs between EMS and ENU with regard to SCE induction. It is suggested that RSM not only may be useful in determining the statistical relevance of experimental variables but also may generate hypotheses the evaluation of which could provide additional insights into the underlying mechanisms involved.

Single and joint actions of noise and sinusoidal whole body vibration on TTS2 values and low frequency upright posture sway in men.

In the present study the changes in the TTS2 values and body upright posture sway were examined after exposure of subjects (n = 10) to stable broadband (white) noise (90 dB) alone, to sinusoidal vibration alone [directed vertically at the whole body (Z axis)], and to simultaneous exposure combinations of noise and vibrations of the same type. The frequency of the vibration was 5 Hz, but its acceleration was either 2.12 or 2.44 m/s2. There were six exposure combinations, and subsequently 60 tests were carried out in an exposure chamber. One test consisted of a control period of 30 min, of three consecutive exposure periods of 16 min each and of a recovery period of 15 min. After the three exposure combinations which included noise, half of the subjects were exposed to vibration during the recovery period. Apart from indicating an increase in the temporary hearing threshold, the results showed that simultaneous exposure to noise and vibration increases the instability of the body upright posture. The TTS2 values at the 4 and 6 kHz frequencies increased considerably more rapidly when the subjects were exposed simultaneously to noise and vibration than when exposed to noise alone. Without exception, the TTS2 values increased most during the first exposure period. It was noteworthy that exposure to vibration during the recovery period accelerated the recursion of the TTS2 values, especially in cases where the subjects had been exposed to noise alone. The variance of the body sway amplitudes and the standard deviation increased within the frequency range 0.063-2.000 Hz owing to noise alone and simultaneous noise and vibration. In the directions X and Y, within the frequency ranges 0.063-0.100 Hz and 0.100-0.600 Hz, the means of the maximum amplitudes of body sway increased especially in connection with those tests in which the subjects had been simultaneously exposed to noise and vibration.

THE ROLES OF PLANT HORMONES IN STYLE AND STIGMA GROWTH IN GAILLARDIA GRANDIFLORA (ASTERACEAE)

Style and stigma elongation and stigma unfolding, and the roles of plant hormones in these processes in Gaillardia grandiflora Van Houtte were investigated. Style and stigma elongation in vivo began just after anthesis, and style elongation was accompanied by epidermal cell elongation (greatest near the stigma) and a fresh weight increase, but not by cell division or a dry weight increase. The stigma unfolded after the style and stigma elongated. Style‐stigma units excised from young disc flowers of this composite were measured as they responded to plant growth regulators applied singly, as well as in sequential and simultaneous combinations, in vitro. Style elongation was promoted by auxin, was inhibited by gibberellins and ethylene, and was unaffected by other growth regulators. Stigma elongation followed a similar pattern of response. Endogenous auxin levels and ethylene production showed parallel variation and endogenous gibberellin levels showed inverse variation with style and stigma elongation. Stigma unfolding was more sensitive to auxin applications and was promoted by applied ethylene. Ethylene production showed parallel variation and endogenous auxin levels showed inverse variation with stigma unfolding. AVG and Co2+ applications decreased auxin‐induced style elongation and fusicoccin promoted all of the growth responses of style‐stigma units in vitro. A gibberellin‐auxin‐ethylene‐acid growth interaction mode of control is proposed for these three growth processes.

Chemotherapy of small cell carcinoma of the lung: Comparison of a cyclic alternative combination with simultaneous combinations of four and seven agents

It would appear to be of advantage to treat patients with anaplastic small cell carcinoma with an alternating sequence of non cross-resistant agents. This was explored in two randomized clinical trials involving 142 previously-untreated patients. In the first trial a simultaneous 4-drug combination (regime A) was compared with an alternating sequence of a combination of 4 phase non-specific agents and a combination of 3 phase specific agents (regimen B). In the second trial regimen B was compared with a simultaneous combination of the same 7 agents. In regimen A methotrexate (MTX), vincristine (VRC), cyclophosphamide (CPA) and procarbazine (PCZ) were given for 6 weeks, then for 2 weeks every 4 weeks. In regimen B adriamycin, CCNU, CPA and PCZ were followed after 3 weeks by MTX, VCR and hydroxyurea. The sequence was recycled at 8-week intervals. In regimen C the 7 drugs were given in the first week and repeated every 4 weeks. After 24 weeks of induction, patients with response or stabilization either received or did not receive a maintenance treatment with 3 or 4 of the induction drugs. The tumor response was evaluated after the initial 8 weeks of treatment. The response rates for A, B and C were not significantly different and ranged between 60 and 73%. Performance status and tumor extension did not influence the response rate. The survival was significantly related to the tumor response, the performance status and the tumor extension. The overall median survival was slightly more than 6 months. The longest median survival ( 43 weeks) was found in patients with responsive locoregional tumors. The analysis of survival as per treatment regimen, performance status and tumor extension showed no advantage for the alternative treatment. Toxicity was moderate and equivalent in A, B and C. It is concluded that the response rate and survival achieved with an alternating combination chemotherapy of moderate toxicity in small cell lung cancer are not superior to those observed with simultaneous combinations of equivalent intensity.

Chemotherapy of small cell carcinoma of the lung: Comparison of a cyclic alternative combination with simultaneous combinations of four and seven agents

It would appear to be of advantage to treat patients with anaplastic small cell carcinoma with an alternating sequence of non cross-resistant agents. This was explored in two randomized clinical trials involving 142 previously-untreated patients. In the first trial a simultaneous 4 -drug combination (regime A) was compared with an alternating sequence of a combination of 4 phase non-specific agents and a combination of 3 phase specific agents (regimen B). In the second trial regimen B was compared with a simultaneous combination of the same 7 agents. In regimen A methotrexate (MTX), vincristine (VRC), cyclophosphamide (CPA) and procarbazine (PCZ) were given for 6 weeks, then for 2 weeks every 4 weeks. In regimen B adriamycin, CCNU, CPA and PCZ were followed after 3 weeks by MTX, VCR and hydroxyurea. The sequence was recycled at 8-week intervals. In regimen C the 7 drugs were given in the first week and repeated every 4 weeks. After 24 weeks of induction, patients with response or stabilization either received or did not receive a maintenance treatment with 3 or 4 of the induction drugs. The tumor response was evaluated after the initial 8 weeks of treatment. The response rates for A, B and C were not significantly different and ranged between 60 and 73 %. Performance status and tumor extension did not influence the response rate. The survival was significantly related to the tumor response, the performance status and the tumor extension. The overall median survival was slightly more than 6 months. The longest median survival ( 43 weeks) was found in patients with responsive locoregional tumors. The analysis of survival as per treatment regimen, performance status and tumor extension showed no advantage for the alternative treatment. Toxicity was moderate and equivalent in A, B and C. It is concluded that the response rate and survival achieved with an alternating combination chemotherapy of moderate toxicity in small cell lung cancer are not superior to those observed with simultaneous combinations of equivalent intensity.