[Fixed drug combinations].
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Drug Combinations↗
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Attempts to attenuate the 'cheese effect'. Combined drug therapy in depressive illness.
Although earlier results, employing intravenous tyramine challenge, had indicated that a tricyclic antidepressant plus monoamine oxidase inhibitor drug combination might be free from the 'cheese effect', the experiments reported here, involving oral tyramine challenge during the combined therapy, showed that relaxation of a tyramine-free diet during such a drug regimen might be unsafe. Preliminary observations indicated that combined (-)-deprenyl plus nonselective monoamine oxidase inhibitor therapy might lead to an unacceptable degree of orthostatic hypotension without reduction in tyramine sensitivity.
Adult↗
The superiority of a drug combination over each of its components.
The requirement for approval of a combination drug treatment AB is its demonstrated superiority over each of its components A and B at their most appropriate dose levels. This has led to frequent use of a three-group experimental design that permits separate testing of H0:AB less than or equal to A and H0:AB greater than or equal to B. A type I error can occur if no true treatment effect is present in either or both of the contrasts. The sampling distribution for the larger of the two observed p-values, however, depends on whether a non-null treatment effect is or is not present in one of the contrasts. We propose a strategy in which a conservative experiment-wide type I error is achieved by defining the criterion for significance of the smaller observed treatment effect contingent on the magnitude of the larger observed treatment effect. We also discuss sample size requirements for the three-group design.
Drug Evaluation↗
Application of response surface methodology and factorial designs to clinical trials for drug combination development.
The use of response surface methodology in the analysis of a factorial trial in the development of a combination treatment for hypertension is discussed. The analysis plan and efficacy results are reviewed with special attention to the quadratic response surface methods that were applied. A key issue is how to test to establish the existence of an effective dose combination. This issue also impacts current designs for combination drugs at fixed doses. Several direct approaches using quadratic response surface methods are discussed. Estimating the combination dose that maximizes the minimum gain of combination over each monotherapy seems most promising.
Antihypertensive Agents↗
An approach to the assessment of therapeutic drug interactions with fixed combination drug products.
Several complex clinical and statistical issues are involved in the development of a combination drug product. The medical rationale for the combination, the intended clinical use, drug-drug interactions, and dose response are just a few of the considerations. The factorial design is a useful experimental model for evaluating combination therapies. This paper outlines some of the considerations involved in the use of this design in the study of combination drugs. Questions related to design and methods of analysis are discussed in general and through use of an example. Such a design was applied to study the combination of a vasodilator with a diuretic in the treatment of hypertension. The sample size derivation, the evaluation of "interaction," the use of ANOVA versus regression techniques, and methods of data display are reviewed. It is recognized that although these are complex issues, substantially more information per patient can be obtained than with standard parallel-design approaches. The design could be an especially powerful tool early in the development of a drug.
Clinical Trials as Topic↗
Memory enhancement: supra-additive effect of subcutaneous cholinergic drug combinations in mice.
The amnesias characteristic of Alzheimer's disease and other age-related dementias are refractory to conventional pharmacotherapy. A recent treatment strategy is to combine present drugs to improve their memory enhancing effect. We used mice weakly trained on active avoidance in a T-maze to compare the effect of cholinergic drugs, given alone and in two-drug combinations, on retention test performance. All drugs were injected SC immediately after training. Memory retention was tested 1 week later. A dose-response curve was determined for each of four drugs (arecoline, edrophonium, oxotremorine, tacrine) and for each of the six possible two-drug combinations. Each drug and each combination improved retention test performance up to an optimal dose; the improvement decreased with further increases in dose. A striking reduction (66.2%-95.7%) in the optimal dose for enhanced retention was observed with these two-drug combinations.
Animals↗
Memory retention: potentiation of cholinergic drug combinations in mice.
The amnesias characteristic of Alzheimer's disease and other age-related dementias are refractory to conventional pharmacotherapy. A recent strategy is to combine present drugs, to improve their memory enhancing effect. We utilize mice weakly trained on active avoidance in a T-maze in order to compare the effect on retention test performance of cholinergic drugs given alone and in two-drug and three-drug combinations. All drugs were injected intraventricularly immediately after training. Memory retention was tested one week later. A dose-response curve was determined for each of four drugs (arecoline, edrophonium, oxotremorine, deanol) and for several of their fixed-ratio combinations. The results indicate that each drug and each combination improved retention test performance up to an optimal dose; the improvement decreased with further increases in dose. A striking reduction (as much as 95%) in the optimal dose for enhanced retention was observed with these two-drug combinations, and further reduction with a three-drug combination. The practical implications of planned drug interactions as an improved means of treating amnesias associated with aging are under investigation.
Animals↗
Combination drug therapy for combined hyperlipidemia.
Combination therapy for hyperlipidemia, especially combined hyperlipidemia, may have advantages over single drug therapy, affording better improvement in lipoprotein risk factors and possibly better prevention of atherothrombotic events. Although preliminary experience has been gained using treatment combinations of niacin with statins, and fibrates with statins, few studies have focused on angiographic or clinical outcomes. Both of these treatment combinations increase the risk of drug-induced myopathy and rhabdomyolysis. Current estimates of myopathy incidence are much lower than original estimates, but the relative safety of combined therapy might depend upon employing low or moderate statin doses. Safety depends critically upon educating the patient to respond appropriately to muscle symptoms, to intercurrent illness, and to concurrent use of certain other medications. Other useful drug combinations include those derived by addition of fish oil, bile acid binding resins, or stanol esters, as well as nonstatin combinations such as niacin-resin or fibrate-niacin.
Arteriosclerosis↗
[Consequeces of the elimination of a combination drug. Transition from combination antisacer: attention].
Antisacer compositum, a commonly prescribed speciality which associated phenobarbitone and phenytoin in a dose ratio of 1:4, was withdrawn after demonstration of a negative interaction of this formula. A retrospective analysis is presented of phenytoin plasma levels during bitherapy and after passage to monotherapy, in 13 adult epileptics followed as outpatients. Phenytoin plasma levels increased over twofold in 12 cases, of whom 5 continued to take the same doses, while 7 received higher doses on, and in one case two weeks after, the withdrawal of phenobarbitone. Plasma level decreased slightly in the thirteenth in spite of increased doses. Five phenytoin intoxications occurred after this change of prescription: one amongst the 5 cases with identical doses, and 4 amongst the 7 cases with increased doses. The initially high levels of phenytoin tend to decrease after several months. Physicians required to change the prescription should be aware of the risk of initial intoxication and later underdosage.
Adult↗
Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles.
Acquired drug resistance is a major problem in cancer treatment. To explore the genes involved in chemosensitivity and resistance, 10 human tumour cell lines, including parental cells and resistant subtypes selected for resistance against doxorubicin, melphalan, teniposide and vincristine, were profiled for mRNA expression of 7400 genes using cDNA microarray technology. The drug activity of 66 cancer agents was evaluated on the cell lines, and correlations between drug activity and gene expression were calculated and ranked. Hierarchical clustering of drugs based on their drug-gene correlations yielded clusters of drugs with similar mechanism of action. Genes correlated with drug sensitivity and resistance were imported into the PathwayAssist software to identify putative molecular pathways involved. A substantial number of both proapoptotic and antiapoptotic genes such as signal transducer and activator of transcription 1, mitogen-activated protein kinase 1 and focal adhesion kinase were found to be associated to drug resistance, whereas genes linked to cell cycle control and proliferation, such as cell division cycle 25A and signal transducer of activator of transcription 5A, were associated to general drug sensitivity. The results indicate that combined information from drug activity and gene expression in a resistance-based cell line panel may provide new knowledge of the genes involved in anticancer drug resistance and become a useful tool in drug development.
Antineoplastic Agents↗
Ifosfamide-based drug combinations: preclinical evaluation of drug interactions and translation into the clinic.
Ifosfamide is an alkylating antineoplastic agent with documented activity against a variety of solid tumor types, most notably lung cancer, testicular cancer, and sarcoma. Ifosfamide has been included in various drug combination protocols, usually on an empirical basis. To gather more insight into the mechanisms that underlie these drug interactions and to develop guidelines for further improvement of clinical combination protocols, we performed a broad preclinical evaluation program of ifosfamide-based combination regimens using isobologram analysis of drug interactions. In established cisplatin-sensitive and cisplatin-refractory ovarian carcinoma cell lines, a schedule-dependent drug interaction between paclitaxel and activated hydroperoxy-ifosfamide (4-OOH-IF) could be demonstrated. When both drugs were given for 2 hours, simultaneous exposure or the sequence of paclitaxel followed by 4-OOH-IF were additive or synergistic. In contrast, application of 4-OOH-IF before paclitaxel resulted in pronounced antagonism. Based on the sequence-dependent synergistic interactions a phase I trial was initiated with paclitaxel given on day 1 and ifosfamide given on days 2 to 5 in patients with cisplatin-refractory ovarian cancer. Four dose levels were evaluated in 18 patients. The maximum tolerated dose was paclitaxel 175 mg/m2 on day 1 and ifosfamide 2,000 mg/m2 on days 2 to 5, with central nervous system toxicity and nephrotoxicity being dose-limiting. The recommended dose for further evaluation of this combination was paclitaxel 175 mg/m2 on day 1 and ifosfamide 1,500 mg/m2 on days 2 to 5. Although all patients were heavily pretreated with multiple agents, nine of 18 patients achieved an objective response. Ifosfamide also has been shown to reduce cellular glutathione content; thus, a series of experiments evaluated the ability of activated cyclophosphamide or ifosfamide to deplete cellular glutathione in vitro. It was demonstrated that glutathione depletion is dose- and time-dependent, with 4-OOH-IF leading to a more pronounced suppression of cellular glutathione compared with 4-OOH-Cy. The decrease in cellular glutathione content was maximal at 2 hours after drug treatment; however, cellular glutathione levels returned to normal within 24 hours. When 4-OOH-IF was combined in vitro with cisplatin, schedule-dependent interactions again became obvious. The highest antitumor activity was seen when both drugs were given concurrently; sequential application with 4-OOH-IF given before cisplatin resulted in antagonism. Since adequate glutathione levels are necessary for multidrug resistance protein (MRP) function, glutathione depletion might lead to reversal of MRP-mediated drug resistance. Preliminary data showed that 4-OOH-IF significantly decreases glutathione concentrations in MRP-expressing human HT1080/DR4 sarcoma cells, leading to maximum steady-state reduction after a 90-min exposure to 4-OOH-IF. Taken together the data reported here demonstrate that in vitro ifosfamide may potentiate the antitumor activity of a variety of cytotoxic agents and therefore merits further clinical evaluation in drug combinations (eg, taxanes, anthracyclines).
Antineoplastic Agents, Alkylating↗
[Application and problems of combination drug therapy--the combination of antibiotics and non-antibiotics].
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Anti-Bacterial Agents↗
Drug combination against single drug treatment in radiation protection of the bone marrow CFU.
The ability of WR-2721 to protect normal tissues against ionizing radiation is limited at its maximum protective dose owing to the toxicity of the drug per se. Previous studies had indicated that MPG (2-mercaptopropionylglycine) neutralizes to some extent the toxic effects of WR-2721 without impairing the protective efficiency. The effectiveness of two doses of WR-2721 (300 mg/kg and 150 mg/kg body weight) alone or in combination with an optimal dose (20 mg/kg body weight) of MPG, on the mouse bone marrow was studied by the exogenous spleen colony assay (CFU-s) after a single whole body exposure to 4.5 Gy of gamma radiation. Both the drugs individually increased the number of spleen colonies significantly above that of the irradiated control indicating higher stem cell survival. WR-2721 treatment gave better protection than MPG. MPG was more effective when administered within 5 min before or after irradiation than when given 30 to 25 min before irradiation. The combination of WR-2721, at either dose, with 20 mg/kg MPG gave an increase in the stem cell survival as compared to the single drug treatments and this effect was synergistic at 300 mg/kg WR-2721. MPG treatment within 5 min after irradiation produced a slightly higher CFU-s count than when the drug was injected before irradiation, though the difference was not statistically significant. It is concluded that in addition to the doses of the drug, the time of administration also could influence the effect of drug combinations.
Amifostine↗
Selecting drug combinations for treatment of drug-resistant mycobacterial diseases.
Mixtures of antituberculosis drugs were evaluated for their in vitro effects on drug-resistant isolates of Mycobacterium tuberculosis and M. avium-intracellulare. The response of individual isolates to representative drug combinations was not always predictable from the results of single-drug sensitivity assays. For the case of M. tuberculosis, combinations of drugs were often bactericidal even under conditions where two or more drugs were without effect when tested singly. The more widely drug-resistant M. avium-intracellulare demonstrated increased growth inhibition when subcultured in the presence of single drugs, particularly rifampin and streptomycin. However, these conditions favored the selection of highly resistant strains. Alternatively, multiple drugs were often bacteriostatic; and under conditions where isolates demonstrated growth inhibition, the selection of highly drug-resistant strains was delayed. These results suggest a role for multiple-drug sensitivity assays in selecting drug combinations to be used in the treatment of drug-resistant mycobacterioses.
Antitubercular Agents↗
Synergistic effects of antimycobacterial drug combinations on Mycobacterium avium complex determined radiometrically in liquid medium.
A technique to determine the effects of combining antimycobacterial drugs in liquid medium employing the radiometric growth readings in the Bactec system was tested using 20 Mycobacterium avium complex strains. Ten of the strains had been isolated from children with lymphadenopathy and ten from adults with pulmonary disease. All isolates were resistant to streptomycin, rifampicin, isoniazid and ethambutol when tested with a conventional resistant ratio technique on Löwenstein-Jensen medium. Synergistic interactions were shown for the two-drug combinations streptomycin + ethambutol and ethambutol + rifampicin against all 20 strains. Good efficacy was also found for all three-drug combinations containing ethambutol. Thus, although most isolates of the Mycobacterium avium complex are resistant to first-line antituberculous drugs when tested individually, they are susceptible in vitro to certain combinations of these drugs. This rapid radiometric assay is an efficient means for detecting such synergy.
Adult↗
Age and dose of chemotherapy as major prognostic factors in a trial of adjuvant therapy of osteosarcoma combining two alternating drug combinations and early prophylactic lung irradiation. French Bone Tumor Study Group.
From January 1978 to May 1983, 41 patients with primary high-grade osteogenic osteosarcoma of a limb were treated with a combination of intensive chemotherapy and prophylactic lung irradiation (PLI) intercalated between the first two cycles of chemotherapy. The primary tumor was treated according to its size and location by amputation, resection, high-dose radiotherapy, and salvage amputation for a tumor progressing under radiotherapy. Two weeks after surgery or simultaneously with radiotherapy, a three-drug regimen (cycle A) consisting of mitomycin C on day 1, vincristine followed by a 6-hour infusion of methotrexate on day 2 was given. Folinic acid rescue was started 6 hours after the end of the methotrexate infusion. A PLI of 20 G was given from day 10 to 22. On day 28, a four-drug regimen (cycle B) combining doxorubicin on day 1, vincristine on day 2 and dacarbazine with cyclophosphamide on days 3 to 6 was administered. Thereafter, five additional cycles of A and B were administered provided that the absolute number of polymorphonuclear cells and platelets had recovered. When these values were not attained, treatment was delayed until recovery. After a mean follow-up of 60.6 months, 16 patients have developed distant metastases, associated in four cases with local recurrence. Sixteen patients have died: 15 with metastases, one with no evidence of disease (toxic death). The overall survival of the entire group is 66% and the continuously disease-free survival 58% at 5 years. Alopecia, nausea, vomiting, asthenia, anorexia, and infraclinical and reversible impairment of lung ventilatory function were universal. A noticeable hematologic toxicity also was seen. One toxic death occurred after a pulmonary infection. Two patients developed cardiomyopathy. A multiparametic analysis of prognostic factors shows the very significant influence of age on treatment outcome. The continuous disease-free survival among the 17 patients younger than 15 years is 41% compared to 79% in older patients. The prognostic influence of age was independent of other factors. The delay (for more than two cycles) of methotrexate administration was the second independent prognostic factor. These results raise the question of using different protocols of adjuvant chemotherapy for patients younger or older than 15 years in order to optimize the curability/toxicity ratio.
Adolescent↗
[Drug interactions in combination drug therapy].
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Drug Interactions↗
[Potentiation of drug effectiveness in combination drug therapy].
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Bacterial Infections↗