PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Drug Combinations”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1990

[Biochemical aspects of the evaluation of fixed drug combinations].

Various disciplines have to contribute to the general problem of the evaluation of fixed dose combination drugs, as for instance (clinical) pharmacology, biometry, scientific drug regulations and public health officials. The EC guideline 75/318/EWG and its eludications as well as the German "Arzneimittelprüfrichtlinien" of Dec. 14, 1989 (as referred to in the "Arzneimittelgesetz" of 1986) required that such issues concerning fixed dosage combination drugs must be considered and taken into account. In this framework it is the responsibility of biometry to both to guarantee the use of a valid study design to assure interpretation of the results and to quantify the reliability of pharmacological and clinical considerations. The following paper is concerned with biometrical aspects of the combination drug problem. Basic considerations from a clinical or a pharmacological point of view with respect to the question of whether fixed combination drugs are reasonable or not are not discussed. To support the use of combinations of drugs, a central argument is the improvement of the benefit risk relation compared with that of an adequate monotherapy. Beyond this the fixed combination drugs require additional arguments regarding the enhencement of the safety or the simplicity of the therapy fixing the ratio. It follows that fixed combination drugs have to be supported twice, first with respect to the combination itself, and second with respect to the fixed mixing ratio of its components. The biometrical aspects of the assessment of the gains from (fixed) drug combinations are related to the kind of benefit/risk improvement that is expected. In the first section we discuss some possible types of benefit and risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1978

Chemotherapy of advanced small-cell anaplastic carcinoma. Superiority of a four-drug combination to a three-drug combination.

A controlled clinical trial compared three-drug and four-drug combination chemotherapy in 109 patients with advanced small-cell anaplastic carcinoma of the lung. The combination of vincristine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), cyclophosphamide, and methotrexate was significantly superior to the combination of the last three drugs alone with regard to median survival (230 versus 176 days) (P less than 0.01) and to duration of response (186 versus 112 days) (P less than 0.01). Objective response occurred in 78% and 75%, respectively. No significant difference in these values was observed in the comparison of the three subtypes of small-cell anaplastic carcinoma using the World Health Organization classification.

Aged↗
PubMed1990

Time course of cycloplegia induced by a new phenylephrine-tropicamide combination drug.

A motorized and computer-interfaced phoropter was used to track the development of cycloplegia and recovery of accommodation over a 60-min period, after the topical application of a phenylephrine 5%-tropicamide 0.8% drug combination (Phenyltrope). Phenyltrope was introduced into the Canadian market about 2 years ago (Compendium of Pharmaceuticals and Specialties, 1987), and advertised as a fast acting cycloplegic and mydriatic drug. Here we report the results of our investigation of the depth of action and the temporal aspects of cycloplegia for this drug combination as a function of iris color. We also compare the action spectrum of Phenyltrope to that of tropicamide 1% under similar test conditions. Our results indicate that the latency for cycloplegia was shorter for tropicamide, the maximum rate of accommodative loss similar for both drugs, and the resultant cycloplegia at 20 min deeper for Phenyltrope. Recovery from induced cycloplegia was greater for tropicamide 60 min after drug administration. For both Phenyltrope and tropicamide, no significant differences in any of the parameters investigated were observed as a function of iris color. We conclude that even though Phenyltrope induced a measurably deeper cycloplegia than did tropicamide, the amount of residual accommodation present at 20 min (about 38%) is insufficient for most refractive purposes.

Accommodation, Ocular↗
PubMed1988

Combination drug therapy for ventricular arrhythmias.

The role of drug combinations for the treatment of patients with ventricular arrhythmias is reviewed. The use of single drugs to suppress ventricular arrhythmias is often unsatisfactory; a drug may be ineffective or cause intolerable adverse effects. Simultaneous use of antiarrhythmic agents with different but compatible electrophysiologic effects may control arrhythmias refractory to single-drug therapy. Patients may tolerate combination therapy fairly well because dosages in combination therapy are often lower than those employed when either drug is used alone. Although comparison of drug trials is hampered by nonuniformity among study protocols, the data suggest that drug combinations can be effective in treating some patients. Pairs of drugs showing the most promise have been a class IA drug (procainamide, quinidine, or disopyramide) with a class IB drug (usually mexiletine), and a class IA drug with a beta blocker. Amiodarone should be combined with a class I drug only as a last resort. There is little evidence to support the simultaneous use of two class IA drugs. Selection of a drug combination should be guided by consideration of the patient's medical history, concurrent disease states, and risk of sudden cardiac death. The efficacy of combination therapy should be evaluated by electrophysiologic testing or ambulatory electrocardiography. Combination antiarrhythmic therapy should be reserved for patients in whom single-drug therapy has been ineffective or poorly tolerated. More studies are needed to further define the efficacy, safety, and role of drug combinations in the treatment of ventricular arrhythmias.

Arrhythmias, Cardiac↗
PubMed1988

Problems of combination drug therapy in children.

Despite the current trend toward monotherapy, polytherapy in children with epilepsy is still common. A drug combination is advantageous only if it achieves a higher efficacy:toxicity ratio (therapeutic index) or if its antiepileptic spectrum is wider. Studies of brain concentrations of antiepileptic drugs have so far shown that a higher efficacy:toxicity ratio is not achieved by most combinations. Problems are associated with drug combinations. First, numerous pharmacokinetic interactions are documented. These interactions, which can be associated with significant changes in blood levels at a given dose, make frequent measurements and dosage readjustments necessary. They can also alter the concentration of active metabolites or the free fraction of a drug. Second, toxicity can be assumed to be at least partially cumulative, since reduction in polytherapy has been shown to be associated with a reduction in side effects. Third, the therapeutic range appears to depend on whether a drug is taken alone or in combination, so that polytherapy confuses the interpretation of serum drug measurements. Fourth, the presence of more than one drug will add to the difficulty in evaluating the efficacy or side effects of any single drug. Finally, a pharmacodynamic interaction between valproate and several other antiepileptics, particularly the barbiturates, can lead to a stuporous state. Transition from polytherapy to monotherapy is much more difficult to achieve than the opposite.

Anticonvulsants↗
PubMed1989

Application of a new radiometric system for identification of potentially useful drug combinations for treatment of human gastrointestinal adenocarcinoma.

As an alternative to empirical clinical evaluation of combined drug effects in human tumors, and in an attempt to establish whether the combination of mitoxantrone (DHAD) with other standard drugs would be of any benefit to the patient with advanced gastrointestinal cancer, we have examined the results of simultaneous single-agent testing in vitro in a panel of 8 human colorectal (HCC) and 5 gastric cancer (HGC) cell lines. Cytotoxic drug effects were measured by the use of a new semiautomated radiometric technique (Bactec system), and were quantitated with attention to potentially clinically relevant plasma concentrations. Among several different drug combinations tested, maximal synergistic cell kill was found for DHAD + 5-fluorouracil; continuous incubation of the cells at 1/100 of the peak plasma concentration achievable in humans yielded in vitro responses in 8/8 HCC and 5/5 HGC cell lines. With regard to our results of single-agent testing, our finding of a significant level of in vitro arabinoside-C activity, using prolonged exposure at an in vitro dose corresponding to a clinical high-dose regimen, may provide a rational basis for (re)evaluation of the compound in gastrointestinal cancer patients.

Adenocarcinoma↗
PubMed1985

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↗
PubMed1989

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↗
PubMed1977

[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↗
PubMed1990

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↗
PubMed1988

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↗
PubMed1991

Effect of drug combinations on bilirubin-albumin binding.

Drugs which compete with bilirubin for albumin binding may increase the risk of kernicterus. Fortunately, few drugs are strong competitors. However, in neonatology, many drugs are used simultaneously. We have studied the effect of drug combinations on bilirubin binding using human serum albumin and the peroxidase method. Combinations of aminophylline with phenobarbital, cefotaxime and vancomycin were studied as well as the combination of vancomycin and cefotaxime. The results show that the bilirubin-displacing effect of the drug combinations cannot be predicted from each drug's individual effect. These results are consistent with a flexible model of albumin binding. Combinations of drugs which are both albumin-bound and reach high serum concentrations should be tested for their combined effect on bilirubin binding and this information used in deciding on treatment in sick, premature infants.

Aminophylline↗