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At least 19 recordsLinked to original sources
PubMed2006

Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice.

Anticancer drug combinations can act synergistically or antagonistically against tumor cells in vitro depending on the ratios of the individual agents comprising the combination. The importance of drug ratios in vivo, however, has heretofore not been investigated, and combination chemotherapy treatment regimens continue to be developed based on the maximum tolerated dose of the individual agents. We systematically examined three different drug combinations representing a range of anticancer drug classes with distinct molecular mechanisms (irinotecan/floxuridine, cytarabine/daunorubicin, and cisplatin/daunorubicin) for drug ratio-dependent synergy. In each case, synergistic interactions were observed in vitro at certain drug/drug molar ratio ranges (1:1, 5:1, and 10:1, respectively), whereas other ratios were additive or antagonistic. We were able to maintain fixed drug ratios in plasma of mice for 24 hours after i.v. injection for all three combinations by controlling and overcoming the inherent dissimilar pharmacokinetics of individual drugs through encapsulation in liposomal carrier systems. The liposomes not only maintained drug ratios in the plasma after injection, but also delivered the formulated drug ratio directly to tumor tissue. In vivo maintenance of drug ratios shown to be synergistic in vitro provided increased efficacy in preclinical tumor models, whereas attenuated antitumor activity was observed when antagonistic drug ratios were maintained. Fixing synergistic drug ratios in pharmaceutical carriers provides an avenue by which anticancer drug combinations can be optimized prospectively for maximum therapeutic activity during preclinical development and differs from current practice in which dosing regimens are developed empirically in late-stage clinical trials based on tolerability.

Animals↗
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↗
PubMed2000

Analysis of drug interactions in combined drug therapy by reflection method.

AIM: To set up a new method to analyze multidrug interaction in combined drug therapy. METHODS: Based on a dose-effect curve of the combined drugs and the equieffective test, a new mathematical model was set as Q = (Eo - Et)/L (-1 < Q < 1 addition, Q < or = 1 antagonism, Q > or = 1 synergism) where Eo = an observed value (or its fitted value) of combined effect, Et = an expected value of combined effect, and L = an equieffective cutoff between Eo and Et, decided by the equieffective criterion of a special field, the number of data points, and the experimental error. The different types of experimental data were analyzed by the new model. RESULTS: This reflection method could deal with data in combined drug therapy, unnecessary to distinguish between independent and similar action, or exclusive and non-exclusive case among drugs. The number of drugs for combination did not need to be limited. But the experimental data should be enough to fit a dose-effect curve of drugs in combination. If every dose-effect curve of drugs for combination was made, a series of Q values was obtained from all levels of dose-effect for a systematic analysis. To large animal or human experiment, the points of dose-effect of each drug used alone could be reduced to even 1 point. The results of analysis took the criterion of a special field and laboratory error into account in this method. CONCLUSION: The reflection method is an effective method for analysis of multidrug interaction in combined drug therapy.

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↗
PubMed2000

[Overview of drug interactions. Combining drugs correctly!].

Drug interactions may be of two basic types: pharmacodynamic and pharmacokinetic. Pharmacodynamic interactions may be direct, in that two drugs intervene synergistically or antagonistically in the same biological system, or indirect, meaning that one drug may modify a parameter of central importance to a system, which in turn may influence the activity of the second drug. Of the two possibilities pharmacokinetic interactions are the more difficult to recognize since they have nothing to do with the biological action proper. Here, the absorption and metabolism of the drug are the most important factors. A compounding factor is the fact that the activity of a drug may show marked individual, genetically determined, differences.

Drug Interactions↗
PubMed1993

The misuse of analysis of variance to detect synergy in combination drug studies.

Drug combination studies often examine the possibility of synergy between drugs. Synergy is defined as an effect of a combination of drugs greater than that expected from the effects of the drugs given individually. One technique used by several investigators is the use of analysis of variance (ANOVA) to determine synergy. In this discussion, the argument is made that due to the pharmacology of drug combination studies the conditions necessary to support the use of ANOVA to detect synergy are typically not met. Therefore, the ANOVA technique is invalid for these drug combination studies.

Analysis of Variance↗
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↗
PubMed2000

Patterns of utilization of antihypertensive drug combinations in Bahrain: do they conform with international guidelines?

OBJECTIVES: To explore the prescribing pattern and rationale of antihypertensive combination drug therapy at the level of primary health care centers; and to analyze the extent of physicians' adherence to dosage range of antihypertensives in combination regimens as recommended by Guidelines Subcommittee of WHO/ISH 1999. SUBJECTS, MATERIAL AND METHODS: A prescribing survey of antihypertensive combination regimens among patients with uncomplicated essential hypertension was conducted in 7 out of a total of 18 health centers in Bahrain. The relevant data for our study was collected using cards designed for chronically ill patients. RESULTS: A total of 2414 hypertensive patients (62.9%), of a 3838 study population, were on monotherapy, whereas 1414 (37.1%) were on antihypertensive combination therapy. Among those who were treated with drug combinations, 85.1% (n = 1212) received two-drug, 14.2% (n = 202) received three-drug and four- and five-drug regimens were used by 0.6% and 0.07%, respectively. Prescription analysis revealed that 17 different two- and three-antihypertensive drug combinations were prescribed for each category. The four major two-drug regimens were ranked in the following order: a beta-blocker with a diuretic (40.4%) used more frequently in females than in males (p < 0.0001), a beta-blocker with a calcium channel blocker (19.7%), a beta-blocker with an ACE inhibitor (12.8%) and a diuretic with an ACE inhibitor (7.3%) - used more frequently in males than in females (p = 0.001, 0.01, and 0.028, respectively). The most frequently prescribed three-drug regimens were diuretic and a beta-blocker plus either an ACE inhibitor (30.7%) or a calcium channel blocker (22.3%), beta-blocker plus an ACE inhibitor and a calcium channel blocker (16.3%), and a diuretic plus an ACE inhibitor and a calcium channel blocker (11.4%). There was no gender-related difference among triple-drug regimens. There was a trend towards using high doses of the beta-blocker atenolol, ACE inhibitors and methyldopa. CONCLUSION: The prescribing patterns of some practising physicians were analyzed in terms of conformity with guidelines of combination of drugs and dosages. The use of antihypertensive combination therapy and the doses of individual drugs in combination regimens seem to be partly non-compliant with guidelines issued by WHO recommendations; this is illustrated by excessive prescription of some irrational combinations, as well as limited prescription of some rational combinations. In addition, a tendency to use high doses of certain classes of antihypertensive combinations was observed.

Antihypertensive Agents↗
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↗
PubMed1983

[Lesions of the oral mucosa caused by drugs and drug combinations].

The drugs and drug combinations responsible for cutaneo-mucosae reactions are extremely numerous and only the most frequently responsible are mentioned. Pathogenic processes are described: immune-allergic, overdosing, idiosynerasy, drug interactions, etc... Alterations provoked are various and vary from erythema up to acute skin necrosis. We would suggest caution, in prescribing drugs and drug combinations.

Drug Combinations↗
PubMed2005

[Clinical efficacy of a novel antimicrobial drug combination containing ciprofloxacin and tinidazole in the treatment of patients with skin and soft tissue infections].

Clinical and microbiological efficacies of a combined drug, a fixed combination of ciprofloxacin and tinidazole in the form of tablets (Cifran ST, Ranbaxy, India) were studied. The drug was given to 40 patients with skin and soft tissue infections in the complex surgical treatment. The clinical effect and bacteriological efficacy were observed in 97.5 and 75% of the cases respectively. The drug tolerability was good and no adverse reactions were stated.

Adult↗