[Current therapy: combined drug therapy of hyperuricemia, gout and alcohol induced fatty liver].
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OBJECTIVE: To evaluate the role of combination therapy with proton-pump inhibitors (PPIs) and histamine(2) receptor antagonists in gastroesophageal reflux disease (GERD). DATA SOURCES: Clinical literature identified through MEDLINE (January 1966-August 2001). Key search terms included gastroesophageal reflux, benzimidazoles; omeprazole; lansoprazole; pantoprazole; rabeprazole; receptor antagonists, histamine(2); therapy, combination drug; therapy, combined modality; and combinations, drug. DATA SYNTHESIS: Approximately 80-90% of patients show healing of reflux esophagitis after 8 weeks of once-daily PPI therapy. Patients taking PPI therapy twice daily still have nocturnal acid breakthrough (periods of gastric pH <4 lasting for > or =60 min during the night) as much as 70% of the time. The clinical application of this finding has not been shown. One trial has shown that omeprazole in the morning plus ranitidine at bedtime is not as effective as omeprazole twice daily given before the morning and evening meals at controlling nocturnal acid breakthrough. Further, 1 small trial in healthy subjects without GERD showed that the addition of a 1-time dose of ranitidine at bedtime to a twice-daily regimen of omeprazole may decrease the occurrence of nocturnal acid breakthrough. However, the clinical significance of this finding is not clear. CONCLUSIONS: No studies in patients with GERD demonstrate that the addition of histamine(2) receptor antagonists to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far--nocturnal acid breakthrough--has not been proven to correlate with improvement of GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in patients refractory to standard doses of PPIs.
A combination drug therapy (Poly-5: ibuprofen 12.5 mg/kg, methylprednisolone 30 mg/kg, cimetidine 150 mg, diphenhydramine 10 mg/kg, and ketanserin 0.2 mg/kg) given at 20 and 120 minutes after starting continuous intravenous Pseudomonas (Ps, 5 X 10(8) CFU/20 kg/min) was studied in three groups of swine: saline control (C, n = 9), Ps alone (Ps, n = 8), and Ps plus Poly-5 (n = 5). PaO2, systemic (SAP) and pulmonary arterial (PAP) pressures, cardiac index (CI), thermal-cardiogreen extravascular lung water (EVLW), pulmonary albumin flux (slope index, SI), and arterial blood serotonin levels (5-HT) were measured. Ps produced significant (p less than 0.05) increases in PAP, EVLW, and SI with decreases in PaO2, CI, and SAP. 5-HT fell significantly compared to baseline. Poly-5 prevented (p less than 0.05) the rise in EVLW and SI and the fall in PaO2 and CI compared to Ps. PAP and SI were maintained at C until 90 and 150 minutes, respectively. SAP fell significantly from C at 30, 60, and 180 minutes. 5-HT was significantly lower than Ps throughout, and significantly lower than baseline at 180 minutes. Combined blockade of arachidonic acid metabolites, histamine, and serotonin receptors prevented hypoxemia, increased pulmonary capillary permeability, and cardiovascular deterioration in this porcine septic ARDS model.
Combination chemotherapy with methotrexate, actinomycin D. and an alkylating agent (MAC) has become widely used for patients with "high-risk" gestational choriocarcinoma. When such chemotherapy fails to obliterate this disease the prognosis has been uniformly poor. Chemotherapy failure may result from excessive toxicity or tumor resistance. Two patients are presented who failed treatment with MAC. Both have achieved sustained clinical and serum beta subunit-hCG titer remission of choriocarcinoma with the use of the drugs cis-platinum, vinblastine, and bleomycin.
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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.
The frequency with which a psychotropic agent is used in combination with another drug preparation is emphasized. The authors present an update of the clinical and theoretical knowledge bearing on combination drug therapy in psychopharmacology. Drug combination interactions that enhance clinical efficacy and those that either diminish it or even endanger the patient are described. The authors hope to create an awareness on the part of physicians of the importance of being knowledgeable in the area of combination drug therapy. Any unexpected or unusual drug action should be examined for the possibility of a drug combination interaction.
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OBJECTIVE: The following is a case presentation of congenital syphilitic keratitis in a boy 6 years of age who was successfully treated with an immunosuppressive drug combination therapy. METHODS: Congenital syphilitic keratitis was diagnosed by clinical findings and laboratory tests. The child was unresponsive to traditional treatment; thus, systemic immunosuppressive therapy, which consisted of oral cyclosporine 4 mg/kg/d, 6 days per week, and oral low-dose steroids (fluocortolone 0.8 mg/kg a week, given every other day), was initiated. RESULTS: Corneal disease showed great improvement with this therapy, with progressive healing of lesions in the first month of treatment and no signs of toxic renal, hepatic, or growth abnormalities. Recurrences of uveitis have not occurred, and corneal interstitial keratitis episodes have been limited to 3 in an 8-year period. After 6 months with no recurrences, a tapering off of the systemic therapy was initiated, and the child is still asymptomatic and without flare-ups. CONCLUSIONS: Congenital syphilitic keratitis is usually treated with topical steroids and cycloplegic drugs, which not only can be ineffective but can also lead to complications such as cataract and glaucoma. In the present case report, a pediatric patient affected by syphilitic interstitial keratitis was treated successfully with an immunosuppressive drug combination therapy.
The importance of polichemotherapy in multibacilar leprosy (LL and LD) in patients without any previous therapy as in those diagnosticated and under monotherapy most of all in the resistance patients is presented. Sulphones, clofazimine and rifampicine are selected as first rate drugs and protionamide-etionamide as second rate drugs. The therapy plans with the association of two and three drugs and the convenience of continuing indefinitely with at least one of the drugs are presented insisting on the advantages of the clofazimine-sulphones and rifampicine-sulphones associations. The necessity of immunotherapy for recover of celular immunity against the bacilus, is the only form of preventing relapses and drug resistance.
STUDY OBJECTIVE: To compare the efficacy of gemfibrozil and colestipol with gemfibrozil and lovastatin in patients with familial combined hyperlipidemia. DESIGN: A prospective, randomized trial. SETTING: An outpatient clinical research center in a tertiary care center. PATIENTS: Seventeen patients with familial combined hyperlipidemia documented by studies of first-degree relatives; nine patients with type 2b hyperlipoproteinemia, and eight patients with type 4 hyperlipoproteinemia. INTERVENTIONS: Baseline lipid, lipoprotein, and apolipoprotein levels were obtained during control periods on diet alone and on gemfibrozil therapy. Patients then received gemfibrozil and colestipol or gemfibrozil and lovastatin in a randomized order. MEASUREMENTS AND MAIN RESULTS: In patients with type 2b hyperlipoproteinemia, gemfibrozil alone significantly reduced total cholesterol by 11%, and low density lipoprotein (LDL)-apolipoprotein B by 18%, did not change LDL-cholesterol, and raised high density lipoprotein (HDL)-cholesterol levels by 26%. Addition of either colestipol or lovastatin reduced LDL-cholesterol levels by 17% and 25%, respectively, compared to gemfibrozil alone. However, colestipol mitigated the HDL-cholesterol raising effect of gemfibrozil and did not further reduce LDL-apolipoprotein B levels. In contrast, addition of lovastatin caused an additional reduction of LDL-apolipoprotein B 19% compared with gemfibrozil alone. In patients with type 4 hyperlipoproteinemia, gemfibrozil alone reduced triglycerides by 40%, raised HDL-cholesterol by 26%, and increased LDL-cholesterol levels by 29%. The addition of either colestipol or lovastatin reduced LDL-cholesterol levels by 34% and 33%, respectively (compared with gemfibrozil alone), but greater reductions of LDL-apolipoprotein B (30% with lovastatin compared with 15% with colestipol, compared with gemfibrozil alone), and increases in HDL-cholesterol levels (8% increase with lovastatin compared with 10% decrease with colestipol, compared to gemfibrozil alone) were seen with the lovastatin combination. CONCLUSIONS: Although gemfibrozil with either colestipol or lovastatin favorably altered lipoprotein levels in patients with hypertriglyceridemia and familial combined hyperlipidemia, the combination of gemfibrozil and lovastatin appeared superior overall.
A novel phenotypic anti-human immunodeficiency virus type 1 (HIV-1) drug resistance assay is described. Three drugs at concentrations equivalent to those determined in in vivo pharmacokinetics, were mixed in a well, serially diluted by 10-folds, and added to incubations of clinical HIV-1 isolates and CCR-5 expressing HeLa/CD4+ cells which was previously reported as the MAGIC-5 cells (Antimicrob. Agents Chemother. 45 (2001) 495) to determine the 95% inhibitory dilution (ID(95)) of the combination regimens. The ID(95) of efavirenz (EFV)-containing regimens was ten-times lower than that of nevirapine (NVP)-containing regimens against HIV-1 isolated from antiviral therapy naive patients. However, the difference was not apparent by the conventional fold resistance measurement based on the 50% inhibitory concentration. Furthermore, the synergistic effects of drug combinations against clinical HIV-1 isolates can be evaluated by our assay. The ID(95)s of EFV- and nelfinavir (NFV)- containing regimens against HIV-1 from naive patients were less than 0.01 whereas those against resistant viruses were over 0.05, although the clinical cut-off values are to be determined in larger clinical studies. Our assay, designated "All-in-One Assay", that can examine resistance to three drugs simultaneously under consideration of in vivo drug concentrations described above might be useful in practice.
The dosage levels for a number of frequently prescribed psychotropic drugs, used singly or in combination, were determined in 902 long-term psychogeriatric hospital patients. The data failed to support the hypothesis that physicians prescribe lower dosages when combination therapy is used. Rather, the tendency was toward higher dosages under these circumstances.
For the past 3 to 4 decades, clinical outcomes trials have shown that drugs that favorably alter serum lipid levels reduce the risk of coronary artery disease (CAD) events. However, despite these successes, the reduction in serum low-density lipoprotein (LDL) cholesterol levels with monotherapy lipid-altering drugs does not "cure" CAD to the same degree that antibiotics "cure" many infections, nor do they "prevent" CAD in the same way that childhood immunizations "prevent" the onset of such conditions as measles, mumps, and rubella. Clinical outcome trials of monotherapy lipid-altering drugs have demonstrated a reduction in the relative risk of CAD in only a minority of patients. Thus, although safe and very effective in lowering serum LDL cholesterol levels, drugs that predominantly lower cholesterol do not "cure" atherosclerotic disease, nor have they been shown to "prevent" most CAD events in numerous clinical outcome trials. The reason for the suboptimal CAD outcomes benefits of monotherapy lipid-altering drugs is likely because atherosclerosis is a complex pathologic process with many important risk factors involved in the initiation and progression of atherosclerotic lesions and involved in the onset of the CAD event itself. An elevated serum LDL cholesterol level is an important CAD risk factor, but it is not the only lipid risk factor. A decreased serum high-density lipoprotein (HDL) cholesterol level is another important risk factor for CAD. Combination therapy through existing drugs (or possibly, in the future, through investigational lipid-altering drugs) may not only improve LDL cholesterol but also improve serum HDL cholesterol levels. This more global, multidimensional approach to lipid-altering drug treatment may provide the best chance to prevent CAD.
Combined drug therapy with cholestyramine and compactin was found to be extremely effective against heterozygous cases of familial hypercholesterolemia. With a single drug regimen, compactin at a dosage of 15 mg/day produced a cholesterol reduction of 23% (70 mg/dl) in cases of combined hyperlipidemia, while twice the dosage (30 mg/day) was needed to produce a comparable effect with heterozygous familial hypercholesterolemia. When compaction was combined with cholestyramine (in a 4 g dose three times a day), the cholesterol-lowering effect of compactin was strongly improved with heterozygous familial hypercholesterolemia; half the dosage of compactin was enough to produce the additive effect compared with the effect produced by each single drug regimen.
Atherogenic dyslipidemia is prevalent in various conditions associated with central obesity, hypertension, hyperurecemia, and impaired beta-cell function (ie, the metabolic syndrome). Because of clinical trial evidence, most high-risk patients with atherogenic dyslipidemia require statin therapy. Coadministration of drugs targeted to reduction of low-density lipoprotein precursors, however,is likely to improve the metabolic profile of all non-high-density lipoproteins and produce a significant rise in high-density lipoprotein cholesterol. Large-scale clinical trials with combined drug therapy that show coronary heart disease (CHD) risk reduction or improvement in CHD are needed. It is also possible that new drugs are needed to target fatty acid metabolism and inflammation. As understanding of the metabolic origins of atherogenic dyslipidemia increases, it is possible that new targets of therapy will be identified and that new drug combinations will prove to be even more efficacious than those currently available for treatment of this condition.
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.
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