Efficient designs for studying synergistic drug combinations

Distinguishing between pharmacologically additive and synergistic drug combinations requires experimental designs and statistical analyses that often require appreciable numbers of animals and much experimenter time. The current study employed a design in which individual dose-effect data from each drug were translated into theoretically additive total dose combinations, in a fixed drug proportion, in order to produce a composite additive dose-effect relation that could be compared with that of an actual mixture having the same proportion. Results from this approach, using a combination of intrathecal doses of morphine and clonidine, were virtually identical to those using isobolographic analysis of the same data set. Both analyses showed significant synergism for this combination and, in each method, it was not necessary to constrain the drug regression lines to parallelism. In contrast to the isobole approach, the use of the composite additive dose-effect relation also allows observation of the interaction over a range of effects while reducing the size of the data sets needed.     

Effect of drug preparation combinations on intrauterine development

On the 13th day of pregnancy chloridine (50 mg/kg) or 6-mercaptopurine (60 mg/kg) was administered to rats. Thirty minutes before this the anomals received insulin (40 IU/kg), pentoxyl (100 mg/kg), ethonium (15 mg/kg), dimexide (5500 mg/kg), or magnesium sulphate (250 mg/kg). Oi the 20th day of preganancy the animals were sacrificed. While chloridine and 6-mercaptopurine caused abnormal development in all live embryos, their damaging (teratogenic and embryolethal) and action was sharply reduced when teratogens were used in combination with other drugs. The author feels that the normalizing effect of the study agents is due to the influence of these compounds on the functioning of the lysosome-segregational system.     

Usefulness of multiple burr-hole operation for child Moyamoya disease]

The purpose of this study was to examine the cephalometric changes that occur with palatal expansion/facemask therapy for Class III malocclusion. Pretreatment and posttreatment lateral cephalograms from 21 patients were traced and analyzed by traditional cephalometric measures, an x-y coordinate system, and along the functional occlusal plane. Differences between T1 and T2 values were analyzed with paired t-tests. Mean ages were 7.26 years (T1) and 8.18 years (T2). Average treatment time was 11.05 months. Statistically significant anterior movement of the maxilla occurred with increases in SNA (+2.35), maxillary depth (+2.22), and ANB (+3.66), and anterior movement of A-point (+3.34 mm) and ANS (+3.17 mm). The maxilla rotated counterclockwise, with PNS moving down more than ANS (-2.21 mm and -0.82, respectively). The mandible rotated clockwise with mild decreases in SNB (-1.32) and facial depth, (-1.2) but significant downward movement at menton (-4.34 mm). Occlusal plane analysis demonstrated that the correction was due more to the maxilla than the mandible (+2.35 and -1.88 mm, respectively). The maxillary molars moved forward (+1.70 mm) as did the incisors (+1.75 mm). Soft tissue changes included the nose and upper lip moving forward (3.43 and 3.67 mm, respectively), and menton moving downward (-3.49 mm). The results indicate that facemask/palatal expansion therapy improves Class III malocclusion by a combination of skeletal and dental changes that occur the anteroposterior dimension and in the vertical plane of space.     

Treatment of drug resistant scabies]

The theory that narcotic-induced protracted biological changes are responsible for relapse of opiate-reinforced behavior was examined in the rat. Groups of rats were conditioned to prefer a distinctive environment by pairing it with morphine doses from 1-200 mg/kg, and were retested for persistence of this preference after a 3-week abstinence period. They were then observed for protracted signs such as sensitivity to naloxone, tolerance to morphine analgesia, hyperaggression, or changes in endocrine activity. Acquisition and relapse of the preference, as well as long-term tolerance, were dose related. None of the purported protracted signs showed any consistent relationship to the tendency to relapse. However, relapse correlated significantly with original acquisition scores in all relapsing groups. The results suggest that original conditioning factors, rather than protracted changes, are responsible for the observed relapse.     

Various combinations of antihypertensive drugs: comparative assessment in elderly patients]

Our objective in this study was a comparative evaluation of efficiency of modern drug alternatives to treat peptic ulcer, based on new algorithms of diagnosis and treatment. The results obtained suggest to us that in a major proportion of cases uncomplicated duodenal ulcers might be efficiently managed in an outpatient-clinic setting even with a two-to-four week monotherapy. The best results of treatment are recordable in those groups of patients having received inhibitors of proton pump.     

Cerebral blood flow effects of sodium valproate in drug combinations in the baboon model

Sodium valproate (CAS 1069-66-5, Epilim) has been used in the management of epilepsy during the last three decades. Although important information on the pharmacological actions and efficacy of sodium valproate has accrued to date, limited research has been conducted on its effects on cerebral blood flow. In recent years, with the aid of SPECT (single photon emission computed tomography) and PET (positron emission tomography) it has been shown that marked cerebral blood flow changes occur in epileptic patients. Furthermore it was established recently that sodium valproate influences the cerebral blood flow in children by decreasing the flow significantly. The present study investigated the effects of sodium valproate on the cerebral blood flow, using 99mTc-HMPAO (hexamethylpropylene amino oxime) and SPECT, in a primate model, as well as the effects of its drug interactions with therapeutic agents that influence cerebrovascular dynamics, e.g. sumatriptan, nimodipine and acetazolamide. The current study using single dose treatment with sodium valproate did not detect a decrease or increase of the cerebral blood flow when compared with control baseline results. Drug interaction between sodium valproate and nimodipine may occur as a reduction of 25% in cerebral blood flow from the baseline control was observed in this case. The effects observed for the combinations of sodium valproate respectively with sumatriptan and acetazolamide are attributed to the influences of the sumatriptan (decrease) and acetazolamide (increase) alone. The cerebral blood flow effects of these drugs and possible interactions during an acute epileptic seizure need to be investigated.     

In vitro activities of novel antifolate drug combinations against Plasmodium falciparum and human granulocyte CFUs

The potency of antimalarial dihydrofolate reductase inhibitors, alone and in synergistic combination with dihydropteroate synthetase inhibitors, against the Kenyan K39 strain of Plasmodium falciparum (pyrimethamine resistant) and against normal replicating human bone marrow cells in in vitro culture has been studied. Therapeutic indices and rank order of synergistic potency were derived. Trimethoprim, pyrimethamine, and the quinazolines WR159412 and WR158122 had the smallest therapeutic indices (1.39, 4.38, 2.56, and 90.0, respectively), while the three triazines clociguanil, WR99210, and chlorcycloguanil had the largest (3,562, 3,000, and 2,000, respectively). In rank order of decreasing activity against P. falciparum, the six most potent drug combinations were WR99210-dapsone, chlorcycloguanil-dapsone, WR158122-dapsone, WR159412-dapsone, WR159412-sulfamethoxazole, and chlorcycloguanil-sulfamethoxazole; pyrimethamine-sulfadoxine was the least potent combination. These experiments form a basis for the selection of rapidly eliminated antifolate combinations for further clinical testing.     

Macrolides and drug interactions: review of the literature]

Annexin I is a member of the annexin family of calcium-dependent membrane binding proteins. The core domain of these proteins is similar in all annexins but the N-terminal domain is specific for each member. This domain is thought to regulate annexin function through phosphorylation. In annexin I, Ser-27 is one of the amino acids that can be phosphorylated by protein kinase C. Phosphorylations are thought to regulate some annexin I functions by increasing calcium requirement. Two mutants were prepared in this study: S27E and S27A proteins. The first mimics phosphorylation while the second prevents phosphorylation at residue 27. Wild-type annexin I and S27A mutant protein showed the same calcium dependence for phospholipid vesicles aggregation, while S27E mutant protein showed a higher calcium requirement and a low maximal extent of aggregation. By contrast, liposome binding and self-association required identical calcium concentrations for the wild-type and the two mutant proteins. To examine whether the regulation observed is due to modification of the N-terminal structure, we investigated conformational changes by using two approaches. Firstly we analysed proteinase sensibility. Limited proteolysis of the N-terminal tail showed similar patterns for the three proteins. Using drastic conditions of proteolysis, we observed strong resistance of the core domain to digestion in the presence of calcium. Secondly, since Ser-27 is located on the N-terminal domain that contains a tryptophan located at position 12, the fluorescence of this residue was analysed during Ca2+-binding of wild-type annexin I and S27E mutant protein. The results demonstrated that Ca2+ induces a slight change in the Trp environment of wild-type annexin I, corresponding to a burying of the residue. No changes in fluorescence features were observed with S27E mutant protein. The results obtained show that phosphorylation of the N-terminal tail plays a regulatory role in phospholipid vesicle aggregation, which is based on a mechanism distinct from protein self-association. This phosphorylation induces a conformational change in the tail probably related to aggregation property.     

Bioavailability of rifampicin, isoniazid and pyrazinamide from fixed-dose combination capsules

Due to the observation of severe neurological symptoms in single patients as well as brain imaging, neuropsychological and neurophysiological abnormalities, the long-term prognosis of treated phenylketonuria is still under discussion. We investigated the neurological outcome of 57 (24 male, 33 female) patients with phenylketonuria (diet onset < 3 months) at a mean age of 23.6 (17-33) years in comparison to control subjects. Methods used were a clinical-neurological examination, tests for fine motor abilities, IQ test (WAIS-R), a neuropsychological attention task and MRI (30 patients only). Tremor was increased in the patients (28%) compared to controls (15%). Fine motor abilities were significantly reduced in three areas: hand-wrist steadiness, finger-hand dexterity and hand-wrist speed. Tremor as well as reduced fine motor skills were not associated with treatment-related variables, e.g. diet onset, strictness of biochemical control or amount of MRI white matter change. IQ was lower in patients (mean 97.6) compared to matched control subjects (mean 105.5). IQ at 12 years was correlated with biochemical control from birth up to the age of 12 and remained stable up to adult age, independent of biochemical control after 12 years of age. In contrast to the other outcome parameters, the performance in a neuropsychological attention task was influenced by the concurrent plasma phenylalanine concentration. Specific late-onset neurological impairment was not identified in this sample of early-treated adults with phenylketonuria. CONCLUSION: Careful neurological investigation revealed subtle symptoms of brain damage even after early-initiated treatment in adult patients with phenylketonuria. At present it cannot be excluded that further neurological deterioration could emerge later in life. Thus, patients with phenylketonuria - either on or off diet - should be monitored throughout life.     

Adverse drug reactions. Nursing should notify them]

Professionals in the nursing field need be conscious of the importance of their role in the detection of suspected cases of adverse reactions to medication, in light of nurses' role in the control and follow-up of pharmacological treatment. Both the ignorance of the Medication Law, which obliges that notice of an adverse reaction to medication be served to the Center of Pharmacological Vigilance, as well as of the tools necessary for this notice, a yellow card, are the main causes why the number of these notifications is so low in the nursing profession.     

Usefulness of CO measurement in expired air in the study of tobacco consumption by youths and adolescents]

The objective of our work was to know the relationship between carbon monoxide (CO) levels in expired air and smoking habits among school youths and the relationships that can be established between CO level and some peculiar attitudes regarding consume by youths, such as the number of cigarettes, inhaling technique and time elapsed since the last cigarette was smoked. The study, of cross-sectional design, was performed in two high school centres and a total of 777 students who answered a questionnaire and had an expired air CO sample in their own schoolroom tested were enrolled. CO determination in the schoolroom was a simple and attainable technique for the pupils, as only 32 cases (4.1%) had to be excluded due to poor collaboration or poor technique. The mean (mean and SD) CO level in the control group (n = 247), made up by non-smokers nor tobacco tasters was 4.75 (2.46) ppm, statistically lower than among smokers (p < 0.001), but with no differences compared with non smokers (n = 563), who had a CO level of 5.23 (3.4) ppm. This figure was also lower (p < 0.001) than that obtained in the smokers (12.6 [6.3] ppm), made up of 214 pupils, with a mean consume of 2.7 (1.69) cigarettes/day. Among smokers the mean abstinence time since the last cigarette was smoked was 26 (44) minutes and 54% of them admitted to have smoked in the last 10 minutes. CO in expired air correlated significantly with the number of smoked cigarettes (r = 0.58; p < 0.001). Likewise, it correlated significantly with abstinence minutes (r = -0.38; p < 0.001). The time required for CO level to decrease below 10 ppm was 140 minutes in four cases and 120 minutes in 33 cases.     

Antihypertensive effectiveness of a very low fixed-dose combination of moexipril and hydrochlorothiazide

Rest-redistribution 201Tl imaging is currently being used for myocardial viability detection, but the ideal parameters for territory classification have not yet been defined. The aim of this study was to define the optimal criteria for detecting viable myocardium and predicting postrevascularization recovery with rest-redistribution 201Tl SPECT. METHODS: In 29 patients with left ventricular dysfunction, tracer activity within asynergic segments was quantified on rest and redistribution 201Tl SPECT. Viability was defined by the presence of functional recovery, which was detected by comparing wall motion in baseline and follow-up echocardiography. Discriminant function analysis and receiver operating characteristic (ROC) curve analysis were used to evaluate the relationship between 201Tl data and viability. RESULTS: Of 214 dysfunctioning segments (135 a-/dyskinetic), viability was demonstrated in 115 (75 a-/dyskinetic). Both rest and redistribution 201Tl activity in these segments were significantly higher than they were in the nonviable segments (p < 0.0001). Significant (> 10%) reversibility was observed in 39% of the viable and in 36% of the nonviable segments (p = 0.81). Discriminant analysis identified redistribution activity, followed by rest activity, as the most effective predictors of functional recovery. Similar areas were found under the ROC curve for rest (0.68 +/- 0.037) and for redistribution activity (0.70 +/- 0.036) (p = 0.13). ROC curve analysis identified the optimal cutoff for redistribution activity at < 60%, with 147 of 214 (69%) segments correctly classified (sensitivity = 78% and specificity = 58%). In the subset of a-/dyskinetic segments, redistribution activity presented a significantly larger ROC curve area (0.81 +/- 0.038 compared to 0.77 +/- 0.042, p < 0.05), and 103 of 135 (76%) segments were correctly classified (sensitivity = 81% and specificity = 70%). CONCLUSION: Redistribution activity is the most important parameter to be considered in rest-redistribution 201Tl to differentiate viable from nonviable segments; rest activity is also valuable, whereas the meaning of reversibility appears limited. Cutoff values about 60% appear to give the most reasonable balance between sensitivity and specificity.