A modern approach to the evaluation of combined effects of two active drugs, A and B, in clinical trials is described, based on modern understanding of actions and interactions of drugs which act at distinct molecular sites. It rests on a comparison of observed combined effects with calculated effects of independent action of A plus B--greater than independent effects are considered as a potentiated response. It is illustrated by reanalysis of single-dose and time-course studies of the antisecretory action of pirenzepine and H2-receptor antagonists (cimetidine, ranitidine). Briefly, peptone-stimulated acid output was measured in 15 min periods over 3 h after the injection of drugs in three trials, one with five duodenal ulcer patients, two of them with 8 healthy volunteers each. The doses of pirenzepine and H2-blockers were fixed in each trial. The results were either expressed by the total acid output (single-dose analysis) or by the acid secretion over 15 min as time course. The results with the drug combination show greater reduction in acid secretion in all three trials with respect to independent effects. The time-course studies more clearly showed greater reduction in acid output than the analysis of total acid output, not the least with respect to p-values of differences between observed combined effects and calculated independent effects. They were obtained by the chi-square (chi 2) goodness-of-fit test, recently applied for the evaluation of dose-response curves.(ABSTRACT TRUNCATED AT 250 WORDS)
Verapamil is a calcium channel blocker widely used as an antihypertensive agent, and its pharmacological effects may partly be due to some degree of beta blockade. In order to evaluate the changes occurring in beta-2 adrenoceptor density, 40 patients with mild to moderate hypertension received verapamil 240 mg (once a day) or captopril 20 mg (twice a day) during 30 days, in a double-blind randomized study, after a placebo run-in period. The lymphocytic membrane beta-2 adrenoceptor density (Bmax) was determined before the administration of active drugs and after a 15-day treatment. After a month of treatment, most patients showed a marked reduction of their diastolic blood pressure: from 98.2 +/- 3.2 mmHg to 81.2 +/- 4.0 mmHg (p < 0.05), in the verapamil group, and from 95.0 +/- 6.0 mmHg to 82.5 +/- 4.8 mmHg (p < 0.05) in the captopril group. After 15 days of treatment, verapamil induced an up-regulation of beta-2 adrenoceptors from 39.5 +/- 8.3 fmol/mg protein to 58.5 +/- 12.0 fmol/mg protein (p < 0.05), whereas the Bmax in the captopril group did not significantly change. No significant change occurred in the two dissociation constants. This up-regulation phenomenon, common among beta-2 blockers, supports the hypothesis of verapamil's beta blockade potency.
A single dose comparative bioavailability study and an in vitro evaluation were conducted on two sustained-release formulations of diclofenac sodium (Voltaren "V" and Diclogesic "D"). The two products were found similar in weight and content uniformity. The in vitro dissolution, however, revealed that product D has a significantly faster rate of drug release compared to product V. The bioavailability study was carried out on 15 healthy male volunteers, who received a single oral dose (100 mg tablet) of each product according to a randomized crossover design. Blood samples were obtained over a 12 h period, and drug concentrations were determined by an HPLC assay. The two products were not found to be statistically different with respect to the lag time between dosing and appearance of the drug in the serum (0.8 +/- 0.2 and 0.6 +/- 0.1 h for V and D, respectively), or in the time needed to attain the peak concentrations (4.5 +/- 0.8 and 4.1 +/- 0.9 h for V and D, respectively). The two products, however, varied in the peak serum concentration (736 +/- 125 and 536 +/- 63 ng.ml-1 for V and D, respectively), but this difference was not statistically significance. In terms of the extent of absorption, assessed by estimating the area under the concentration-time curve over 12 h, the two products were not significantly different (3,340 +/- 270 and 3,045 +/- 294 ng.h.ml-1 for V and D, respectively). These in vitro and in vivo findings indicate that Diclogesic is characterized by sustained-release properties which are comparable to Voltaren.
The effect of in vitro carbamylation of serum protein with potassium cyanate on protein binding of penbutolol, a basic agent exclusively bound to alpha 1 acid glycoprotein (AAG), was investigated. Carbamylation of serum resulted in a weak increase on free fraction of penbutolol (4.45 +/- 0.54% before carbamylation vs 5.66 +/- 0.40% after; p < 0.025). Parallelly, potassium cyanate added to pure AAG and incubated for 90 min induced carbamylation of this protein (38 mumoles of 14C cyanate incorporated per gram of protein). A study in serum from patients with chronic renal disease (pre and postdialysis) showed no changes in protein binding of penbutolol, although AAG levels were significantly higher. However, Scatchard [1949] plot for penbutolol binding to serum from renal patients (both pre and postdialysis) showed a decrease in affinity constant (nKa = 11.13 x 10(5) M-1 in healthy volunteers, vs 5.56 x 10(5) M-1 in patients before dialysis and 4.57 x 10(5) M-1 after dialysis). We concluded that carbamylation of serum AAG in uremic patients could explain, in part, the absence of changes in protein binding of any basic drugs in this pathological condition. It appears that a decreased affinity constant could balance the effect of increased AAG levels.
In order to enable the setting of regulatory criteria for the equivalence of absorption rates on a sound scientific basis, the variation of Cmax/AUC and Cmax was evaluated. Under most conditions, the variation of Cmax/AUC was 10-25% higher than that of AUC independently of the variability of the extent of absorption. By contrast, the variation of Cmax was 50-60% higher than that of AUC and was strongly dependent on the variability of the extent of absorption. Therefore, it is recommended that for establishing the equivalence of absorption rates, the 90% confidence limits for the percentage ratio of the Cmax/AUC values of two drug products should be (based on their logarithmic averages or medians) between 75 and 133%. Regulatory decisions based on Cmax, while not favored, should expect that the 90% confidence limits for the percentage ratio of the Cmax values of two drug products be (based on their logarithmic averages or medians) between 70 and 143%. These recommendations parallel and are contingent upon the internationally harmonized criterion for the equivalence of extents of absorption which requires that the 90% confidence limits for the percentage ratio of two AUC values (based on their logarithmic averages or medians) be between 80 and 125%.
Tumor necrosis factor-alpha (TNF alpha), a potential regulator of HIV-1 replication, is involved in the progression of AIDS and associated disorders such as muscle wasting, fever and gastrointestinal problems. HIV-seropositive patients were assigned to receive zidovudine (ZDV; 100 mg 4-5 times/d) alone (n = 14), pentoxifylline (PTX; 400 mg every 8 h), a drug known to block TNF alpha release (n = 7), or PTX and ZDV (n = 11) for 12 weeks in a prospective, open-label study. Weekly compliance checks and biweekly blood and 24-h urine samples were obtained for immunological assessments. Baseline TNF alpha levels were elevated in all study patients, independent of disease stage. There were no appreciable differences in immunologic variables (CD4 counts, total and unbound p24 antigen, TNF alpha, beta 2-microglobulin, and urinary neopterin levels) between groups. The mean HIV-1 viral load, as measured by a quantitative polymerase chain reaction technique, was 1.9-fold above baseline values after 12 weeks of ZDV and PTX compared with 8- to 9-fold greater levels in patients given either agent alone (p < 0.05). TNF alpha levels correlated with viral load (r = 0.67; p < 0.0001) in patients given the combined drug regimen. Virological evidence of lack of progression in AIDS patients suggests the beneficial use of ZDV and PTX in delaying progressive HIV-1 disease compared with each drug alone.
Pharmacokinetic measurements were performed in two groups of patients with coronary heart disease (CHD) after single and multiple dosing of 2 mg linsidomine (SIN 1). The drug was administered by intravenous short time infusion in 12 CHD-patients with renal insufficiency (RI group, Clcr: 11 +/- 6 ml/min) and in 12 CHD-patients with normal kidney function (control group, Clcr: 88 +/- 22 ml/min). The measurement of plasma concentration time courses of total SIN 1C (SIN 1 + SIN 1C) was found to be suitable for an estimation of the SIN 1C related half-life of the terminal phase (t50% = 1.5 +/- 0.5 h), as SIN 1 was eliminated from plasma rapidly (t50% = 12 to 20 min). Furthermore, the mean total SIN 1C plasma profiles were equal after single and multiple administration of the drug giving evidence that SIN 1C is not accumulating during repetitive dosing of SIN 1 in patients with renal disease. The mean maximum renal fraction of total SIN 1C excretion of RI-subjects (fe = 0.8 +/- 0.8% of dose) was significantly different from the corresponding mean value of the control group (fe(N) = 5.8 +/- 5.1% of dose). No differences were found for fe and fe(N) between day 1 and day 4. As SIN 1 is degraded in plasma very rapidly and as SIN 1C is cleared mainly extrarenally, any restrictions concerning repetitive SIN 1 dosage regimen should not be considered for CHD-patients with renal failure.
The interactions of chlorpromazine, clomipramine, maprotiline and viloxazine hydrochlorides, and of clorazepate dipotassium salt and diazepam with polyvinyl chloride (PVC) and Stedim 6 infusion bags were studied. Stedim 6, is anew multilayer film whose inner layer is made of polyethylene. The drugs were in 5% dextrose and 0.9% sodium chloride isotonic solutions and the influence of these was also considered. The remaining concentrations of each drug were determined at regular time intervals in a 24-h period, by a spectrofluorometric method for chlorpromazine hydrochloride and by ultraviolet spectrophotometric methods for the other drugs. No binding was observed for viloxazine and maprotiline hydrochlorides whatever the infusion solution and the plastic container. A slight retention in PVC bags, but not in Stedim 6 ones, was noted for clomipramine hydrochloride and clorazepate dipotassium salt. This was more marked in the sodium chloride solution than in the dextrose one. Diazepam and chlorpromazine hydrochloride were bound both in PVC and Stedim 6 bags, but more in the former and more again in the sodium chloride solution than in the dextrose one. The results were explained in terms of the degree of crystallinity of the plastic material and the degree of lipophilicity of the drugs. Practical consequences are discussed.
Twenty-one healthy, caucasian, male volunteers completed this randomized single blind, multiple-dose, crossover bioavailability study during which either phentermine HCl capsules (Minobese Forte, reference product) or phentermine base capsules (Duromine, test product) were ingested once daily for 14 days. A washout period of 14 days was allowed between the two treatment phases. On profile days (day 14 of each treatment phase) subjects remained recumbent for 24 hours after drug administration. Serial venous blood samples were drawn over the 24 hour dosing interval for plasma phentermine assay by gas chromatography. The 90% confidence intervals for the "test/reference" mean ratios of the pharmacokinetic variables Cmax,norm, Cmin,norm, AUCnorm (normalized for difference in the dose of phentermine base), %PTF and T75% Cmax, all fell within the bioequivalence range of 80% to 125%. With the aid of trough plasma phentermine concentrations, it was established that steady-state was reached after 14 days of once daily administration of either product. Adverse events experienced on both treatments included prolonged or recurrent episodes of insomnia, nausea, headache, dry mouth and dizziness. No clinically relevant changes in clinical chemistry or hematology variables occurred during the study.
Two new bioavailability parameters were recently suggested [Koeleman et al. 1991] to define (i) the time that the concentration in the blood stays above a defined minimum effective concentration, te and (ii) the onset of the effect, to. In addition to conventional bioequivalence parameters, the new bioavailabilty parameters (to and te) were calculated in this study and statistically compared for penicillin, chloroquine, oxytetracycline, amoxycillin and flucloxacillin from available bioequivalence data. For oxytetracycline, flucloxacillin and amoxycillin, the conventional bioavailability parameters indicated partial equivalence whereas using the te and to parameters, more realistic indications of the possible extent of the performance of a drug from dosage forms were obtained than with the conventional bioequivalence parameters. The new parameters gave additional information for a better evaluation of the performance of a drug from a dosage form.
Triazolam is an effective hypnotic that can cause amnesia and psychomotor performance decrements, particularly after a 0.5 mg dose. Previous pharmacodynamic studies suggested a relationship between these effects and triazolam plasma concentration. A novel dual release bilayer tablet was designed to mimic the onset of action of a 0.25 mg dose and to maintain the duration of a 0.5 mg dose without the side effects associated with the 0.5 mg dose. The immediate release component of the bilayer tablet contained 0.25 mg triazolam while the sustained release component contained 0.15 mg triazolam. Two prototype formulations of the bilayer tablet, differing in rate of release in the sustained release component, were tested against a conventional 0.5 mg triazolam compressed tablet and placebo in a single-dose, double-blind, four-way crossover study in healthy male subjects. Triazolam plasma concentration time profile was obtained over 12 hours following single administration of each treatment. Effects of triazolam on central nervous system function were evaluated using psychomotor performance tests, immediate and delayed recall tests and rating of sedation. The triazolam plasma concentrations were not significantly different among the active drug treatments, although the dual release tablets did give the expected profiles. There were significant differences in triazolam effects on memory and psychomotor performance. The slowest releasing dual-release tablet showed significantly less psychomotor impairment and memory deficit than the conventional tablet. There was no difference in sedation among the active drug treatments.(ABSTRACT TRUNCATED AT 250 WORDS)
Plasma kinetics and beta-receptor blocking and -binding activity of timolol was studied in six healthy volunteers following its intravenous 0.25 mg dose. Timolol concentrations were measured using radioreceptor assay (RRA), blocking activity by comparing the dose ratios (DRs) of the infusion rates of isoprenaline required to increase heart rate by 25 bpm (I25) and binding activity by determining the extent to which timolol occupied beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes in undiluted plasma samples. Timolol was eliminated from plasma with a mean half-life for the elimination phase of 2.6 hours. The dose antagonized potently isoprenaline-induced tachycardia at least for four hours. The effect was excellently correlated with the estimated beta 2-receptor binding activity of timolol in the circulating plasma. In conclusion, the small intravenous timolol dose was eliminated from plasma by a fashion, which was very similar to its eighty-fold higher oral doses reported earlier in the literature. The 0.25 mg dose was of considerable systemic beta-receptor blocking and -binding activity, that may help to explain its reported side-effects following ocular drug administration. The extent to which beta-blocking agents occupy rabbit lung beta 1- and rat reticulocyte beta 2-receptors in the circulation appears to predict the intensity and selectivity of their beta-blocking effects in healthy volunteers.
Cocaine abuse today has reached greater heights than it did during the first cocaine epidemic in the late nineteenth century. It is estimated that one out of every four Americans has used cocaine and some six million people in the US use it regularly. Although cocaine affects all systems in the body, the central nervous system (CNS) is the primary target. Cocaine blocks the reuptake of neurotransmitters in the neuronal synapses. Almost all CNS effects of cocaine can be attributed to this mechanism. Euphoria, pharmacological pleasure and intense cocaine craving share basis in this system. The effects of cocaine on other organ systems, in addition to its effects on the CNS, account for the majority of the complications associated with cocaine abuse. In this paper, the CNS effects following cocaine administration and their treatment are discussed.
The aim of the study was to investigate the extent of prescription drugs administered for common disorders during the post partum period. This is a prospective survey of disorders and drug use in 1) immediate postpartum mothers (n = 200) admitted to the maternity wards, 2) in post-natal hospital follow-up clinic (n = 200) and in 3) the rural home based community (n = 100). A pretested questionnaire was filled in by medical officers after interviewing the mothers. The mean age of the mothers was 25 years and a literacy rate of 50% above the 10th grade. Over 80% of the women were multigravida in the entire sample; 45% underwent Caesarean Section in a hospital; 97.6% had a normal delivery in the community. In the hospital settings 4.1% infants had jaundice and 1% had congenital anomalies. In the community setting, diarrhoea and pneumonia was seen in 2.6% of the infants. Apart from the use of nutritional supplements, such as iron, calcium, multivitamins etc., most commonly prescribed drugs were analgesics (in 70% of patients in the hospital settings, 56% of the patients in the postnatal clinic and 37.6% patients in the community), and antibiotics (90% of the patients in the hospital settings, 86% of the patients in the postnatal clinic and 13% of the community based patients). Antihypertensives agents (2.5% of the patients), digoxin (1.5% of the patients), bronchodilators (1% of the patients) and sedatives (3.5% of the patients) were prescribed to admitted patients.(ABSTRACT TRUNCATED AT 250 WORDS)
In this brief review the preclinical safety studies on iron protein succinylate (synonym: ITF 282) are presented. Iron protein succinylate is an iron-protein complex, in which iron is present in ferric form. It has been developed for oral iron-supplementation therapy and is characterized by a very favorable tolerability profile. The acute toxicity of iron protein succinylate to rodents is very low, indicating a substantial margin of safety with respect to accidental child poisonings. In chronic toxicity studies of 52-week duration in rats and dogs, there were no findings of toxicological significance. In particular, there were no alterations in hematological parameters and no histopathological findings consistent with iron overload damage. Some deposition of iron was noted in the spleen and liver of the treated dogs. A series of reproductive toxicology studies were performed to assess the effects on fertility (in the rat), peri- and postnatal reproductive function (in the rat) and fetal toxicity (in the rat and the rabbit). Treatment with iron protein succinylate did not result in any adverse effect on reproductive performance nor did it affect the incidences of malformations, visceral and skeletal anomalies or skeletal variants. There was no evidence of mutagenic activity in a comprehensive series of in vitro and in vivo mutagenicity studies. No secondary pharmacological effects of the product were noted in a wide range of single and repeated administration studies. Overall, the available toxicology and safety profile of this product offers ample assurances of the safety of iron protein succinylate in clinical use.
In diseases with generalized edema caused by decompensated heart and liver diseases or kidney failure digitalis preparations, diuretics and theophylline -- if lung disease accompanies one of the above states -- are often used. Literature dealing with theophylline, digoxin and furosemide pharmacokinetics in edematous diseases was analyzed as well as theophylline or digoxin interactions with furosemide. The results obtained in these investigations are very dissimilar, even contradictory. In all the drugs investigated, it was found that serum drug concentration was reduced, that there were no changes in comparison with non-edematous diseases and that drug concentrations were elevated in edematous diseases. Many problems in this field remain unsolved requiring further investigations of digoxin, theophylline and furosemide pharmacokinetics in liver, heart and kidney diseases accompanied by edema. As these drugs are often administered in these states, and having in mind their narrow therapeutic range (digoxin, theophylline), intoxication or a drug concentration decrease below the possibility of inducing any therapeutic effect are possible.
We administered xylitol intravenously to normal subjects to investigate the mechanism of xylitol-induced increase in the purine degradation in humans. Xylitol increased the plasma concentrations of hypoxanthine, xanthine and uric acid but decreased the blood concentration of pyruvic acid. The erythrocyte concentrations of IMP, AMP, ADP, glyceraldehyde 3-phosphate and fructose 1,6-diphosphate as well as the urinary excretion of hypoxanthine and xanthine were increased, while the erythrocyte concentration of ATP was decreased. In addition, the in vitro incubation studies using erythrocytes demonstrated that both xylitol-induced purine degradation and xylitol-induced inhibition of the conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate were protected by pyruvic acid. These results indicate that xylitol-induced impairment of glycolysis in erythrocytes contributes to the observed xylitol-induced increase in the purine degradation in the body.
A total of 502 children up to the age of 14 years were treated for iron deficiency or overt anemia. ITF 282 was prescribed to 256 children, and a commercially available ferrous polystyrene sulphonate preparation to 246, in a randomized double-blind, double-dummy, ten-center trial. One oral vial of ITF 282 (60 mg iron) was administered once a day to children weighing up to 40 kg; and twice a day to children with body weight equal or superior to 40 kg. In the reference group, oral vials of polystyrene sulphonate (52.5 mg iron) were administered once a day to children weighing up to 40 kg, and twice a day to children weighing 40 kg or more. Treatments lasted 60 days. The treatments' efficacy and tolerability were evaluated taking into consideration: special hematology, symptomatology, safety hematology and hematochemistry, urinalysis. At the end of treatment, the trend was detected to the normalization of the main hematologic parameters in both groups (hemoglobin, hematocrit, ferritin, blood iron, transferrin saturation, MCHC). Although in the first month the reference treatment appears to provide somewhat faster results, significantly greater values of blood iron are observed at the end of the observation in the ITF 282 group, indicating a more progressive and steady therapeutic effect. The overall clinical rating was, although not significant, in favor of ITF 282, with a failure rate of 18.0 vs 24.0%. The general tolerance, although favorable with both treatments, was significantly more favorable with ITF 282. With this medication, 13 patients complained of 13 events (1 heartburn, 6 constipation, 6 abdominal pain) vs 48 events reported by 43 patients with the reference medication (1 heartburn, 2 epigastric pain, 14 constipation, 14 abdominal pain, 3 skin rash, 14 vomiting). These observations confirm that, although the most modern preparations of ferrous ions exhibit a relatively low frequency of adverse events of limited clinical concern, it is nevertheless possible to decrease (with the use of more "physiologic" preparations in which the iron is reversibly bound to a protein carrier) the prevalence and, tendentially, duration and intensity of such events without prejudice for the clinical efficacy. Therefore, the good clinical tolerability of ITF 282 effectively removed one of the main obstacles to the correct compliance with iron treatments (necessarily to be taken long-term), as reduced the risks of undesired events in a particularly susceptible population subgroup, such as children.
A prospective, open, multicenter clinical trial was set up to evaluate the potential interaction of ITF 282 with H2-receptor antagonists in patients affected with iron deficiency. Patients treated with H2 blockers and affected with iron deficiency or iron deficient anemia were given one tablet of ITF 282 (60 mg iron) twice daily for 60 days. A second group of iron deficient patients with no anti H2 concurrent treatment were admitted to the same iron treatment, lasting 60 days. To evaluate the outcome of the iron treatment, a comprehensive assessment of laboratory and clinical determinations was adopted in all the patients: special hematology, symptomatology, safety hematology and hematochemistry, urinalysis. Fifty-three patients with iron deficiency and 47 patients affected with overt iron deficient anemia entered the study. After treatment, a significant trend toward the normalization of the main hematologic parameters in both groups was detected. The general tolerability was apparently more favorable in the patients who had also the antiulcer (1 event of diarrhoea) than in those who had ITF 282 alone (2 heartburn, 3 constipation, 2 abdominal pain). There were no indications of subgroups of patients particularly at risk of adverse events, all of which resulted reversible without the need to reduce the dose of medication or to take other medical action. ITF 282 resulted, also when administered together with H2-receptor antagonists, in the expected therapeutic efficacy, with the expected clinical tolerability and biological safety, without signs of possible interaction, negative or positive.(ABSTRACT TRUNCATED AT 250 WORDS)
For about 6 years after the marketing of oral formulations of fosfomycin calcium (FOM-Ca) in December, 1980, we collected the data on 35,481 cases and analyzed it regarding safety. Primary side-effects consisted mainly in gastrointestinal disturbances, damage to skin and adnexa, liver and bile duct disorders. Specifically, diarrhea, nausea, abdominal pain, anorexia, eruption and increased serum transaminase were frequent. Serious and newly detected side-effects after marketing were pseudomembranous colitis and melena, one case each. As for the oral administration of FOM-Ca to 83 patients hypertensive to beta-lactams, gastrointestinal side-effects were seen but none of them developed hypersensitivity, an allergic reaction.
