[Challenges and concerns in early-phase clinical trials].
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Clinical Trials, Phase I as Topic↗
Biomedical subjects
A Gordin
Publications and source records attributed to A Gordin.
The circadian heart rate but not blood pressure profile is influenced by the timing of beta-blocker administration in hypertensives.
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Atenolol↗
Inhibition of human erythrocyte and gastroduodenal catechol-O-methyltransferase activity by nitecapone.
The effect of increasing single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor, nitecapone, on enzyme activity in red cells (RBC) and gastroduodenal COMT activity has been studied in healthy male volunteers. A dose-dependent decrease in RBC COMT activity was seen in all cases after 1 to 150 mg of the drug. The highest dose of 300 mg did not produce much more inhibition of COMT than 150 mg. The inhibition was not complete; at the highest doses the COMT activity was reduced by 50-60%. The effect and the duration of the inhibition in RBC COMT was strongly correlated with plasma nitecapone concentrations in the dose range up to 150 mg. RBC COMT activity recovered fully in 4 h after medication. Gastric mucosal COMT activity was several-fold higher than that in RBCs. It was also dose-dependently inhibited at the two doses (25 and 100 mg) studied. The inhibition of gastric and duodenal COMT was greater than that in RBCs. This also indicates that nitecapone is locally active in the gastroduodenal tract. The results confirm nitecapone as a potent COMT inhibitor in human tissues. New COMT inhibitors may provide a valuable approach to the treatment of Parkinson's disease in combination with L-dopa and dopa decarboxylase inhibitor therapy.
Adult↗
Penetration of erythromycin into periapical lesions after repeated doses of erythromycin acistrate and erythromycin stearate: a pilot study.
In 26 patients who had undergone apicectomy and extirpation of granulomas (n = 9) or radicular cysts (n = 17), concentrations of erythromycin, 2'-acetyl erythromycin, and their anhydro forms were determined with a novel chemical method in plasma and periapical lesions after at least 2 days of treatment with erythromycin acistrate (EA) (400 mg three times daily, n = 11) or erythromycin stearate (ES) (500 mg three times daily, n = 15). Oral surgery was performed 2 1/2 to 3 hours after the last dose. Blood samples were collected at the time of operation, and immediately before antibiotic treatment, and 1, 2, and 6 hours after treatment. At all time points EA produced at least twice the total antibiotic (2'-acetyl erythromycin plus erythromycin) concentrations in plasma as ES. Erythromycin levels in plasma were at least as high after EA treatment as after ES. In periapical lesions erythromycin concentration after EA was three times higher (1.34 +/- 0.28 micrograms/gm) than after ES treatment (0.40 +/- 0.17 micrograms/gm). Although the total drug concentration in periapical lesions was about the same after EA (2.64 micrograms/ml) and ES (3.41 micrograms/ml), most of the drug recovered after ES was antimicrobially inactive anhydroerythromycin (3.01 micrograms/gm). The concentration of anhydroerythromycin in plasma was approximately the same as that of erythromycin after ES throughout the dose interval. After EA treatment both plasma and the periapical lesion samples contained hardly detectable amounts of anhydroerythromycin. Hence EA has a good bioavailability essential for treatment and prophylaxis of bacterial infections in dentistry.
Adult↗
COMT inhibition with nitecapone does not affect the tyramine pressor response.
Nitecapone (OR-462) is a new selective COMT inhibitor with gastroprotective properties. The aim of the present study was to determine whether nitecapone potentiates the haemodynamic effects of a tyramine-induced increase in catecholamine release. The systolic blood pressure response to tyramine was studied in 11 healthy male volunteers (age 20-32 years). Tyramine was given i.v. as rapid bolus injections in increasing doses without drug intake and after oral intake of single doses of 25 mg and 100 mg of nitecapone. The tyramine dose required to increase systolic blood pressure by 30 mm Hg ('pressor dose') was 4.98 mg, 5.04 mg and 4.88 mg after no medication, and with 25 mg and 100 mg of nitecapone, respectively. There were also no differences in the systolic blood pressure response vs time curves between the three regimens. COMT inhibition with nitecapone did not potentiate the haemodynamic responses to tyramine-induced catecholamine release.
Adult↗
Effect of erythromycin on the oro-caecal transit time in man.
Erythromycins often cause gastrointestinal side-effects due to an increase in motility or to change in the intestinal bacterial flora. In order to evaluate the effect of erythromycin on gastrointestinal motility. 11 healthy volunteers were given placebo, erythromycin stearate (ES) 1000 mg or a therapeutically equivalent single dose of erythromycin acistrate (EA.2'-acetyl erythromycin stearate) 800 mg in a double-blind trial. The oro-caecal transit time was measured using the hydrogen breath test with lactulose as the substrate. The transit time was estimated from the H2-peak (ppm) in end-expiratory breath by two methods, t1 representing the "front" and t2 the "bulk" of lactulose reaching the colon. t1 was 51 min in the placebo group, 38 min in the EA and 31 min in the ES group (p less than 0.05, ES vs placebo). t2 was 74 min, 64 min, and 46 min, respectively (p less than 0.05, ES vs placebo). The difference between EA and ES was also significant. Six subjects in the ES group but none in the EA group recorded adverse gastrointestinal effects attributable to medication. It was concluded that erythromycin shortens the oro-caecal transit time in man and that EA effects the transit time slightly less than ES.
Adult↗
Exercise hemodynamics and catecholamine metabolism after catechol-O-methyltransferase inhibition with nitecapone.
The effect of catechol-O-methyltransferase inhibition with nitecapone (OR-462) on the hemodynamic responses to exercise and catecholamine metabolism was studied in 10 healthy male volunteers (aged 19 to 26 years). Nitecapone, a new specific and selective catechol-O-methyltransferase inhibitor, was given at increasing single oral doses up to 100 mg. Nitecapone did not influence resting or exercise heart rate, blood pressure, systolic time intervals, or plasma catecholamine levels. It altered the metabolic profile of catecholamines as shown by (1) an increase of 140% in the plasma concentration of the monoamine oxidase-dependent metabolite 3,4-dihydroxyphenylethyleneglycol (p less than 0.001), (2) a decrease of 27% in the plasma concentration of its methylation product 3-methoxy-4-hydroxyphenylethyleneglycol (p less than 0.05), and (3) a 25% reduction in the urinary excretion of the methylated metabolites 3-methoxy-4-hydroxymandelic acid and homovanillic acid (p less than 0.05). Nitecapone was well tolerated and seemed to be hemodynamically safe in humans.
Adult↗
Effect of a novel catechol-O-methyltransferase inhibitor, nitecapone, on the metabolism of L-dopa in healthy volunteers.
A new catechol-O-methyltransferase (COMT) inhibitor, nitecapone, was given in increasing doses of 0-100 mg concomitantly with L-Dopa/carbidopa (100/25 mg or 100/100 mg) to healthy male volunteers. Plasma concentrations of L-Dopa, 3-O-methyldopa (3-OMD), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), as well as the excretion of catecholamine metabolites in urine were followed to evaluate the changes in the metabolism of L-Dopa after nitecapone. Plasma concentrations of nitecapone and the soluble COMT activity in erythrocytes were also measured. The area under the plasma concentration-time curves (AUC) values for plasma nitecapone, L-Dopa and its metabolites were calculated. Nitecapone dose-dependently inhibited the soluble COMT activity in erythrocytes at 30 min after drug intake. Nitecapone slightly but significantly increased the relative bioavailability of L-Dopa. The AUC values of plasma 3-OMD decreased dose-dependently after nitecapone, and those of HVA decreased less, whereas the AUC values of DOPAC increased significantly. The elevation of the dose of carbidopa from 25 to 100 mg increased the AUC value of L-Dopa, but the effect of nitecapone was not clearly modified. Nitecapone decreased the excretion of the methylated dopamine metabolites 3-methoxytyramine (3-MT) and HVA at an L-Dopa/carbidopa dose of 100/25 mg. At a dose of 100/100 mg, the excretion of metanephrine, in addition to 3-MT and HVA, was also significantly decreased by nitecapone. The biochemical changes in L-Dopa metabolism and erythrocyte COMT activity indicate that nitecapone is an active COMT inhibitor in humans, when given orally in single doses. The changes in L-Dopa metabolism by COMT inhibitor warrant further clinical studies in Parkinson's disease.
Adult↗
Effect of Lactobacillus GG yoghurt in prevention of antibiotic associated diarrhoea.
The efficacy of Lactobacillus GG yoghurt in preventing erythromycin associated diarrhoea was studied. Sixteen healthy volunteers were given erythromycin acistrate 400 mg t.i.d for a week. The volunteers were randomly assigned into two groups taking twice daily 125 ml of either Lactobacillus GG fermented yoghurt or pasteurized regular yoghurt as placebo during the drug treatment. Subjects receiving Lactobacillus GG yoghurt with erythromycin had less diarrhoea than those taking pasteurized yoghurt. Other side effects of erythromycin, such as abdominal distress, stomach pain and flatulence, were less common in the GG yoghurt group than in the placebo yoghurt group. The subjects receiving Lactobacillus GG yoghurt were colonized with these bacteria even during erythromycin treatment as measured by faecal counts of total Lactobacillus GG. No Lactobacillus GG was found in the faecal samples of volunteers in the group taking pasteurized yoghurt.
Adolescent↗
Sulpiride and perphenazine in schizophrenia. A double-blind clinical trial.
Seventeen patients with acute schizophrenia and 30 with chronic schizophrenia were included in a randomized, double-blind parallel-group trial comparing sulpiride and perphenazine. Patients were evaluated using the 16-item Brief Psychiatric Rating Scale (BPRS) prior to the onset of treatment and 1 and 2 weeks, and 1, 2, 3, and 4 months thereafter. In patients with acute schizophrenia, total BPRS scores declined significantly at the end of the trial compared with pretreatment values in sulpiride-treated patients but not in schizophrenics treated with perphenazine. Differences in response between the groups did not reach statistical significance, however. For patients suffering from chronic schizophrenia, a statistically significant decline was observed in total BPRS scores at 4 months compared with pretreatment scores in both sulpiride and perphenazine groups. There was no significant difference in the treatment response between the groups. Sulpiride appeared to be somewhat more effective than perphenazine for treatment of acute schizophrenia. Efficacy of both compounds was less marked in chronic forms of schizophrenia.
Acute Disease↗
Effect of erythromycin acistrate and erythromycin stearate on human colonic microflora.
The effects of erythromycin acistrate (2'-acetyl erythromycin stearate), a new erythromycin derivative, and erythromycin stearate on the faecal microflora were compared in a randomized cross-over study. 12 healthy volunteers were given either drug 500 mg t.i.d. for 1 week. Their faeces were studied before, immediately after, and 1 week after the drug administration period. After a wash-out period of 4 weeks, the drugs were interchanged. Both erythromycin acistrate and erythromycin stearate induced changes in the normal colonic microflora to about the same extent. The most marked effect was the suppression of gram-negative anaerobic and aerobic rods. Clostridium difficile appeared in 1 subject on both drugs. Also the counts of aerobic gram-positive cocci were altered; enterococci increased in number. An increased resistance to erythromycin was noted among staphylococci and enterococci after both drugs.
Adolescent↗
The effect of calcium channel blocking on immune capacity of cardiovascular patients.
Calcium channel blocking drugs are widely used in the treatment of cardiovascular diseases. In vitro these drugs have been shown to block mitogen-induced lymphocyte proliferation. Their possible immunosuppressive effect has been tested especially in combination with cyclosporine A. In the present work, the effect of the calcium channel blocking drug verapamil on immune functions of cardiovascular patients was studied. The changes in leukocyte subpopulations, mitogenic responses and immunoglobulin production were determined during a three-month therapy. A significant increase in suppressor/cytotoxic cell number was detected and a decrease in the CD4/CD8 ratio, although the values were still within normal range. The responses to T and B cell mitogens remained unchanged. No significant decrease could be detected in immunoglobulin production either, despite minor changes in IgM. Our results indicate that the immunologic effects of verapamil at therapeutic doses are of little clinical significance.
Adult↗
Comparison of potassium alone and potassium-magnesium supplementation in patients with heart failure using hydrochlorothiazide.
Supplementation of potassium alone and in combination with magnesium was compared in 10 patients with chronic compensated heart failure receiving hydrochlorothiazide 50 mg twice daily for the whole trial. After a 3-week run-in period, the patients were randomized to receive active supplementation for 6 weeks in a double-blind cross-over manner. A 3-week wash-out period was kept in between. Addition of 2 g potassium chloride daily (27 mmol K+) did not efficiently correct the serum potassium concentration. After the combined supplementation of 2 g potassium and 1 g magnesium (27 mmol K+ and 17 mmol Mg2+ daily), both serum potassium and magnesium concentrations increased statistically significantly during the first 2 weeks of treatment. After a longer treatment of 6 weeks, the effect of combined supplementation was less clear, even though a trend toward a better maintenance of serum potassium was still evident.
Aged↗
Bilateral Baker's cyst as the presenting symptom of paraneoplastic syndrome.
Paraneoplastic syndrome is defined as a systemic malignancy producing prostaglandins or other substances that lead to various manifestations, syndromes or diseases. In the following report we present a case of a young patient complaining of bilateral Baker's cysts who ultimately was diagnosed as suffering from gastric lymphoma. Following subtotal gastrectomy the Baker's cysts disappeared with no specific treatment.
Adult↗
Efficacy and tolerability of erythromycin acistrate and erythromycin stearate in acute skin infections of patients with atopic eczema.
The efficacy and tolerability of a new erythromycin derivative, erythromycin acistrate (EA), were compared with that of erythromycin stearate (ES) in 42 patients with infected atopic eczema. The dosage of EA was 400 mg tid and that of ES 500 mg tid. The duration of treatment ranged from five to 12 days. The patients were hospitalized and evaluated before treatment and on the last day in hospital. The infective pathogen was usually Staphylococcus aureus in both groups. Without local antibacterial treatment both drugs eradicated the bacteria in more than 60% of the cases. Gastrointestinal side effects were frequently reported with both drugs, more often in the ES- than in the EA-group, but the difference was only statistically significant (p less than 0.05) with respect to diarrhoea. One patient in each group discontinued treatment because of gastrointestinal side effects. No elevations in liver enzymes of clinical significance were reported in either group.
Administration, Cutaneous↗
Erythromycin acistrate and erythromycin stearate in the treatment of non-gonococcal urethritis.
The antibacterial efficacy and tolerability of erythromycin acistrate (EA) and erythromycin stearate (ES) were compared in 100 male patients with non-gonococcal urethritis (NGU). The dosage of EA was 400 mg tid and that of ES 500 mg tid. Mean duration of treatment was ten days. When the final evaluation of the trial was made, the patient material was divided into two groups. One group consisted of patients with chlamydia-positive culture before treatment, the other of chlamydia-negative patients with signs of infection in the direct smear. There were 17 patients with chlamydial infection in the EA-group, and the microbiological cure rate was 100%. In the ES-group there were 21 patients with chlamydial infection and the microbiological cure rate was 95%. In the EA-group, the cure rate of chlamydia-negative NGU patients was 78%, and the corresponding figure in the ES-group was 86%. There was no difference in the cure rates between the two groups on either drug. In the EA-group, 25 patients (50%) reported side effects, in 22 these were gastrointestinal. In the ES-group, 26 patients (52%) reported side effects; in 22 these were gastrointestinal. Two patients in the EA-group discontinued the treatment because of gastrointestinal side effects. There were no differences between the groups in the frequency, severity and duration of side effects.
Adolescent↗
Tonsillar penetration of erythromycin and its 2'-acetyl ester in patients with chronic tonsillitis.
Concentrations of erythromycin and 2'-acetyl erythromycin were analysed in serum or plasma and tonsil tissue after repeated dosage of erythromycin acistrate (EA), a new erythromycin prodrug, in two separate studies in 61 young patients. The reference preparations were: (1) enterocoated tablets of erythromycin base (EB enterotablets, (2) erythromycin base as enterocoated pellets (EB enterocapsules) and (3) erythromycin stearate (ES). All drugs were given 500 mg tid for three days before scheduled tonsillectomy. Tonsils were removed about 3 h after intake of the last dose. Blood samples were collected at 0, 2 and 6 h and at the time of tonsillectomy. At all time points EA produced several-fold higher total drug (erythromycin + 2'-acetyl erythromycin) concentrations in serum or plasma than any of the reference preparations. Similarly, after EA the mean total antibiotic levels in tonsil tissue exceeded the erythromycin levels after the reference preparations by at least a factor of 3. Tonsil/serum or plasma ratios of the total antibiotic were quite similar with all preparations (means 38-50%). Peak erythromycin levels in circulation did not differ significantly from each other in spite of two nonabsorbers after EB enterotablets. The same was true of tonsil tissue. There were, however, 15 tonsils with undetectable erythromycin: 4/25 (16%) with EA, 5/12 (42%) with EB enterotablets, 2/12 (17%) with EB enterocapsules and 4/12 (33%) with ES. The degree of hydrolysis of 2'-acetyl erythromycin to erythromycin was 23-43% higher in tonsil tissue than in circulation.
Adolescent↗
Comparison of erythromycin acistrate and enterocoated erythromycin base in acute respiratory infections.
The efficacy and tolerability of erythromycin acistrate (EA), a new erythromycin derivative, and enterocoated erythromycin base (EB) were studied in 183 outpatients belonging to the personnel of Helsinki University Central Hospital. The patients had acute respiratory tract infections. The dosage of EA was 400 mg tid and that of EB 500 mg tid, and the treatment period ranged from seven to 14 days. The cure rate of patients taking full courses of treatment was good in both treatment groups, 96% in the EA-(n = 81) and 93% in the EB-group (n = 73). EA caused statistically significantly (P less than 0.05) less gastrointestinal side effects than EB. These side effects were also milder in the EA- than in the EB-group. The treatment was discontinued in seven patients (7%) in the EA- and in 12 patients (13%) in the EB-group because of gastrointestinal side effects. Neither of the drugs caused clinically important elevations in liver enzymes, nor were changes observed in the laboratory safety parameters measured. EA seems thus to be as effective as and better tolerated than enterocoated EB.
Acute Disease↗