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Biomedical subjects

J M van Gerven

Publications and source records attributed to J M van Gerven.

At least 19 recordsLinked to original sources
PubMed2001

Concentration-effect relationships of two infusion rates of the imidazoline antihypertensive agent rilmenidine for blood pressure and development of side-effects in healthy subjects.

AIMS: The aim of this study was to compare the effect profiles of i.v. administered rilmenidine aimed at the same target plasma concentration, but attained with different rates. METHODS: The study was placebo-controlled, randomized, double-blind, double-dummy, three-way, cross-over in nine healthy volunteers. All subjects randomly received either a fast infusion, a slow infusion or a placebo infusion. The target concentration was set at 8 ng ml-1 with a fivefold difference in the time to reach the maximum concentration. Saccadic eye movements, electroencephalography (EEG), blood pressure and heart rate were measured every half hour. Drug plasma concentrations, adverse events, salivary flow and visual analogue scales were obtained every hour. RESULTS: Changes in systolic/diastolic blood pressure at the end of the infusion were (mean +/- s.d.) 13.3 +/- 16.4/7.9 +/- 7.5 mmHg with the fast infusion and 16.3 +/- 12.7/10.2 +/- 7.9 mmHg during the slow infusion, compared with 0.0 +/- 13.2/1.3 +/- 8.3 mmHg for the placebo occasion. Decrease of saccadic peak velocity (SPV) at the end of the infusion was 18.0 +/- 5.2% during the fast infusion, 23.0 +/- 7.0% with the slow infusion, and 6.1 +/- 5.2% with placebo. PK/PD analysis showed similar concentration-dependent linear reduction in SPV and blood pressure up to the maximum observed rilmenidine plasma level for both the fast and the slow infusion. CONCLUSIONS: The rate of infusion of rilmenidine in healthy volunteers does not influence the PK/PD relationship of saccadic eye movements and blood pressure up to the maximum observed rilmenidine plasma concentrations. Rilmenidine causes clear concentration-dependent blood pressure reductions in healthy volunteers.

Adult↗
PubMed2001

Biomarkers for the effects of antipsychotic drugs in healthy volunteers.

Studies of novel antipsychotics in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and antipsychotics; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of neuroleptics in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 65 different studies, investigating the effects of 23 different neuroleptics on 101 different (variants of) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness, and of visual-visuomotor-auditory and motor skills were most sensitive to antipsychotics, although over half of all the studies failed to show statistically significant differences from placebo. The most consistent effects were observed using prolactin response and saccadic eye movements, where 96% and 83% of all studies resp. showed statistically significant effects. The prolactin inducing dose equivalencies relative to haloperidol of 19 different antipsychotic agents correlated with the lowest recommended daily maintenance dose (r(2) = 0.52). This relationship could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind prolactin release and antipsychotic activity (probably D2-receptor antagonism). The number of tests used in human psychopharmacology appears to be excessive. Future studies should look for the most specific and sensitive test within each of the domains that are most susceptible to neuroleptics.

Antipsychotic Agents↗
PubMed2000

A pharmacodynamic Markov mixed-effects model for the effect of temazepam on sleep.

BACKGROUND: A hypnogram shows how sleep travels through its various stages in the course of a night. The sleep stage changes can be quantified to study sedative drug effects. METHODS: Hypnograms from 21 patients with primary insomnia were collected during a randomized, placebo-controlled crossover study of 20 mg temazepam. A separate daytime session was performed to determine the pharmacokinetics of 20 mg temazepam and its effect on saccadic eye movement and electroencephalogram. A first-order Markov model was developed to describe the probability of sleep stage changes as a function of time after drug intake and time after last sleep stage change. The influence of temazepam concentration on the probability to change sleep stage was incorporated into the model. RESULTS: Transitions between sleep stages were profoundly influenced by the time of the night and by the time since the last change of sleep stage. Temazepam reduced the time spent awake. This effect could be attributed to four mechanisms: (1) transition to "deeper" sleep was facilitated, (2) transition to "lighter" sleep was inhibited, (3) regardless of sleep stage, the transition to wake state was inhibited, and (4) return to sleep was facilitated. Daytime sensitivities to temazepam, measured with the surrogate markers saccadic peak velocity and electroencephalogram beta activity, each correlated with one of the transition probabilities influenced by temazepam. CONCLUSIONS: By the development of a Markov model for these non-ordered six categorical data, the effect of temazepam on the sleep-wake status could be interpreted in terms of known mechanisms for sleep generation and benzodiazepine pharmacology.

Adolescent↗
PubMed2000

A comparison of the effects of propofol and midazolam on memory during two levels of sedation by using target-controlled infusion.

UNLABELLED: We examined memory during sedation with target-controlled infusions of propofol and midazolam in a double-blinded five-way, cross-over study in 10 volunteers. Each active drug infusion was targeted to sedation level 1 (asleep) and level 4 (lethargic) as determined with the Observer Assessment of Alertness/Sedation scale. At the target level of sedation, drug concentration was clamped for 30 min, during which time neutral words were presented. After 2 h, explicit memory was assessed by recall, and implicit memory by using a wordstem completion test. Venous drug concentrations (mean +/- SD) were 1350 ng/mL (+/-332 ng/mL) for propofol and 208 ng/mL (+/-112 ng/mL) for midazolam during Observer Assessment of Alertness/Sedation scale level 4; and 1620 ng/mL (+/-357 ng/mL) and 249 ng/mL (+/-82 ng/mL) respectively during level 1. The wordstem completion test frequencies at low level sedation were significantly higher than spontaneous frequencies (8.7% + 2.4%; P: < 0.05 in all cases), and lower than during placebo (33.6% + 23%) (P: < 0.05 in all cases, except P: = 0.076 for propofol at level 4). Clinically distinct levels of sedation were accompanied by small differences in venous propofol or midazolam concentrations. This indicates steep concentration-effect relationships. Neutral information is still memorized during low-level sedation with both drugs. The memory effect of propofol and midazolam did not differ significantly. IMPLICATIONS: Implicit memory can occur during different states of consciousness and might lead to psychological damage. In 10 volunteers, implicit memory was investigated during sedation with propofol and midazolam in a double-blinded, placebo-controlled study. To compare the effects of both drugs, they were titrated using a computer-controlled infusion system to produce similar high and low levels of sedation.

Adult↗
PubMed1999

MDMA study.

Explore the source record for details and available documents.

Animals↗
PubMed1999

Bioequivalence of subcutaneous injections of recombinant human follicle stimulating hormone (Puregon(R)) by Pen-injector and syringe.

A randomized, single-centre, cross-over study was designed to compare the bioavailability of two pharmaceutical formulations of recombinant human follicle stimulating hormone (recFSH; Puregon(R)): (i) a dissolved cake injected by a normal syringe; and (ii) a ready-for-use solution injected using a device referred to as Puregon(R)Pen. Twenty-two healthy female volunteers underwent one of two administration sequences: Puregon(R)Pen/syringe or syringe/Puregon(R)Pen, by which they received a single subcutaneous dose of recFSH (150 IU). Endogenous gonadotrophin production had been previously suppressed using an oral contraceptive (Lyndiol(R)). Pharmacokinetic parameters characterizing rate [peak concentration (Cmax) and time of peak concentration (tmax)] and extent [area under the curve (AUC) and clearance (CL)] of absorption were obtained from 20 subjects. After injection with both formulations, serum FSH concentrations reached a peak of 3.4 IU/l at 13 h after injection. The elimination half-life was approximately 34 h, irrespective of formulation. A difference of approximately 18% was found between serum FSH concentrations obtained using the two formulations, which was caused by differences between the anticipated and the actual volume injected with the normal syringe. After correction for injection losses by weighing the amount injected with a normal syringe, the two formulations were found to be bioequivalent with respect to Cmax, AUC and CL. For tmax, bioequivalence could not be proven due to high intra-subject variability and broad absorption peaks of FSH. Both methods were well tolerated, local reactions being generally mild and short-lived.

Adolescent↗
PubMed1999

The sensitivity of pharmacodynamic tests for the central nervous system effects of drugs on the effects of sleep deprivation.

Various methods are used to quantify sedative drug effects, but it is unknown how these surrogate measures relate to clinically relevant sleepiness. This study assessed the sensitivity of different surrogates of sedation to clinically relevant sleepiness induced by sleep deprivation. Nine healthy volunteers completed a balanced three-way cross-over study with 1-week wash-out periods. Adaptive tracking, smooth-pursuit and saccadic eye movements, body sway, digit symbol substitution (DSST), visual analogue scales (VAS) and electroencephalograms (EEG) were evaluated on three occasions: (1) during the day after normal sleep, (2) during wakefulness at night; and (3) during the day after a night of sleep deprivation. VAS of alertness showed a gradual decline at night and a constant average reduction of 38 percent [95% Confidence intervals (CI), 28-47%] during the day after sleep deprivation. Average mood scores diminished by 14 percent (95%, CI 2-24%) during the day after sleep deprivation. Adaptive tracking, saccadic eye movements and body sway tended to deteriorate at night, but overall this was not statistically significant. After a night of sleep deprivation, adaptive tracking decreased by 21 percent (95% CI, 11-30%), saccadic eye movements decreased by 9-10 percent (95% CI, 5-13%/6-15%) and body sway increased by 37 percent (95% CI, 5-79%). In contrast, EEG beta2-amplitudes declined significantly at night by 18 percent (95% CI, 6-29%), without changes during the day after sleep deprivation. Smooth pursuit, DSST and other EEG-amplitudes remained unchanged. These results emphasize that reductions in adaptive tracking, saccadic peak velocity and body sway caused by sedative drugs really reflect sedation. They also provide a level of clinical significance for these surrogates of sedation. EEG parameters and smooth pursuit were unaffected by sleep deprivation, so drug-induced changes in these measures may not reflect sedation in a stricter sense. The motivation and alertness necessary for DSST may overcome mild sedation.

Adult↗
PubMed1998

The influence of cisapride and clarithromycin on QT intervals in healthy volunteers.

OBJECTIVE: Recently a few cases of long QT syndrome were reported during treatment with cisapride. In most of these cases, risk factors for cardiac arrhythmias or pharmacologic interactions might have been involved, and the role of cisapride remained unclear. Macrolides such as clarithromycin potentially interact with the metabolic elimination of cisapride and have overlapping indication areas. We therefore studied whether combined treatment with clarithromycin and cisapride leads to pharmacokinetic changes and increased QT intervals. METHODS: The study was an open, randomized, 2-way crossover study with washout periods of 1 week. Twelve healthy volunteers were recruited. Treatments were cisapride (10 mg 4 times a day) for 10 days with concomitant clarithromycin (500 mg twice a day) from days 6 through 10, or clarithromycin (500 mg twice a day) for 10 days combined with cisapride (10 mg 4 times a day) from days 6 through 10. Frequent ECG recordings were performed for 24 hours before drug treatment (baseline). After 5 days of monotherapy and combination therapy, frequent ECG recordings and assessments of plasma drug levels were performed for 24 hours. RESULTS: Clarithromycin alone was associated with a minimal increase in QTc intervals. Monotherapy with 10 mg cisapride 4 times a day led to a concentration-dependent QTc elevation, amounting to 6 ms during steady state. Combination of cisapride and clarithromycin caused an average QTc increase of 25 ms above pretreatment values and 3-fold increases in cisapride concentrations. CONCLUSIONS: QTc elevations after cisapride or clarithromycin alone remained within the normal range of diurnal variation. Coadministration of cisapride and clarithromycin produced a substantial QT prolongation. The data support the recently purported interaction between cisapride and clarithromycin and thus the filed contraindication to combine these drugs.

Adult↗
PubMed1998

Estimating potency for the Emax-model without attaining maximal effects.

The most widely applied model relating drug concentrations to effects is the Emax model. In practice, concentration-effect relationships often deviate from a simple linear relationship but without reaching a clear maximum because a further increase in concentration might be associated with unacceptable or distorting side effects. The parameters for the Emax model can only be estimated with reasonable precision if the curve shows sign of reaching a maximum, otherwise both EC50 and Emax estimates may be extremely imprecise. This paper provides a solution by introducing a new parameter (S0) equal to Emax/EC50 that can be used to characterize potency adequately even if there are no signs of a clear maximum. Simulations are presented to investigate the nature of the new parameter and published examples are used as illustration.

Adjuvants, Anesthesia↗
PubMed1998

Pharmacodynamics and pharmacokinetics of a single oral dose of nitrazepam in healthy volunteers: an interethnic comparative study between Japanese and European volunteers.

Potential interethnic differences in drug disposition and effects between Japanese and white subjects hamper the registration in Japan of medications already used in Western countries. This double-blind, placebo-controlled, crossover study was conducted to compare the pharmacodynamics and pharmacokinetics of a single oral dose of nitrazepam (5 mg) in age- and sex-matched Japanese (n = 8) and white (n = 8) healthy volunteers. The study was performed in centers in Japan and the Netherlands using the same methods and study design. Subjects were individually matched for gender, age, and body stature. Drug effects were measured by means of saccadic and smooth pursuit eye movements and visual analog lines obtained from the scales of Bond and Lader. There were no pharmacokinetic differences between the Japanese and white subjects. Clearance of nitrazepam was 0.91 +/- 0.165 mL/min/kg and 1.17 +/- 0.492 mL/min/kg, and half-life (t1/2) was 22.1 +/- 4.96 hours and 21.5 +/- 7.51 hours for the Japanese and European groups, respectively. Pharmacokinetic parameters showed no significant correlation with age, height, or weight. The average time-effect curves for the different parameters were comparable between groups. Compared with placebo, both groups showed similar significant reductions in average peak velocity and increases in saccadic inaccuracy and reaction time. Visual analog scores showed clear sedation in the white subjects, but insignificant effects in the Japanese subjects. Smooth pursuit did not change significantly in either group. Slope and intercept of the concentration-effect relationships for saccadic peak velocity showed considerable intersubject variability, but no clear differences between groups. The pharmacokinetics and pharmacodynamics of nitrazepam were similar in matched healthy Japanese and white subjects. Interethnic comparative studies are feasible, and provide meaningful information about potential racial differences in disposition and action of drugs. Such studies can form a rational basis for comparative clinical trials.

Administration, Oral↗
PubMed1997

A study of the effects of long-term use on individual sensitivity to temazepam and lorazepam in a clinical population.

AIMS: The central effects of benzodiazepines may be attenuated after chronic use by changes in pharmacokinetics, pharmacodynamics or both. This attenuation may be influenced by the dosing pattern and the characteristics of the user population. The objectives of this study were to evaluate drug sensitivity in long-term users of temazepam and lorazepam in a clinical population. METHODS: The sensitivity to benzodiazepine effects in chronic users (1-20 years) of lorazepam (n = 14) or temazepam (n = 13) was evaluated in comparison with age and sex matched controls. Drug sensitivity was evaluated by plasma concentration in relation to saccadic eye movement parameters, postural stability and visual analogue scales. RESULTS: Pharmacokinetics of lorazepam and temazepam did not differ between patients and control subjects. Chronic users of lorazepam showed clear evidence of reduced sensitivity, indicated by lack of any pharmacodynamic difference between patients and controls at baseline, when drug concentrations were similar to the peak values attained in the control subjects after administration of 1-2.5 mg of lorazepam. In addition, there was a two- to four fold reduction in the slopes of concentration-effect plots for measures of saccadic eye movements and body sway (all; P < or = 0.01). By contrast, sensitivity in chronic users of temazepam was not different from controls. The difference between the temazepam and the lorazepam group appears to be associated with a more continuous drug exposure in the latter, due to the longer half-life and a more frequent intake of lorazepam. This pattern of use may be partly related to the more anxious personality traits that were observed in the chronic users of lorazepam. CONCLUSIONS: Chronic users of lorazepam show evidence of tolerance to sedative effects in comparison with healthy controls. Tolerance does not occur in chronic users of temazepam. The difference may be related to pharmacological properties, in addition to different patterns of use, associated with psychological factors.

Adult↗
PubMed1997

Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

AIMS: This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48-6791, compared with midazolam, in healthy subjects during first administration to man studies. METHODS: The study was double-blind and five-way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48-6791 was administered as a slow i.v. infusion in doses of 0.1-0.3-1 mg in the first group, and 1-2-3 mg in the second. Midazolam was infused at 0.1 mg kg(-1). The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min(-1)) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two-compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (beta-power). These parameters were used for pharmacokinetic/pharmacodynamic modelling. RESULTS: Ro 48-6791 and midazolam were both well tolerated. Most clinical events were dose-dependent central depressant effects. The volume of distribution (V(SS)) and plasma clearance of Ro 48-6791 were on average markedly larger than those of midazolam (171 +/- 65 vs 41 +/- 10 l and 2.2 +/- 0.9 vs 0.42 +/- 0.11 l min(-1), respectively). The doses of Ro 48-6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48-6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action for saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in beta-power than Ro 48-6791 at the highest administered dose. Ro 48-6792, a metabolite of Ro 48-6791, showed a considerably longer half-life than the parent compound. Although there were no indications of a discernable effect of Ro 48-6792 in the present study, the effects of possible accumulation during prolonged administration should be investigated further. CONCLUSIONS: This first study with Ro 48-6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.

Adjuvants, Anesthesia↗
PubMed1997

Integrated pharmacokinetics and pharmacodynamics of Ro 48-8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

AIMS: This study aimed to investigate the pharmacodynamics and pharmacokinetics of ascending doses of Ro 48-8684, compared with midazolam, in healthy subjects during first administration to man. METHODS: The study was double-blind and five-way crossover (three ascending doses, placebo, fixed midazolam dose), performed in two groups of five males. Ro 48-8684 was infused in doses of 0.1-0.3-1 mg in the first group, and 1-3-10 mg in the second, with different infusion rates (expressed as mg min(-1)) among doses. Midazolam was infused at 0.1 mg(-1) kg. Infusions were stopped after 20 min or if sedation became too strong for proper performance of saccadic eye movements. Pharmacokinetics and pharmacodynamics and their relationships were evaluated as described in the companion article. RESULTS: Ro 48-8684 caused dose-dependent sedation. No serious adverse events occurred. The volume of distribution and clearance of Ro 48-8684 were larger than of midazolam (337+/-114 vs 50+/-121 and 2.4+/-0.5 vs 0.47+/-0.11 l min(-1), resp). The recovery of saccadic eye movements from equal levels of sedation was on average almost half an hour faster for Ro 48-8684 than for midazolam, with considerable interindividual differences (range 2, 55 min). The doses of Ro 48-8684 leading to the same clinical endpoint as midazolam were comparable, but the corresponding predicted effect compartment concentrations of Ro 48-8684 were on average 2.6 times lower (range 1.5, 4.9 times). The slope of the linear concentration-effect-relationship for saccadic peak velocity was on average 2.2 times steeper for 10 mg Ro 48-8684 than for midazolam (range 1.3, 3.3). The slope decreased on average 4.4-fold (range 1.6, 7.3 times), with doses of Ro 48-8684 increasing from 1 to 10 mg. The metabolite Ro 61-2466 had a longer half-life than the parent compound Ro 48-8684. The influence of this metabolite during prolonged administration should be further investigated. CONCLUSIONS: These results show that Ro 48-8684 has a considerably shorter duration of action than midazolam. There may be a reduction of sensitivity to Ro 48-8684 with repeated administration of rising doses due to as yet undetermined factors.

Adult↗
PubMed1996

Self-medication of a single headache episode with ketoprofen, ibuprofen or placebo, home-monitored with an electronic patient diary.

1. The objective of this study was to investigate the efficacy of home-medicated non-steroidal anti-inflammatory (NSAID) analgesics, using an electronic patient diary. Single doses of ketoprofen 25 mg and ketoprofen 50 mg were compared with ibuprofen 200 mg and placebo in the treatment of a single occasion of episodic tension-type headache, using a double-blind, randomized, parallel group design. 2. A total of 166 patients with headache compatible with episodic tension-type headache and no refractory headaches or contraindications to NSAIDs were contacted by advertisements and selected by questionnaires. Patients performed the study at home, using an electronic diary for headache assessment, with a form to allow comments and corrections. Visual analogue scales (VAS 10 cm) of headache severity, five-item headache relief rating (HRR) scales, and time of intake of 'escape' analgesics were scored regularly, for 4 h following intake of trial medication. 3. VAS-scores (n = 1407) and HRRs (n = 452) were returned by 159 patients. Of these scores, 1.5% were inadvertently omitted from the electronic diary or modified on the comment forms. 4. Headache (VAS and HRR) improved more with all three NSAIDs than with placebo, although the effect of ibuprofen was significant for HRR only. After 2 and 4 h respectively, the reduction in VAS-ratios was 17 and 19% with placebo, 18 and 53% with ibuprofen 200 mg, 41 and 61% with ketoprofen 25 mg, and 47 and 59% with ketoprofen 50 mg. After 4 h, headache improved strongly (highest HRR) in 18% of patients on placebo, 39% on ibuprofen 200 mg, 62% on ketoprofen 25 mg, and 55% on ketoprofen 50 mg. Headache disappeared completely (VAS-score = 0) in one patient (3%) with placebo (after 180 min), 10% with ibuprofen 200 mg (average 211 min), 18% with ketoprofen 25 mg (159 min), and 28% with ketoprofen 50 mg (146 min). 5. The effects of ketoprofen 50 mg were more pronounced than those of ibuprofen 200 mg, which seemed to start later. Ketoprofen 25 mg and 50 mg were very similar, suggesting a maximal effect of the lower dose. Mild to moderate adverse events were reported by 9% of the patients, half of which occurred with ketoprofen 50 mg. Treatment of headache with ketoprofen can start with 25 mg, and possibly less. 6. Although a direct comparative study would be necessary to determine the relative benefits of the novel electronic patient diaries over traditional paper-and-pencil methods, this study has shown the usefulness of this newer technique to detect differences in efficacy between low doses of analgesics under ambulant conditions, with very limited loss of data. Electronic patient diaries appear to be an important new attribute for the efficacy assessment of self-medicated drugs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

The efficacy of aldose reductase inhibitors in the management of diabetic complications. Comparison with intensive insulin treatment and pancreatic transplantation.

Recently, aldose reductase inhibitors (ARIs) have been registered in several countries for the improvement of glycaemic control. However, their efficacy is still controversial. ARIs inhibit the enhanced flux of glucose through the polyol pathway. As such, they can never be more effective than normoglycaemia, and so their potential benefits and limitations should be considered relative to the effects of prolonged euglycaemia. The clinical effects of ARIs can be put into perspective by assessing the effects of improved glycaemic control attained in randomised trials of intensive insulin treatment [such as the Diabetes Control and Complications Trial (DCCT)] and after pancreatic transplantation. Although direct comparison of these 3 interventions is hampered by differences in patient populations, duration and methods of follow-up and in the potency of ARIs, the effects of these 3 metabolic interventions and their course in time appear remarkably similar. For neuropathy, all 3 interventions induce an increase in average motor nerve conduction velocity of approximately 1 m/sec during the first months of treatment. At the same time, improvement of painful symptoms may occur. These changes probably largely represent a metabolic amelioration of the condition of the nerves. Around the second year of treatment with all 3 forms of metabolic improvement, an acceleration of nerve conduction of a similar magnitude occurs, with signs of structural nerve regeneration and some sensory recuperation. Experience with ARIs in nephropathy is still limited, but similar improvements in glomerular filtration rate and, less consistently, in urinary albumin excretion were found during short term normoglycaemia produced by all 3 forms of treatment. Comparison of a small number of studies, however, shows differences between intensive insulin regimens, pancreatic transplantation and ARIs in effects on retinopathy. Retinopathy often temporarily deteriorates in the early phases of improved glycaemic control, but this is not noted with ARIs. New microaneurysm formation was slightly reduced in a single long term study with the ARI sorbinil, but the preventive effects on the overall levels of retinopathy seemed less strong than in normoglycaemia trials of similar duration. However, the pharmacodynamic effects on inhibiting the polyol pathway differ among ARIs, and the half-life of the inhibiting effect of sorbinil may have been too short for a complete reduction of polyol pathway activity. The trials of prolonged intensive insulin therapy and pancreatic transplantation have demonstrated that very strict metabolic control must be maintained continuously for many years before a significant reduction of complications can be demonstrated.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

The effects of an ACTH (4-9) analogue on development of cisplatin neuropathy in testicular cancer: a randomized trial.

The efficacy of the ACTH (4-9) analogue Org 2766 in the prevention of subclinical cisplatin neuropathy was assessed in a double-blind placebo-controlled multi-centre study in patients with testicular cancer or adenocarcinoma of unknown primary. Forty-two patients received at least four cycles of cisplatin (100 mg/m2 per cycle), together with subcutaneous injections of Org 2766 (2 mg/day for 5 consecutive days) or placebo. Vibratory threshold was used as a measure of neuropathy. For each individual patient, the influence of cisplatin on vibratory perception was quantified by the slope of the regression line between the natural logarithm of the vibratory thresholds and the number of cycles. From the slopes, the proportional increase of vibratory threshold per cycle of cisplatin was calculated. On average, vibratory thresholds increased by 42% with each cycle of 100 mg/m2 of cisplatin in the placebo group, and by 19% during treatment with Org 2766. The influence of cisplatin on vibratory thresholds was highly significant in the placebo group (P < 0.0001), and of borderline significance in the group treated with Org 2766 (P = 0.06). The difference in slopes between the two groups was of borderline statistical significance (Wilcoxon's two-sample test: P = 0.06; analysis of variance: P = 0.04). These results show that Org 2766 cannot completely prevent cisplatin neuropathy in young men with testicular cancer, but nerve damage may be ameliorated by the use of this ACTH (4-9) analogue.

Adenocarcinoma↗
PubMed1994

Effects of aldose reductase inhibition with tolrestat on diabetic retinopathy in a six months double blind trial.

To study the effects of the new aldose reductase inhibitor tolrestat on diabetic retinopathy, 31 diabetic patients with various degrees of retinopathy were randomly assigned to either tolrestat (200 mg once daily) or placebo treatment for six months. Separate morphological features of diabetic retinopathy were assessed by fundus photography and fluorescein angiography before and at the end of the study. The results showed some amelioration of clinical signs of diabetic retinopathy during aldose reductase treatment. Hard exudates, intraretinal hemorrhages and focal fluorescein leakage increased on average in the placebo and decreased in the tolrestat group. The difference was statistically significant for focal fluorescein leakage only. The permeability of the blood retinal barrier was determined by vitreous fluorophotometry before and at the end of the study. No change in permeability values was found.

Administration, Oral↗