Individual Dose Titration Research Articles

Transdermal iontophoresis of rotigotine: influence of concentration, temperature and current density in human skin in vitro

Iontophoretic transport of rotigotine across human stratum corneum (HSC) was studied in vitro in side by side diffusion cells according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis followed by 5 h of passive diffusion. A current density of 0.5 mA cm −2 was applied. The parameters studied were the influence of the rotigotine concentration in donor phase and the influence of the molecular weight of the co-ions. To this end, Na + was replaced by tetra ethyl ammonium (TEA +) or tetra butyl ammonium (TBA +) (both at pH 5 and 6). In addition, the influence of the acceptor phase temperature (32 °C versus room temperature), the replacement of HSC by dermatomed human skin (DHS), and the relation between drug transport and current density were examined. The estimated steady-state flux (Flux ss) gradually increased with the drug concentration in the donor phase in a linear manner. The flux was also linearly correlated with the applied current density providing a convenient approach to individual dose titration. The use of TEA + as co-ion increased the rotigotine iontophoretic flux significantly, while TBA + did not. Replacing HSC by DHS reduced the iontophoretic rotigotine transport, while an increase in temperature to 32 °C increased the rotigotine flux. The maximum Flux ss achieved was around 80 nmol cm −2 h −1 indicating that by means of iontophoresis, a therapeutic level of rotigotine might be achieved with a reasonable patch size.

Naloxone reversal of opioid anesthesia revisited: clinical evaluation and plasma concentration analysis of continuous naloxone infusion after anesthesia with high-dose fentanyl.

In spite of several advantages, the need for postoperative ventilatory support limits the use of high-dose opioid anesthesia. We prospectively evaluated the effectiveness of naloxone infusion for the reversal of high-dose fentanyl anesthesia. Anesthesia was maintained with fentanyl in patients undergoing major abdominal surgery. After anesthesia, the trachea was extubated when intravenous naloxone, which was titrated in separate 50- micro g doses, established an acceptable level of consciousness and arterial blood gas (ABG) status under spontaneous respiration; this was followed by continuous infusion started at the rate of the sum of the bolus doses per hour. The naloxone infusion was terminated based on evaluation of the level of consciousness, ABG, and acute abstinence symptoms. Postoperative pain was evaluated using self-reported four-step categorical terms (none, mild, moderate, and severe). Plasma concentrations of fentanyl and naloxone were analyzed in 12 patients, using high-performance liquid chromatography. Fifty-seven out of 59 eligible patients were successfully extubated at 34 +/- 14 min after termination of fentanyl (total dose, 127 +/- 64 micro g.kg(-1); mean +/- SD) with naloxone (total bolus, 3.4 +/- 2.6 micro g.kg(-1)). All these patients recovered fully without ventilatory support under the naloxone infusion, which was terminated at 11 +/- 7 h. The reduction of the naloxone infusion rate effectively relieved the increased pain, and no supplemental analgesic was used in any patients during the naloxone infusion. Pharmacokinetic analysis did not indicate any correlations between plasma fentanyl and naloxone concentrations. The results suggest that naloxone infusion with individual dose titration facilitates the use of high-dose opioid anesthesia, maintaining the advantager of this anesthesia.

Pharmacokinetics of SLI381 (ADDERALL XR), an Extended-Release Formulation of Adderall

To assess the pharmacokinetic (PK) properties of a single daily dose of Adderall (mixed amphetamine salts) and the extended-release formulation, SLI381 (ADDERALL XR), in pediatric attention-deficit/hyperactivity disorder (ADHD). Fifty-one children (aged 6-12 years) with ADHD participated in a 6-week, seven-visit, PK and pharmacodynamic study. PK sampling occurred during visit 1 and again at visit 7. At visit 1, subjects received an initial oral dose of SLI381, 20 mg. At visit 7 subjects completed 1 week of medication treatment following random assignment to once-daily orally dosed SLI381 10 mg, 20 mg, or 30 mg; Adderall 10 mg; or placebo. PK parameters evidenced substantial intersubject variability (coefficients of variation = 28-56%). Time to maximum concentration (Tmax) for SLI381 versus Adderall showed average increases of 3.0 hours for dextroamphetamine (t = -2.35, p = .04, df = 8.6) and 3.2 hours for levoamphetamine (t = -2.39, p = .04, df = 9.2). The d- and l-isomer concentrations were highly correlated and approximated a 3:1 ratio. SLI381 showed extended Tmax values compared with Adderall and appears suitable for once-daily dosing. Intersubject variability underscores the need for individual dose titration.

Pharmacokinetics of recombinant factor IX in relation to age of the patient: implications for dosing in prophylaxis.

The aims of this study were to investigate possible age-related changes in the disposition of factor IX procoagulant activity (FIX:C) after administration of recombinant factor IX (rFIX) and to translate the pharmacokinetic findings into suggestions for dosing of rFIX during prophylactic treatment of haemophilia B. Pharmacokinetic data were available from a previous study on 56 patients, aged 4-56 years (one of whom was excluded from analysis). FIX:C curves during prophylactic dosing were computer-simulated from the single-dose data. Clearance and volume of distribution at steady state of FIX:C increased linearly with body weight of the patients, consequently increasing during childhood and adolescence but remaining fairly constant during adulthood. The terminal half-life of FIX:C showed no correlation with age, while in vivo recovery (in U dL(-1) per U kg(-1) given) tended to increase. Computer-predicted trough levels of exogenous FIX:C during repeated doses of rFIX (50 U kg(-1)) and, conversely, doses (in U kg(-1)) needed to maintain a 1-U dL(-1) trough level showed little or no dependence on age. There was considerable interindividual variation in disposition and required doses of rFIX, emphasizing the need for individual dose titration. Dosing of rFIX according to lean body mass instead of body weight did not reduce this variability. During prophylaxis a 1-U dL(-1) trough level can normally be maintained by dosing every 2-3 days, the former schedule resulting in, on average, a 45% lower consumption of rFIX.

Management of postoperative pain in children

Opioid usage requires individual dose titration and careful monitoring of side-effects (respiratory monitoring, sedation score). The strong opioids piritramide and morphine may advantageously be administered as either continuous, or patient-controlled iv- infusion (PCA). In addition to infiltration anesthesia, intraoperatively applied nerve blocks provide excellent pain relief. Epidural analgesia with local anesthetics and/or opioids via a thoracic or lumbar epidural catheter is a therapeutic option after thoracic or abdominal surgery, or after extensive orthopedic or urological interventions. Adjuvant analgesics and nonpharmacologic interventions, i. e. transcutaneous electrical nerve stimulation (TENS), are primarily indicated in patients suffering from neuropathic pain. The establishment of pain services and the comprehensive education of both the nursing and the medical staff should help to improve postoperative pediatric pain therapy.

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Monitoring Relapse Drinking During Disulfiram Therapy by Assay of Urinary 5‐Hydroxytryptophol

Screening for recent alcohol use by testing urine for the ratio of 5-hydroxytryptophol (5HTOL) to 5-hydroxyindole-3-acetic acid (5HIAA) was performed in 10 methadone patients on disulfiram (Antabuse) maintenance therapy in an outpatient setting. Apart from alcohol ingestion, treatment with aldehyde dehydrogenase inhibitors such as disulfiram is the only known cause of an abnormally high 5HTOL/5HIAA ratio. After introduction of drug therapy, increased ratios were observed in all patients. The new higher level reached was relatively stable over time within the same patient but variable between patients. Four patients continued to consume alcohol, as evidenced by 5HTOL/5HIAA ratios well above the new individual plateau, while still taking 400 mg disulfiram 3 times per week under strict supervision. To try to achieve sobriety in two patients who drank frequently while on therapy, the disulfiram dose was doubled. Continued testing demonstrated this to increase the 5HTOL/5HIAA steady-state level further, and the absence of extreme values above this new baseline level indicated adherence to abstinence with possibly one single relapse. When disulfiram administration was discontinued, as planned, by five of the patients, four of them returned to drinking very soon. The present results show that during disulfiram maintenance the continuous inhibition of aldehyde dehydrogenase produces a new higher and dose-related 5HTOL to 5HIAA steady state level in urine, but relapse to drinking will still lead to further increased 5HTOL/5HIAA ratios. It is also suggested that an individual dose-titration regimen, whereby the disulfiram dose is raised gradually until 5HTOL/5HIAA testing indicates sobriety, will improve therapeutic effectiveness.

Monitoring Relapse Drinking During Disulfiram Therapy by Assay of Urinary 5-Hydroxytryptophol

Screening for recent alcohol use by testing urine for the ratio of 5-hydroxytryptophol (5HTOL) to 5-hydroxyindole-3-acetic acid (5HIAA) was performed in 10 methadone patients on disulfiram (Antabuse) maintenance therapy in an outpatient setting. Apart from alcohol ingestion, treatment with aldehyde dehydrogenase inhibitors such as disulfiram is the only known cause of an abnormally high 5HTOL/5HIAA ratio. After introduction of drug therapy, increased ratios were observed in all patients. The new higher level reached was relatively stable over time within the same patient but variable between patients. Four patients continued to consume alcohol, as evidenced by 5HTOL/5HIAA ratios well above the new individual plateau, while still taking 400 mg disulfiram 3 times per week under strict supervision. To try to achieve sobriety in two patients who drank frequently while on therapy, the disulfiram dose was doubled. Continued testing demonstrated this to increase the 5HTOL/5HIAA steady-state level further, and the absence of extreme values above this new baseline level indicated adherence to abstinence with possibly one single relapse. When disulfiram administration was discontinued, as planned, by five of the patients, four of them returned to drinking very soon. The present results show that during disulfiram maintenance the continuous inhibition of aldehyde dehydrogenase produces a new higher and dose-related 5HTOL to 5HIAA steady state level in urine, but relapse to drinking will still lead to further increased 5HTOL/5HIAA ratios. It is also suggested that an individual dose-titration regimen, whereby the disulfiram dose is raised gradually until 5HTOL/5HIAA testing indicates sobriety, will improve therapeutic effectiveness.

Intraindividual Differences in Pain Relief and Functional Improvement in Osteoarthritis with Diclofenac or Tramadol

To investigate how individual patients with painful osteoarthritis (OA) respond to the non-steroidal anti-inflammatory drug (NSAID) diclofenac and the centrally acting analgesic tramadol when individual on-demand dose titration is allowed. In addition, we studied whether the differences in the mode of action of the different analgesics were important for functional outcome in OA patients. This was performed as a double-blind, crossover, randomised study in 60 patients with OA of the hip (19 patients) or knee (41 patients) without clinical joint inflammation. Patients received either tramadol (50 to 100mg up to three times daily, on demand) for 4 weeks, followed by diclofenac (25 to 50mg up to three times daily, on demand) for 4 weeks, or vice versa. The multidimensional 'Western Ontario and McMaster Universities Osteoarthritis Index' (WOMAC) questionnaire (pain, stiffness and functional impairment) was used to assess the effect of the drugs on pain and functional capability. 54 patients completed both study periods. The mean (+/- SD) daily dose of tramadol consumed was 164.8mg (+/- 54.1mg) and that of diclofenac was 86.9mg (+/- 21.4mg). Both treatments modestly improved median pain intensity, paralleled by an improvement in functional parameters, and there were no statistically significant differences between the groups. However, individual treatment effects varied greatly, and within individual patients there were considerable variations in analgesic effectiveness between the two treatments. Consistently, pain relief correlated linearly with functional improvement. More patients reported adverse events with tramadol than with diclofenac (20 vs 3%, p = 0.0056), but there was no difference in adverse event-related withdrawals (p = 0.69). OA patients' response to analgesic treatment was highly individual and the response to one drug was not predictive of that to another drug. A significant proportion of patients were not treated satisfactorily with diclofenac or tramadol alone. The results obtained from a descriptive analysis of group effects (means, medians) were inappropriate for drawing conclusions on individual treatment benefits. Improvement of functional capability apparently was a consequence of pain relief. Effective pain relief should therefore be the main therapeutic goal in patients with OA where inflammation is less prominent.

Individualized dose titration of growth hormone (GH) during GH replacement in hypopituitary adults.

Until now, GH treatment in GH-deficient adults has employed dose schedules of GH based on body weight or body surface area and has ignored individual responsiveness to GH. This trial has studied the effects of an individualized GH dose adjusted to match a combination of clinical response, normalization of serum IGF-I concentration and body composition. Two closely-matched groups, each comprising 30 GH-deficient adults, 38 men and 22 women aged 48 years, were treated with GH for 12 months. The high dose (HD) group received a target dose of 12 micrograms/kg per day and the individualized dose (ID) group received an initial daily GH dose of 0.17 or 0.33 mg per day (0.5 and 1 IU, respectively), independent of body weight, with dose adjustments thereafter. Serum concentrations of IGF-I, lipoprotein(a), insulin, calcium, intact PTH, osteocalcin and blood glucose were measured. Body composition was determined according to a 4-compartment model using total body potassium and tritiated water as input variables. Total body nitrogen was measured by in vivo neutron activation and total body bone mineral content by dual energy X-ray absorptiometry. At 12 months, the daily dose of GH was 0.55 +/- 0.03 mg and 0.45 +/- 0.03 mg in the HD and ID groups, respectively (P < 0.05). In the HD group, the mean serum IGF-I increased to levels well above the predicted level, while in the ID group the mean serum IGF-I normalized. Side-effects were experienced by 70% of the subjects in the HD group and by 30% in the ID group (P < 0.001). A similar response to GH in terms of body composition, glucose homeostasis, lipoprotein(a) and blood pressure was obtained in both treatment groups. However, the treatment response in terms of serum calcium, intact PTH and osteocalcin was more marked in the HD group. Similar efficacy, with a lower dose of GH and fewer side-effects, was obtained by considering individual responsiveness to GH as compared to higher doses of GH adjusted to match body weight.

Angiotensin-Converting Enzyme Inhibitors in Preventing Remodeling and Development of Heart Failure After Acute Myocardial Infarction: Results of the German Multicenter Study of the Effects of Captopril on Cardiopulmonary Exercise Parameters (ECCE)

Early action of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction (MI) has been shown in large scale clinical trials to reduce mortality over the first weeks. However, the mechanisms involved are yet unclear and several trials showed a tendency toward a small, albeit unexpected, rise in cardiogenic shock or mortality. Since cardiopulmonary exercise testing (CPX) has become a “gold standard” in assessing the severity of heart failure, we studied—after finishing a pilot trial—the effect of captopril versus placebo in 208 patients who were individually titrated (titrated dose, mean 46/69 mg/day after 7 days/4 weeks, respectively) in order to preserve their blood pressure in the acute phase of myocardial infarction; we followed the development of congestive heart failure (CHF) over 4 weeks by measuring oxygen consumption. After 4 weeks, overall oxygen consumption at the anaerobic threshold (VO2-AT; 13.7 vs 13.1), maximal oxygen consumption (VO2max 19.3 vs 18.9 mL/kg per min) and exercise duration (896 vs 839 sec) showed a nonsignificant difference in favor of the captopril group. The predefined, categorized, combined endpoint of severe heart failure or death (heart failure necessitating ACE inhibition, VO2max <10 mL/kg per min, or death) was significantly reduced in the captopril group (n = 7/104) versus placebo (n = 18/104; p = 0.03). Differences were mainly caused by fewer CHF events (Δ n = 10). We conclude that ACE inhibition with individualized dose titration markedly reduces the 4-week incidence of severe heart failure or death; >10 patients per 100 treated gained major benefits from this therapy.

Dose-related haemodynamic effects and pharmacokinetics of oral nicorandil in patients evaluated for chest pain

We studied the acute haemodynamic dose response of nicorandil, a combined nitrate and potassium channel opener, in patients evaluated for chest pain. Single dose oral nicorandil (5, 10, 20, or 30 mg) or placebo was given to 42 right-heart catheterized patients using a randomized block design. Persistent, significant ( P < 0.05) haemodynamic changes occurred primarily after 30 mg. Arterial systolic pressure fell significantly after all doses and remained reduced (maximum, 31 mmHg) up to 6 h after 30 mg; heart rate increased significantly up to 1 h. Individual haemodynamic sensitivity varied and three patients (1, 10 mg; 2, 30 mg) developed transient symptomatic hypotension associated with bradycardia. Pulmonary artery systolic pressure (diastolic was unchanged) declined significantly (maximum, 5 mmHg) up to 6 h after 30 mg whereas pulmonary capillary wedge (baseline normal) and mean right atrial pressures decreased transiently. Cardiac index (baseline normal) declined slightly (significantly after 30 mg); however, stroke volume index and stroke work index were significantly and persistently reduced after all doses. Total systemic vascular resistance declined slightly after 30 mg. Individual plasma nicorandil concentrations were variable and systemic bioavailability was reduced compared with values reported in healthy subjects. Nicorandil demonstrated cardiac unloading actions. Variable plasma concentrations, haemodynamic effects, and patient sensitivity warrant low initial doses with individual dose titration, especially if cardiac filling pressures are low.

Effects of Desipramine, Amitriptyline and Fluoxetine on Pain in Diabetic Neuropathy

Abstract Background. Amitriptyline reduces the pain caused by peripheral-nerve disease, but treatment is often limited by side effects related to the drug's many pharmacologic actions. Selective agents might be safer and more effective. Methods. We carried out two randomized, double-blind, crossover studies in patients with painful diabetic neuropathy, comparing amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients, and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients. Fifty-seven patients were randomly assigned to a study as well as to the order of treatment, permitting comparison among all three drugs and placebo as the first treatment. The patients rated the degree of pain present each day using verbal descriptors, and they also assessed the extent of pain relief globally at the end of each treatment period. Results. After individual dose titration, the mean daily doses of the drugs were as follows: amitript...

A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites.

After ingestion, disulfiram (DSF) is rapidly converted, probably in the stomach, to its bis (diethyldithiocarbamato) copper complex. Consequently, absorption and distribution via the gastrointestinal mucosa into the blood might involve both the parent drug and its copper complex. In the blood, both compounds are rapidly degraded to form diethyldithiocarbamic acid (DDC), which is unstable and is further degraded to form diethylamine and carbon disulphide. DDC is also a substrate of phase II metabolism, which involves formation of diethyldithiomethylcarbamate (Me-DDC) and the glucuronic acid of DDC. Me-DDC also undergoes oxidative biotransformation to diethylthiomethylcarbamate (Me-DTC), which is further oxidized to its corresponding sulphoxide and sulphone metabolites. Me-DTC may to act as a suicide inhibitor with a preference for the mitochondrial low Km isozyme of aldehyde dehydrogenases (ALDH 1), whereas the two S-oxidized metabolites, especially the sulfone metabolite, are more potent inhibitors not only of ALDH 1, but also of the cytosolic high Km isozyme of ALDH (ALDH 2). The inhibitory reaction between the enzyme and each of the three metabolites is characterized by a covalent adduct formation, probably with the cysteine residue at the active site of the enzymes. The adduct formed is nonreducible at a physiological concentration of glutathione, and inactivation in the presence of this endogenous tripeptide was increased by action in vitro of the sulphoxide and sulphone metabolites. Those findings are all in concordance with the in vivo observations made on DSF. In human volunteers treated with increasing doses of DSF and challenged with ethanol between each of the dosage periods, the mean plasma concentrations of Me-DTC at steady state were proportional to the DSF doses given. There was also a close relationship between increased oxidative metabolic formation of Me-DTC, high oxidative formation of acetaldehyde, and the full complements of a valid disulfiram ethanol reaction (DER). Consequently, Me-DTC in plasma may not only serve as a marker of the oxidative metabolic function of the liver, but also of the therapeutic effectiveness of the treatment in subjects at steady state. Obviously, there is a need for individual dose-titration regimens. In patients with alcohol-related severe hepatocellular damage, the oxidative P 450 catalyzed formation of the Me-DTC and probably also of its sulfoxide and sulphone metabolites is impaired, and thus inactivation of ALDH activity in the liver appears to be delayed or even completely absent. The consequence for the patient may be an insufficient DER.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of Desipramine, Amitriptyline, and Fluoxetine on Pain in Diabetic Neuropathy

Amitriptyline reduces the pain caused by peripheral-nerve disease, but treatment is often limited by side effects related to the drug's many pharmacologic actions. Selective agents might be safer and more effective. We carried out two randomized, double-blind, crossover studies in patients with painful diabetic neuropathy, comparing amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients, and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients. Fifty-seven patients were randomly assigned to a study as well as to the order of treatment, permitting comparison among all three drugs and placebo as the first treatment. The patients rated the degree of pain present each day using verbal descriptors, and they also assessed the extent of pain relief globally at the end of each treatment period. After individual dose titration, the mean daily doses of the drugs were as follows: amitriptyline, 105 mg; desipramine, 111 mg; and fluoxetine, 40 mg. There was moderate or greater relief of pain in 28 of the 38 patients (74 percent) who received amitriptyline, 23 of the 38 patients (61 percent) who received desipramine, 22 of the 46 patients (48 percent) who received fluoxetine, and 19 of the 46 patients (41 percent) who received placebo. The differences in responses between amitriptyline and desipramine and between fluoxetine and placebo were not statistically significant, but both amitriptyline and desipramine were superior to placebo. Amitriptyline and desipramine were as effective in patients who were not depressed as in depressed patients, but fluoxetine was effective only in depressed patients. Desipramine relieves pain caused by diabetic neuropathy with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the latter. Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of these antidepressant drugs in diabetic neuropathy. Fluoxetine, which blocks serotonin uptake, is no more effective than placebo for the relief of pain.

Comparison of Response Rates to the Angiotensin-Converting Enzyme Inhibitor Ramipril in Mild-to-Moderate Hypertension in a Double-Blind, Parallel-Group Study and an Open Single-Blind Study

Appropriate clinical trial methodologies in general practice and suitable end points for dose-finding studies are discussed with reference to antihypertensive drugs in general and angiotensin-converting enzyme (ACE) inhibitors in particular. Two clinical studies were conducted with ramipril, a new nonsulfhydryl ACE inhibitor, to identify the minimum effective dose for the management of mild-to-moderate hypertension. Study 1 was a double-blind, parallel-group, randomized design with three treatment groups (placebo and 2.5 and 5 mg of ramipril), and study 2 was an open, single-blind design with individual dose titration from 2.5 to 5 mg of ramipril if the diastolic blood pressure (DBP) was greater than 90 mm Hg after 3 weeks. Response rates and DBP reductions with 2.5 mg of ramipril were similar in both studies, although overall response rates, DBP reductions, and side effect incidence appeared to be greater in the open, single-blind, dose-titration study. It is concluded that study methodology apparently influences efficacy and tolerability.

Clinical Effects of the 5-HT1A Partial Agonists in Depression

The azapirone class of anxiolytic drugs is being evaluated for clinical use in the treatment of depression. Buspirone, a serotonin (5-hydroxytryptamine, 5-HT) partial agonist active at the 5-HT1A receptor subtype, was evaluated in the treatment of depression in a series of five placebo-controlled, parallel group studies involving 382 patients with DSM-III major depression and significant associated anxiety symptoms (both Hamilton depression [HAM-D] and Hamilton anxiety [HAM-A] scales greater than or equal to 18). Buspirone therapy was initiated at 15 mg/day with individual dose titration to a maximum of 90 mg/day and resulted in marked improvement in both depressive and anxiety symptoms. Analyses of the composite data base from the five studies show significant (p less than 0.05) improvement in mean HAM-D, HAM-A, and Clinical Global Impression-Global Improvement scale ratings for buspirone-treated compared with placebo-treated patients. Of particular interest was significant improvement in cardinal depression symptoms, e.g., depressed mood, guilt, work and interest, anergia, and diurnal variation of mood. Subset analyses revealed that patients with melancholic-type major depression and patients with more severe symptoms (judged by higher initial HAM-D or HAM-A total scores) responded better to buspirone than did patients who were less ill. The buspirone dose most frequently associated with clinically significant improvement was 40 mg/day. Gepirone, an analogue of buspirone with highly selective binding affinity for the 5-HT1A receptor subtype, also shows promise of antidepressant efficacy in preliminary controlled clinical trials. These data suggest that azapirones, which as partial agonists modulate 5-HT1A receptor function, have clinically important antidepressant properties.

Clinical pharmacokinetics of isradipine

The pharmacokinetics and bioavailability of isradipine (DynaCirc) were studied in different populations (young and elderly normal participants, renal- and liver-impaired patients, hypertensive patients) under various dosing conditions (single and multiple oral doses, administration with and without food, and in combination with other drugs) and using several dosage forms (solution, standard capsule, modified-release tablet). Isradipine showed rapid, complete, dose-proportional absorption, but low bioavailability (19 percent) resulting from first-pass metabolism. Reduction of the absorption rate by dosage-form manipulation yielded sustained isradipine levels without loss of bioavailability. Food had no appreciable effect on the rate and extent of absorption; coadministration with hydrochlorothiazide had no effect on the bioavailability of either drug. Elimination of isradipine (half-life of approximately eight hours) occurred exclusively via biotransformation to metabolites that were eliminated in the urine and bile (feces), with a ratio 2:1. In healthy, elderly subjects, the bioavailable isradipine fraction was 24 percent; in mildly to moderately renally impaired and in liver-impaired subjects, 22 to 25 percent; but in severely renally impaired or anuric subjects, 14 percent. A population pharmacokinetic screen of hypertensive patients confirmed the likelihood of higher isradipine levels in the elderly but revealed no additional correlations with demographic variables or other patient characteristics. The absence or small magnitude of plasma-level differences between the populations studied suggest that specific dosing-adjustment recommendations other than individualized dose titration are unnecessary.

Treatment of Alcoholic Organic Brain Syndrome with the Serotonin Reuptake Inhibitor Fluvoxamine:

The chronic effects of fluvoxamine (200 mg per day for 4 weeks) were studied in ten alcoholic organic brain syndrome patients in a double-blind cross-over design. Complete neuropsychological evaluation was performed as well as measurement of neurochemical changes in CSF. Fluvoxamine produced a small but significant improvement in memory performance. An analysis of fluvoxamine minus placebo difference scores showed a significant correlation between memory functioning and CSF 5HIAA levels. Alcohol amnestic syndrome patients who had the highest blood levels of fluvoxamine demonstrated the largest changes in CSF 5HIAA and improvement in memory performance under fluvoxamine. These findings implicate a role of serotonergic mechanisms in alcoholic organic brain syndrome and suggest that with individual titration of the drug dose, fluvoxamine might be a clinically useful agent in the treatment of this syndrome.

Dose-related haemodynamic effects of nicardipine during rest and exercise and variable anti-anginal effects in patients with chronic stable angina.

The effects of increasing doses of i.v. nicardipine (2.5, 5.0 and 7.5 or 10.0 mg) on blood pressure, heart rate and exercise performance were studied in 12 patients with chronic effort angina. Plasma nicardipine concentrations correlated closely with the infused doses (r = 0.90). Resting haemodynamic changes after nicardipine included a dose-related fall in systolic (5%, 13%, 15%) and diastolic (0%, 6%, 8%) blood pressure and a rise in heart rate (10%, 19%, 30%). Rate-pressure product was slightly increased after the highest dose (10%). During exercise, maximal systolic blood pressure decreased (3%, 9%, 9%) and heart rate increased (2%, 4%, 9%) but the rate-pressure product remained unchanged. Exercise tolerance improved in 10 patients as indicated by prolonged exercise duration in all, delayed appearance of ST-segment depression in 6, decreased maximal ST-segment depression in 5, and abolished (N = 3) or diminished (N = 4) anginal pain at the end of exercise after optimal nicardipine dose. Five of the 10 patients obtained maximum benefit after the highest dose. The other five patients improved after 2.5 or 5.0 mg but deteriorated (N = 4) or had no further benefit when the dose was increased (N = 1). One patient deteriorated even after the lowest dose, whereas one patient neither improved nor deteriorated after any dose. The patients who deteriorated after low or high doses tended to be more severely diseased than those who tolerated the maximal dose well. The results stress the importance of individual dose titration of nicardipine to ensure maximum benefit in patients with chronic effort angina.