Duration of L-dopa and dopamine agonist monotherapy in Parkinson's disease.

The expected duration of initial antiparkinson monotherapy before the need for supplementation is not clearly defined for routine practice. The aim of this study was to define the length of L-dopa (L-3, 4-dihydrophenylalanine) and dopamine agonist monotherapy. The duration of monotherapy and discontinuation rates were investigated in a natural observational setting by plotting Kaplan-Meier survival curves. Out of 345 patients, 180 (52.2%) received L-dopa and 165 (47.8%) received a dopamine agonist as initial monotherapy. Half of the patients starting L-dopa received supplementary therapy with- in 3.6 years (95% confidence interval, 3.2-4.6), significantly longer than for dopamine agonist monotherapy (half required a second agent at 2.3 years [2.0-2.9]; P = 0.00017). Discontinuation of L-dopa therapy was 1%. Dopamine agonists were stopped (due to side-effects like impulse control disorders [6%], somnolence [4%] and light-headedness [3%]) in 20% over four years. The duration and tolerability of L-dopa and dopamine agonists as initial Parkinson's disease monotherapy are defined in this study; this may form part of the information exchange with patients.

Correlation of Parkinson's disease severity and duration with 123I-FP-CIT SPECT striatal uptake.

The variability in clinical features and the masking effects of drug therapy in Parkinson's disease (PD) can affect clinical assessment of disease severity. The aim of this study was to assess the imaging of dopamine transporters using 123I-FP-CIT SPECT and its correlation with disease staging, severity, and duration. Differences between the clinical severity of the onset and non-onset side and the corresponding striatal uptake ratios were also examined. Forty-one patients with PD (nine unilateral, 32 bilateral clinical features) were studied. Clinical severity was determined by using the Unified Parkinson's Disease Rating Score (UPDRS). Unilateral UPDRS was calculated from unilateral arm and leg resting and action tremor, rigidity, finger taps, hand movements, alternating movements, and leg agility. 123I-FP-CIT striatal uptake was expressed as the ratio of specific:nonspecific (SP:NS) uptake for defined brain areas. Patients with PD who had unilateral symptoms showed a significant difference between the ipsilateral and contralateral SP:NS ratios in both the caudate and putamen, but there was a considerable overlap between between the two sides. This result was repeated in patients with bilateral symptoms and there was overlap of SP:NS ratios between the two groups. For the whole group of patients with PD, striatum, caudate, and putamen SP:NS ratios correlated with disease severity assessed by UPDRS and duration of disease. The SP:NS ratios correlated with the bradykinesia subscore but not with rigidity or tremor subscore. In conclusion, this study provides further evidence that the SP:NS ratio is a robust measure of disease severity correlating with duration of PD. However, variability in uptake values suggest that factors other than nigrostriatal degeneration may contribute to disease severity. Correlation with bradykinesia but not with tremor may indicate an origin for tremor outwith the dopamine transporter system. 123I-FP-CIT SPECT offers significant potential in defining the nigrostriatal changes in PD.

Anticonvulsant therapy in the elderly--a need for placebo controlled trials.

Epileptic seizures are common in the elderly, yet data concerning the long-term clinical course and apparent impact of anticonvulsant therapy are scant. We studied 73 consecutive elderly patients with a diagnosis of seizures [remote symptomatic (52%), acute symptomatic (23%), progressive symptomatic (10%), cryptogenic (15%)] during a median period of clinical review of 33 (range 3-72) months. Sixty-seven patients received anticonvulsant drugs, 38 phenytoin (PHT), 21 carbamazepine (CBZ), 6 sodium valproate (VPA) and 2 phenobarbitone. Six patients were untreated with drugs and three of these had no further seizures over a median review period of 26 months. Forty-one (61%) treated patients remained seizure free and a further nine patients suffered less than three fits per year. Seventeen patients had poorer control (three to five seizures per year in six patients and more than five seizures per year in eleven patients). Mean daily dosage of anticonvulsants (PHT 248 mg, CBZ 320 mg, VPA 571 mg) and serum concentrations were modest. Anticonvulsant side effects were reported by 27% of all treated patients (22% of those who were seizure free). Both adverse effects and satisfactory seizure control were associated in the majority of patients with serum anticonvulsant concentrations at the lower limit or below recommended therapeutic ranges utilised in the young. This study suggests that placebo controlled studies are warranted to appraise the extent to which anticonvulsant drugs modify a generally favourable prognosis for seizure disorders in the elderly and to adequately define the benefit-risk ratio of such drugs.

Placebo-controlled trial of doxazosin in management of patients with hypertension and hypercholesterolaemia.

The blood pressure (BP)- and lipid-lowering activities of the alpha 1-antagonist, doxazosin, were investigated in hypertensive, hypercholesterolaemic patients. Thirty-one patients satisfactorily completed the study, and there was no significant difference between doxazosin and placebo in terms of reported adverse events. After 3-month treatment, BP was significantly reduced by doxazosin by 24/14 mm Hg supine and by 33/22 mm Hg erect as compared with corresponding reductions of 2/9 and 2/2 mm Hg with placebo. There were concomitant improvements in the plasma lipid profile with, in particular, significant net reductions of 30% for triglycerides and 20% for apoprotein B. There was no adverse effect on glucose metabolism. The principal aim of this study was assessment of the clinical utility and acceptability of doxazosin in a heterogeneous population of patients with several cardiovascular risk factors. The results confirm that doxazosin is an effective antihypertensive agent that has modest additional beneficial effects on the plasma lipid profile.

A comparison of the haemodynamic and behavioural effects of moxonidine and clonidine in normotensive subjects.

1. This randomised double-blind placebo controlled crossover study in healthy normotensive males compared the haemodynamic and behavioural responses following single oral doses of moxonidine (200 micrograms), clonidine (200 micrograms) and placebo. 2. Both active drugs significantly reduced blood pressure as compared with placebo: on average (over the study day) by -5.6/-0.8 with moxonidine and by -13.3/-5.3 mm Hg with clonidine. The hypotensive effect of clonidine was significantly greater (95% CI 3.2-12.2). Heart rate was unchanged by either drug. 3. Psychomotor testing, salivary flow and side effect reporting showed a consistent treatment rank order similar to that of the hypotensive response: clonidine greater than moxonidine greater than placebo. 4. Although moxonidine produced less adverse effects than clonidine, an equivalent hypotensive response was not demonstrated in normal subjects. Further study at comparable antihypertensive doses is required to clarify the relative side effect profile of these agents.

Terodiline causes polymorphic ventricular tachycardia due to reduced heart rate and prolongation of QT interval.

Recent reports have suggested an association between terodiline hydrochloride and cardiac arrhythmias. We report 4 patients presenting over a six month period who developed polymorphic ventricular tachycardia (polymorphic VT) while receiving treatment with this agent. In each case there was prolongation of QT interval on electrocardiogram (ECG). Two patients had hypokalaemia associated with diuretic therapy. In the 3 cases in which follow-up ECG was available, QT interval returned to normal after discontinuation of terodiline. In order to define the effects of terodiline on corrected QT interval (QTc) and heart rate in the elderly, a prospective study was performed in 8 elderly in-patients treated with terodiline for urinary incontinence. After 7 days treatment with terodiline 12.5 mg twice daily, there was a significant increase in QT by a mean of 29 ms, QTc by 15 ms and a decrease in resting heart rate by a mean of 6.7 beats.min-1. Terodiline increases QTc and reduces resting heart rate in elderly patients. Both these effects may be associated with polymorphic VT, a potentially life threatening arrhythmia. This drug should be avoided in patients with other known risk factors for polymorphic VT, particularly hypokalaemia and cardiac disease.

The effects of age on the pharmacokinetics, antihypertensive efficacy and general tolerability of dilevalol.

1. This study investigated the influence of age on the pharmacokinetics, pharmacodynamics, general tolerability and concentration-effect relationships in 18 patients with essential hypertension (age range 23-73 years) during treatment with dilevalol, a non selective beta-adrenoceptor antagonist with vasodilator properties. 2. There were no significant age-related changes in pharmacokinetics for either acute or chronic treatment with dilevalol, although there were significant changes in elimination half-life from 7.8 to 11.7 h (P less than 0.05) and in AUC from 261 to 352 ng ml-1 h (P less than 0.005) following translation from acute to chronic dosing. 3. In absolute terms, dilevalol treatment (as compared with placebo) produced numerically larger falls in average blood pressure in the six oldest as compared with the six youngest patients: for example, supine blood pressure fell by, respectively, 29/15 and 10/7 mm Hg during chronic treatment. 4. Using an integrated kinetic-dynamic model, blood pressure responsiveness was characterised by relating the fall in blood pressure (mmHg) to the plasma drug concentrations in each individual patient. No independent age-related effect was demonstrated. There was a significant relationship between response and the height of initial blood pressure which tended to be higher in the elderly patients. 5. Patient tolerability was generally satisfactory and there was no differential age-related effect. 6. This study has shown that the antihypertensive efficacy of dilevalol is not attenuated in the elderly and that there are no significant age-related differences in pharmacokinetics or pharmacodynamics.

Clinical pharmacokinetics and kinetic-dynamic relationships of dilevalol and labetalol.

Dilevalol and labetalol are examples of a growing number of new beta-blockers which combine nonselective beta-adrenoceptor antagonism with vasodilator activity. Dilevalol is one of the 4 stereoisomers of labetalol, and is estimated to form approximately 25% of the racemic drug. Labetalol itself is an alpha 1-antagonist but dilevalol, which has negligible affinity for alpha-receptors, exerts its vasodilator effect via beta 2-agonism. Both drugs are rapidly and completely absorbed in 60 to 90 min and subject to extensive first-pass hepatic metabolism; the average bioavailability after oral administration is around 20 to 35%, and there is wide interindividual variability in plasma drug concentrations and dosage requirements. The volume of distribution of dilevalol (17 to 25 L/kg) is higher than that reported for labetalol (3 to 16 L/kg), although both drugs are concentrated in the extravascular compartment. Correspondingly, the elimination half-life of dilevalol at steady-state is around 15h compared with 8h for labetalol. There is evidence that the pharmacokinetics of dilevalol change (a reduction in clearance) in translation from single-dose to long term therapy. There is no clinically significant effect of age on the steady-state disposition of either drug and the pharmacokinetics of labetalol appear to be unchanged during pregnancy. Although there is a linear relationship between dose and area under the concentration-time curve, early studies found no evidence of a simple relationship between dose or plasma drug concentration and the fall in blood pressure. However, an integrated pharmacokinetic-pharmacodynamic model has been used to correlate concentrations of both drugs with reductions in systolic and diastolic blood pressure in individuals. This approach derives a mathematical description of antihypertensive response which integrates pharmacokinetic and pharmacodynamic information and also takes account of placebo effects and changes in drug concentration and blood pressure during the dosage interval. The pharmacokinetic-pharmacodynamic relationships of labetalol are characterised by a linear model. For example, in a group of healthy volunteers, the 'responsiveness' to labetalol was -0.19mm Hg/micrograms/L. In contrast, the relationships of dilevalol are best described by a Langmuir maximum effect model, and so individual responses to short and long term treatment have been quantified by the concentration-effect parameters of maximum effect and drug concentration required to produce 50% of this.(ABSTRACT TRUNCATED AT 400 WORDS)

The influence of age on the pharmacokinetics and antihypertensive responses to dilevalol.

Age may influence the response to antihypertensive drug treatment either indirectly, by altering the plasma drug concentrations, or directly, by altering the nature and magnitude of the blood pressure reduction. This study investigates the effect of age on the pharmacokinetics and antihypertensive responses following acute and chronic treatment with dilevalol in 18 patients (age range 28-73 years) with essential hypertension. There were no significant age-related changes in pharmacokinetics for either acute or chronic treatment with dilevalol. Correspondingly, there was no evidence of any age-related difference in the antihypertensive response and, in absolute terms, this was slightly greater in the six oldest patients in whom blood pressure fell by 18/10 mmHg, supine, and 16/8 mmHg, erect, after the first dose of dilevalol, compared to 4/3 and 6/3 mmHg, respectively, in the six youngest patients. When allowance was made for the differences in starting (pretreatment) blood pressure, there was no significant difference in the antihypertensive response of the elderly compared to the young patients. This study has shown that the antihypertensive efficacy of dilevalol is not attenuated in the elderly and that there are no age-related differences either in pharmacokinetics or in antihypertensive responsiveness.

Use of influenza vaccine in long-stay geriatric units.

A postal questionnaire sent to all consultant geriatricians in Great Britain and Northern Ireland determined that less than one consultant in five offered influenza vaccine to patients in continuing-care wards. The main reasons given were that vaccine was inappropriate or unnecessary. This information prompted a prospective study of viral illness during the winter months of 1986-87 in eight continuing-care wards with a population of 196 patients. There were 70 episodes of influenza-like illness (ILI), but only 17 viruses were isolated, the commonest being rhinovirus (seven patients). As most cases of ILI in this population were caused by viruses other than influenza, the reluctance of most geriatricians to give influenza vaccine to continuing-care patients appears justified.

Thyroid hormone concentrations in epileptic patients.

Anticonvulsants are associated with decreased serum thyroid hormone concentrations. We have studied thyroid function in 54 epileptic patients on a variety of drugs (19 on carbamazepine, 13 on phenytoin, 10 on sodium valproate, 12 on polypharmacy). For comparison, 14 untreated epileptics and 11 healthy unmedicated volunteers were included as controls. Total thyroxine (T4) concentrations were reduced in patients taking enzyme-inducing drugs (carbamazepine and/or phenytoin) compared with both controls and patients taking sodium valproate. Similar differences were shown with each individual drug. All nine patients whose circulating T4 was below the lower limit of the reference range were taking enzyme inducers. Free thyroxine concentrations were also reduced in individuals treated with carbamazepine and phenytoin with five values falling beneath the reference range. Tri-iodothyronine and thyrotropin appeared unaffected by anticonvulsant administration. Thyrotropin releasing hormone stimulation revealed no true hypothyroidism. The lowering effect of anticonvulsant drugs on circulating total and free T4 was not exhibited by the non-inducing sodium valproate. These data support the influence of enzyme induction as a likely mechanism for reduced thyroxine concentrations in treated epileptic patients.

A simple screening test for hearing impairment in elderly patients.

This study investigated the reliability of simple bedside free-field voice testing in the detection of hearing impairment in patients admitted to a geriatric unit. Sixty-two consecutive admissions were assessed at four graduated levels of loudness by geriatrician and otolaryngologist independently. Pure tone audiometry was then performed blind. Voice testing by both observers was concordant in 88% of all ears and in 100% of ears able to hear a whispered voice (WV) at 2 ft (approximately 0.6 m). The WV at 2 ft was the most discriminant test with a sensitivity of 100%, a specificity of 84% and a predictive value of 92% for hearing impairment likely to benefit from provision of a hearing aid. Free-field voice testing appears a simple, reliable and reproducible test for detecting hearing impairment in elderly patients.

Circulating hormones and pituitary responsiveness in young epileptic men receiving long-term antiepileptic medication.

Impairment of libido and sexual potency are commonly reported by male epileptic patients. This may be partly a consequence of medication. Circulating hormones were measured in 53 postpubertal male epileptic patients less than 45 years of age and in an age-matched control group (n = 40), consisting of 14 untreated epileptic patients and 26 unmedicated healthy subjects. A subgroup also underwent a combined gonadotrophin- and thyrotrophin-releasing hormone (LH-RH/TRH) pituitary stimulation test. Untreated patients did not differ from healthy subjects for any parameter, and their data were combined for comparison with the treated epileptic patients. Total testosterone (T), androstenedione, and basal follicle-stimulating hormone concentrations were similar in all patient groups. Patients receiving more than one drug had higher sex hormone binding globulin (SHBG) (p less than 0.01) and lower free T and dehydroepiandrosterone sulphate (DHAS) levels (both p less than 0.001) than controls. Carbamazepine (CBZ) monotherapy also reduced free T (p less than 0.05) and DHAS (p less than 0.001) and increased basal prolactin (p less than 0.01). In these two groups of patients, basal luteinising hormone (LH) was elevated (p less than 0.01), presumably as a pituitary response to increased T catabolism. There was a negative correlation between free T and circulating CBZ (r = -0.54, p less than 0.05) in the monotherapy patients. Phenytoin (PHT) was associated with a rise in SHBG (p less than 0.01) and a fall in DHAS (p less than 0.001). Basal LH was also elevated, but this just failed to reach statistical significance (p less than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of sodium valproate on haem biosynthesis in man: implications for seizure management in the porphyric patient.

The short-term effects of sodium valproate (VPA) on haem biosynthesis were assessed in a placebo-controlled crossover trial in eight healthy male subjects who ingested VPA 500 mg t.i.d. and matched placebo for 5 days. All showed augmented activity of leucocyte 5-aminolaevulinate synthase (ALA-S) activity, the rate-limiting enzyme of the haem biosynthetic pathway, following 3 and 5 days of VPA treatment (P less than 0.001). This was accompanied by increased urinary excretion of 5-aminolaevulinic acid (ALA; P less than 0.02) and total porphyrins (P less than 0.01). Mean (+/- SD) total VPA concentrations on day 3 (89 +/- 16 mg 1-1) and day 5 (91 +/- 22 mg 1-1) were within the target range for the drug. The long-term effects of VPA administration were examined in epileptic patients on established monotherapy. Leucocyte ALA-S activity (P less than 0.001), and daily urinary excretion of porphobilinogen (P less than 0.01) and total porphyrins (P less than 0.01) were all higher than in age-matched controls. No significant differences in erythrocyte ALA-dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase activities were found between the groups. These data suggest that VPA is porphyrinogenic in man and cannot be recommended as safe for seizure management in the porphyric patient.

The effects of chronic carbamazepine treatment of haem biosynthesis in man and rat.

The anticonvulsant drug carbamazepine has been reported to produce a condition clinically and biochemically similar to acute intermittent porphyria (AIP). We have determined the effect of chronic carbamazepine treatment on the activities of the enzymes of haem biosynthesis in circulating blood cells and on the urinary excretion of porphyrins and their precursors in 53 epileptic patients receiving monotherapy and in 42 age- and sex-matched controls. In the patients the mean activity of leucocyte 5-aminolaevulinic acid (ALA) synthase, the rate-limiting enzyme of the pathway, was 218% of control values (p less than 0.001) and ALA-dehydratase activity was reduced by 37% (p less than 0.001). Circulating carbamazepine concentrations correlated negatively with ALA dehydratase (rs = -0.45; p less than 0.01). Porphobilinogen deaminase and uroporphyrinogen decarboxylase appeared unaffected by carbamazepine treatment. Significant quantitative increases in the urinary excretion of porphobilinogen and total porphyrins (both p less than 0.05) accompanied the changes in enzyme activity. Similar dose-dependent effects on ALA synthase and ALA dehydratase were shown to occur in rats treated for 5 days with 3 different doses of carbamazepine. These findings further support the porphyrinogenicity of carbamazepine, but the pattern of enzyme alteration differs from that found in AIP.

Effect of sodium valproate on carbamazepine disposition and psychomotor profile in man.

1 The effect of sodium valproate (VPA; 500 mg thrice daily for 7 days) and matched placebo on the disposition and psychomotor profile of a single dose of carbamazepine (CBZ; 10 mg kg-1) was studied in eight healthy male subjects using a randomised balanced crossover design. 2 VPA alone had no effect on antipyrine clearance, urinary 6 beta-hydroxycortisol excretion and a battery of psychomotor function tests after 3 days' treatment despite achieving a mean steady-state concentration (90 +/- 6 mg 1(-1)) well within the target range (50-100 mg 1(-1)) for the drug. 3 VPA pre-treatment did not alter total CBZ area under the concentration-time curve (AUC 0-59 h) but did prolong CBZ elimination half life by 12% (P less than 0.01). AUC 0-59 h for free plasma CBZ was 13% higher (P less than 0.02) and half-life of unbound CBZ 16% longer (P less than 0.02) during VPA treatment. CBZ-10,11 epoxide (CBZ-E) levels (52%) and CBZ-E/CBZ ratios (45%) were both elevated by concurrent VPA (P less than 0.05) and free CBZ fraction was increased by 7% (P less than 0.02). 4 The sole effect of VPA on the psychomotor profile of CBZ was prolongation of card sorting time (P less than 0.05), although CBZ-related side effects were reported as more severe when VPA was also taken (P less than 0.01). 5 These data suggest that VPA displaces CBZ from plasma protein binding sites and inhibits the metabolism of both the parent drug and its epoxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Intradose and circadian variation in circulating carbamazepine and its epoxide in epileptic patients: a consequence of autoinduction of metabolism.

Total and free carbamazepine (CBZ), and CBZ 10,11 epoxide (CBZ-E) concentrations were measured over 24 h in 19 patients receiving CBZ 400 mg b.i.d. either as monotherapy (n = 13) or combined with another anticonvulsant (n = 6). Differences in CBZ and CBZ-E disposition between day and night dosing were minor. Mean plasma CBZ concentrations were higher and CBZ-E/CBZ ratios were lower in the monotherapy patients. Variations in total and free plasma CBZ levels were comparable in the monotherapy and polypharmacy groups. Peak free and total CBZ concentrations coincided at approximately 4 h postdose. Free CBZ levels correlated significantly with total in each patient. The extent of variation in total plasma CBZ concentration during 24 h correlated significantly with antipyrine clearance in the monotherapy group. Circadian rhythms are unlikely to influence CBZ disposition to a clinically relevant extent. Measurement of peak and trough CBZ concentrations should improve the value of therapeutic drug monitoring. The diurnal variation in CBZ concentration appears related to the degree of autoinduction of metabolism and is substantial enough to warrant the development of a slow-release preparation of the drug.