[Survival of patients with intracranial tumors before and after CT]. / Overlevelsen ved intrakranial tumor før og efter CT.

Survival was compared between 135 patients (II) with intracranial tumours (IT) diagnosed with the aid of CT and 170 cases of IT (I) diagnosed in the same department prior to the introduction of CT. Apart from fewer cases of oligodendrogliomata in group II, the distribution into histological types was identical in the two groups. The age and sex distributions were identical. The percentages in the groups (I/II) of operations (85.7/60.7), autopsy (41.1/15.3) and histological determination of the tumour (87.6/58.5) had decreased considerably while employment of chemotherapy had increased (1.8/20.7). On the whole, survival from the time of diagnosis was found to be better in group (II) (p = 0.026). Survival from the onset of the disease was the same (p = 0.47) indicating that CT had resulted in earlier diagnosis but not a generalized improvement in survival in the entire group of tumour patients. Significantly better survival was found for the histologically verified malignant tumours in group II both for the primary tumours (p = 0.001) and for metastases (p = 0.0058). In this group, survival was found to be improved both from the time of diagnosis (p = 0.0001) and from the onset of symptoms (p = 0.015). It appears from the literature that there is a generalized tendency to omit histological verification of IT frequently in cases where CT suggests a hopeless prognosis. Greater advantages as regards survival with CT may probably be obtained with more frequent employment of stereotactic biopsy.

Clinical and electrodiagnostic findings in breast cancer patients with radiation-induced brachial plexus neuropathy.

The clinical and neurophysiological characteristics of radiation-induced brachial plexopathy (RBP) were assessed in 79 breast cancer patients without signs of recurrent disease at least 60 months after radiotherapy (RT). Clinically, 35% (95% confidence limits: 25-47%) had RBP. Fifty percent (31-69%) had affection of the entire plexus, 18% (7-36%) of the upper trunk only, and 4% (1-18%) of the lower trunk. In 28% (14-48%), assessment of a definite level was not possible. In most, symptoms began during or immediately after RT, thus being without significant latency. Numbness or paresthesias (71%, 52-86%) and pain (43%, 25-62%) were the most prominent symptoms, while the most prominent objective signs were decreased or absent muscle stretch reflexes (93%, 77-99%) closely followed by sensory loss (82%, 64-93%) and weakness (71%, 52-86%). Neurophysiological investigations were carried out in 46 patients (58%). The most frequent abnormalities in patients with RBP were signs of chronic partial denervation with increased mean duration of individual motor unit potentials, and decreased amplitude of compound muscle and sensory action potentials. Nerve conduction velocities were normal.

Radiation-induced brachial plexus neuropathy in breast cancer patients.

The incidence and latency period of radiation-induced brachial plexopathy (RBP) were assessed in 79 breast cancer patients by a neurological follow-up examination at least 60 months (range 67-130 months) after the primary treatment. All patients were treated primarily with simple mastectomy, axillary nodal sampling and radiotherapy (RT). Postoperatively, pre- and postmenopausal patients were randomly allocated chemotherapy or antiestrogen treatment. All patients were recurrence-free at time of examination. Clinically, 35% (25-47%) of the patients had RBP; 19% (11-29%) had definite RBP, i.e. were physically disabled, and 16% (9-26%) had probable RBP. Fifty percent (31-69%) had affection of the entire plexus, 18% (7-36%) of the upper trunk only, and 4% (1-18%) of the lower trunk. In 28% (14-48%) of cases assessment of a definite level was not possible. RBP was more common after radiotherapy and chemotherapy (42%) than after radiotherapy alone (26%) but the difference was not statistically significant (p = 0.10). The incidence of definite RBP was significantly higher in the younger age group (p = 0.02). This could be due to more extensive axillary surgery but also to the fact that chemotherapy was given to most premenopausal patients. In most patients with RBP the symptoms began during or immediately after radiotherapy, and were thus without significant latency. Chemotherapy might enhance the radiation-induced effect on nerve tissue, thus diminishing the latency period. Lymphedema was present in 22% (14-32%), especially in the older patients, and not associated with the development of RBP. In conclusion, the damaging effect of RT on peripheral nerve tissue was documented. Since no successful treatment is available, restricted use of RT to the brachial plexus is warranted, especially when administered concomitantly with cytotoxic therapy.

Double-blind placebo-controlled evaluation of flunarizine as adjunct therapy in epilepsy with complex partial seizures.

Flunarizine was compared to placebo in a double-blind cross-over trial of 2 16-week treatment periods separated by a 4-week wash-out period. The patients had epilepsy with complex partial seizures with or without secondary generalised seizures. Twenty-nine patients entered the trial, but 7 dropped out. Of the 22 patients completing the trial, 13 were women; the median was 39 years (range 15-58) and the median duration of epilepsy 23 years (range 4-55). There was no statistically significant difference between flunarizine 15 mg daily and placebo as adjunct therapy in total seizure frequency, neuropsychological tests, and patient's preferences. No interactions with concomitant antiepileptic drugs and no laboratory abnormalities were registered.

Progabide in the treatment of hyperkinetic extrapyramidal movement disorders.

The ability of the selective GABA-receptor agonist, progabide, to suppress abnormal involuntary movements was evaluated in a preliminary open pilot study. 17 patients, 10 males and 7 females, aged 10-78 years, with hyperkinetic movement disorders were included in the study. Daily doses of progabide ranged from 900 to 3600 mg (median 2400 mg) corresponding to 14-45 mg/kg (median 45 mg/kg), while the duration of treatment varied from 2 to 52 weeks. Improvement, with a reduction of involuntary movements exceeding 25%, occurred in two of four patients with Gilles de la Tourette's syndrome, and in two of three patients with postanoxic intention myoclonus, while no consistent beneficial effects were registered in ten patients with Huntington's chorea, postanoxic choreoathetosis, torsion dystonia, tardive dyskinesia, action tremor, essential myoclonus, or oro-branchio-respiratory myoclonus.

The effect of the GABA-agonist, progabide, on stretch and flexor reflexes and on voluntary power in spastic patients.

The action of the GABA-receptor agonist, progabide , was investigated in a double-blind study with cross-over to placebo. The stretch and flexor reflexes and voluntary power were measured in 16 patients with spasticity. 2-week treatment periods were used; the median daily oral dosage of progabide was 24.3 mg/kg. The Achilles tendon (T) reflex was significantly suppressed whereas the Hoffmann (H) reflex remained unchanged: the T/H ratio was thus reduced. Hmax /M (direct motor)max ratio and the vibration-induced suppression of the T- and H-reflexes were unchanged. These findings indicate an effect of progabide on the spindles or on the controlling fusimotor system (probably acting on spinal interneurons), whereas influence on presynaptic inhibition and alpha-motoneuron excitability is unlikely. The flexor reflex threshold was increased during progabide treatment and latency at threshold decreased towards normal latency. This indicates some influence of progabide on flexor reflex activity attributed to reinforcement of action of GABAergic interneurons at the spinal level. Isokinetic measurement of voluntary power of knee extension revealed particularly good progress for the fastest movements during progabide treatment, whereas isometric measurement of sustained handgrip remained unchanged, probably reflecting a reduction of spasticity without reduction of voluntary power in non-spastic muscles.

The clinical effect of the GABA-agonist, progabide, on spasticity.

In a double-blind cross-over trial of two 2-week periods, the clinical effect of progabide was compared to placebo. 16 patients with spasticity in a stationary phase completed the trial. 14 had multiple sclerosis, 2 hereditary spastic paraplegia. 5 were female and 11 male. The median age was 45.5 years (range 30-62 years). The median daily dosage of progabide was 24.3 mg/kg (range 14.3-32.7 mg/kg). During progabide treatment, there was a reduction in spastic hypertonia (P less than 0.01), a suppression of tendon reflexes (patellar) (P less than 0.01), and a reduction in the frequency of flexor spasms (P less than 0.05). No significant changes in voluntary power were registered. The global clinical impression revealed a therapeutic effect in 87% of the patients (95% confidence limits 61-98%). The improvement was judged as medium or important in 50% of the patients (95% confidence limits 23-77%). No side-effects or laboratory abnormalities were seen.

The effect of the GABA-agonist, progabide, on benign essential tremor. A controlled clinical trial.

In a double-blind crossover trial of two 2-week treatment periods, to which 18 patients with benign essential tremor were admitted, there was no statistically significant different between progabide 11.4-20.2 mg/kg X day (median 14.2 mg/kg X day) and placebo in tremor score and tremor amplitude. However, there was a definite placebo and period effect with reduction of tremor score and tremor amplitude during the second period of treatment compared to the first period of treatment, regardless of the treatment regime. This was presumably a result of prolonged treatment and habituation to the test situation and not an effect of the active drug. No side-effects were registered and no laboratory abnormalities were seen.

Pharmacokinetics and bioavailability of intravenous and intramuscular lorazepam with an adjunct test of the inattention effect in humans.

Single dose pharmacokinetics and bioavailability of intravenous and intramuscular lorazepam were investigated in 6 younger healthy human volunteers of either sex. The plasma concentration profile after intravenously administered lorazepam could in all cases be fitted by NONLIN to a biexponential function of time with a mean terminal (biological) half-life of 14.10 hrs +/- 2.94 S.D. (range 9.68 - 18.42 hrs). The mean half-life of the initial alpha-phase of distribution was 0.31 hrs +/- 0.11 S.D. The mean apparent volume of distribution derived from AUC, Vd-area (=Vd beta), was 1.24 1 kg-1 +/- 0.17 S.D. Mean plasma clearance of the drug was 62.17 ml kg-1 hr-1 +/- 8.85 S.D. The apparent central volume of distribution characterizing the open two-compartment pharmacokinetic model was 0.59 1 kg-1 +/- 0.19 S.D. After intramuscular administration to the same subjects the plasma concentration time lapse could be described by either tri- or bi-exponential kinetics, which are representative of open two- and one-compartment models with absorption phases, respectively. Mean biological half-life was 14.01 hrs +/- 2.31 S.D. and Vd-area 1.24 l kg-1 +/- 0.14 S.D., both values in full agreement with the findings based on intravenous administration. Half-life of the absorption phase varied from 0.08 to 1.76 hrs. Mean systemic availability of the drug was 88.8% +/- 8.3 S.D. The inattention effect of lorazepam was assessed by exposing the subjects during the intravenous pharmacokinetic experiments to a binaural stimulation test, which revealed various degrees of acute reduced attention in only three of the subjects.

The acute effect of the GABA-agonist, THIP, on proprioceptive and flexor reflexes in spastic patients.

THIP (Lu 2-030) is pharmacologically a specific and potent GABA-receptor-agonist which in animal studies depresses monosynaptic and, to a smaller extent, polysynaptic spinal reflexes. 5 spastic patients were investigated by means of neurophysiological tests comparing the acute effect of a single oral dose of THIP (15-25 mg) to "the test situation without drug administration" with an interval of 2 days. The neurophysiological tests included quantitative studies of proprioceptive reflexes (T-reflex, vibratory inhibition of the T-reflex, resistance to passive movement of a spastic muscle and clonus) and of the flexor reflex (threshold and latency). The voluntary power was measured by a static technique. THIP clearly reduced the monosynaptic T-reflex and reinforced vibratory inhibition of the IA monosynaptic pathway. The flexor reflex threshold was slightly increased during THIP administration, but the changes were not significant. Flexor reflex latency, resistance to passive movement, clonus and voluntary power were unchanged.

Prophylactic treatment of migraine with clonidine. A controlled clinical trial.

In a double-blind crossover trial of two 12-week treatment periods with a 4-week treatment free interval, to which 21 patients were admitted, there was no statistically significant difference between clonidine 75 microgram twice daily and placebo in the total number of headache days, migraine indices, duration of attacks, number of severe attacks and consumption of acute attack treatment. However, there was a marked reduction in number of headache days, migraine indices, duration of attacks and consumption of acute attack treatment during the second treatment period compared to the first treatment period, regardless of the treatment regime. This was presumably a result of prolonged treatment and frequent attention and not an effect of the active drug. 32 patients entered the trial, but 11 dropped out. Of the 21 patients completing the trial, 16 were women; the median age was 34 years (range 17-54 years) and the median duration of headaches 12 years (range 1-40 years). Only mild side-effects were registered and no laboratory abnormalities were seen.