Vestibular dysfunction in adult patients with osteogenesis imperfecta.

Progressive hearing loss is a major symptom in osteogenesis imperfecta (OI), a genetic brittle bone disease. Vertigo is frequently associated with otosclerosis in which the hearing loss clinically resembles that in OI. Vertigo is also common in basilar impression (BI) found in up to 25% of adult OI patients. In order to evaluate the cause, frequency, and characteristics of vertigo in OI, 42 patients were studied by interview, clinical examination, and audiological examination supplemented with electronystagmography (ENG) and lateral skull radiography. Audiometry showed hearing loss in 25 patients (59.5%). Nine patients (21%) displayed abnormal skull base anatomy in the forms of basilar impression, basilar invagination, or both, all designated here as BI. Twenty-two patients (52.4%) reported vertigo, mostly of floating or rotational sensation of short duration. Patients with hearing loss tended to have more vertigo than patients with normal hearing. Vertigo was not correlated with type of hearing loss or auditory brain-stem response (ABR) pathology. ENG was abnormal in 14 patients (33.3%). No dependency was found between vertigo and deviant ENG results. Patients with BI tended to have more vertigo than patients with normal skull base but the difference was not statistically significant. Neither ENG pathology, nor the presence or type of hearing loss showed correlation with BI. In conclusion, vertigo is common in patients with OI. In most cases, it may be secondary to inner ear pathology, and in only some patients does BI explain it. Since some OI patients without BI or hearing loss also suffer from vertigo, further clinical and neurological studies are needed to define the pathogenesis of vertigo in OI.

Treatment of respiratory tract infections with erythromycin acistrate and two formulations of erythromycin base.

Erythromycin acistrate (EA)--a new ester of erythromycin--was compared with erythromycin base as enterocoated pellets in capsules (EB enterocapsules) and enterocoated tablets of erythromycin base (EB enterotablets) in the treatment of respiratory tract infections. The present double-blind, multicentre study, conducted in eight occupational health centres, included 474 patients; 236 treated with EA, 117 with EB enterocapsules and 121 with EB enterotablets. The diagnoses included tonsillitis, sinusitis, otitis media, bronchitis and pneumonia. The patients were examined on admission and at the end of the treatment. The dosage of EA was 400 mg tid and that of the two erythromycin base preparations 500 mg tid. The treatment was given for seven to 14 days. In the EA-group, 97% of patients were clinically cured by the end of the treatment, while the cure rates for EB enterocapsules and EB enterotablets were 95% and 94%, respectively. Gastrointestinal side effects were reported by 36% of the patients on EA, 54% on EB enterocapsules and 50% on EB enterotablets. Discontinuations due to adverse effects occurred in 8% in the EA, in 21% in the EB enterocapsule and in 12% in the EB enterotablet groups. All three preparations were thus equally effective, but EA caused statistically significantly less gastrointestinal side effects overall (P less than 0.01), especially nausea (P less than 0.01) and abdominal pain (P less than 0.05), than the two formulations containing erythromycin base. Also discontinuations due to side effects occurred statistically significantly less frequently in the EA-group.

The auto-induction of carbamazepine during long-term therapy.

Healthy male volunteers during regular therapy of carbamazepine had a statistically significant decrease in their plasma drug levels during a period of 28 days. The same phenomenon was also registered in epileptic patients in the course of their long-term monotherapy with carbamazepine. Neither in volunteers nor in epileptics did any statistically significant change in the plasma levels of carbamazepine-10,11-epoxide occur. Wide fluctuations between the fasting and peak plasma level of carbamazepine were found in epileptics. Neither the fasting nor peak plasma levels of the drug correlated in a statistically significant degree with the daily dose of carbamazepine.

Human pharmacokinetics of nitrazepam: effect of age and diseases.

Plasma concentrations of nitrazepam were measured by gas-liquid chromatography in: young healthy volunteers, in geriatric and psychiatric patients and in epileptic children. The disposition of nitrazepam was described in terms of a two-compartment open model. After a single oral dose of nitrazepam 5 mg the most prominent differences between the experimental groups were in the beta-phase half-life mean 29 h in the young volunteers and 40 h in geriatric patients , and in the apparent volume of distribution during the beta-phase of 2.4 vs 4.8 1/kg. Total plasma clearance and the average steady state concentration in both groups were equal. The plasma level rose at a rate proportional to the beta-phase half-life, and so, they were achieved more rapidly in the young than in the old subjects (3.5 vs 7.5 d). No change in steady-state level or in the half-life of nitrazepam were found during long term treatment, which indicates lack of enzyme induction or inhibition. In 95% of the epileptic children with a good to fair clinical response, the plasma concentration of nitrazepam was 40-180 ng/ml (mean 114 ng/ml). As all of the patients were on combined antiepileptic therapy, no attempt was made to correlate plasma level with therapeutic response.

Pharmacokinetics of Carbamazepine in man: a review.

Gas-liquid chromatographic methods for determining plasma concentrations of the anticonvulsant drug carbamazepine are described. The pharmacokinetics of carbamazepine (absorption, protein binding, distribution, metabolism, and elimination) are reviewed, as well as the relationship between dose and plasma level and between plasma level and drug effects. Interactions with other drugs are noted.

Bioavailability of four different pharmaceutical preparations of carbamazepine.

The bioavailabilities of two tablet brands carbamazepine (CBZ) (Tegretol, A; Neurotol, B) were compared with two new experimental preparations (C,D). Formulation A showed a more sustained release nature than did the other formulations. The AUCs0 leads to infinity gave no significant differences between treatment A and three other treatments. However, if AUC0 leads to 72 was calculated instead of AUC0 leads to infinity, the preparation A gave the significantly lower bioavailability than the other compounds. Formulations A and B are marketed as generically equivalent preparations in Finland. However, their pharmacokinetic parameters after a single dose were different.

The pharmacokinetics of carbamazepine in plasma and saliva of man.

The excretion of carbamazepine in the saliva of six normal adults after receiving a single oral dose of 400 mg carbamazepine is described. There was a good correlation between carbamazepine concentrations in the plasma and saliva (r = 0.94, P less than 0.001). This indicates that the concentrations of carbamazepine in the saliva can be used to monitor carbamazepine therapy. The half-life of carbamazepine in the plasma was not significantly different from the half-life in the saliva. Thus areas under concentration-time curves, apparent volumes of distribution (Vd) and the total body clearances were significantly dependent (P less than 0.001) upon the distribution of carbamazepine between plasma and saliva. Calculated from saliva concentrations, 75% of the total carbamazepine plasma concentration is bound to protein while 25% is unbound in diffusional equilibrium with saliva. These figures are consistent with data in the literature.

Carbamazepine: placental transport, tissue concentrations in foetus and newborn, and level in milk.

The pharmacokinetics of carbamazepine were studied during pregnancy and early childhood by investigating the extent of its placental penetration and its distribution in the foetal and neonatal tissues at autopsy. In foetuses the liver and kidney contained high levels of carbamazepine, whereas brain and lungs had low values. Carbamazepine-10,11-epoxide was also detected in the foetal circulation. At autopsy material, carbamazepine was localized mostly in the cerebral cortex, heart, liver and kidney. The concentration of carbamazepine in the milk was found to be 60 per cent of the respective plasma value.

The significance of the simultaneous determination of carbamazepine and its 10,11-epoxide from plasma and human erythrocytes.

The distribution of carbamazepine and its 10,11-epoxide derivative into human erythrocytes was studied in child and adult epileptics on long-term therapy. Firstly, it was found that carbamazepine penetrated into erythrocytes, where the mean concentration of the drug was in rational agreement with the unbound fraction in plasma. Secondly, the relationship between the percentage of carbamazepine concentration in red cell and the drug level in plasma resembled the relationship between the percentage of unbound carbamazepine and the drug level in plasma, which relation has been described in literature recently. This similarity favors this: by determining the ratio of carbamazepine in red cells to the drug in plasma, the unbound fraction can be deduced. Thirdly, carbamazepine-10,11-epoxide was not found in red cells.

Secretion of human growth hormone and insulin in levodopa test during carbamazepine therapy.

The effect of oral administration of carbamazepine for a period of three weeks on serum growth hormone, serum immunoreactive insulin, and blood glucose was studied in healthy volunteers using a levodopa stimulation test. Serum growth hormone rose significantly from 1.3 +/- 0.3 ng/ml to 16.3 +/- 3.4 ng/ml in 60 minutes after levodopa administration (1000 mg orally) before carbamazepine, and almost similarly from 2.3 +/- 0.5 ng/ml to 15.1 +/- 4.0 ng/ml after carbamazepine during the test. No consistent changes were found in blood glucose concentrations in the levodopa test before or after carbamazepine. Levels of serum IRI were also normal throughout the test and no impairment in insulin secretion was seen during carbamazepine treatment. It is suggested that carbamazepine does not lead to an altered anterior pituitary function or to an impairment in insulin secretion. This is of advantage when growing children or subjects with a risk factor for diabetes are treated.

Carbamazepine and its 10,11-epoxide in children and adults with epilepsy.

The plasma concentrations of carbamazepine and its 10,11-epoxide were measured in 37 children and 13 adults with epilepsy during maintenance therapy. The children formed relatively more of the epoxy metabolite than adults. The daily dose, expressed as mg/kg or mg/m2, showed a statistically significant correlation with blood level in children, but not in adults. The cerebrospinal fluid concentrations of carbamazepine and carbamazepine-10,11-epoxide in nine children were 33 and 41 per cent, respectively, of the concomitant plasma level.

Serum concentration of carbamazepine: comparison of Herrmann's spectrophotometric method and a new GLC method for the determination of carbamazepine.

A specific direct gas chromatographic method to determine carbamazepine and, semiquantitatively, 10,11-epoxy carbamazepine in serum is described. The average recovery of carbamazepine is 98%, and the error on duplicate determination is +/- 4%. The method is compared with Herrmann's classic spectrophotometric method. In material of 103 patients the mean serum concentration of carbamazepine was 25.5 +/- 12.8 mumoles/1 with GLC and 23.0 +/- 12.6 mumoles/1 with spectrophotometry. The difference was highly significant. The blood sample volume is one-tenth of that needed in spectrophotometry.