Interactions of serum albumin, valproic acid and carbamazepine with the pharmacokinetics of phenytoin in cancer patients.

Phenytoin dosing is critical in cancer patients as to decreased absorption secondary to chemotherapy-induced gastrointestinal toxicity, increased phenytoin metabolism in the liver secondary to chemotherapy, extreme patient profile that falls outside the predicted pharmacokinetic population, frequent hypoalbuminaemia and polydrug treatment. A retrospective study to assess the variability of free phenytoin and the free fraction of phenytoin, as well as the influence of comedication on these parameters was performed in cancer patients by using a population approach. Two hundred fifty-eight data pairs of total phenytoin and free phenytoin were analysed from 155 cancer patients on stable phenytoin using non-linear mixed-effect modeling (NONMEM). Total and free phenytoin were determined using a fluorescence polarization immunoassay. An extensive model building procedure was subsequently used for covariate testing on the free fraction of phenytoin. Mean total phenytoin concentration was 11.7 mg/l, free phenytoin 1.25 mg/l and phenytoin free fraction 0.107. Free phenytoin was <1 mg/l on 132 occasions (51.2%) and >2 mg/l on 37 occasions (14.3%). Total and free phenytoin were significantly correlated (r(S)=0.827, P<0.01). The free fraction of phenytoin was independent of time after drug intake. Serum albumin concentrations and comedication with valproic acid or carbamazepine were identified by NONMEM as significant determinants of phenytoin free fraction. Co-medication with valproic acid and carbamazepine led to a 52.5% and 38.5% increase of the free fraction of phenytoin, respectively, and a 10 g/l decrease of serum albumin to a 15.1% increase of the free fraction of phenytoin. Phenytoin pharmacokinetics could reliably be estimated from oral doses and steady-state concentrations of protein-bound and free phenytoin. The variability in the free fraction of phenytoin could partly be explained by the influence of albumin concentrations and antiepileptic comedication. Significant alterations of the free fraction of phenytoin and free phenytoin by co-administration of valproic acid or carbamazepine suggest therapeutic drug monitoring of free phenytoin to be of potential benefit in cancer patients.

Retinal arterial changes correlate with cerebral small-vessel disease.

OBJECTIVE: To examine the relation between retinal artery disease and cerebral small-vessel disease (SVD). METHODS: In a prospective cohort of patients with symptomatic atherosclerotic disease, the authors performed retinal photographs and brain MRI. Two ophthalmologists, not aware of the MR results, independently assessed retinal arterial narrowing, crossings, sclerosis, and tortuosity according to standard scoring lists. Two observers independently assessed white matter lesions (WML) and lacunar infarcts on the MR images. Lesions were considered abnormal only when both ophthalmologists or MR raters agreed. Cerebral SVD was defined as the presence of WML or lacunar infarcts. RESULTS: In 179 patients, retinal photographs and brain MRI were performed. Of the 108 patients with MR signs of SVD, 92% had at least one retinal vascular abnormality; of the 71 patients without SVD, 77% had retinal pathology (p < 0.01). All types of retinal vascular pathology occurred more frequently in patients with SVD, but only retinal arterial narrowing and sclerosis differed significantly. In the 109 normotensive patients, the presence of any retinal vascular change correlated with signs of SVD (p = 0.01). CONCLUSION: Pathologic changes in the retinal arteries parallel changes in the small cerebral arteries that cause WML and lacunes, both in hypertensive and in normotensive patients.

Response of leptomeningeal metastases from breast cancer to hormonal therapy.

Intraventricular chemotherapy with radiotherapy is the standard treatment of leptomeningeal metastasis (LM) from breast cancer; this treatment increases median survival only to about 3 months and is frequently complicated by serious side effects. The authors describe two patients with LM from breast cancer who were treated with hormonal therapy, which provided a neurologic response of at least 12 months and a survival of 14+ and 19 months. Hormonal therapy can be effective and nontoxic for patients with LM from breast cancer.

The relevance of intraventricular chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study.

To assess the benefit of intraventricular chemotherapy, patients with leptomeningeal metastasis (LM) from breast cancer were randomised to treatment including intraventricular (IT) chemotherapy (n=17) or to non-intrathecal (non-IT) treatment (n=18). Appropriate systemic therapy and involved field radiation therapy (RT) were given in both arms. Intention-to-treat analysis showed neurological improvement or stabilisation in 59% of the IT and in 67% of the non-IT group, with median time to progression of 23 weeks (IT) and 24 weeks (non-IT). Median survival of IT patients was 18.3 weeks and 30.3 weeks for non-IT patients (difference 12.9 weeks; 95% Confidence Interval (CI) -5.5 to +34.3 weeks; P=0.32). Neurological complications of treatment occurred in 47% (IT) vs 6% (non-IT) (P=0.0072). In conclusion, standard systemic chemotherapy with involved field RT for LM from breast cancer is feasible. Addition of intraventricular chemotherapy does not lead to survival benefit or improved neurological response, and is associated with an increased risk of neurotoxicity.

Intravascular coagulation: a common phenomenon in minor experimental head injury.

Fibrin microthrombi were demonstrated by an immunoenzymehistochemical method in the small blood vessels of the lung and, to a lesser extent, in the brain in rats after minor experimental head injury. It was concluded that intravascular coagulation is a common phenomenon in head injury.

Hemostasis and intracranial surgery.

Preoperative and postoperative coagulation studies were performed in 25 patients undergoing various intracranial surgical procedures. Coagulation abnormalities, mostly consisting of an increase of fibrin/fibrinogen degradation product concentration, either appeared or increased postoperatively in 18 patients. This incidence of postoperative appearance or increase of coagulation abnormalities is higher than that reported in a comparable study of patients after general surgical procedures, and also higher than that of coagulation abnormalities in a previous study of patients after blunt head injury. Although the coagulation abnormalities after intracranial surgery were usually small, they tended to be larger in patients with more extensive intracranial procedures.

Hemostasis and computerized tomography in head injury. Their relationship to clinical features.

Coagulation studies (plasma fibrinogen, ethanol gelation test, and fibrin-fibrinogen degradation product concentration) and computerized tomography (CT) scan examinations were performed in 55 patients with blunt head injury. The frequency of abnormalities in both coagulation study results and CT scans was higher in patients with severe clinical features and clinical course than in less severely injured patients; in these same patients the coagulation results were abnormal (64%) more frequently than the CT scans (40%). Very high fibrin-fibrinogen degradation product (FDP) concentrations were found to be associated with combined hemorrhagic lesions and mass effect on CT scans, but not with a specific localization of brain-tissue damage. It was concluded that: 1) FDP concentration reflects the amount of brain-tissue damage rather than its location, and 2) in the absence of other possible causes of disseminated intravascular coagulation, coagulation studies may be more sensitive than CT scanning in demonstrating brain contusion.

Head injury and coagulation disorders.

Coagulation studies (plasma fibrinogen, ethanol gelation test, and fibrin/fibrinogen degradation product concentration) were done in 150 patients who were admitted after blunt head injury. Results were abnormal in 60 patients and were found to be correlated with the level of consciousness and with the presence of neurological signs. Many of these patients had fractures, but findings in a control group of 26 patients with major fractures without head injury indicate that fractures were not of paramount importance in causing clotting changes. Conclusive evidence of disseminated intravascular coagulation was found in 12 patients. Cases with a fatal clinical course were mostly associated with very high fibrin/fibrinogen degradation product concentrations. Some case histories are reported, confirming the hypothesized correlation between coagulation results and brain tissue destruction rather than brain compression. It was concluded that some degree of disseminated intravascular coagulation in patients with blunt head injury occurs more often than expected and that coagulation studies might have both diagnostic and prognostic value.

'Dementia with contractures' as presenting signs of secondary adrenocortical insufficiency.

Report of a 61-year-old man with progressive mental deterioration and flexion contractures of abdominal muscles and legs as initial signs of hypopituitarism. Five years after onset of symptoms, an endocrinologically non-functioning pituitary adenoma was demonstrated. Thyroid replacement therapy had no effect, but administration of hydrocortisone was followed by rapid recovery. The opportunity to treat such cases of curable dementia is easily missed.

Different types of plasminogen activator activity in human brain tumours: relation with peritumoral oedema?

In 20 tissue samples from human brain tumours the concentrations were measured of (1) total plasminogen activator activity, (2) tissue-type plasminogen activator (t-PA) activity, (3) urokinase-type plasminogen activator (u-PA) activity, and (4) t-PA antigen. Most tumours contained a considerable amount of t-PA, but a high interindividual and in a few cases even an intra-individual variability was observed. A weak but significant negative correlation was found between t-PA concentration and the oedema/tumour ratio, as calculated from the preoperative computerized tomography (CT) brain scanning. No correlation was found with u-PA activity. It is concluded that t-PA and u-PA are probably not important factors in the production of peritumoral cerebral oedema, but a correlation between locally different amounts of t-PA or u-PA and the locally different extent of surrounding oedema has not yet been excluded.

[Acute psychosis in a patient with a combination of sickle cell disease and hemoglobin-C disease]. / Acute psychose bij een patiënt met een combinatie van sikkelcelziekte en hemoglobine C-ziekte.

A 35-year-old negroid patient, known to have sickle cell-haemoglobin C disease, after heavy exercise developed an acute thrombotic crisis localised mainly in the brain. The clinical manifestations were those of an acute psychosis with severe confusion, aggressiveness, unco-operative behaviour and incontinence for faeces and urine. With adequate therapy he recovered after a few days. This so-called cerebral sickle cell crisis, confirmed by multiple small encephalomalacia lesions on the MRI which are typical of this disease, is a rare complication and difficult to diagnose.

[Problems in weaning from artificial ventilation: 'motor neuron disease']. / Problemen bij het ontwennen van kunstmatige ventilatie: 'motor-neuron disease'.

Three patients, two men aged 71 and one aged 73 years, were given artificial respiration because of acute respiratory failure. Subsequently they could not be weaned from artificial respiration, due to causes that were not immediately clear. It was ultimately found that the patients suffered from 'motor neuron disease', in two of them due to progressive spinal muscular atrophy, while the third, apart from loss of anterior horn motor cells, also had thoracic hydromelia. The patients died after termination of the artificial respiration.

Brain metastases in patients with pelvic or abdominal malignancy do not prevail in the posterior fossa: a retrospective study.

Pelvic and gastrointestinal tumors are generally considered to have a predilection to metastasize to the posterior fossa rather than to the supratentorial brain. Review of imaging of 100 patients with brain metastases from pelvic and gastrointestinal primary tumors and of 100 patients with brain metastases from other primary tumors did not reveal a difference in distribution of brain metastases between the two groups of patients. So, there is no evidence that pelvic and gastrointestinal tumors metastasize preferentially to the posterior fossa.

Significant variation in mortality and functional outcome after acute ischaemic stroke between Western countries: data from the tinzaparin in acute ischaemic stroke trial (TAIST).

BACKGROUND: The medical care of patients with acute stroke varies considerably between countries. This could lead to measurable differences in mortality and functional outcome. OBJECTIVE: To compare case mix, clinical management, and functional outcome in stroke between 11 countries. METHODS: All 1484 patients from 11 countries who were enrolled into the tinzaparin in acute ischaemic stroke trial (TAIST) were included in this substudy. Information collected prospectively on demographics, risk factors, clinical features, measures of service quality (for example, admission to a stroke unit), and outcome were assessed. Outcomes were adjusted for treatment assignment, case mix, and service relative to the British Isles. RESULTS: Differences in case mix (mostly minor) and clinical service (many of prognostic relevance) were present between the countries. Significant differences in outcome were present between the countries. When assessed by geographical region, death or dependency were lower in North America (odds ratio (OR) adjusted for treatment group only = 0.52 (95% confidence interval, 0.39 to 0.71) and north west Europe (OR = 0.54 (0.37 to 0.78)) relative to the British Isles; similar reductions were found when adjustments were made for 11 case mix variables and five service quality measures. Similarly, case fatality rates were lower in North America (OR = 0.44 (0.30 to 0.66)) and Scandinavia (OR = 0.50 (0.33 to 0.74)) relative to the British Isles, whether crude or adjusted for case mix and service quality. CONCLUSIONS: Both functional outcome and case fatality vary considerably between countries, even when adjusted for prognostic case mix variables and measures of good stroke care. Differing health care systems and the management of patients with acute stroke may contribute to these findings.

Early diagnosis and treatment of spinal epidural metastasis in breast cancer: a prospective study.

This prospective study evaluated the usefulness of myelography in breast cancer patients who present with radiculopathy or myelopathy. A total of 124 consecutive myelograms were performed in 100 patients. Epidural metastasis (EM) was diagnosed in 67 myelograms (54%). Multiple epidural metastases were diagnosed in 15 (22%) of those, resulting in a total of 87 epidural lesions. A complete block was found in 13 EM (15%) and an incomplete block in 14 EM (16%). Clinical data could not predict the site of EM in 29 cases (33%). Fifteen asymptomatic EM were detected in myelograms with multiple EM. Plain radiographs were of no value in determining the site of EM in 29 cases (33%), including 13 cases (15%) without vertebral metastasis at the site of EM. Treatment consisted of radiotherapy (RT) with or without systemic treatment in 52 cases (80%), systemic treatment alone in 11 cases (17%) and surgery in two patients (3%). Clinical improvement was noticed in 72%, no change in 13%, and deterioration in 15%. No difference in response was noticed between RT and systemic therapy. Before treatment 21% and after treatment 15% of the patients could not walk. The one year survival was 42%. The ambulatory status at presentation was the most important prognostic factor. Examination of the spinal fluid, obtained at myelography, disclosed meningeal carcinomatosis in 9% of the patients. Imaging of the whole spinal canal with cytological examination of the spinal fluid is recommended in breast cancer patients suspected of epidural tumour with features of radiculopathy or myelopathy, irrespective of further clinical data and plain spinal radiographs.