The effects of paroxetine on the pharmacokinetics of paliperidone extended-release tablets.

INTRODUCTION: Co-morbid medical and psychiatric conditions are common in individuals with schizophrenia. As such, selecting antipsychotic medications with a low potential for drug-drug interactions (DDIs) is crucial, as many are extensively metabolized by hepatic cytochrome P450 (CYP) isozymes. METHODS: This randomized, crossover study examined the effects of paroxetine (a potent CYP2D6 inhibitor) on the pharmacokinetic parameters of a single dose of the novel antipsychotic agent, paliperidone extended-release tablets (paliperidone ER), in healthy subjects. RESULTS: The mean C (max) and AUC of paliperidone were slightly higher and paliperidone clearance was slightly lower following co-administration of paliperidone ER with paroxetine. There was a ratio of geometric treatment means of 116.48% for AUC (infinity) [90% CI: 104.49-129.84]. However, the increase in total exposure to paliperidone was not considered clinically relevant. The incidence of adverse events was lower when subjects received the combination of paliperidone ER and paroxetine compared with paroxetine alone. DISCUSSION: Results suggest that no clinically relevant pharmacokinetic interaction occurs when paroxetine and paliperidone ER are co-administered and, therefore, initiation or discontinuation of concomitant treatment with CYP2D6-inhibiting drugs does not appear to warrant an adjustment in paliperidone ER dosage.

Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.

The aim of this study has been twofold: 1--to examine the impact of oral anticoagulant (OAC) use on a possible recent rise in the admission rate of intracerebral haemorrhages to Aberdeen Royal Infirmary (ARI), and 2--to estimate the absolute risk of intracranial haemorrhage for outpatients followed up in the OAC Clinic at ARI. The number of patients admitted to ARI with intracerebral bleedings increased by 60% between 1993 and 1998. A corresponding increase in the proportion of patients with concurrent OAC use (4.7% vs 15.7%, p = 0.055) cannot sufficiently explain the increase in the total number of intracerebral haemorrhages. The average annual incidence of intracranial haemorrhages for the OAC Clinic at ARI is found to be acceptably low at 0.33% per year. Further audit of the large number of patients receiving warfarin outwith the supervision of the clinic is urgently required.

Course, management and outcome of oral-anticoagulant-related intracranial haemorrhages.

The aim of this study was to compare the clinical course and radiological features of oral anticoagulant (OAC)-related intracranial haemorrhages with those of haemorrhages unrelated to OAC use admitted over the last six years to a tertiary care centre in the North of Scotland. We furthermore wished to determine the measures taken for reversal of OAC therapy and the resulting short-term outcome. Sixty-eight patients had been treated with OACs at the time of intracranial haemorrhage (32% subdural, 62% intracerebral). Patients admitted with OAC-related and unrelated haemorrhages did not differ significantly in any of the clinical features considered. On CT scan, there was no significant difference according to OAC use in the mean size of subdural (depth 15 +/- 5 vs. 18 +/- 8 mm, p = 0.36), or intracerebral haematomas (max. diameter 40 +/- 21 vs. 41 +/- 20 mm, p = 0.73). No reversal measures were taken in 38% of OAC-treated patients. In-hospital mortality was significantly higher for OAC-related haemorrhages compared to unrelated haemorrhages (38% vs. 18%, p = 0.001). To further elucidate the effects of anticoagulant reversal on the outcome of OAC-related intracranial haemorrhages, a large-scale prospective study is warranted.

Prediction of functional outcome and in-hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Early survival of patients with intracerebral hemorrhage in general is known to be most strongly dependent on the Glasgow Coma Scale score on admission. The aim of this study was to examine the factors determining functional outcome and in-hospital mortality of patients admitted with an intracerebral hemorrhage related to oral anticoagulant (OAC) use. METHODS: Correlation studies and multiple logistic regression analyses were performed on data from a retrospective series of 42 patients admitted with OAC-related intracerebral hemorrhages over a 6-year period to a tertiary care center in the north of Scotland. RESULTS: The functional outcome after an OAC-related intracerebral hemorrhage was dependent on maximum diameter of hematoma on CT scan (R:=-0.72, P:<0. 001) and international normalized ratio (INR) (R:=-0.35, P:=0.024). Hematoma diameter and INR were not themselves strongly correlated (R:=0.31, P:=0.099). In-hospital mortality can be predicted by the Glasgow Coma Scale score alone (R:(2)=0.36, overall predictive accuracy 68%) but more accurately by a logistic regression model including hematoma diameter and CT signs of cerebrovascular disease (R:(2)=0.70, predictive accuracy 83%). CONCLUSIONS: Neither functional outcome nor in-hospital mortality appears to be strongly dependent on INR measured on admission. CT scan, however, provides essential information and allows accurate predictions about the short-term outcome of OAC-related intracerebral hemorrhages.

Analysis of risk factors involved in oral-anticoagulant-related intracranial haemorrhages.

We examined risk factors for intracranial bleeding while on oral anticoagulants (OACs) in 68 patients admitted to hospital over a 6-year period, and 204 out-patient controls followed-up in an OAC clinic. Under multivariate analysis, significant risk factors for OAC-related intracranial bleeds were hypertension (OR (95%CI) 2.69 (1.04-6.97), duration of OAC therapy < or =12 months (OR 3.74 (1.21-11.56)), duration > or =96 months (OR 0.25 (0.07-0.88)), and International Normalized Ratio on admission >4.5 (OR 10.92 (2.46-48.43)). A logistic regression model including the above variables along with a history of 'cerebrovascular disease' (OR 2.32 (0.98-5.46)) correctly predicted intracranial bleeding (or its absence) during OAC therapy in 85% of all patients. The risk associated with advanced age and concomitant aspirin use was not significantly increased in this analysis. It is important to achieve tight control of INR, particularly in the early months of treatment. Patients with previous cerebrovascular disease are at increased risk of intracranial bleeding on warfarin, and hypertensive patients should have especially close monitoring and optimal control of their blood pressure.

Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome.

OBJECTIVE: Previous studies have revealed that hormonal disturbances may accompany the chronic fatigue syndrome (CFS). Changes in the secretion of the pituitary-adrenal axis have been demonstrated, as well as abnormalities in the GH-IGF-I axis. However, data have not always been well characterized and were sometimes conflicting. The small number of CFS patients investigated in earlier studies may have played a role in the interpretation of the results. SUBJECTS AND DESIGN: Hormonal testing was performed in 73 nonobese CFS patients and nonobese 21 age-and gender-matched healthy controls. We investigated GH, ACTH and cortisol responses to insulin-induced hypoglycaemia. In a subgroup of patients arginine and clonidine stimulation for GH was also performed. Nocturnal secretion of GH, ACTH and cortisol were determined. Serum levels of IGF-I, prolactin, TSH, and free thyroxine were also measured. Visceral fat mass was assessed by CT scanning. RESULTS: GH response to insulin induced hypoglycaemia assessed by peak value (17.0 +/- 13.1 microg/l vs. 22. 1 +/- 9.8 microg/l; P = 0.01) and by AUC (450.0 +/- 361.3 microg/l vs. 672.3 +/- 393.0 microg/l; P = 0.002) was significantly decreased in CFS patients vs. controls. Nocturnal GH secretion assessed by GH peak value (5.4 +/- 3.7 vs. 9.0 +/- 5.1 microg/l; P = 0.44) and by AUC (34.4 +/- 20.2 vs. 67.4 +/- 43.1; P = 0.045) was also significantly impaired in CFS patients. Arginine and clonidine administration showed no differences in GH secretion between CFS patients and controls. In the CFS group, GH peak values were significantly higher after ITT than after arginine (P = 0.017) or clonidine (P = 0.001). No differences in serum IGF-I levels were found between CFS patients and controls. Except for a significantly lower nocturnal cortisol peak value, no differences were found in ACTH and cortisol secretion between CFS patients and controls. Significantly higher serum prolactin levels (7.4 +/- 4.7 microg/l vs. 4.4 +/- 1.3 microg/l; P = 0.004) and significantly higher serum TSH levels (1.6 +/- 1.0 mU/l vs. 1.0 +/- 0.4 mU/l; P = 0.011) were found in CFS patients. Serum free thyroxine was comparable in both groups. Visceral fat mass was significantly higher in CFS patients (86.6 +/- 34.9 cm2 vs. 51.5 +/- 15.7 cm2; P < 0.001). CONCLUSIONS: We observed a significant impairment of GH response during insulin-induced hypoglycaemia and a low nocturnal GH secretion in CFS patients. These changes did, however, not lead to different concentrations in serum IGF-I. The clinical expression of this inadequate GH secretion can thus be questioned, although the alteration in body composition may be related to this relative GH deficiency. Significantly increased prolactin and TSH levels were found when compared to controls. These findings give support to the hypothesis of a decreased dopaminergic tone in CFS. Further investigations are required in order to identify specific adaptations within the neurotransmitter system in CFS and to determine the clinical importance of the impaired GH homeostasis.

A giant prolactinoma presenting with unilateral exophthalmos: effect of cabergoline and review of the literature.

We report the case of a 45-year-old male presenting with unilateral exophthalmos due to a large tumoral mass invading the skull base. Ophthalmologic examination did not show any visual field defects. Imaging techniques demonstrated extension of a huge tumor (approx. 8x8x8 cm) into the right orbit and nasopharynx. Endocrine work-up revealed grossly elevated serum prolactin (PRL) levels (26,466 microg/l, nl. < 12), pointing to a large, invasive macroprolactinoma. Stimulation tests indicated associated partial adrenal and growth hormone deficiencies. Planned surgery was abandoned, and the patient was instead treated with the long-acting dopamine agonist, cabergoline. Over a period of one year, serum PRL dropped to 131 microg/l, while the tumor mass shrank to less than 50% of its original volume (with 3.5 mg/week of cabergoline). The exophthalmos disappeared, and the patient did not develop rhinorrhea or any other side effects from treatment with cabergoline. The efficacy was maintained throughout the second year (ultimate serum PRL 74 microg/l, and final size less than 10% of the original). With reference to this case, we review other macroprolactinomas reported in the recent literature for associated exophthalmos, grossly elevated serum PRL levels (> or = 15,000 microg/l), and/or "giant" size (> or = 4 cm in maximum diameter). We highlight the use of dopamine agonists in the treatment of prolactinomas with such unusual characteristics.

Cushing's syndrome in pregnancy treated by ketoconazole: case report and review of the literature.

We report on a 30-year-old female with a pituitary-dependent Cushing's disease, who refused transsphenoidal surgery and was treated with ketoconazole and cabergoline. After approximately 3 years of therapy, the patient herself decided, without the knowledge of her treating physician, to interrupt contraception. As the patient became pregnant she ceased the intake of all medication (between the third and seventh week), but resumed it soon after pregnancy was diagnosed because of relapsing clinical signs. Pregnancy and vaginal delivery at 37 weeks gestation passed uneventfully. The newborn male infant did not demonstrate any congenital malformations and was normally sexually developed. With reference to this case, we discuss the difficulties in the medical treatment of Cushing's syndrome during pregnancy. Whereas outside pregnancy only efficacy and side-effects are taken into account, teratogenicity is an important question in these patients. Experience with different drugs is listed. This is only the second time that ketoconazole has been used during pregnancy for the treatment of Cushing's syndrome. We argue that ketoconazole may be safe as well as effective in pregnancy and, furthermore, without any consequences for the child.

Corticotropin-dependent Cushing's syndrome in older people: presentation of five cases and therapeutical use of ketoconazole.

BACKGROUND: Cushing's syndrome is a rare disorder. The corticotropin (ACTH)-dependent form of this syndrome generally results either from excessive ACTH secretion by a pituitary adenoma or ectopic secretion by a malignant tumor. Theoretically, the latter type can be assumed to occur more frequently in old age as the incidence of malignancy increases. METHODS: Diagnostic procedures for these five cases of Cushing's syndrome consisted of 24-hour urinary cortisol excretion, plasma ACTH and serum cortisol levels, oCRH stimulatory test, low-dose and high-dose dexamethasone suppression tests, CT scan or MR imaging of the pituitary region, and bilateral inferior petrosal sinus sampling. Patients were treated with ketoconazole, if possible, and evaluated according to clinical response and 24-hour urinary cortisol excretion. PATIENTS: The five cases presented were selected on the basis of age--75 years or older--from a total of about 100 patients presenting with Cushing's syndrome. In only three cases were signs of hypercorticism found on clinical examination. The other two patients were evaluated for adrenocortical excess because of severe hypokalemia and the fortuitous finding of enlarged adrenal glands on CT scan, respectively. RESULTS: As a result of endocrine testing, pituitary-dependent Cushing's disease was suspected in three patients and ectopic Cushing's syndrome in two patients. Imaging techniques demonstrated only one pituitary adenoma in the first three patients and a lung tumor in one of the latter two patients. Inferior petrosal sinus sampling confirmed the suspected origin of the Cushing's syndrome in the three patients in which this procedure was performed. All three patients with pituitary-dependent Cushing's disease underwent successful clinical and biochemical treatment with ketoconazole. CONCLUSION: Pituitary-dependent Cushing's disease may occur more frequently in patients older than 75 years of age than has previously been assumed. Because surgical treatment is not always easily tolerated by older patients, the steroidogenesis inhibitor, ketoconazole, can be a valuable alternative for the control of hypercorticism.

Obstructive hydrocephalus as complication of a giant nonfunctioning pituitary adenoma: therapeutical approach.

We report the case of a 61-year-old male presenting with a giant nonfunctioning pituitary tumour extending into the third ventricle and thereby causing obstructive hydrocephalus. The main complaints consisted of disturbed vision and somnolence. The patient was initially treated by ventriculoperitoneal shunting, with immediate improvement of his mental status. Transcranial resection of the tumour was performed shortly thereafter, but only a limited part of the tumour could safely be removed. By immunohistochemistry the diagnosis of gonadotroph adenoma was made. After the operation, the patient's vision deteriorated temporarily. Because of the risk of further damage to the optic nerve, radiation therapy was postponed. Instead, treatment with the long-acting dopamine agonist cabergoline was instituted, which resulted in a gradual improvement of vision. Two years later a transsphenoidal operation was performed because of acute worsening of the visual fields due to central tumour necrosis with slight volume expansion. Vision improved considerably after surgery. Radiotherapy is scheduled in the near future. This case is an illustration of the complications of giant nonfunctioning pituitary adenomas. The therapeutical approach to obstructive hydrocephalus in these instances is reviewed.

Secretion of growth hormone in patients with chronic fatigue syndrome.

Decreased serum levels of insulin-like growth factor I (IGF-I) are common in patients with fibromyalgia, which is frequently associated with chronic fatigue syndrome (CFS). Twenty patients with CFS (7 men, 13 women; age range, 30-60 years) and age- and sex-matched controls were tested for peak GH responses to insulin-induced hypoglycaemia and arginine administration. Nocturnal secretion of GH and serum levels of IGF-I were also measured. Serum IGF-I SDS (+/- SD) was significantly lower in patients with CFS than in controls (SDS, -0.39 +/- 1.07 vs 0.33 +/- 0.84; P = 0.02). Patients with CFS also tended to have reduced nocturnal secretion of GH (area under the curve, 32.4 +/- 18.3 vs 62.7 +/- 43.7 microg/l/15 minutes; P= 0.06), but peak GH responses to insulin-induced hypoglycaemia and arginine administration did not differ significantly between the two groups. It is not clear whether the tendency for impaired spontaneous nocturnal GH secretion in patients with CFS is a cause or an effect of the condition.

Serum creatine, creatinine, and other guanidino compounds in patients with thyroid dysfunction.

Serum levels of creatine (CT), creatinine (CTN), urea, guanidinosuccinic acid (GSA), guanidinoacetic acid (GAA), guanidine (G), arginine (Arg), homoarginine (Harg), argininic acid (ArgA), and alpha-keto-delta-guanidinovaleric acid (alpha-K-delta-GVA) were measured in 54 patients with hyperthyroidism, 56 with subclinical hyperthyroidism, 28 with subclinical hypothyroidism, and 51 with hypothyroidism compared with 62 euthyroid controls. In agreement with previous reports, serum CT increased (+35%) and CTN decreased (-17.6%) in hyperthyroidism as compared with normal thyroid function, whereas the opposite was seen in hypothyroidism (-17.7% and +11%, P < .0001). Original findings from this study are a highly significant decrease in GSA (-41.7%) and GAA (-36.8%) in hyperthyroidism and an increase in GSA (+36%) in hypothyroidism (P < .0001). In addition, a slight decrease in hyperthyroidism and hypothyroidism was noted for Arg (-6.2% and -13.2%, P = .001) and Harg (-14.8% and -18.1%, P = .05). By contrast, no significant change was seen in levels of urea, G, ArgA, and alpha-K-delta-GVA. No major differences were found for any of the compounds between subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism. There was a highly significant positive linear correlation between urea and GSA levels in hyperthyroidism, euthyroidism, and hypothyroidism (r = .68, r = .77, and r = .75, P < .0001), taking into account that for the same increase in urea, GSA increased threefold more in hypothyroid versus hyperthyroid patients. In conclusion, apart from CT and CTN, significant changes can be found in serum levels of GSA, GAA, Arg, and Harg in patients with thyroid dysfunction. Subclinical thyroid dysfunction does not seem to induce changes in serum levels of guanidino compounds. Decreased serum GSA and GAA levels might be an additional indicator of hyperthyroidism.

Role of hepatic arterial embolisation in the treatment for metastatic insulinoma. Report of two cases and review of the literature.

Malignant insulinomas are very rare. They have typical clinical and biochemical characteristics that allow an early detection and distinction from other sorts of islet cell carcinoma. As a result a curative resection can occasionally be managed. Nevertheless, for more advanced stages the same treatment options as for other metastatic neuroendocrine tumours must be considered: palliative surgery, medical treatment, chemotherapy and hepatic arterial (chemo-) embolisation. Especially the last kind of treatment has recently gained interest. We report two cases of metastatic insulinoma treated in this way. In the first case we are able to record an unusually long survival through the single use of sequential embolisation, following palliative resection of the primary tumour. In the second case we describe the current way to use this technique, i.e. in combination with chemotherapy. We argue that it might be more important in the treatment of metastatic insulinoma to combine hepatic arterial embolisation with other types of local or systemic therapy, rather than the choice of this most efficient technique on its own.

Thyrotoxic periodic paralysis, an unusual cause of hypokalemic periodic paralysis.

Over a two-year period two patients were admitted to the hospital with episodes of paralysis and hypokalemia. In the first patient, familial hypokalemic periodic paralysis was initially suspected. Only several months later was Graves' disease diagnosed and this diagnosis linked to thyrotoxic periodic paralysis. The second patient came to notice after treatment with thyreostatic drugs was stopped prematurely and paralysis together with hypokalemia developed. Thyrotoxic periodic paralysis, being rare outside Asia, closely mimics the clinical presentation of familial hypokalemic periodic paralysis. Mainly men in the third decade with a negative family history are affected. Graves' disease is the most common cause of hyperthyroidism. This disorder is not always clinically apparent since signs of hyperthyroidism may be easily missed. Therefore thyroid function tests are part of the diagnostic workup of hypokalemic periodic paralysis. Correction of thyroid function is essential to treatment. The pathophysiology is still controversial.