Pharmacokinetics of zidovudine in end-stage renal disease: influence of haemodialysis.

OBJECTIVE: To study the pharmacokinetics of zidovudine (ZDV) and its glucoronide metabolite (G-ZDV) in a patient with end-stage renal disease in haemodialysis. DESIGN: Pharmacokinetics study performed during and between haemodialysis sessions. METHODS: The patient was treated with oral ZDV (100 mg every 8 h). Concentrations of ZDV and G-ZDV were measured by radioimmunoassay. A monocompartmental model was used to calculate pharmacokinetic parameters. RESULTS: The peak plasma concentrations of ZDV and G-ZDV after drug administration between haemodialysis sessions were 0.57 and 10.01 micrograms/ml, respectively. The half-lives of ZDV and G-ZDV rose to 3.2 and 14.2 h, respectively. The total body clearance for ZDV in the period between haemodialysis sessions (0.44 l/kg/h) was 66% lower than normal values. The ZDV half-life was normalized by haemodialysis, the total body clearance of ZDV increased (1.12 l/kg/h) and the G-ZDV half-life shortened (5.9-7.9 h). Neither G-ZDV accumulation nor derived ZDV toxicity occurred. CONCLUSIONS: Our data suggest that ZDV is safe and an efficient drug when administered at a dosage of 100 mg three times daily in patients with end-stage renal disease in haemodialysis sessions, and that ZDV and G-ZDV are cleared by haemodialysis.

The growth hormone (GH)-releasing hormone-GH-insulin-like growth factor-1 axis in patients with fibromyalgia syndrome.

Fibromyalgia (FM) is a painful syndrome of nonarticular origin, characterized by fatigue and widespread musculoskeletal pain, tiredness, and sleep disturbances, without any other objective findings on examination. Interestingly, some of the clinical features of FM resemble the ones described in the adult GH-deficiency syndrome. Furthermore, insulin-like growth factor (IGF)-1 levels are frequently reduced in patients with FM. To gain further insight into the mechanisms leading to dysregulation of the GH-IGF-1 axis in these patients, we assessed 24-h spontaneous GH secretion, GH responses to GHRH, and IGF-1 and IGF binding protein (BP)-3 levels before and after 4 days treatment with human (h)GH. We found that, in comparison with controls, patients with FM exhibited a marked decrease in spontaneous GH secretion as assessed by mean GH secretion (2.5 +/- 0.4 microg/L in controls vs. 1.2 +/- 0.1 microg/L in FM, P < 0.05), pulse height (4.7 +/- 0.8 microg/L in controls vs. 2.5 +/- 0.3 microg/L in FM, P < 0.05), and pulse area (4.7 +/- 1 min/mg x L in controls vs. 2.3 +/- 0.3 min/mg x L in FM, P < 0.05). In contrast, GH responses to GHRH (100 microg, i.v.) were similar in controls (mean peak, 13.5 +/- 2.5 microg/L) and in patients with FM (12.2 +/- 3 microg/L). Finally, treatment with hGH (2 IU, s.c. daily), over 4 days, led to a clear-cut increase in plasma IGF-1 and IGFBP-3 levels in patients with FM. In conclusion, our data show that patients with FM exhibited a marked decrease in spontaneous GH secretion, but normal pituitary responsiveness to exogenously administered GHRH, thus suggesting the existence of an alteration at the hypothalamic level in the neuroendocrine control of GH in these patients. Furthermore, our finding of increased IGF-1 and IGFBP-3 levels after GH treatment, over 4 days, opens up the possibility of testing the therapeutic potential of hGH in patients with FM.

[Pharmacokinetic study of zidovudine in parenteral drug addicts with human immunodeficiency virus infection]. / Estudio farmacocinético de zidovudina en adictos a drogas parenterales con infección por el virus de la inmunodeficiencia humana.

BACKGROUND: The aim of this study was to know the pharmacokinetics of zidovudine (ZDV) in steady state in patients with infection by the human immunodeficiency virus (HIV) in whom the risk factor was intravenous drug use. METHODS: The study was carried out in 8 patients in stage IV of the Centers for Disease Control (CDC) with no acute intercurrent process, with normal liver and renal function, orally receiving 250 mg of ZDV every 6 hours. Blood samples were taken between 30 and 360 minutes from the last doses taken during fasting. Plasma concentrations of ZDV and glucuronide zidovudine (G-ZDV) were determined by radioimmunoassay with the data being adapted to a monocompartmental pharmacokinetic model. RESULTS: The maximum concentration (Cmax) of ZDV was 0.81 +/- 0.38 microgram/ml demonstrating high interindividual variability with values between 0.35 microgram/ml and 1.45 microgram/ml. The mean Cmax of G-ZDV was 1.44 +/- 0.64 microgram/ml. The mean t1/2 of ZDV and G-ZDV was 1.63 +/- 0.75 hours and 1.12 +/- 0.32 hours, respectively, with values oscillating between 0.99 and 3.14 h in the case of ZDV. The area below the curve concentration/time (AUC) of ZDV was 1.43 +/- 0.34 microgram-h/ml and in the case of G-ZDV the AUC was 2.73 +/- 0.91 microgram-h/ml. Total body clearance (Clb) of ZDV was 2.11 +/- 0.64 l/kg/h and the volume of distribution (Vd) of ZDV was 5.6 +/- 1.73 l/kg. CONCLUSIONS: The results of this study demonstrate that there is a marked interindividual variability in the pharmacokinetics of zidovudine suggesting the need for adapting dosage to patients weight and monitoring plasma concentration.

Evaluation of the pituitary-adrenal axis before, during and after pituitary adenomectomy. Is perioperative glucocorticoid therapy necessary?

Under the supposition that ACTH secretion will be compromised by surgical trauma, patients with pituitary adenomas undergoing transsphenoidal adenomectomy are frequently given corticoids, even though this therapy is controversial. We studied 10 patients with pituitary adenomas whose adrenocortical function was sufficient prior to surgery. The ACTH and cortisol levels rose significantly during surgery in all of these patients. Five patients completed a two-year postoperative follow-up period and their ACTH and cortisol values remained within normal limits. It may be that patients undergoing transsphenoidal surgery for pituitary adenomas do not need perioperative glucocorticoid treatment, since the hypophyseal-adrenal axis does retain its integrity.

Enhanced growth hormone (GH) responsiveness to GH-releasing hormone after dietary restriction in patients with Cushing's syndrome.

OBJECTIVE: In patients with Cushing's syndrome, decreased growth hormone (GH) secretion is observed although the basic mechanism is not yet understood. A short-term hypocaloric diet is known to increase both spontaneous and GHRH-stimulated GH secretion in normal subjects. In order to gain further insight into the altered GH secretion in patients with Cushing's syndrome, we assessed the effect of a short-term hypocaloric diet on GH responses to GHRH in these patients. DESIGN: Two GHRH tests (1 microgram/kg i.v.) were performed, the first under basal conditions (normocaloric diet) and the second after a 3-day hypocaloric diet (650 cal/day). PATIENTS: Six female patients with untreated Cushing's disease. MEASUREMENTS: Plasma GH levels were measured by immunoradiometric assay. RESULTS: GHRH-induced GH release was impaired in patients with Cushing's disease on a normal diet (mean peak 12.4 +/- 6.4 mU/l, area under the curve (AUC) 744 +/- 332 mU/l/120 min). Following a hypocaloric diet, GH responses to GHRH were markedly enhanced in the same group of patients (mean peak 46.2 +/- 14.8 mU/l, AUC 3142 +/- 1032 mU/l/120 min, P < 0.05). CONCLUSIONS: This study demonstrates that in patients with Cushing's disease the somatotroph hyporesponsiveness to growth hormone releasing home is improved after a short-term hypocaloric diet. Therefore, blunted growth-hormone secretion in chronic hypercortisolism is a potentially reversible state and the secretory capacity of the somatotroph appears not to be severely compromised in patients with Cushing's disease.

Influence of hepatitis C virus infection on the mortality of antiretroviral-treated patients with HIV disease.

The aims of this study were to analyze the mortality directly attributable to chronic viral hepatitis in HIV-1 infected patients and to investigate the influence of hepatitis virus infections on the survival of this population. A cohort of 328 HIV-1 infected, antiretroviral-treated patients, followed up from 1989 to 1996, was investigated in the study. The median follow-up period of the cohort was 120 weeks. The median baseline CD4 + cell count of the cohort was 303 cells/mm3. Hepatitis C virus, hepatitis B virus and hepatitis D virus infections were present in 214 (65%), 16 (4.9%) and 9 (2.7%) patients, respectively. Sixty-seven (20.4%) subjects died but there was no information on the vital status of 36 patients (11%). The causes of mortality were AIDS in 49 (73%), liver failure in 3 (4.5%) and other causes in 15 (22.4%). The cohort was divided into two groups for survival analysis, the groups consisting of persons infected by a hepatitis virus and persons without hepatitis virus infection. There was no difference in survival between the two groups (p = 0.31, log-rank). It is concluded that mortality among HIV-1/hepatitis virus coinfected patients with moderate to severe immunosuppression is mostly due to AIDS, and that the survival of these subjects is not influenced by the presence of hepatitis virus infections, particularly hepatitis C virus.

Absence of effect of trimethoprim-sulfamethoxazole on pharmacokinetics of zidovudine in patients infected with human immunodeficiency virus.

Pharmacokinetic parameters of zidovudine (ZDV) were not altered in 16 patients receiving concomitant therapy with ZDV and trimethoprim-sulfamethoxazole by oral administration. ZDV areas under the concentration-time curves were (means +/- standard deviations) 1.80 +/- 0.70 and 1.69 +/- 0.64 micrograms.h/ml in the absence and presence of trimethoprim-sulfamethoxazole, respectively. ZDV clearances were 1.57 +/- 0.61 and 1.74 +/- 0.66 liters/h/kg, respectively.