In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence.

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [11C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1-4 days (n=14) or 24 days (n=1) after their last drink. Linear mixed modeling of partial-volume-corrected [11C]PBR28 data revealed a main effect of alcohol dependence (P=0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P<0.035). Peripheral immune response was assessed in a subset of subjects by measuring cytokine expression from monocytes cultured both in the presence and absence of lipopolysaccharide. Peripheral monocyte response to lipopolysaccharide stimulation was lower in alcohol-dependent subjects compared with controls for the proinflammatory cytokines interleukin-6 and interleukin-8. Thus, alcohol-dependent individuals exhibited less activated microglia in the brain and a blunted peripheral proinflammatory response compared with controls. These findings suggest a role for pharmaceuticals tuning the neuroimmune system as therapeutics for alcohol dependence.

Pharmaceutical care needs of patients with angina.

OBJECTIVE: The aim of this study was to evaluate patient knowledge and assess the management of angina for patients receiving sublingual glyceryl trinitrate (GTN) METHOD: Prospective data collection and patient interview was undertaken in 17 community pharmacies. RESULTS: During the study 488 angina patients presented to the participating pharmacies. Data were collected for 347 patients receiving sublingual GTN. Problems with administration technique were identified for 108 patients (31%) and knowledge of when to seek medical help appropriately after failed GTN use was unsure for 134 patients (39%) or poor for 88 patients (25%). Eighty five patients (24%) were not receiving regular symptomatic therapy. Aspirin was prescribed or purchased by 253 patients (73%). Seven pharmacies participated in GP referral (data collected for 201 patients); 31 patients (15%) were referred usually with a recommendation to add aspirin. The outcome of 20 of these referrals was assessed; advice was taken for 13 patients, 3 patients failed to attend GP, aspirin was contraindicated for 3 patients and one patient already attended pharmacist medication review. CONCLUSION: This study demonstrated the potential contribution community pharmacists could make at the time of dispensing to the management of patients with angina.

Resection of an intracardiac metastasis from malignant teratoma of the testis.

Nonseminomatous germ cell testicular neoplasm is a disease cured primarily by platinum-based combination chemotherapy. Operation is reserved for those patients who continue to harbor residual masses after chemotherapy. Locoregional lymph nodes and lungs are common sites for residual deposits. Intracardiac metastases are very rare. We report a case of successful resection of bilateral lung and single intracardiac secondary deposits from a malignant teratoma, treated by orchidectomy 6 years previously.

Fatal trauma: a five year review in a Dublin hospital.

The autopsy reports and clinical data of 96 patients presenting to St. James's Hospital with trauma of fatal outcome, between January 1, 1986 and December 31, 1990, were analysed. Eighty-one (84%) deaths were due to road traffic accidents and all were the result of blunt trauma. Ninety-five (99%) had an Abbreviated Injury Scale (AIS) score > or = 3 in at least one anatomical category. Cerebral trauma (41%) and shock and haemorrhage secondary to multiple injuries (40%) were the commonest causes of death. Sixty-eight (71%) patients were dead on arrival at the hospital. Of the twenty-eight deaths occurring after admission to hospital nine (32%) were potentially preventable. The mean (sem) Injury Severity Score (ISS) for those with preventable deaths was 24.1 (3.8). These data have implications for the development of trauma care facilities in Ireland.

Gastrointestinal complications after cardiac surgery.

Gastrointestinal complications after cardiac surgery are uncommon, but are associated with a high morbidity and mortality. Over 11 years 8559 procedures requiring cardiopulmonary bypass were performed in this unit and 35 patients were identified who developed gastrointestinal complications after surgery, an incidence of 0.41%. There were nine deaths in this group, a mortality of 25.7% compared with an overall mortality after cardiac surgery in Ireland ranging from 3.24% to 4.81%. These complications required surgery in 21 patients. The most common indication for surgical intervention was upper gastrointestinal bleeding in 10 patients, three patients had acute pancreatitis, two patients had perforated peptic ulcer; two patients had intestinal ischaemia, with five cases of colon pathology. The difficulties of making an early diagnosis are outlined and a low threshold to exploratory laparotomy is recommended.

Operation for cavitating invasive pulmonary aspergillosis in immunocompromised patients.

Invasive pulmonary aspergillosis is a specific form of pulmonary Aspergillus infection that occurs almost exclusively in immunocompromised patients. It differs both histologically and in its clinical course from classic aspergillomas. During a 5-year period (1986-1990), 8 patients underwent resection for cavitating invasive pulmonary aspergillosis that developed as a consequence of neutropenia during chemotherapy for malignancy. There were no perioperative deaths and no complications. This contrasts with reports of operation for classic aspergillomas. Histologic examination of the resected specimens showed that cavitating invasive pulmonary aspergillosis differed from classic aspergillomas. They consisted of necrotic lung tissue invaded by fungus with separation from the surrounding lung so that the sequestrum had the appearance of a fungus ball. Pulmonary aspergillosis is a common complication of profound neutropenia. The first hemoptysis in this group of patients is often life-threatening. The excellent results of operation in our series of patients may be attributed to their young age, good pulmonary function, and limited operation. This has lead us to recommend early surgical intervention in invasive aspergillosis once cavitation develops.

Population pharmacokinetics of rectal theophylline in neonates.

The population pharmacokinetics of theophylline were studied in 35 neonates receiving aminophylline suppositories for the treatment of apnoea of prematurity. Routinely measured theophylline serum concentrations (n = 138, range 3-20 mg/L) were modelled in NONMEM according to a one-compartment model. The influence of a number of clinical and demographic factors, e.g., weight (range 0.8-2.5 kg) and postnatal age (2-80 days), on clearance/bioavailability (CL/F) and volume/bioavailability (V/F) was investigated. Both these parameters were found to significantly correlate to weight alone in a directly proportional manner: CL/F = 40 +/- 2 ml/h/kg and V/F = 1.3 +/- 0.2 L/kg. The absorption was best described by a first-order process, having a half-life of 1.6 +/- 0.7 h. The interindividual variability in CL/F was 25%, whereas the same estimates in V/F and in the first-order absorption rate constant could not be obtained. The residual variability in theophylline concentrations was modelled with additive error with an estimated standard deviation of 1.78 mg/L. From these results, it was concluded that rectal administration of aminophylline in neonates is a therapeutically acceptable alternative to oral administration. The convenience gained by rectal, compared to oral, administrations may compensate, in many instances, for the possibly slightly higher variability in CL/F of the former.

Completion pneumonectomy: indications, complications, and results.

From 1958 through 1985, a total of 113 consecutive patients had completion pneumonectomy (CP). Indications for pulmonary resection resulting in CP were lung cancer (LC) in 64 patients, pulmonary metastases (PM) in 20, and benign lung disease (BLD) in 29. Operative mortality was 12.4% (14 deaths) but varied according to the indication for CP. Mortality was 9.4% for LC, 0% for PM, and 27.6% for BLD. Forty-three patients (38.1%) had major complications (26 of 64 with LC, 40.6%; 1 of 20 with PM, 5.0%; and 16 of 29 with BLD, 55.2%). Five-year actuarial survival for patients with LC was 26.4% but varied according to stage. Five-year survival for patients with PM was 40.8% and with BLD was 27.2%. We conclude that CP for BLD carries marked operative mortality and morbidity, usually due to intense reaction around hilar structures and concurrent active infection or fistula. In contrast, CP for LC and PM can be performed with low mortality, acceptable morbidity, and gratifying long-term survival.

Phenytoin monitoring: clinical or scientific?

Phenytoin is an established therapy for post-herpetic neuralgia. In order to maintain serum phenytoin levels in the normal therapeutic range, serum phenytoin monitoring is required. This range may, however, be misleading in certain clinical conditions. We report here a patient with hypoalbuminaemia who developed marked clinical phenytoin toxicity despite maintenance of the serum total phenytoin concentration within the therapeutic range.

Population pharmacokinetics of gentamicin in neonates.

The influence of a number of clinical characteristics on the population pharmacokinetics of gentamicin were examined using routine drug-monitoring data from a group of 113 neonates. The data were analyzed using the programme NONMEM. Clearance was 0.053 litres.h-1.kg-1 and was reduced in neonates with postconceptional age less than or equal to 34 weeks (X 0.83) and 5-min Apgar score less than 7 (X 0.82). Volume of distribution was 0.47 litres.kg-1. These population mean parameter estimates were used to generate dosage regimens to achieve concentrations within the therapeutic range.

Evaluation of a new Seralyzer assay for carbamazepine.

The performance of a new dry-phase, strip immunoassay technique for the analysis of serum carbamazepine concentrations (Seralyzer), was compared to a standard high performance liquid chromatography (HPLC) method. One hundred blood samples were collected from 87 patients and analysed using both techniques. There was no significant difference between the concentrations measured by either technique, and the results were highly correlated (r = 0.97). The Seralyzer is a rapid and accurate method for use in carbamazepine therapeutic drug monitoring.

Pharmacokinetics of high-dose metoclopramide in cancer patients.

The introduction of new cytotoxic drug regimens has been associated with an increase in the incidence and severity of adverse effects. This in turn has highlighted the need for more effective adjuvant therapy. The use of metoclopramide for the prophylaxis of nausea and vomiting, in high intravenous doses (50 to 1000 mg), has become established since 1981. As a lipid-soluble drug, metoclopramide has a large volume of distribution. The reported mean values after high doses range between 2.8 and 4.6 L/kg. The mean values for total body clearance and terminal half-life range from 0.31 to 0.69 L/kg/h and from 4.5 to 8.8 hours, respectively. The values of these pharmacokinetic parameters are essentially similar to those obtained after conventional doses (less than 50mg). Pharmacokinetic parameters appear unaffected by age, although no high-dose study has been conducted in children. Bodyweight is apparently correlated with clearance. An influence of renal function indices on terminal half-life and clearance has been shown, which is rather surprising since renal clearance accounts for only 20% of the total clearance. No thorough investigations exist which examine the influence of hepatic disease, cancer type and cytotoxic drug regimen on the disposition of metoclopramide. A relationship between dose (or concentration) and therapeutic or adverse effects of metoclopramide is outlined. The therapeutic benefit of high doses (up to 14 mg/kg) may be dependent on age, and on the combination of cytotoxic drugs. The advantages of high doses of metoclopramide are most apparent when the drug is used as protection against the adverse effects of high doses of cisplatin (greater than 60 mg/m2). Despite considerable pharmacokinetic variability, intravenous administration of high doses of metoclopramide is relatively safe due to its large therapeutic index.

The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease.

High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/- 0.13 (s.d.) l h-1 kg-1, mean volume of distribution at steady state was 3.8 +/- 1.2 (s.d.) l/kg and mean elimination half-life was 8.3 +/- 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h-1 kg-1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg-1 h-1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h-1 kg-1) = 0.57 - [0.036 X urea (mmol/l)].

Evaluation of a high pressure liquid chromatographic technique for metoclopramide analysis.

High-dose metoclopramide has found an established place in the prophylaxis of nausea and vomiting which may be induced by cancer chemotherapy. A simple reliable high pressure liquid chromatographic technique for the measurement of this drug in serum has been developed and evaluated. The methodology will find application in the study of metoclopramide pharmacokinetics and in the monitoring of high-dose metoclopramide therapy in individual patients with neoplastic disease.