Selective prophylactic solvent-detergent plasma and cryoprecipitate transfusion to prevent intraventricular hemorrhage in extreme preterm infants: A case-historical control.

BACKGROUND: Contradictory evidence exists whether a prophylactic coagulation factor transfusion in the first hours of life (HOL) prevents intraventricular hemorrhage (IVH) in extreme preterm infants (EPI, <28 weeks gestation). We aimed to determine whether selective prophylactic solvent-detergent plasma and cryoprecipitate transfusion within 12 hours of life (SP-SDP/Cryoprecipitate-T) could prevent IVH in EPI. METHOD: This is a retrospective analysis, case-historical control, of prospectively collected data from a pre-existing electronic neonatal database at a Saudi tertiary neonatal intensive care unit. We compared the IVH rate in EPI born in the first 4 years (Jan 2010-Dec 2013) of the SP-SDP/Cryoprecipitate-T period with that of EPI born during the last 4 years (Jan 2006-Dec 2009) of the rescue SDP/Cryoprecipitate-T period. RESULTS: The IVH rate was lower in the SP compared to the rescue- SDP/Cryoprecipitate-T period (30.8% versus 51.2%, odds ratio 0.42, 95% confidence interval 0.21, 0.88, p = 0.02). This difference remained significant after controlling for six other IVH risk factors. CONCLUSIONS: Early SP-SDP/Cryoprecipitate-T may reduce the IVH rate in EPI. A large multicenter clinical trial is required for confirm the short and long-term benefit and risk of this intervention. Until then, early SP-SDP/Cryoprecipitate-T may be considered by an institution with a persistently high IVH rate.

Altered activities of kininase II, an angiotensin converting enzyme, prekallikrein, and nitric oxide in Kuwaiti patients with type 2 diabetes.

The current investigation was conducted to examine kininase II or angiotensin converting enzyme (ACE), plasma prekallikrein (PK), and nitric oxide (NO) concentrations in healthy Kuwaiti subjects and newly diagnosed Kuwaiti type 2 diabetic patients before and after treatment for 6 weeks with metformin hydrochloride 500 mg twice daily after meal. With the consent of volunteers, blood and urine samples were collected after an overnight fasting. Samples were collected from the diabetic patients before and after treatment for 6 weeks. Enzyme linked immunosorbent assay (ELISA) was carried out on the aliquoted samples to measure the concentration of kininase II. NO was detected via colorimetry. Plasma Kininase II or ACE levels were significantly (P <0.01) increased by 18% in untreated diabetics when compared with healthy volunteers. However, after treatment there was a significant decrease of 20% in their ACE levels. Plasma prekallikrein levels were raised significantly (P <0.01) by 28% in diabetic patients in contrast with the control subjects and the levels were significantly reduced (P <0.0001) by 44% after treatment with metformin hydrochloride. NO levels were found to be significantly decreased in plasma by 56% and in urine by 62% in untreated diabetic patients as compared with the healthy subjects. However, when the treated diabetic patients were compared with untreated diabetics, there was an increase of 50% in plasma and 37% in urine samples. The high levels of kininase II, prekallikrein, and reduced NO may be partly responsible for the induction of renal, cardiac, and hypertensive complications associated with type 2 diabetes. Reduced NO level is an indication of endothelial dysfunction resulting in increased blood pressure. Oral anti-diabetic treatment is associated with protective effects through the reduction of kininase II (ACE), prekallikrein, and elevation of NO levels.

Bradykinin-forming components in Kuwaiti patients with type 2 diabetes.

Diabetes is the most common risk factor in inducing hypertension, nephropathy and retinopathy. The bradykinin (BK)-forming system has been proposed to protect cardiovascular and renal functions. We therefore evaluated urinary active and proactive kallikrein, total kininogen, plasma tissue kallikrein, plasma creatinine, plasma glucose and plasma HbA1c in newly diagnosed untreated type 2 diabetic patients and healthy subjects. In diabetic patients, urinary and plasma tissue kallikrein concentrations were significantly increased. In addition, plasma prekallikrein levels were also significantly higher. However, urinary kininogen values were significantly reduced in diabetic patients when compared with healthy subjects. This is the first investigation among Kuwaiti Arab patients with type 2 diabetes showing abnormal activities in the BK-forming system. High levels of plasma prekallikrein may be a risk factor for developing high blood pressure as well as nephropathy. The urinary and plasma tissue kallikrein concentrations were higher in diabetic patients, which could indicate the hyperactivities of these components, and may result in increased levels of plasma glucose to induce diabetes. Furthermore, the urinary kininogen levels were reduced in diabetic patients. These alterations might reflect the utilization of urinary kininogen to form BK, a potent inflammatory agent. However, this hypothesis needs further investigation.

Isoniazid acetylation phenotyping in Saudi Arabs.

AIMS: The present study is designed to investigate the acetylator status in Saudi Arabs. METHODS: Isoniazid (INH) acetylation phenotyping was studied in 136 Saudi Arabs in Riyadh, Saudi Arabia, using a single plasma sample taken 3 h post-INH oral dose of 200 mg. Metabolic ratio (MR) of plasma acetyl-INH (Ac-INH) to INH was used to determine the acetylation phenotype. RESULTS: The MR had a bimodal distribution with an antimode of 1.0. The frequency distribution of slow acetylators (MR < 1.0) was 94.9% (n = 129). Using Hardy-Weinberg Law, the gene frequency (q) of the recessive allele determining slow acetylator phenotype was found to be 0.97. CONCLUSION: INH phenotyping suggests a high frequency of slow acetylators among Saudi Arabs. There was no association between the MR of plasma Ac-INH/INH and age or gender.

Effect of lamotrigine on the pharmacokinetics of carbamazepine and its active metabolite in dogs.

The effect of lamotrigine (LTG) on the pharmacokinetics of carbamazepine (CBZ) and its active metabolite; carbamazepine-epoxine (CBZ-E), was investigated in dogs. Five male dogs received CBZ (2 x 200 mg tab, p.o.) daily for a period of 1 week. After the end of this period, blood samples were collected serially for up to 24 hrs. After a wash-out period of I week, LTG (100 mg tab, p.o.) was coadministered with the CBZ dose (2 x 200 mg tab, p.o.) for 7 days. Blood samples were again serially collected and plasma levels of CBZ and CBZ-E were analysed by high performance liquid chromatography (HPLC). Concurrent administration of LTG with CBZ did not have any significant effect on the pharmacokinetic parameters of CBZ. There was also no significant difference between the plasma concentration ratio (CBZ-E to CBZ) vs time profiles in the two schedules of drug administration signifying the absence of pharmacokinetic interaction between LTG and CBZ or its active metabolite in this animal model.

Lung volume reduction surgery in emphysema: a systematic review.

The aim of this study was to systematically review the literature regarding the safety and efficacy of lung volume reduction surgery (LVRS) in patients with emphysema. Studies on LVRS to August 2000 were identified using MEDLINE, Embase, Current Contents, and the Cochrane Library. Human studies of patients with upper, lower or diffuse distributions of emphysema were included. All types of bullous emphysema were excluded. A surgeon and researcher independently assessed the retrieved articles for their inclusion in the review. When LVRS was compared with medical management, at 2 years LVRS was associated with a higher FEV1 and at least equivalent survival. The use of staple excision of selected areas of lung appeared to be more efficacious than laser ablation. There is insufficient evidence to show preference for median sternotomy or videoscopically assisted thoracotomy, as the more safe and efficacious procedure. In highly selected patients with emphysema LVRS is deemed an acceptable treatment. To fully evaluate the safety and efficacy of LVRS, outcomes beyond 2 years must be included. The results of prospective randomized trials between medical management and LVRS, now in progress, are essential before a final assessment can be made.

Effect of vigabatrin and gabapentin on phenytoin pharmacokinetics in the dog.

This study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A daily dose of PT (12 mgkg(-1)i.v.) was given to a group of five beagle dogs for a period of 1 week. On day eight, plasma samples were serially collected over 24 h, after administration of the PT dose. PT administration was continued, along with supplementary oral VGB (60 mgkg(-1)) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mgkg(-1), i.v.)-GBP (300 mg caps., p.o.) study on a separate group (n= 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parenteral PT. However VGB markedly changed the drug's kinetics, as evidenced by a 31% (P= 0.015) reduction in total body clearance (CL) and an increase of over 45% in half-life (t(1/2)), (P= 0.013) and area under the plasma PT concentration-time curve (AUC), (P= 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in a marked reduction in systemic clearance of the latter in the dog.

Effect of vigabatrin and gabapentin on phynytoin pharmacokinetics in the dog.

The study was aimed at investigating whether or not the kinetics of intravenously administered phenytoin (PT) was altered by oral administration of vigabatrin (VGB) or gabapentin (GBP). A group of five beagle dogs were given a daily dose of PT (12 mg/kg, i.v.) for a period of 1 week. On day 8, plasma samples were serially collected over 24 hr. after administration of the PT dose. PT administration was continued with oral supplementary dose of VGB (60 mg/kg) for another week and then plasma samples were collected for analysis of PT levels. The same protocol was followed for the PT (12 mg/kg, i.v.)-GBP (300 mg caps., p.o.) study on a separate group (n = 5) of dogs. Orally administered GBP did not significantly alter the pharmacokinetic parameters of parental PT. VGB, however markedly changed the drug's kinetics as evidenced by a 31% (P = 0.015) reduction in total body clearance (CL) and increase of over 45% in half-life (t1/2), (P = 0.013) and area under the plasma PT concentration-time curve (AUC), (P = 0.044). GBP does not appear to have any pharmacokinetic interaction with PT, while coadministration of VGB and PT results in marked reduction in systemic clearance of the latter in the dog.

Liquid chromatographic determination of six antiepileptic drugs and two metabolites in microsamples of human plasma.

A simple, rapid, sensitive, and reproducible high-performance liquid chromatographic (HPLC) method for simultaneous determination of the antiepileptic drugs (ethosuximide, primidone, lamotrigine, phenobarbital, phenytoin, and carbamazepine) and two metabolites (carbamazepine-diol and carbamazepine-epoxide) in human plasma is described. The procedure involves extraction of the drugs from human plasma (100 microL) with ether using 9-hydroxymethyl-10-carbamyl acridan as an internal standard. The extract was evaporated and reconstituted with mobile phase and then injected onto the chromatograph. The drugs and the internal standard were eluted from a Supelcosil LC-18 stainless steel column at ambient temperature with a mobile phase consisting of a 0.01M phosphate buffer/methanol/acetonitrile (65/18/17, v/v/v) adjusted to a pH of 7.5 with phosphoric acid and a flow rate of 1 mL/min. The effluent was monitored at 220 nm. Quantitation was achieved by using peak area ratio of each drug to the internal standard. The intraassay and interassay coefficients of variation (CV) ranged from 2.43% to 6.25% and from 3.02% to 5.85%, respectively. The absolute (extraction) and relative (analytical) recoveries for the drugs ranged from 70.7% to 104.4% and from 88.3% to 106.1%, respectively. Stability tests showed that the drugs were stable in plasma for at least 4 weeks when stored at -20 degrees C. The method was applied clinically for monitoring the AEDs in epileptic patients.

Effects of pregnancy on the pharmacokinetics of lamotrigine in dogs.

PURPOSE: This study was designed to evaluate the effects of pregnancy on the kinetics of lamotrigine (LTG). METHODS: Five pregnant dogs were given a daily dose of LTG (100 mg) for a period of 1 week. Two months after parturition, the same subjects were given the LTG dose (100 mg) over the same period. On both occasions, plasma LTG concentrations were determined by a sensitive, high-performance liquid chromatographic (HPLC) method, over a 30-h period after the last dose. RESULTS: The mean maximum plasma concentration (Cmax), volume of distribution (Vd/F), and oral body clearance (Cl/F) for LTG (+/- SD) during pregnancy were 7.63+/-2.46 microg/ml 1.74+/-0.29 L/kg, and 0.19+/-0.04 L/h/kg, respectively. After pregnancy, the same variables were 6.12+/-2.24 microg/ml, 2.36+/-1.10 L/kg, and 0.30+/-0.13 L/h/kg, respectively. None of these pharmacokinetic parameters was found to be significantly different between the two groups. CONCLUSIONS: The apparent lack of change in the relevant pharmacokinetic parameters of LTG during pregnancy may indicate that pregnancy has little or no effect on glucuronidation; the principal pathway for the drug's elimination.

Effect of valproic acid on the pharmacokinetic profile of oxcarbazepine in the rat.

The pharmacokinetics of oxcarbazepine (30 mg kg-1, po), administered for 1 week, was studied in rats pre-treated for 2 weeks with valproic acid (100 mg kg-1, po). Oxcarbazepine (OXC) plasma levels were measured over a period of 24 h from dosing, using a sensitive HPLC method. No significant changes were observed in the mean values of OXC pharmacokinetic parameters (Cmax, Tmax, t1/2 and AUC0-infinity) between the control and the pre-treated groups. The findings of this study suggest that OXC metabolism in the rat is apparently not affected by valproic acid, and the lack of effect may be attributed to the different pathways of biotransformation of the two drugs.

A rapid liquid chromatographic method for the determination of lamotrigine in plasma.

A rapid sensitive and simple high-performance liquid chromatographic (HPLC) method for the determination of lamotrigine in plasma is described. The drug was extracted from 100 microliters of plasma with chloroform:isopropanol (95:5% v/v) in the presence of 100 microliters of phosphate buffer (10 mM). The extract was evaporated and the residue was reconstituted with mobile phase and injected onto the HPLC system. The drug and the internal standard (chloramphenicol) were eluted from a Symmetry C18 stainless steel column at ambient temperature with a mobile phase consisting of 0.01 M potassium-acetonitrile-methanol (70.20:10% v/v/v), adjusted to pH 6.7, at a flow rate of 1.3 ml min-1 and the detector was monitored at 214 nm. Quantitation was achieved by measurement of the peak-area ratio of the drug to the internal standard and the lower limit of detection for lamotrigine in plasma was 20 ng ml-1. The intraday precision ranged from 3.34 to 6.12% coefficient of variation (CV) and the interday precision ranged from 2.15 to 8.34% CV. The absolute and relative recoveries of lamotrigine ranged from 86.93 to 90.71% and from 95.18 to 107.13%, respectively. The method was applied in studying the pharmacokinetics of lamotrigine administered orally to rabbits. This reliable micro-method would have application in pharmacokinetic studies of lamotrigine where only small sample sizes are available, e.g. paediatric patients.

The efficacy of open lung biopsy.

BACKGROUND: The morbidity and mortality of open lung biopsy was assessed, and the ability to provide a specific diagnosis in the assessment of patients with diffuse radiographic pulmonary infiltrates was determined. METHODS: A retrospective analysis was undertaken from January 1990 to May 1995 of all patients undergoing open lung biopsy during the study period. A total of 127 biopsies were performed. The indications were diffuse, infiltrative or multinodular disease. Forty-two (33%) patients had previously undergone non-diagnostic trans-bronchial biopsy. RESULTS: Open lung biopsy obtained a histological diagnosis in 121 (95.3%) patients. Postoperative in-hospital mortality was 4.7% (six patients). Three of the four patients being ventilated at the time of biopsy died. Thirty-six (28.3%) patients suffered one or more morbid events. Patients with decreased lung function, as measured by forced expiratory volume, experienced a higher risk of a morbid event (P < 0.01). There was no significant correlation between the chance of a morbid event and age, sex or the use of multiple biopsy sites. A presumptive diagnosis was made prior to biopsy in 71 patients (55.9%) and was proven correct in 43.6% of cases. CONCLUSIONS: Open lung biopsy in patients with diffuse pulmonary disease is an accurate diagnostic tool and has an acceptable morbidity and mortality associated with the procedure.

Evaluation of bosentan, pinacidil and nitroprusside on human pulmonary arteries: comparison with rat pulmonary arteries.

Bosentan (endothelin ETA/ETB antagonist), pinacidil (potassium channel opener) and nitroprusside (nitric oxide donor) were examined on isolated ring preparations of human intralobar pulmonary artery (3rd-5th generation, internal radius > or = 1 mm), rat main pulmonary artery (1st generation; internal radius > or = 1 mm) and rat intralobar pulmonary artery (3rd generation; internal radius 0.1-0.3 mm). The potency of endothelin-1 was the same in all three artery types. In human intralobar artery and rat main pulmonary artery, bosentan (3 and 10 microM) shifted the endothelin-1 concentration response curve to a higher concentration range (endothelin-1 concentration ratios, in human intralobar and rat main pulmonary artery, respectively: 3 microM bosentan, 4.5 and 8.1; 10 microM bosentan, 13.5 and 19.5), but caused no significant block of endothelin-1 in rat intralobar artery. The latter finding may be due to the reported presence of ETB receptors in rat intralobar arteries and the higher potency of bosentan on ETA than on ETB receptors. In contrast, the potencies of nitroprusside and pinacidil (relaxation of submaximal contractions to the thromboxane-mimetic, U46619) agreed on human and rat intralobar arteries but were 6 to 16-fold lower than on rat main pulmonary artery. We conclude that data obtained on pulmonary arteries from rats can be useful in predicting the effects of vasoactive drugs in human pulmonary arteries but selection of the most appropriate rat artery for study will depend on the drug group under investigation. For potassium channel openers and nitric oxide donors, good agreement between human and rat data will be found when using pulmonary arteries from the same anatomical location even though they differ markedly in size. In contrast, for endothelin antagonists, agreement is more likely to be found in arteries of comparable size, despite their different anatomical locations.

Rapid micromethod for simultaneous measurement of oxcarbazepine and its active metabolite in plasma by high-performance liquid chromatography.

A rapid method for the simultaneous determination of oxcarbazepine (OXC) and its active metabolite (10-hydroxycarbazepine) in human and rat plasma by reversed phase high-performance liquid chromatography is described. The method involves a simple one-step extraction of the drugs from plasma with dichloromethane. The extract was evaporated and the residue was reconstituted with mobile phase and injected onto a Novapak C18 column. The eluting solvent was 20% acetonitrile in water at a flow rate of 1.5 ml/min and the detector was monitored at 215 nm. The detection limit of OXC and 10-hydroxycarbazepine was 50 and 20 ng/ml, respectively. The within-day and between-day coefficients of variation for OXC and its active metabolite were 2.57-6.95% and 4.21-8.3%, respectively. The relative and absolute recoveries varied between 71.4% and 104.0%. The applicability of the analytical procedure to pharmacokinetic studies was illustrated.

Pleurectomy for persistent pain in benign asbestos-related pleural disease.

BACKGROUND: Persistent severe pain is a rare complication of benign asbestos-related pleural disease. METHODS: Four patients are described in whom pain persisted for more than one year (range 18 months to five years) which was incompletely relieved by opioid medication and nerve blocking procedures. All underwent pleurectomy in an attempt to relieve it. RESULTS: At operation the pleura was considerably thickened in all cases. Two of the four patients had successful relief of pain. The other two had a neuralgic component to their pain before surgery which persisted afterwards. One of these patients underwent successful cervical cordotomy. CONCLUSIONS: Pleurectomy may provide relief in patients with constant pleuritic pain due to benign asbestos-related pleural thickening. It seems, however, that patients in whom the pain has a neuralgic component are unlikely to benefit.

Asphyxia while swallowing solid food caused by bronchial compression: a variant of the pneumonectomy syndrome.

A 40 year old man presented with recurrent episodes of dyspnoea whilst swallowing solid food. He had undergone right pneumonectomy and thoracoplasty for recurrent pneumonias and empyema 23 years previously. Solid food boluses appeared to cause bronchial obstruction by compressing the surgically distorted left main bronchus. This is a new variant of the post pneumonectomy syndrome.

Chronic intrapulmonary foreign bodies.

Two cases of chronically retained foreign bodies are presented, demonstrating that a long delay may exist between a penetrating injury and the manifestation of a severe symptom, such as haemoptysis or recurrent infection, referable to a retained foreign body. In only one of these cases was the diagnosis of retained foreign body considered the most likely pre-operatively. Some diagnostic and management problems arising in such situations are discussed.

Comparison of a new high-performance liquid chromatography method with fluorescence polarization immunoassay for analysis of methotrexate.

A simple high-performance liquid chromatography (HPLC) method for the determination of methotrexate (MTX) in biological fluids is described. The assay is rapid, the time required for analysis is less than 30 min, and it is sensitive, up to 0.01 microgram/ml, which is three times below the toxic MTX concentration. Fifty plasma samples drawn from acute lymphocytic leukemia (ALL) patients were used to compare this method with that of fluorescence polarization immunoassay (FPIA). A good correlation (r = 0.979) was obtained between the results of the two analyses. FPIA constantly overestimates the concentration in samples collected during elimination and underestimates those collected during infusion. The difference between the means of the two methods was 29% and 13% for the elimination and infusion samples, respectively. The means of the peak height ratio of the metabolite to MTX in the HPLC chromatograms were 3.39 and 0.33 during elimination and infusion, respectively. The results therefore indicate that HPLC is more specific when tracing the washout of MTX concentration. Because of this specificity and simplicity, the method is recommended for therapeutic drug monitoring. The stability of MTX in human saliva was investigated in this study. MTX was found to be stable at room temperature and at -20 degrees C for a minimum of 3 h and 3 weeks, respectively.