CO2 and indomethacin vasoreactivity in patients with head injury

Summary The purpose of this study was to compare the effect of hyper-ventilation and indomethacin on cerebral circulation, metabolism and pressures in patients with acute severe head injury in order to see if indomethacin may act supplementary to hyperventilation. Fourteen severely head injured patients entered the study. Intracranial pressure (ICP), mean arterial blood pressure (MABP) and cerebral perfusion pressure (CPP) were monitored continuously. Within the first four days after the trauma the CO₂ and indomethacin vasoreactivities were studied by measurements of cerebral blood flow (CBF) (Cerebrograph 10a, intravenous¹³³Xe technique) and arterio-venous difference of oxygen (AVdO₂). Ischaemia was evaluated from changes in CBF, saturation of oxygen in the jugular bulb (SvjO₂), lactate and lactate/oxygen index (LOI). Data are presented as medians and ranges, results are significant unless otherwise indicated. Before intervention ICP was well controlled (14.8 (9–24) mmHg) and basic CBF level was 39.1 (21.6–75.0) ml/100 g/min). The arterio-venous oxygen differences were generally decreased (AVdO₂ = 4.3 (1.8–8.1) ml/100 ml) indicating moderate luxury perfusion. Levels of CMRO₂ were decreased (1.54 (0.7–3.2) ml/100 g/min) as well.Duringhyperventilation (APaCO₂ = 0.88 (0.62–1.55) kPa) CBF decreased with 11.8 (–33.4–29.7) %/kPa and ICP decreased with 3.8 (0–10) mmHg. AVdO₂ increased 34.0 (4.0–139.2) %/kPa, MABP was unchanged, CMRO₂ and CPP increased (CPP = 3.9 (–10–20) mmHg). AVD (lactate) and LOI were unchanged. No correlations between CBF responses to hypocapnia and outcomes were observed.An i.v. bolus dose ofindomethacin (30 mg) decreased CBF 14.7 (–16.7–57.4) % and ICP decreased 4.3 (–1–17) mmHg. AVdO₂ increased 27.8 (–40.0–66.7)%, MABP (MABP = 4.9 (–2–21) mmHg) and CPP (CPP = 8.7 (3–29) mmHg) increased while CMRO₂ was unchanged. No changes in AVd (lactate) and LOI indicating cerebral ischaemia were found.Compared to hyperventilation (changes per 1 kPa, at PaCO₂ level = 4.05 kPa) the changes in MABP, CPP and CBF were significantly greater after indomethacin, while the changes in AVdO₂, ICP, SvjO₂, and LOI were of the same order of magnitude.Nocorrelation between relative reactivities to indomethacin and CO₂, evaluated from changes in CBF and AVdO₂, or between the decrease in ICP after the two procedures were found. Thus, some patients reacted to indomethacin but not to hyperventilation, and vice versa.These results suggest that indomethacin and hyperventilation might act independently, or in a complementary fashion in the treatment of patients with severe head injury.     

12% lactate lotion for the treatment of xerosis. A double-blind clinical evaluation

Sixty patients with moderate to severe xerosis participated in a 21-day, randomized, double-blind, contralateral study for efficacy of a specially neutralized 12% lactate lotion compared with a 5% lactic acid lotion and a nonlactated emollient lotion. The severity of xerosis was evaluated on days 0, 7, 14, and 21 during treatment and on days 28 and 35 one and two weeks after treatment was discontinued. All three preparations significantly reduced the severity scores of xerosis. During the "regression" period after treatment was discontinued, patients receiving 12% lactate lotion, compared with those treated with nonlactated emollient lotion, had had significantly greater reductions in the severity scores of xerosis for the lateral calf area at days 28 and 35 and for total severity scores (combined mean differences for lateral, medial, and pretibial areas) at day 35. Compared with 5% lactic acid lotion, the 12% lactate lotion provided significantly greater reductions for total severity scores at days 28 and 35.     

Enantioselective hydroxylation of nortriptyline in human liver microsomes, intestinal homogenate, and patients treated with nortriptyline

The enantioselectivity of hydroxylation of nortriptyline (NT) to E-10-hydroxynortriptyline (E-10-OH-NT) was studied in human liver microsomes, intestinal homogenate, and patients treated with NT. The rate of formation of (-)-E-10-OH-NT was higher than that of (+)-E-10-OH-NT both in the liver microsomes and in the intestinal homogenate. Quinidine, a prototype competitive inhibitor of the cytochrome P450IID6 ("debrisoquin hydroxylase"), inhibited the formation of (-)-E-10-OH-NT in a concentration-dependent manner in liver microsomes, while the formation of (+)-E-10-OH-NT was hardly affected. This indicates that P450IID6 catalyzes the hydroxylation of NT in a highly enantioselective manner to (-)-E-10-OH-NT in the liver. Another P450 isozyme besides IID6 seems to be responsible for the formation of the (+)-enantiomer in the liver. In intestinal homogenate, the formation of both enantiomers of E-10-OH-NT was inhibited to about the same extent by quinidine, the maximum inhibition being much less than in the liver. In the urine of six patients treated with NT, the (-)-enantiomer accounted for 91 +/- 2% of the unconjugated E-10-OH-NT, and for 78 +/- 6% of the glucuronide conjugates. The study shows that NT is hydroxylated in a highly enantioselective way, probably catalyzed by the polymorphic P450IID6, to (-)-E-10-OH-NT both in vitro in human liver as well as in vivo in patients treated with the drug.     

Multicenter phase II study of Nordic fluorouracil and folinic acid bolus schedule combined with oxaliplatin as first-line treatment of metastatic colorectal cancer.

PURPOSE: This Nordic multicenter phase II study evaluated the efficacy and safety of oxaliplatin combined with the Nordic bolus schedule of fluorouracil (FU) and folinic acid (FA) as first-line treatment in metastatic colorectal cancer. PATIENTS AND METHODS: Eighty-five patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1, followed by a 3-minute bolus injection with FU 500 mg/m(2) and, 30 minutes later, by a bolus injection with FA 60 mg/m(2) every second week. The same doses of FU and FA were also given on day 2. RESULTS: Fifty-one of 82 assessable patients achieved a complete (n = 4) or partial (n = 47) response, leading to a response rate of 62% (95% CI, 52% to 72%). Nineteen patients showed stable disease, and 12 patients had progressive disease. Thirty-eight of the 51 responses were radiologically confirmed 8 weeks later (confirmed response rate, 46%; 95% CI, 36% to 58%). The estimated median time to progression was 7.0 months (95% CI, 6.3 to 7.7 months), and the median overall survival was 16.1 months (95% CI, 12.7 to 19.6 months) in the intent-to-treat population. Neutropenia was the main adverse event, with grade 3 to 4 toxicity in 58% of patients. Febrile neutropenia developed in seven patients. Nonhematologic toxicity consisted mainly of neuropathy (grade 3 in 11 patients and grade 2 in another 27 patients). CONCLUSION: Oxaliplatin combined with the bolus Nordic schedule of FU+FA (Nordic FLOX) is a well-tolerated, effective, and feasible bolus schedule as first-line treatment of metastatic colorectal cancer that yields comparable results compared with more complex schedules.     

The impact of hormone replacement therapy on quality of life and willingness to pay

Objective To measure the gain in quality of life due to hormone replacement therapy for women with mild and severe menopausal symptoms.
Design Prospective study where data on quality of life and willingness to pay were collected by interview.
Setting Department of Gynaecology at Sodertalje Hospital near Stockholm.
Participants One hundred and four women aged 45 to 65 years treated for menopausal symptoms for at least one month.
Methods Quality oflife was measured by the time tradeoff and rating scale methods. The willingness to pay for hormone replacement therapy was investigated using the contingent valuation method.
Main outcome measures The quality adjusted life year weight measured with the rating scale and time tradeoff methods, and willingness to pay.
Results The increase in the quality adjusted life year weight due to hormone replacement therapy for women with mild symptoms was 0.26 according to the rating scale method and 0.18 according to the time tradeoff method. For women with severe symptoms the quality adjusted life year weight increased by 0.50 according to the rating scale method and by 0.42 according to the time tradeoff method. The mean willingness to pay for hormone replacement therapy per month was 2300 Swedish krone for women with mild symptoms and 4800 Swedish krone for women with severe symptoms (£1 = 10.3 Swedish krone).
Conclusions Hormone replacement therapy leads to a major improvement in quality of life for women with menopausal symptoms. Both for women with mild and severe menopausal symptoms the willingness to pay for the treatment also greatly exceeds the costs, indicating that hormone replacement therapy is economically beneficial for women with menopausal symptoms.     

Fibrosarcoma in Children: A Rare Tumour with Long-Term Survival even with Advanced Disease A Report of 3 Cases

Fibrosarcoma is a rare tumour in children. The potential of malignancy has been questioned. We present three cases of fibrosarcoma in children. The follow-up periods range from 10 to 37 years. The first patient had pulmonary metastases at the time of diagnosis in 1958. The primary tumour in fossa ischio-rectalis was resected in 1960. Lung metastases were resected in 1960 and 1989. Radiotherapy was given in 1992. He is still alive with metastases 37 years after the first manifestation of disease. The second patient had a primary tumour and several local recurrences in the mandible. He is alive without evidence of disease 4 years after resection of pulmonary metastases and 21 years after resection of the primary tumour. The third patient has no signs of recurrence or metastasic spread 10 years after a wide excision of subcutanous tumours of the left upper arm. The cases demonstrate a special tumour-entity of low-grade malignancy, which show a good prognosis and a wide spectrum of biological behaviour.     

Aneuploidy of chromosome 8 as detected by interphase fluorescence in situ hybridization is a recurrent finding in primary and metastatic breast cancer

Previous work from our laboratory demonstrated aneuploidy for several chromosomes by interphase fluorescence in situ hybridization (FISH) in a high proportion of breast cancer specimens. In the literature, only limited data are available concerning chromosome 8 anomalies in breast cancer. To determine chromosome 8 ploidy status in primary and metastatic specimens from 81 breast cancer patients, FISH analysis with a DNA probe recognizing chromosome 8 centromeres was performed. In all primary tumor specimens (n=30), significant proportions of cells were aneuploid exhibiting gain of chromosome 8 copy numbers; in 75% of effusion specimens previously classified as malignant by cytology and/or FISH for various chromosomes (n=40), cell populations aneuploid for chromosome 8 were detected; effusions previously classified non-malignant (n=11) were diploid in 10 cases, whereas one specimen contained rare hyperdiploid cells. Among these cells complex chromosomal aneuploidy could be demonstrated by two-color FISH, suggesting malignancy. Trisomic and tetrasomic clones were predominant in the majority of samples, but a marked intratumor cytogenetic heterogeneity was observed in most cases. Primary tumors and corresponding positive axillary lymph nodes revealed similar distributions of chromosome 8 copy numbers, analogous to previous findings with other chromosomes. This implies that, by using suitable FISH probes after examination of the respective primary tumor, an efficient search for (micro)metastasis might be feasible.