A multinational investigation of the impact of subcutaneous sumatriptan. I: Design, methods and clinical findings

This report describes the design, methods and clinical results of a prospective sequential multinational (5 countries) study conducted to evaluate the effects of subcutaneous sumatriptan on health-related quality of life, workplace productivity, clinical parameters and patient satisfaction. Adult patients with moderate to severe migraine initially received customary therapy for migraine episodes for 12 weeks, followed by 24 weeks' treatment with self-administered subcutaneous sumatriptan 6 mg. Demographic, baseline, health-related quality of life and patient satisfaction rating data were collected during visits to the clinic. Data relating to migraine symptoms, migraine therapy, work productivity and non-work activity time were collected on diary cards filled out by the patients. 749 patients were recruited to the study and 637 received at least 1 dose of sumatriptan. Overall, 75.5% of migraines were successfully treated within 2 hours with sumatriptan compared with 31.9% with customary therapy; 36% of patients reported complete relief at 2 hours with sumatriptan treatment compared with 1% of patients receiving customary therapy. 69% of patients successfully treated 70% of their migraines with sumatriptan within 2 hours, compared with 12% of patients with customary therapy. No serious adverse events were reported; 50% of patients reported an adverse event during the 12-week customary therapy phase and 89% of patients during the 24-week sumatriptan phase. These clinical results, which are consistent with those reported in randomised blinded studies of subcutaneous sumatriptan, suggest that relief of migraine symptoms occurs more often, and in less time, in patients receiving subcutaneous sumatriptan rather than customary therapy as their primary medication.     

Development of a new biodegradable intravascular polymer stent with simultaneous incorporation of bioactive substances

OBJECTIVE: Due to the thrombogenicity and permanent implant nature of metallic stents, bioresorable synthetic polymers have been proposed for stents and local drug delivery systems. Bioresorbable polyesters like poly(D,L-lactide) demonstrated excellent biocompatibility in various tissues. This paper describes a novel method for the molding of these polymers. The specific CESP-process (Controlled Expansion of Saturated Polymers) is characterised by the use of the plasticizer carbon dioxide and allows the incorporation of bioactive substances at physiologic temperatures into the polymer bulk and the production of complex designed implants. METHODS: The CESP-process is characterised by the exposure of an amorphous polymer to an inert gas at high pressure with a significant lower glass transition point. The plasticizing effect makes it possible to process polylactides at a temperature close to room temperature. The low process temperature constitutes a key advantage for thermally sensitive polymers and allows the incorporation of thermally sensitive pharmaceutical additives. To obtain some preliminary information on the biocompatibility, in vitro cell toxicity testing as well as drug release assessment was performed. RESULTS: Different polymer sheets were produced using the CESP-process. Cytotoxicity was not observed in any molded polymer material. According to the mechanical and biocompatibility results Poly(D,L-lactide) (P-DL-LA) was investigated in the CESP-process. Finite element analysis was used to test the possible geometry of an adequate stent. A helical design was chosen and a stent-prototype was produced using the CESP-process. Peroxidase activity as an incorporated marker enzyme could be measured over 6 weeks. Different drug release profiles were obtained due to various pore sizes of the polymer. CONCLUSIONS: The new CESP-process can be used to process biodegradable polymers and to mold different stent geometries without inducing cytotoxic effects to the material. Furthermore, this procedure permits the simultaneous incorporation of bioactive substances during the molding process. Drug release kinetics can be regulated by different pore sizes of the material.     

Bupivacaine 2.5 mg/ml versus bupivacaine 0.625 mg/ml and sufentanil l microg/ml with or without epinephrine 1 microg/ml for epidural analgesia in labour

We have compared three different methods of epidural analgesia in labour, bupivacaine 2.5 mg/ml (group B), bupivacaine 0.625 mg/ml + sufentanil 1 microg/ml (group BS) and bupivacaine 0.625 mg/ml + sufentanil 1 microg/ml + epinephrine 1 microg/ml (group BSE). One hundred and forty parturients with a singleton fetus with cephalic presentation were randomly allocated to one of the three groups. Group BSE had significantly less pain than groups B and BS. Group B had a significantly higher degree of motor blockade assessed on the Bromage scale. Significantly, more women in group B required urinary bladder catheterization than in the two other groups and they also had significantly less urge to push during active delivery. The incidence of mild pruritus was 18% in group BS and 36% in group BSE. The frequency of instrumental delivery and caesarean section was low (12% and 6.4%, respectively) with no significant differences between the groups. All women were highly satisfied with the method of analgesia and 97% would prefer the same kind of pain alleviation at the next delivery. We conclude that epidural analgesia with low-dose bupivacaine and sufentanil is as good an analgesic method as high-dose bupivacaine. Addition of low-dose epinephrine improves the analgesia.     

Mechanisms of hypercoagulability

Following certain major operative procedures, large amounts of tissue factor may be released from damaged tissues to venous blood. Mechanical and chemical injury to the collecting veins exposes subendothelial procoagulant proteins. This initiates a marked local hypercoagulable process. Subsequently, venous bloodborne procoagulant debris induce a substantial thrombin generation as blood passes the lung capillaries. Thus, the lungs seem to have a central role in the mechanisms of hypercoagulability in high-risk patients. Hypercoagulable blood is squeezed out in the peripheral circulation and may favor thrombosis formation both in central and peripheral vessels. In addition, reduced venous blood flow for several days to weeks after the operation may put these patients at-risk for thromboembolic complications for a long time. Several predisposing genetic and acquired factors associated with thrombophilia have been proposed to contribute to this hypercoagulable process. However, few studies and conflicting results have been reported. The clinical penetrance of the described thrombophilic abnormalities and their contribution to the hypercoagulable process in "high-risk" patients are, at present, unclear. The post-traumatic hypercoagulability seems to be a systemic phenomenon, at least following major orthopedic surgery. Cardiorespiratory and vascular complications play a prominent role as a cause of death and morbidity during and after this kind of surgery.     

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.