Heat shock proteins form part of a danger signal cascade in response to lipopolysaccharide and GroEL.

An increasing number of cell types, including peripheral blood mononuclear cells (PBMCs), have been demonstrated to release heat shock proteins (Hsps). In this paper we investigate further the hypothesis that Hsps are danger signals. PBMCs and Jurkat cells released Hsp70 (0.22 and 0.7 ng/10(6) cells, respectively) into medium over 24 h at 37 degrees C. Release of Hsp70 was stimulated 10-fold by GroEL (P < 0.001) and more than threefold by lipopolysaccharide (LPS) (P < 0.001). Although Hsp60 could be detected in the medium of cells cultured at 37 degrees C for 24 h, the low rates of release were due probably to cell damage. Significant release of Hsp60 was observed when Jurkat cells were exposed to GroEL (2.88 ng/10(6) cells) or LPS (1.40 ng/10(6) cells). The data are consistent with the hypothesis that Hsp70 and Hsp60 are part of a danger signalling cascade in response to bacterial infection.

A confidential study of deaths after emergency medical admission: issues relating to quality of care.

In this retrospective pilot study we examine the feasibility of establishing a confidential enquiry into why some patients die after emergency admission to hospital. After excluding those who died in the first hour or who were admitted for palliative care, pairs of physicians were able to collect quantitative and qualitative data on 200 consecutive deaths. Both physicians reported shortfalls of care in 14 patients and one of the pair in 25 patients whose deaths would not have been the expected outcome. In 25, the shortfalls of care may have contributed to their deaths. Major problems were delays in seeing doctors, inaccurate diagnoses, delays in investigations and initiation of treatment. They occurred mostly in those admitted at night. It is possible that establishing the correct diagnosis and starting appropriate treatment may have been delayed in 64% of the 200 patients. The headline figures appear worse than some previous external assessment studies but this study did concentrate on those in whom problems were more likely. Nevertheless, the frequency is too high to be overlooked. In this feasibility study we have demonstrated that it is practicable for local staff to collect and assess data in hospitals and that the types of problems identified are relevant to anyone planning how to organise emergency care. A larger definitive study should be performed.

Co-morbid factors in trauma patients.

A variety of factors influence the survival of trauma patients including the severity and site of injury, and the timing and quality of care. However, host factors including age and gender have also been reported as independent risk factors that adversely influence outcome. In addition, the presence of co-morbid or pre-existing factors has been shown to increase mortality and morbidity after trauma. This chapter reviews the evidence for these associations and considers their impact on assessment and management of the trauma patient.

The use of TIPS to control bleeding caput medusae.

Two patients with cirrhosis and portal hypertension had persistent bleeding from caput medusae and ascites. Transjugular intrahepatic portosystemic shunt (TIPS) resulted in regression of the caput medusae and ascites in both cases.

Penetration of trovafloxacin into cerebrospinal fluid in humans following intravenous infusion of alatrofloxacin.

A single-dose study was conducted to determine concentrations of trovafloxacin (CP-99,219) achieved in the cerebrospinal fluid (CSF) relative to those in the serum of healthy subjects after intravenous infusion of alatrofloxacin (CP-116,517), the alanyl-alanyl prodrug of trovafloxacin. Twelve healthy subjects were administered single doses of alatrofloxacin at a trovafloxacin equivalent of 300 mg as an intravenous infusion over 1.0 h. CSF samples were taken by lumbar puncture at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 24 h after the start of the infusion; each subject was sampled at only one time point. Serum samples were taken from each subject at the time of CSF collection. A mean concentration of 5.8 microg of trovafloxacin per ml was present in serum 1.0 h after the start of the infusion. CSF/serum ratios ranged from 0.14 to 0.33 in the postdistribution phase (5 to 24 h postinfusion), with a mean ratio of 0.25. The most common adverse events were dizziness, nausea, and rash and were mild or moderate in intensity. The potency of trovafloxacin against susceptible organisms, coupled with its rapid penetration of CSF following the intravenous administration of alatrofloxacin, suggests that it may be useful in the treatment of bacterial meningitis in humans.

Whither the acute medical patient?

The continual change in NHS structure demands reappraisal of both the services provided and the allocation of resources to ensure appropriate standards of care. Unfortunately this equation never seems to balance. Although the overall goal is to have an excellent standard of care, the necessary resources nearly always are lacking. As a consequence "we" often have to critically analyse and change clinical practice to achieve this goal. Nowhere in medicine is this point more pertinent than in the management of acute medical emergencies. This article examines not only how the changing face of medicine influences this situation but also possible solutions to the question who will manage these patients in the future.

Acyclovir-induced colitis.

Three patients developed acute colitis, either de novo, or as an exacerbation of pre-existing colitis, following the use of oral acyclovir, prescribed for Herpes zoster or Herpes simplex infection. Rechallenge with oral acyclovir was performed in one patient, and resulted in a recurrence of colitic symptoms. It is speculated that acyclovir can have a direct irritant effect on large bowel mucosa.

Platelet activating factor: release from colonic mucosa in patients with ulcerative colitis and its effect on colonic secretion.

Inflammatory mediators have been implicated in the pathophysiology of ulcerative colitis. They may stimulate intestinal secretion and contribute to the production of diarrhoea. Platelet activating factor (PAF) may be responsible for a high proportion of this secretory response. Biopsy specimens from inflamed and quiescent mucosa of patients with ulcerative colitis and normal human colonic mucosa were cultured or co-cultured. The release of PAF, prostaglandin E2, and leukotriene D4 into the culture medium was measured and the ability of this culture medium, from inflamed and normal tissues, to influence secretion in rat colonic mucosa was assessed. PAF was liberated by inflamed tissue. Its release from quiescent but not normal tissue was stimulated by medium in which inflamed mucosal biopsy tissues had been cultured and by exogenous bradykinin and 5-hydroxytryptamine, but not by histamine. PAF stimulated eicosanoid production. The rise in short circuit current produced in vitro by inflamed tissue culture medium was inhibited by the PAF receptor antagonist (CV 6209) (46%) (32.4 (2.9) v 17.5 (1.19) muA.cm-2, p < 0.005) and further by combined cyclooxygenase and lipoxygenase inhibition (indomethacin plus ICI 207968) (58%) (32.4 (2.9) v 13.6 (1.9) muA.cm-2, p < 0.005). Mepacrine and hydrocortisone attenuated considerably the electrical response evoked by medium from inflamed mucosa to a similar extent (32.4 (2.9) v 6.3 (1.2) v 5.1 (0.9) muA.cm-2, p < 0.001). These data suggest that PAF accounted for 46% of the culture medium secretory effect. Thus, any attempt to block its release in patients with ulcerative colitis may have only a partial effect on their symptoms.

Safety/tolerability trial of SDZ ENA 713 in patients with probable Alzheimer's disease.

SDZ ENA 713 (ENA 713) is an acetylcholinesterase inhibitor being developed as a potential treatment for Alzheimer's disease (AD). A prior Phase II safety and efficacy study used an upper dose limit of 6 mg/day ENA 713. The present study was designed to assess the safety and tolerability of higher doses of ENA 713 in probable AD patients. Fifty AD patients (22M; 28F, mean age 68 yrs, range 45-90) were assigned to a fixed, nine-week dose escalation schedule in which they were randomized to receive up to 12 mg/day of ENA 713 bid (n=20) or tid (n=20), or placebo (n=10) followed by a one-week washout. Mg/day dose escalation for the bid and tid ENA 713 groups was identical, beginning with 2 mg/day on Days 1 to 3 and escalating to 12 mg/day in Weeks 8 and 9. Doses through 12 mg/day were well tolerated. Most adverse events were mild to moderate in severity and of limited duration, most commonly headache, nausea, dizziness, and diarrhea. Three of forty patients on ENA 713 discontinued, all due to adverse events. Two experienced nausea and vomiting; the third experienced an unrelated mild atrial fibrillation.

The safety and tolerance of xanomeline tartrate in patients with Alzheimer's disease.

Xanomeline tartrate (active ingredient xanomeline) is a muscarinic agonist that has demonstrated specificity for the M1 receptor in preclinical studies and has been well tolerated at dosages up to 50 mg three times a day in healthy elderly subjects. To define the maximum tolerated dose (MTD) of xanomeline tartrate in patients with Alzheimer's disease, 48 patients (20 men, 28 women) with probable Alzheimer's disease were enrolled in a double-blind, placebo-controlled inpatient study to determine the safety and tolerability of 8 fixed dosages of xanomeline tartrate (25, 35, 50, 60, 75, 90, 100, and 115 mg, all three times a day) given for 7 days. For each dosage the treatment panel consisted of six patients (four taking xanomeline tartrate and two taking placebo). With the discontinuation of two patients because of severe intolerable adverse events, a minimum intolerated dose was reached at 115 mg three times a day, and 100 mg three times a day was defined as the MTD. This MTD in patients was two-fold greater than the MTD previously determined in healthy elderly volunteers.

Acetylcholinesterase inhibition by zifrosilone: pharmacokinetics and pharmacodynamics.

OBJECTIVE: To determine the pharmacokinetics, pharmacodynamics and safety of the acetylcholinesterase inhibitor zifrosilone in healthy male volunteers. METHODS: Pharmacokinetics, pharmacodynamics, and tolerance of zifrosilone were studied in a double-blind, sequential, single-escalating-dose, randomized panel design. Each panel consisted of six subjects, with four subjects receiving zifrosilone (10, 30, 60, 90, 120, 150, 200, 250, and 300 mg orally) and two subjects receiving matching placebo. Serial blood samples were obtained for zifrosilone plasma concentrations and red blood cell acetylcholinesterase and butyrylcholinesterase activities. Participating subjects (n = 54) were men between the ages of 18 and 45 years. Each subject had a normal physical examination, electrocardiogram, serum chemistries, hematology, urinalysis, and test for human immunodeficiency virus at screening. RESULTS: A greater than proportionate increase in mean plasma concentration values for area under the curve from time zero to infinity was observed over the 200 to 300 mg dose range groups. Red blood cell acetylcholinesterase showed a dose-inhibition relationship, with a mean maximum inhibition of 20.9% at 10 mg that increased to 62.1% at 300 mg. Butyrylcholinesterase activity was relatively unaffected by zifrosilone (< 20% inhibition at 300 mg). For doses > or = 200 mg, an Emax pharmacodynamic model was used to describe the relationship between zifrosilone plasma concentration and red blood cell acetylcholinesterase inhibition (Emax = 83.8%; EC50 = 0.65 ng/ml). CONCLUSIONS: Zifrosilone showed dose-dependent pharmacokinetics after oral administration and was effective in causing selective inhibition of red blood cell acetylcholinesterase.

Effects of the cholinomimetic SDZ ENS-163 on scopolamine-induced cognitive impairment in humans.

Scopolamine-induced cognitive impairment was used in healthy men to evaluate the central nervous system activity of the new cholinomimetic SDZ ENS-163. Eighteen subjects were treated in a crossover design with oral placebo/intravenous saline, 50 mg of oral SDZ ENS-163/intravenous saline, oral placebo/0.4 mg of intravenous scopolamine, and 50 mg of oral SDZ ENS-163/0.4 mg of intravenous scopolamine. The administration of placebo with scopolamine caused significant cognitive impairment, as assessed by the Computerized Neuropsychological Test Battery (CNTB), and also decreased salivation and heart rate. In contrast, SDZ ENS-163 with saline had no effect on CNTB scores, increased salivation, and increased heart rate. Despite the observed cholinomimetic effects of SDZ ENS-163 when administered with saline, the changes in CNTB scores, heart rate, and salivation were indistinguishable between placebo/scopolamine and SDZ ENS-163/scopolamine. Thus, 50 mg of oral SDZ ENS-163 has cholinomimetic activity in normal men, but this dose is insufficient to reverse the muscarinic effects of 0.4 mg of intravenous scopolamine.

Orthostasis in Alzheimer disease: a retrospective analysis.

Vitiello et al. (1993) recently reported statistically significant decreases in systolic blood pressure upon standing in patients with Alzheimer disease (AD) (n = 60) as compared with healthy elderly controls (n = 20), which would suggest a possible autonomic dysfunction associated with AD. To investigate this issue, we conducted a retrospective analysis of blood pressures and heart rates of 31 patients 55-85 years of age (mean 69.6) who met National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association criteria for probable AD. The patients were selected from a pool of placebo-treated patients with AD in five inpatient phase I clinical trials. All patients met rigorous entrance criteria and thus were in excellent physical health except for AD. Blood pressure and pulse were assessed after 3-5 min of lying down and after 1-3 min of standing. Systolic and diastolic blood pressures showed decreases upon standing of 12 mm Hg (8.6%) and 6 mm Hg (8.2%), respectively, on day 1 and decreases of 10 mm Hg (7.6%) and 4 mm Hg (5.7%), respectively, on day 7 of hospitalization (p < 0.05). Pulse rates increased upon standing by 17% and 13% on days 1 and 7, respectively (p < 0.05). Our data support the finding of Vitiello et al. of significant postural decreases in systolic blood pressure in patients with AD. Well-controlled, prospective studies of orthostasis in AD and healthy elderly subjects should be conducted to determine its prevalence in both populations and to determine whether the orthostatic changes seen in AD differ from those in normal aging.

A "bridging" (safety/tolerance) study of besipirdine hydrochloride in patients with Alzheimer's disease.

Besipirdine hydrochloride is a novel compound with cholinergic and adrenergic activity being investigated as a treatment for Alzheimer's disease (AD). The pharmacodynamics of some anti-dementia drugs are known to differ in patients with AD as compared with elderly normals. The present study was designed to determine the maximum tolerated dose (MTD) of multiple oral doses of besipirdine in AD patients. Twelve AD patients (NINCDS/ADRDA criteria; 7M, 5F, ages 58-75, mean age 65) were randomized to besipirdine (n = 9) or placebo (n = 3) in a double-blind, parallel-group, rising-dose design. Doses were 10, 20, 30, and 40 mg bid for 2 days each, followed by 50 and 60 mg bid for 5 days each. The most common adverse events were asymptomatic postural hypotension and asymptomatic bradycardia. Two patients on active drug developed severe adverse events: 1 after 3 days at 50 mg bid (nausea and vomiting); 1 after 3 days at 60 mg bid (angina). Due to the anginal episode, the study was terminated on Day 17. Plasma concentrations increased linearly with dose for besipirdine and its major metabolite. The two patients who developed severe adverse events had the highest plasma concentrations measured. Besipirdine 50 mg bid was considered the maximum tolerated dose (MTD).

Potential role for interleukin-1 in the pathophysiology of ulcerative colitis.

1. Biopsies of colonic mucosa from patients with ulcerative colitis liberated more interleukin-1 beta, prostaglandin E2, leukotriene C4 and platelet-activating factor into the medium in which they were cultured than biopsies from patients with irritable bowel syndrome and histologically normal mucosa. 2. Addition of interleukin-1 stimulated release of greater quantities of all these inflammatory mediators, including interleukin-1 itself, from inflamed and normal mucosa. 3. Blockade of cyclo-oxygenase with indomethacin or of lipoxygenase with ICI 207968 or of phospholipase A2 with mepacrine inhibited release of prostaglandin E2 or leukotriene C4 or both of these plus platelet-activating factor, respectively. 4. Interleukin-1 stimulated the short-circuit current across isolated rat colonic mucosa mounted in flux chambers in a dose-dependent manner (Km 2 x 10(-11) mol/l). This stimulation was markedly inhibited by the removal of chloride from the bathing media. 5. Indomethacin or ICI 207968 inhibited the short-circuit current response to interleukin-1 and a combination of these antagonists produced a greater inhibition. Mepacrine caused an even greater inhibition whereas tetrodotoxin plus mepacrine inhibited the current completely. 6. These data indicate that interleukin-1, released in excess from inflamed colonic mucosa, stimulates the release of a range of inflammatory mediators as well as of more interleukin-1. It probably acts by stimulating phospholipase A2 in inflammatory cells, probably lymphocytes, and can do so in normal and inflamed mucosa. Since, in rat colonic mucosa it stimulated an electrical response in very low concentrations, it is feasible that it is involved in the chloride secretion, and hence the diarrhoea, which may occur in inflammatory reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Inter-relationships between inflammatory mediators released from colonic mucosa in ulcerative colitis and their effects on colonic secretion.

Metabolites of arachidonic acid have been implicated in the pathophysiology of ulcerative colitis-they can stimulate intestinal secretion, increase mucosal blood flow, and influence smooth muscle activity. The influence on the mucosal transport function of culture medium in which colonic mucosal biopsy specimens had been incubated was investigated using rat stripped distal colonic mucosa in vitro as the assay system. Colonic tissue from patients with colitis and from control subjects was cultured. Medium from inflamed tissue contained more prostaglandin E2 (PGE2) and leukotriene D4 (LTD4) and evoked a greater electrical (secretory) response in rat colonic mucosa than control tissue medium. In inflamed tissue, cyclo-oxygenase inhibition (indomethacin) attenuated PGE2 but increased LTD4 production; conversely lipoxygenase inhibition (ICI 207968) inhibited LTD4 production but enhanced PGE2 output. Each inhibitor alone enhanced the electrical response in the rat colon. Inhibition of both enzymes (indomethacin plus ICI 207968) caused a fall in both PGE2 (82%) and LTD4 (89%) production and in the electrical response (57%). Inflamed tissue treated with a phospholipase A2 inhibitor (mepacrine) produced less PGE2, LTD4, and electrical responses when compared with inflamed tissue, either untreated (91%, 92%, and 79% respectively) or treated with cyclo-oxygenase and lipoxygenase inhibition. Incubation with bradykinin stimulated eicosanoid release and electrical response, while a bradykinin antagonist caused a modest inhibition. Analysis of these observations suggests that a combination of arachidonic acid derivatives accounts for about half the secretory response. Other products of phospholipase A2 activity are probably responsible for much of the remainder, leaving up to 20% the result of types of mediator not determined in this study.

A pilot clinical trial of the angiotensin-converting enzyme inhibitor ceranapril in Alzheimer disease.

This pilot clinical trial was a 15-week, double-blind, controlled, three-way crossover study evaluating cognitive effects of ceranapril in subjects with dementia of the Alzheimer type (age range 50-75 years). Computerized (CNTB) and noncomputerized cognitive test batteries revealed no significant results (p > 0.05). On further analysis of the data, however, a study of longer duration and/or higher dosages may be warranted.