Cyclic analogues of Thr6-bradykinin,N8-Lys-bradykinin and endo-Lys8a-vespulakinin 1

Syntheses are described of the endo-Lys^8a-vespulakinin 1 and of cyclo-Thr⁶- and cyclo-N^ε-Lys-bradykinin. The linear peptides covering the entire sequences of endo-Lys^8a-VSK-1 and Thr⁶-BK, and the decapeptide containing all residues constituting Lys-BK, with a Arg-Lys peptide bond involving the ε-amino function of lysine, were prepared by the solid-phase procedure based on Fmoc chemistry. Cyclization was carried out by the diphenylphosphorazide method. The amino-terminal octapeptide sequence of vespulakinin 1, Fmoc-Thr(tBu)-Ala-Thr(tBu)-Thr(tBu)-Arg(Pmc)-Arg(Pmc)-Arg(Pmc)-Gly-OH, and its N^α-Boc-[(Gal β)Thr³, (Gal β)Thr⁴]-analogue, were used to prepare N^α-(1–8 VSK 1)-cyclo-N^ε-kallidin and N^α-[(Gal β)Thr³, (Gal β)Thr⁴, 1–8 VSK 1]-cyclo-N^ε-kallidin. Peptides and glycopeptides were characterized by amino-acid analysis, optical rotation, analytical HPLC and FAB-MS. Consistent with previous findings, preliminary pharmacological experiments on smooth muscle preparations showed that the cyclic, or partially cyclic, analogues were significatively less potent than the linear ones. © Munksgaard 1995.     

Frusemide and Its Acyl Glucuronide Show a Short and Long Phase in Elimination Kinetics and Pharmacodynamic Effect in Man

The pharmacokinetics of 80 mg frusemide given orally were investigated in normal subjects using a direct HPLC method for parent drug and its acyl glucuronide conjugate. Two half-lives could be distinguished in the plasma elimination of both frusemide and its conjugate, with values of 1.25 ± 0.75 and 30.4 ± 11.5 h for frusemide and 1.31 ± 0.60 and 33.2 ± 28.0 h for the conjugate. The renal excretion rate-time profile showed two phases; the rapid elimination phase lasted from 0–15 h and the second and slow phase, from 15–96 h. During the first 15 h, 33.3 ± 4.8% of the dosed frusemide was excreted; in the remaining period 15–96 h, 4.6 ± 1.5% was excreted. In the same two periods the excretion of the glucuronide was 13.4 ± 4.7 and 1.9 ± 1.1%, respectively. The mean renal clearance of frusemide was 90.2 ± 16.9 mL min^?1 during the first period and 91.5 ± 29.3 mL min^?1 in the remaining period, during which the stimulation of urine production was absent. The renal clearance of the acyl glucuronide was 702 ± 221 mL min^?1 in the first period, but only 109 ± 51.0 mL min^?1 in the second period. The stimulated urine production in the first 6 h after administration amounted to 2260 ± 755 mL (measured urine production minus baseline value of 1 mL min^?1 (360 mL). During the second or rebound period (6–96 h after drug administration), the quantity of urine was 990 ± 294 mL lower than what would have been expected from the baseline production of 5400 mL. This reduced production (0.82 mL min^?1) is equivalent to an 18% reduction in the average urine flow rate of 1 mL min^?1.     

The effect on immunity of long-term intensive training in elite swimmers

The impact of long-term training on systemic and mucosal immunity was assessed prospectively in a cohort of elite swimmers over a 7-month training season in preparation for national championships. The results indicated significant suppression (P < 0.05) of serum IgA. IgG and IgM and salivary IgA concentration in athletes associated with long-term training at an intensive level. There was also a trend towards lower IgG2 subclass levels in serum in athletes compared with controls (P= 0.07). There were no significant changes in numbers or percentages of B or T cell subsets, but there was a significant fall in natural killer (NK) cell numbers and percentages in athletes over the training season (P < 0.05). After individual training sessions there was a significant decrease in salivary IgA levels for athletes compared with controls (P= 0.02). In athletes there was a downward trend in salivary IgA levels over the 7-month training period in both the pre-exercise (P= 0.06) and post-exercise samples (P= 0.04). There were no significant trends in salivary IgG levels over the study period in either athletes or controls. The only significant change in salivary IgM levels was an increase in detection rate in the pre-competition phase in athletes (P= 0.03). The study suggests that training of elite athletes at an intensive level over both short- and long-time frames suppresses both systemic and mucosal immunity. Protracted immune suppression linked with prolonged training may determine susceptibility to infection, particularly at times of major competitions.     

Dependency of renal potassium excretion on Na,K-ATPase transport rate

Potassium secretion may depend on the transport rate of Na, K-ATPase in basolateral cell membranes of distal tubular cells. To examine this hypothesis experiments were performed in anaesthetized dogs during inhibition of proximal potassium reabsorption by acetazolamide or mannitol (fractional potassium excretion 1.2-1.4) or additional stimulation of potassium secretion by ethacrynic acid (fractional potassium excretion 2.1). Ouabain in a dose which inhibits 70–80% of the Na, K-ATPase activity reduced fractional potassium excretion to 0.8-0.9 by an effect on distal tubular secretion since potassium transport in the proximal tubules was not affected. Ouabain-sensitive potassium excretion varied in proportion to ouabain-sensitive sodium reabsorption during variation in glomerular nitration rate, even at urinary sodium concentrations exceeding 80 mmol 1^-1. In experiments without ouabain, saline infusion raised potassium excretion and sodium reabsorption until maximal Na, K-ATPase transport rate was reached, as judged from heat production measurements, but not during further increments in urine flow. After inhibition of Na, K-ATPase activity by hypokalaemia, potassium excretion and cortical heat production remained constant over a wide range of urine flow and sodium excretion. We conclude that potassium secretion is dependent on intact Na, K-ATPase activity and is stimulated by sodium delivery to the distal nephron until maximal transport rate of the enzyme is reached.     

Combination of methotrexate and sulphasalazine in patients with rheumatoid arthritis: pharmacokinetic analysis and relationship to clinical response

1. The influence of sulphasalazine (SASP) on the pharmacokinetics of low dose methotrexate (MTX) and the relation between pharmacokinetic variables and clinical response was studied in 15 patients with active rheumatoid arthritis despite >6 months of SASP treatment.
2. SASP was stopped for 2 weeks. Thereafter a single oral dose of 7.5 mg MTX was administered after a standard breakfast. Blood was sampled initially every 30 min, thereafter hourly during 8 h. Urine was sampled every hour. Then 2000 mg SASP daily + 7.5 mg MTX weekly was given. After 4 weeks the same procedure was repeated supplemented with concomitant administration of 1000 mg SASP. Clinical measurements included Ritchie articular index, number of swollen joints, ESR and the disease activity score. Pharmacokinetic analysis was performed using a two- compartment model with first order absorption and lag time. Results are given as mean (s.d.). Paired t-test or signed rank test were applied in the statistical analysis.
3. Pharmacokinetics of MTX without vs with SASP, means±s.d. were as follows: AUC: 673±179 vs 628±210 (95% confidence interval [CI] of the difference was −71 to 159) ng ml⁻¹ h, MRT: 5.2±1.3 vs 5.2±1.1 (95% CI −0.4 to 0.4) h, t½,z: 4.3±1.1 vs 4.2±1.1 (95% CI −0.3 to 0.5) h, V /F: 59.3 ±29.3 vs 65.5±25.3 (95% -23.8 to 11.4) l, CL/F: 12.3±5.0 vs 13.5±4.8 (95% CI −4.5 to 2.3) l h⁻¹. CL_R/F: 6.2±1.3 vs 6.3±2.1 (95% CI −1.3 to 1.1) l h⁻¹. All P values were ≥0.3.
4. A weak correlation existed between the change of ESR and the MRT, the t½,z and the V /F (Spearman correlation coefficients of 0.43, 0.50 and 0.50 respectively, 0.05<P<0.1).
5. There is no significant influence of chronic SASP administration on the pharmacokinetics of MTX or vice versa. Of the clinical variables, only the ESR correlated consistently with some pharmacokinetic variables of MTX.

     

Special Hospital seclusion and its clinical variations

Summary

• ? The terminology used in the published literature to indicate that a patient is being denied, or is denying themself, the company of other people is wide and varied.
• ? With ever growing concerns of the rights, both civil and legal, of patients receiving treatment, either solicited or unsolicited, there is a need to identify the patterns of practice in any given organization and to establish their relationship to the terminological semantic.
• ? The Special Hospitals, who cater for those patients requiring a high degree of security, have been assumed to use seclusion to a greater degree than any other form of personal-space facility, either forced by the staff or elected by the patient. However, this has largely been based on hearsay and speculation.
• ? Seclusion may be perceived as a clinical psychiatric intervention to prevent the serious deterioration of a person's mental state or as a method of containment of a dangerous situation when all else fails.
• ? This study was based on a survey of all seclusion facilities within the Special Hospital system and discussions with over 100 nursing staff about the differing types and methods of providing patient withdrawal from the ward community for whatever reason.
• ? The results highlighted a clear uniformity of practice throughout the system despite the differing terminologies used.

     

WHAT BECOMES OF PEOPLE WITH DEMENTIA REFERRED TO COMMUNITY PSYCHOGERIATRIC TEAMS?

Objective: To monitor key processes and outcomes in joint health and social services community psychogeriatric teams. Design: Six month follow-up of new referrals to 4 teams in Cambridge. Data collected from structured clinical assessment forms at baseline and interviews with keyworkers at follow-up. Data for groups with and without dementia were compared. Setting: Two rural and two urban teams in area with relatively large long stay inpatient facility but low independent sector provision. All were routine service teams, rather than run for research purposes. Main outcome measures: The main outcome measures were survival, institutionalisation, key worker assessments of avoidable admissions, appropriateness of placement, unmet needs, carer stress and global outcome for patient and carers. Results: Rates of referral to urban teams were double rural rates. Around forty percent of the dementia group had a social worker as assessor and keyworker. The dementia group was significantly more dependent and received more informal and formal care. After six months, only 54% of the dementia group were alive and living outside institutional care, compared to 79% in the functionally ill group. Unplanned admissions to hospitals or homes were rarely judged avoidable by keyworkers. Outcomes for carers were judged poor in 15% of both groups, and 13% and 11% of carers respectively were judged to be under severe stress. Unmet needs were more common in the dementia group, and related principally to residential care and carer respite. A number of measures, including evidence of geographical inequity and identification of unmet needs, provided an important contribution to local policy development. Further work is needed on the validity of keyworker assessments of carer stress, given the findings of the carer interview sub-study.     

Estrogen receptor β– an independent prognostic marker in estrogen receptor α and progesterone receptor‐positive breast cancer?

Both subtypes of estrogen receptor (ER), ERα and ERβ, are normally present in the mammary gland. The role of ERα as a prognostic marker in breast cancer is well established due to the beneficial effect of providing tamoxifen as adjuvant therapy. The role of ERβ, however, is less clear. To gain insight into the importance of ERβ in breast cancer, 145 primary breast cancers were examined by immunohistochemistry for ERβ, and the expression level was compared with ERα and progesterone receptor (PR) status. Especially, we wanted to examine the significance of ERβ in the contrasting ERα+/PR+ and ERα?/PR? subgroups. In the ERα+/PR+ subgroup (dual positive), the survival difference between patients with low, medium and high ER β level was statistically significant (p = 0.004), with more than 70% of patients with medium and high ERβ levels surviving 100 months, compared with less than 30% in the group with low ERβ level. Further, for ERα+/PR+ patients there was a reduced risk of fatal outcome by multivariate analysis with increasing ERβ levels (p(trend) < 0.01 [univariate analysis]; p(trend) = 0.05 [multivariate analysis]). The risk was 31% and 27% for medium and high ERβ levels, respectively, compared with low ERβ level, adjusting for standard prognostic factors such as tumor diameter, nuclear tumor grade (quantified by mean nuclear area), lymph node status, and patient age at operation. For patients with ERα?/PR? tumors (dual negative), however, there was no association between ERβ levels and patient outcome. Our findings indicate that ERβ expression provides independent prognostic information for breast cancers with ERα/PR‐positive status, a feature typical among screen‐detected breast cancers. The role of ERβ needs to be further evaluated especially in this group of breast cancers.     

Cerebral Blood Flow during Experimental Hypoxaemia and lschaemia in the Newborn Piglet

Odden, J.-P., Stiris, T., Hansen, T. W. R. and Bratlid, D. (Neonatal Research Laboratory, Department of Paediatric Research, Institute for Surgical Research and Department of Paediatrics, Rikshospitalet, University of Oslo, Oslo, Norway). Cerebral blood flow during experimental hypoxaemia and ischaemia in the newborn piglet. Acta Paediatr Scand Suppl 360: 13, 1989.
The effect of selective hypoxaemia or ischaemia on cerebral blood flow was studied in 14 newborn piglets with the microsphere method. Surgery and experiments were performed under general anesthesia with 70% nitrous oxide. The spontaneously breathing piglet was then exposed to either low (zero) oxygen in the inspired air (hypoxaemia), or a graded tourniquet (3–5 kg string weight) of the neck above the level of the tracheostomy (ischaemia). Cerebral blood flow was measured at baseline, during the hypoxaemic/ischaemic insult, and 30 and 60 min thereafter. Brainstem blood flow was remarkably stable during both ischaemia and hypoxaemia. The reduction in blood flow to the cerebrum and to the cerebellum was greater during ischaemia than during hypoxaemia. Reactive hyperaemia followed hypoxaemia but was not obvious after selective ischaemia. Ischaemia and hypoxaemia thus seem to have different effects on cerebral blood flow.