The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

The effect of 7 to 8 months of vitamin/mineral supplementation on the vitamin and mineral status of athletes.

Blood indicators of eight vitamins (B1, B2, B6, C, E, A, B12, folate) and six minerals (Cu, Mg, Zn, Ca, P, Al) were measured in 86 athletes before and after a 7- to 8-month period of training. During this period half consumed a multivitamin/mineral supplement and a matched group took a placebo. Following the supplementation period, blood biochemical indicators of B1, B6, B12, and folate status all increased but there were no significant effects of supplementation on B2, C, E, and A, or on the blood levels of any of the minerals. The supplementation had no effect on red or white cell counts or on hemoglobin levels. Irrespective of the supplementation, some blood measures varied according to sex, females evidencing significantly higher values than males for vitamins C, E, copper, magnesium, and aluminium, with B2 being higher in males. It is concluded that 7 to 8 months of multivitamin/mineral supplementation increased the blood nutritional status of some vitamins but did not affect any blood mineral levels, and that some blood nutritional indicators may vary according to sex.     

AB or ABC: pre-hospital fluid management in major trauma.

Pre-hospital trauma care in the United Kingdom is a neglected field with little consideration being given to this phase. Of the 14,500 annual fatalities from road traffic accidents in this country, 60% die before reaching hospital and it has been estimated that one-third of these fatalities are due to hypovolaemia. The pre-hospital fluid resuscitation of trauma patients is a controversial area and although it would seem sensible to commence intravenous (i.v.) fluids at the roadside, several large studies have failed to show any benefit from this intervention. By delaying departure to hospital, initiation of i.v. fluid replacement may actually worsen outcome. This paper reviews recent studies and discusses current thought on pre-hospital fluid replacement in major trauma.     

LIPOPROTEIN(α) IN HEALTH AND DISEASE

SUMMARY Elevated plasma levels of Lp(a) do seem to influence the progression of atherosclerosis. Evidence is emerging that certain apo(a) isoforms may be more atherogenic than others, and in transgenic mice free apo(a) has been shown to be associated with accelerated atherosclerosis. Currently it is not known whether treating elevated Lp(a) levels will reduce progression of atherosclerosis and, as therapeutic options are limited, mass screening of Lp(a) levels in populations is not indicated. The presence of raised Lp(a) levels, however, warrants aggressive treatment to reduce other cardiovascular risk factors. Continuing research to investigate the relationship of the apo(a) gene to other genes, including the plasminogen gene and apo(a)-related genes, will add further information pertaining to the evolution, function, regulation and clinical implications of Lp(a).     

A randomized trial of two types of adjuvant chemotherapy in radiotherapy-treated patients with clinical stages I and II high-grade non-Hodgkin's lymphoma

Summary This paper reports the 8-year results of comparing the use of two types of adjuvant chemotherapy following involved field radiotherapy for clinical stages I and II high-grade non-Hodgkin's lymphoma. Twenty-four patients received 6 weeks of VAP plus 2 years of oral maintenance chemotherapy, and 30 had six cycles of CMOPP. Four patients were not in complete remission at completion of i. v. chemotherapy (CR rate 91%). Ten patients (18.5%) have relapsed (VAP/M=5; CMOPP=5), with only two of these remaining alive, both of them being disease free. There have been three deaths from intercurrent causes, one from malignant melanoma and the other two from myocardial infarction. The relapse-free survivals at 2, 5 and 8 years were 80%, 76% & 76% respectively. The overall survivals at the same time points were 86%, 72% & 68%. There were no significant differences in either relapse-free or overall survival for either of the two treatment groups. The shorter period of weekly intravenous chemotherapy (VAP/M) was better tolerated than 36 weeks of CMOPP, and the former appears to produce equivalent results.     

Maintenance chlorambucil after CVP in the management of advanced stage, low-grade histologic type non-Hodgkin's lymphoma. A randomized prospective study with an assessment of prognostic factors

One hundred sixty-two patients with Stages III and IV non-Hodgkin's lymphoma of low-grade histologic type were treated with combination chemotherapy using cyclophosphamide, vincristine, and prednisolone (CVP) followed by radiotherapy to sites of previous bulk disease. The patients were randomized to receive either follow-up alone or "maintenance" chemotherapy with 2 years of intermittent chlorambucil. A complete remission was obtained in 56% of patients and the median survival was 64 months (median follow-up, 74 months). Multivariate analysis revealed stage (P less than 0.0001) and Karnofsky performance status (P = 0.021) to predict complete response (CR) and the achievement of a CR (P less than 0.0001), female sex (P = 0.008), the absence of bulk disease (P = 0.038) and low serum alkaline phosphatase (P = 0.002) to predict prolonged survival. The median relapse-free survival (RFS) of the complete responders was 41 months. A prolonged RFS was predicted by low stage (P = 0.014), low serum lactic dehydrogenase (LDH) (P = 0.045) levels, and by the administration of maintenance chlorambucil (P = 0.045). A prolonged survival of the complete responders was predicted by a low number of nodal sites of involvement with lymphoma at presentation (P = 0.022) and lack of liver involvement (P = 0.011). The administration of oral maintenance therapy with chlorambucil for a full 2 years was only possible in 38% of patients, mainly because of progression of disease and the induction of thrombocytopaenia, but despite this it prolonged the median RFS by 38 months and its use could be considered when future studies are being designed.     

Actions of nitric oxide on the acute gastrointestinal damage induced by PAF in the rat

The actions of nitric oxide (NO) on the acute gastrointestinal damage induced by platelet-activating factor (PAF) have been investigated in the rat.S-nitroso-N-acetyl penicillamine, which spontaneously generates NO, dose-dependently inhibited PAF-induced gastrointestinal plasma leakage, a measure of the initiation of vascular damage. The inhibitor of NO synthase,N^G-monomethyl-l-arginine substantially potentiated gastrointestinal damage and plasma leakage induced byE. coli endotoxin, but had no effect on that induced by intravenous infusion of PAF.Endogenous NO may thus have a protective role in the gastrointestinal vascular that can be mimicked by generators of NO. The protection afforded by endogenous NO may, however, be dependent on the nature of the inflammatory stimulus used to induce gastrointestinal damage.