Enalapril maleate and a lysine analogue (MK-521) in normal volunteers; relationship between plasma drug levels and the renin angiotensin system

1 Two single doses of 10 mg each of the converting enzyme inhibitor enalapril maleate or MK-421 and of its lysine analogue (MK-521) were administered p.o. to twelve male volunteers. 2 The active diacid metabolite of MK-421 and the lysine analogue were determined by radioimmunoassay and MK-421 by the active metabolite method following in vitro hydrolysis. 3 Peak serum levels of MK-421, active metabolite and lysine analogue were reached within 1, 3 to 4, and 6 h respectively. Practically all MK-421 had disappeared from serum within 4 h. 4 A close correlation between percent inhibition of plasma converting enzyme activity and the serum concentration of active metabolite was observed ( r = 0.98, n = 171, P less than 0.001). Similarly, converting enzyme blockade as expressed by the ratio plasma angiotensin II/angiotensin I was closely correlated with serum active metabolite levels (r = 0.93, n = 15, P less than 0.001).     

Chelators at the cancer coalface: desferrioxamine to Triapine and beyond.

The importance of iron and copper in cancer biology has been well established. Iron plays a fundamental role in cellular proliferation and copper has been shown to be a significant cofactor for angiogenesis. Early observations with the chelator used for the treatment of iron overload, desferrioxamine, showed that it had promise as an anticancer agent. These results sparked great interest in the possibility of developing more effective iron chelators for cancer therapy. The recent entry into clinical trials of the iron-binding drug, Triapine, provides evidence of the potential of this antitumor strategy. Likewise, chelators originally designed to treat disorders of copper overload, such as penicillamine, trientine, and tetrathiomolybdate, have also emerged as potential anticancer drugs, as they are able to target the key angiogenic cofactor, copper. In this review, we will discuss the development of these and other chelators that show potential as anticancer agents.     

Cocaine injection and ethnicity in parenteral drug users during the early years of the human immunodeficiency virus (HIV) epidemic in New York City

Parenteral drug users have a high prevalence of infection with human immunodeficiency virus (HIV), the etiologic agent of acquired immune deficiency syndrome (AIDS). New York City has had a prolonged and extensive epidemic of HIV infection and AIDS. In this study, we analyze, in relation to antibody to HIV (anti-HIV), available data from sera from parenteral drug users collected in New York City during 1978 through 1983 in the course of studies of liver disease. Among parenteral users of both heroin and cocaine, 30 (52%) of 58 had anti-HIV, compared with six (13%) of 48 injectors of heroin only (P less than 0.0001). Only two (11%) of 18 white patients were HIV-infected, compared with 34 (39%) of 88 black or Hispanic patients (P = 0.03). No other factors studied were linked to anti-HIV. In a multiple logistic regression, anti-HIV was significantly more common in parenteral users of both cocaine and heroin (P less than 0.0001), black patients (P = 0.02), and Hispanic patients (P = 0.049). We conclude that parenteral users of both cocaine and heroin as well as black and Hispanic patients were disproportionately HIV-infected during the early years of the HIV epidemic. Use of cocaine and heroin as well as ethnicity were independently linked to anti-HIV. Measures to prevent or treat drug use, HIV infection, and other medical problems while addressing the specific needs of cocaine users and black and Hispanic patients are urgently needed.     

EFFECTS OF BACTERIAL ENDOTOXIN ON RABBIT PLATELETS : IV. THE DIVALENT ION REQUIREMENTS OF ENDOTOXIN-INDUCED AND IMMUNOLOGICALLY INDUCED PLATELET INJURY

The divalent ion requirements of rabbit platelet injury by endotoxin have been defined by the use of various anticoagulant solutions and have been compared to the divalent ion requirements of platelet injury produced by addition of antigen to immune platelet-rich plasma. The endotoxin-platelet interaction takes place in citrated blood. Platelet damage by antigen is inhibited by citrate, but preincubation of antigen and immune platelet-poor plasma in the absence of citrate results in a substance, presumably antigen-antibody complement complex, which then does injure platelets in the presence of citrate. Neither endotoxin nor preincubated antigen injures platelets in the presence of sodium EDTA in concentrations sufficient to interact with all divalent cations present in plasma. These observations have been interpreted by viewing the platelet-endotoxin interaction as a consequence of platelet phagocytosis of endotoxin, a reaction not requiring complement but requiring definite small concentrations of divalent cations. The interaction of antigen and platelets is regarded as a two phase reaction, the first requiring the participation of complement and concentrations of divalent cation larger than those provided in citrated plasma, the second requiring smaller concentrations of divalent cation, no further participation of complement, and active in citrated plasma. This second phase is regarded as representing platelet phagocytosis of immune complexes.     

Using latent class analysis to identify patterns of hepatitis C service provision in drug-free treatment programs in the U.S

Hepatitis C virus (HCV) infection is a global health problem, and in many countries (including the U.S.), illicit drug users constitute the group at greatest risk for contracting and transmitting HCV. Drug treatment programs are therefore unique sites of opportunity for providing medical care and support for many HCV infected individuals. This paper determines subtypes of a large sample of U.S. drug-free treatment programs (N=333) according to services they provide to patients with HCV infection, and examines the organizational and aggregate patient characteristics of programs in these subtypes. A latent class analysis identified four subtypes of HCV service provision: a "Most Comprehensive Services" class (13% of the sample), a "Comprehensive Off-Site Medical Services" class (54%), a "Medical Monitoring Services" class (8%) and a "Minimal Services" class (25%). "Comprehensive" services class programs were less likely to be outpatient and private for profit than those in the other two classes. It is of concern that so many programs belong to the "Minimal Services" class, especially because some of these programs serve many injection drug users. "Minimal Services" class programs in the U.S. need to innovate services so that their HCV infected patients can get the medical and support care they need. Similar analyses in other countries can inform their policy makers about the capacity of their drug treatment programs to provide support to their HCV infected patients.     

Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature

We performed a meta-analysis of all published studies relating intratumoural microvessel density (MVD) (45 studies) or vascular endothelial growth factor (VEGF) expression (27 studies), both reflecting angiogenesis, to relapse free (RFS) and overall survival (OS) in colorectal cancer (CRC). For each study, MVD impact was measured by risk ratio between the two survival distributions with median MVD as cutoff. Eleven studies did not mention survival data or fit inclusion criteria, six were multiple publications of same series, leaving 32 independent studies for MVD (3496 patients) and 18 for VEGF (2050 patients). Microvessel density was assessed by immunohistochemistry, using antibodies against factor VIII (16 studies), CD31 (10 studies) or CD34 (seven studies). Vascular endothelial growth factor expression was mostly assessed by immunohistochemistry. Statistics were performed for MVD in 22 studies (the others lacking survival statistics) including nine studies (n = 957) for RFS and 18 for OS (n = 2383) and for VEGF in 17 studies, including nine studies for RFS (n = 1064) and 10 for OS (n = 1301). High MVD significantly predicted poor RFS (RR = 2.32 95% CI: 1.39-3.90; P < 0.001) and OS (RR = 1.44; 95% CI: 1.08-1.92; P = 0.01). Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression significantly predicted poor RFS (RR = 2.84; 95% CI: 1.95-4.16) and OS (RR=1.65; 95% CI: 1.27-2.14). To strengthen our findings, future prospective studies should explore the relation between MVD or VEGF expression and survival or response to therapy (e.g. antiangiogenic therapy). Assessment of these angiogenic markers should be better standardised in future studies.