To determine the prevalence, incidence, and types of lung diseases that occur in association with HIV infection, 1,353 subjects, including HIV-seropositive homosexual men, injection drug users, female sexual partners of HIV-positive men, and HIV-seronegative control subjects from the first two transmission categories were evaluated prospectively in a multicenter study. Patients with AIDS at the time of initial evaluation were excluded. One thousand two-hundred ninety-four subjects who had no AIDS-defining diagnosis within 3 mo of enrollment had measurements of FVC, FEV1 and DLCO at the time of enrollment. As a group, all subjects had mean values of FVC and FEV1 close to 100% predicted. Those with CD4 counts below 200/mm3 had slightly reduced DLCO compared with the others. Subjects with a history of HIV-associated symptoms (thrush, weight loss, herpes zoster) also had a reduced DLCO compared with those without symptoms. Injection drug users had reduced FVC, FEV1 and DLCO compared with homosexual men and female sexual partners of HIV-infected men, with DLCO more substantially reduced. Part of the reduction in DLCO in drug users was attributable to factors other than HIV infection, especially cigarette smoking and race. Using predicted values that take cigarette smoking into account, the prevalence of abnormality in DLCO was higher among injection drug users (33.3%) than among homosexual men (11.2%) and female sexual partners (12.7%). These results show that advanced HIV infection, characterized by CD4 count < 200/mm3 or HIV-associated symptoms, and factors unrelated to HIV infection, including race, cigarette smoking, and injection drug use, are all associated with reductions in DLCO measurements.

Despite the central role played by female intravenous drug users (IVDUs) in the worsening AIDS statistics of states in the northeastern United States, the relative paucity of research into the HIV risk behaviors--particularly risky needle practices--of female drug injections has left significant gaps in researchers' understanding of how and to what extent such women may differ in their risks from their better-studied male counterparts. This study, derived from a sample of 769 out-of-treatment IVDUs residing in an area (Paterson, New Jersey) characterized by high levels of AIDS and HIV infection among drug users, attempts to address this lacuna in the research literature by comparing the drug usage, AIDS knowledge, and needle and sexual behaviors of male and female IVDUs that place them at risk for HIV infection. In this sample, gender was found to be unrelated to HIV serostatus, injection frequency and injected drug of choice, and to most dimensions of knowledge about AIDS and the means of HIV transmission. Overall, it appears that the average Paterson female IVDU may be at greater risk for HIV infection as a result of involvement with a drug-using sex partner than because of especially risky needle practices, for females in this sample were significantly more likely than males to report injecting with a sex partner in the previous 6 months, and female IVDUs with one sex partner were more than twice as likely as males with one partner to report that this individual was an IVDU. Condom use was relatively rare, particularly among those with one partner. Moreover, female IVDUs were significantly more likely than males to be daily users of crack cocaine, and significantly more likely to report poorer health. However, current needle and sexual practices were found to be unrelated to HIV seropositivity among both males and females. In logistic regression analysis, only length of IV drug involvement was found to be independently associated with HIV seropositivity for both sexes. Implications of the data for future prevention efforts aimed at female IVDUs are discussed.

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We previously described the design and synthesis of rigid tricyclic phenylalanylleucine (PheLeu) mimetic 1 and its incorporation into 2, an inhibitor of angiotensin I-converting enzyme (ACE, EC 3.4.15.1).' Mimetic 1 was designed2 to closely resemble the anti orientation (XI = 180°, X2 = Oo) of the carboxy terminal histidylleucine (HisLeu) portion of angiotensin I (Chart I). The replacement of His by Phe in mimetic 1 was made with knowledge that His is not essential to ACE bindin? and that neutral endopeptidase 24.11 (NEP, EC 3.4.24.111, a related zinccontaining proteinase, cleaves the PheLeu dipeptide from Leu-enke~halin.~ The cleavage of bradykinin adjacent to Phe(8) by both ACE and NEP6 further suggests that these two metalloproteinases could have shared active-site characteristics. We speculated early on that side chain constrained peptidomimetics would be useful tools to study the conformational preferences in peptide-protein interactions. The similarities and biological significance of these two enzymes made them ideal choices for evaluation by this approach. More recently, NEP has been shown to play a role in the degradation of the natriuretic peptides! a family of hormones, some of which are secreted by the heart into the circulation in increased amounts in patienta with congestive heart failure (CHF).' Because the reninangiotensin-aldosterone system opposess the beneficial natriuretic and diuretic actions of atrial natriuretic peptide (ANP), inhibition of ACE during NEP inhibition should be advantageous. The feasibility of simultaneous ACE and NEP inhibition was investigated utilizing our dipeptide mimic approach. Gros et al. have described close analogs of thiorphan which exhibit equipotent nanomolar ACE and NEP inhibition in vitro and demonstrate enzyme occupation upon oral dosing of a prodrug form.Q We now report the design rationale and synthesis of a new class of subnanomolar dual ACE/NEP inhibitor, a member of which produces blood pressure lowering in animal models of both essential and salt dependent hypertension when orally administered in prodrug form.Derivatives of 1 were used to probe the active site requirements of both ACE and NEP (Chart 11). Whereas 2 was found to be an extremely selective inhibitor of ACE, epimeric tricyclic mercaptomethylene derivatives 3 and 4'0 gave the indication that simultaneous inhibition of ACE and NEP was feasible in spite of the intrinsic conformational constraints of mimetic 1. The mercaptoacetyl derivative of phenylalanylglycine had been reChart I Anglotensln I n Leu-Enkephalln TyrGlyGlj 1 , n Leu-Enkephalln U Chart I1 3 4 K,(ACE) nM 2 r7 2 130 KI(NEP) nM r10,OOO r300 45 5 2ported to inhibit NEP (Ki = 20 nM).I1 The mercaptoacetyl derivative 5 of mimetic 1 was found to be a potent inhibitor of ACE as well as NEP. This result, combined wfth the structural rigidity of mimetic 1, indicates that significant similarities in the SI' and S2' binding domains of these two enzymes exist and that an internal unsubstituted CO-NH function is not essential for binding to this ...