P1,P4-dithio-P2,P3-monochloromethylene diadenosine 5',5'''-P1,P4-tetraphosphate: a novel antiplatelet agent.

We have previously demonstrated in a series of searches for antithrombotic agents that diadenosine 5',5"'-P1,P4-tetraphosphate (AppppA) and its analogues are competitive inhibitors of ADP-induced platelet aggregation. Among various analogues, the P2,P3-monochloromethylene analog of AppppA (AppCHClppA) is superior to unmodified AppppA in its antiplatelet and antithrombotic effects. In this communication, we compare the antiplatelet potency of five newly synthesized agents with that of AppCHClppA. The five new agents include four diadenosine polyphosphate analogues [Ap(s)pCHClpp(s)A (p(s) indicates a thiophosphate), dAppCHClppdA, dAp,pCHClpp(s)dA, and AppCHClpCHClppA], and an adenosine tetraphosphate analogue (AppCHClpCHClp). When tested for their inhibitory effects on platelet aggregation by ADP, the most promising agent among them was Ap(s)pCHClpp(s)A. Both molecular and functional integrity of this compound proved to be stable in blood at 37 degrees C for at least 3 h. It also showed an excellent heat stability. This agent inhibits a number of aspects of ADP-induced platelet activation-e.g., release reaction, cytoplasmic calcium mobilization, thromboxane production, fibrinogen binding sites, and platelet factor 3 activity. Moreover, platelet aggregation induced by agonists other than ADP-e.g., arachidonic acid, collagen, and epinephrine-was inhibited partially by Ap(s)pCHClpp(s)A. It is concluded that (i) Ap(s)pCHClpp(s)A is a promising antiplatelet agent; (ii) it is resistant to blood phosphodiesterases and stable to heat treatment; (iii) platelet aggregation induced by collagen, epinephrine, or arachidonic acid is also inhibited in part by this agent; and (iv) specificity of the inhibitory effects is presented by unmodified adenosine moieties of the agent. Resistance to phosphodiesterases raises the possibility of oral administration.

Urinary tract symptoms: microbiologic evaluation in rural family practice.

In order to define the etiology of urinary symptoms in rural family practice, this study examines 106 patients (88 women, 18 men) who went to their family physicians in private practice or a resident-faculty practice with genitourinary symptoms. Evaluation of each patient included history, physical examination, urinalysis, and urine or cervical cultures for bacteria, Mycoplasma, and Chlamydia. Using agar plate culturing techniques, 37 patients (35 percent) were identified as having significant urine bacteria. Chlamydia was rarely associated with urinary tract symptoms. Mycoplasma hominis, however, was isolated and felt to be etiologic in 19 (22 percent) of the 88 symptomatic women (P = 0.0026). Older women (mean age 42 years, P less than 0.001) with greater than 5 white blood cells per high-power field (WBC/hpf) on microscopic urinalysis (P less than 0.001) were likely to have cystitis and significant bacteria on urine culture. Younger women (mean age 31 years, P less than 0.001) with less than 5 WBC/hpf (P less than 0.001) had negative urine cultures and were likely to have M. hominis as a pathogen. These results demonstrate that the etiology of genitourinary symptoms seen in rural family practice may vary substantially from those seen in other patient care settings.