Acyclovir kinetics after intravenous infusion.

The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1-hr intravenous infusion at doses of 0.5, 1.0, 2.5, and 5.0 mg/kg. At the end of infusion, mean peak plasma levels (+/- SEM), determined by radioimmunoassay, were 6.4 +/- 0.7, 12.1 +/- 2.3, 14.9 +/- 2.7, and 33.7 +/- 7.1 microM. The plasma concentration-time profiles could be described by a biexponential equation. The half-life of acyclovir in the slow disposition phase ranged from 2.2 to 5 hr and the drug was detected in the plasma for at least 18 hr after infusion. The total body clearance ranged from 117 to 396 ml/min/1.73 m2. A proportionality between area under the curve and dose suggests that acyclovir exhibits dose-independent kinetics in the dose range studied. There was wide variation in cumulative urinary excretion of unchanged drug, ranging from 30 to 69% of the dose. From renal clearances of acyclovir, which were higher than creatinine clearances, it appears that both glomerular filtration and tubular secretion contribute to its renal excretion. Analysis of the urine by reverse-phase high-performance liquid chromatography revealed the presence of the metabolite 9-carboxymethoxymethylguanine. There was no indication of toxicity either clinically or from laboratory findings in any of the study subjects. This study demonstrates that in addition to selectivity and low toxicity, the kinetic profile and metabolic disposition of acyclovir make it an attractive candidate for therapy in a variety of herpes infections.

Acyclovir tolerance in humans.

Acyclovir tolerance has been explored in a broad range of human populations and dosage regimens with intravenous, topical, and oral formulations. Phase I pharmacokinetic/tolerance studies assured safety in special populations at unique risk of complicated herpes infections who were simultaneously at increased risk of toxicity to anti-DNA chemotherapeutic agents. Further safety evaluations accompanied placebo-controlled Phase II studies in infected patients who represent future users of acyclovir. These studies confirm acyclovir as the safest antiherpes agent to be explored in clinical studies to date.

Total loss of Teeth in Adults, United States - 1960-1962.

Estimates of the prevalence and distribution of edentulous persons-men and women who have lost all of their natural teeth-are in essence statistical summaries reflecting both the amount and extent of dental disease and the failure to obtain prompt and adequate dental care. Toothdecay and periodontal disease-a degenerative process which affects the structures that support the teeth- are, without question, the two leading causes of tooth loss. It is also true that both disorders are extremely prevalent throughout the United States. When treatment is not delayed too long, however, either can usually be arrested by the skills and methods commanded by most dentists. Failing that, tooth removal is a harsh but inescapable consequence which culminates for many men and women in the loss of all natural teeth. The first estimates which presented in true perspective the magnitude and extent of total tooth loss throughout the United States were published in 1960. The estimates were based on responses to the following question which was asked during 1957-58 at approximately 36,000 households comprising about 115,000 people: "Is there anyone in the family who has lost all of his teeth?" Responses from the interviewed households indicated that about 22 million people-13 percent of the Nation's population had indeed lost all of their permanent teeth. The existence of significant, nationwide trends associated with various demographic characteristics was also clearly revealed. The prevalence of total tooth loss which, as expected, mounted rapidly with age was higher among women than among men, higher among white than among Negro adults, and higher among poorer and less educated people than among more advantaged ones. In addition, some variation in prevalence by region appeared in the estimates. No difference in prevalence associated with population density was found.

Acyclovir therapy of chickenpox in immunosuppressed children--a collaborative study.

A randomized double-blind, placebo-controlled, multicenter investigation assessed the usefulness of acyclovir in the treatment of immunosuppressed children with chickenpox. Twelve patients received placebo and eight received acyclovir. If the event of clinical deterioration, patients could be removed from the study to receive acyclovir. Eighteen patients had skin lesions within 96 hours of admission to the study. Nineteen patients had malignancies. The two groups of patients were similar in age, in concomitant or preceding immunosuppressive therapy, in status of malignancy, and in presenting granulocyte and lymphocyte counts. Zoster immune globulin or plasma had been given to 50% of the placebo group but to only 25% of the acyclovir group. One patient in each group had pneumonitis at entry. Of the patients without pneumonitis at entry, five of the 11 placebo patients compared with none of the seven acyclovir patients developed pneumonitis during treatment (P = 0.054). No evidence of toxicity related to acyclovir was observed.

An Assessment of the Occlusion of the Teeth of Children 6-11Years, United States.

In December 1965 the Division of Health Examination Statistics successfully concluded a survey of the health of the Nation's children aged 6-11 years. The survey began in June 1963 and was the second of the Health Examination Survey programs, or "cycles," which, launched successively, produce statistical information about the health of specific segments of the United States population. The conduct and operation of the children's cycle closely followed a blueprint prepared for the preceding adult cycle. Examinations were conducted at 40 randomly selected locations in 25 States by means of mobile examination centers manned by physicians, dentists, psychologists, nurses, and technicians. Before a child was examined, information was obtained from the parent of the child, including demographic and socioeconomic data on the household members as well as medical history, behavioral, and related data on the child to be examined. The target population totaled approximately 23.8 million children (table III, appendix III). It was defined as all noninstitutionalized children aged 6-11 living in the United States (including Alaska and Hawaii) except those living on lands reserved for the use of American Indians. To obtain statistically valid estimates about the health of so many people, a probability sample was designed and selected by a complex scientific procedure (appendix III). The sample consisted of approximately 7,400 children, or about 185 at each location.

Social identity in adolescence.

Social identity theory (SIT) was used to investigate the effects of social categorization on adolescents' intergroup behaviour. One hundred and forty-nine male adolescents aged 14-15 years made comparisons between an ingroup and an outgroup along a series of dimensions. Participants displayed consistent ingroup-favouring behaviour in their ratings: the ingroup was associated to a greater extent than the outgroup with positively valued dimensions, and to a lesser extent with negatively valued dimensions. Those participants who demonstrated the most discrimination reported highest levels of ingroup identification. The utility of applying predictions from SIT to the study of adolescence is discussed.

Anemia and erythropoiesis in patients with the acquired immunodeficiency syndrome (AIDS) and Kaposi sarcoma treated with zidovudine.

We evaluated the development of anemia as part of a trial of zidovudine therapy in patients with the acquired immunodeficiency syndrome (AIDS) with Kaposi sarcoma. Patients were randomized to one of three treatment groups or a placebo group. Transfusion-requiring anemia (hemoglobin less than 100 g/L) developed in 6 of 15 patients on zidovudine therapy at a mean of 6 weeks after starting treatment. A fall in the reticulocyte count was the earliest peripheral blood indicator of toxicity. Mean corpuscular volume increased markedly in patients on zidovudine therapy not developing anemia yet remained stable or only slightly increased in those who became anemic. Bone marrow examination showed pure red cell aplasia in 2 patients, erythroid maturation arrest in 1, and erythroid hypoplasia in 3. Megaloblastic erythropoiesis was present in 2 of the 6 anemic patients. Erythropoietin levels measured at the time of first transfusion were increased. Thus, the anemia associated with zidovudine therapy is due to red cell hypoplasia or aplasia.

Activity of 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine in the treatment of cytomegalovirus pneumonia.

Ten marrow transplant recipients with biopsy-proven cytomegalovirus pneumonia were treated with the acyclic nucleoside analog 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl]guanine (BW B759U). Viruria and viremia ceased after 4 days of treatment in all patients with cultures initially positive from these sites. Cytomegalovirus was eliminated from respiratory secretions after a median of 8 days. Despite this antiviral effect, only one patient survived the pneumonia. Quantitative cultures of lung tissue before and after treatment confirmed that therapy with BW B759U was associated with substantial antiviral activity, with a mean decrease in viral titers of more than 99.99% after treatment. Neutropenia developed in three patients when mean peak and trough plasma levels exceeded 50 and 10 mu mol/L, respectively, but no other toxicity was seen. BW B759U is the first antiviral agent showing consistent activity against cytomegalovirus in vivo, and it should be evaluated in the earlier management of cytomegalovirus infections after marrow transplantation and in serious cytomegalovirus infections in other immunocompromised patients.

Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation.

Patients undergoing allogeneic bone marrow transplantation who are seropositive for cytomegalovirus are vulnerable to serious cytomegalovirus infection, presumably because of reactivation of latent endogenous virus and severe immunosuppression. We administered intravenous acyclovir from 5 days before to 30 days after allogeneic marrow transplantation for hematologic neoplasms in an effort to prevent cytomegalovirus infection and disease in patients seropositive for cytomegalovirus before transplantation. Eighty-six patients seropositive for both cytomegalovirus and herpes simplex virus before transplantation received acyclovir, whereas 65 patients seropositive only for cytomegalovirus served as controls (acyclovir is the standard prophylactic agent against herpes simplex virus in this setting). The probability that cytomegalovirus infection would develop within the first 100 days after transplantation was 0.70 among acyclovir recipients and 0.87 among control patients at medians of 62 and 40 days after transplantation, respectively (P = 0.0001 by log-rank test). Invasive cytomegalovirus disease developed in 19 acyclovir recipients (22 percent) and 25 control patients (38 percent) (P = 0.008). Survival within the first 100 days after transplantation was better among acyclovir recipients (P = 0.002). Acyclovir prophylaxis was associated with a relative risk of 0.5 or less for the development of cytomegalovirus infection or disease or for death within the first 100 days after transplantation (P less than or equal to 0.04), in proportional-hazards regression analysis. We conclude that prophylaxis with intravenous acyclovir significantly reduced the risk of both cytomegalovirus infection and cytomegalovirus disease in seropositive patients after allogeneic bone marrow transplantation and that it was also associated with significantly improved survival.

Acyclovir halts progression of herpes zoster in immunocompromised patients.

We conducted a placebo-controlled, double-blind study of acyclovir therapy for acute herpes zoster in immunocompromised patients. Of the 94 patients enrolled in the study, 52 had localized skin lesions at entry, and 42 had disseminated cutaneous zoster. A one-week course of intravenous acyclovir (1500 mg per square meter of body-surface area per day) halted progression of zoster in both groups, as determined by development or progression of cutaneous dissemination, development of visceral zoster, or proportion of cases deemed treatment failures. Significantly fewer patients treated with acyclovir within the first three days after the onset of exanthem had complications of zoster, as compared with patients treated with placebo (P = 0.02 by Fisher's exact test), but acyclovir also stopped progression of zoster in patients treated after three days of rash (P = 0.05 by Fisher's exact test). Acyclovir recipients with disseminated cutaneous zoster had a significantly accelerated rate of clearance of virus from vesicles, as compared with placebo recipients (P = 0.05 by the Breslow test).

Zidovudine in patients with human immunodeficiency virus (HIV) infection and Kaposi sarcoma. A phase II randomized, placebo-controlled trial.

STUDY OBJECTIVE: To evaluate the toxicity, effects on immune function, antitumor effects, antiretroviral effects, and pharmacokinetics of zidovudine therapy in patients with early human immunodeficiency virus (HIV) infection and Kaposi sarcoma. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: National Institutes of Health, a referral-based research institution (single site). PATIENTS: Physician-referred volunteer patients with HIV infection, Kaposi sarcoma, CD4+ lymphocyte counts greater than 0.2 x 10(9)/L, and no systemic symptoms or history of opportunistic infection. Of 41 patients enrolled, 4 had not met all entry criteria and were therefore not evaluable. INTERVENTIONS: Patients were randomized to one of four treatment groups for an initial 12-week treatment period: oral placebo (9 patients); zidovudine, 250 mg orally every 4 hours (9 patients); zidovudine, 0.5 mg/kg body weight intravenously every 4 hours (9 patients); and zidovudine, 2.5 mg/kg intravenously every 4 hours (10 patients). After at least 12 weeks of therapy at their assigned dose, patients were treated with oral zidovudine, generally 250 mg every 4 hours, with a mean 42-week follow-up. MEASUREMENTS AND MAIN RESULTS: Anemia and granulocytopenia were the major toxicities. Significant increases in platelet counts and declines in serum HIV antigen and IgG and IgM levels occurred in treated patients. Treated patients were more likely than those on placebo to clear HIV from the cerebrospinal fluid. There were no differences in tumor progression or CD4+ or CD8+ lymphocyte counts among the groups. CONCLUSIONS: Zidovudine was well tolerated and had antiretroviral activity in patients with early HIV infection and Kaposi sarcoma but it had no significant effect on the extent of Kaposi sarcoma or on immune function.