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The pharmacokinetics of ganciclovir after oral valganciclovir versus intravenous ganciclovir were compared in allogeneic stem cell transplant recipients with stable graft-versus-host disease of the gastrointestinal tract. Twenty-two evaluable adult patients were randomized to receive a single dose of open-label study drug (900 mg of oral valganciclovir or 5 mg/kg of intravenous ganciclovir). After a washout period of 2 to 7 days, patients were crossed over to receive the alternate study drug. Ganciclovir and valganciclovir concentrations in plasma were measured over 24 hours after dosing. Noninferiority of 900 mg of valganciclovir relative to intravenous ganciclovir was concluded if the lower limit of the 1-sided 95% confidence interval of the ratio of least-square means of the ganciclovir area under the curve (AUC) for the 2 study drugs was >80%. Valganciclovir was found to be rapidly absorbed and converted into ganciclovir. The ganciclovir exposure after 900 mg of valganciclovir noninferior to that of intravenous ganciclovir (AUC0-infinity, 52.1 and 53.8 microg.h/mL, respectively; 95% confidence interval of the ratio of least square means of AUC0-infinity, 82.48%-118.02%). Oral valganciclovir could be a useful alternative to intravenous ganciclovir in certain stable stem cell transplant patients who require prophylaxis or preemptive therapy for cytomegalovirus infection.

Background: Buprenorphine is a partial mu-opiate agonist and kappa-opiate antagonist with established efficacy in the treatment of opiate dependence. Its efficacy for cocaine dependence is uncertain. This study evaluated buprenorphine for the treatment of concomitant cocaine and opiate dependence., Methods: Two hundred outpatients currently dependent on both cocaine and opiates were randomly assigned to double-blind groups receiving a sublingual solution of buprenorphine (2, 8, or 16 mg daily, or 16 mg on alternate days, or placebo), plus weekly individual drug abuse counseling, for 13 weeks. The chief outcome measures were urine concentrations of opiate and cocaine metabolites (quantitative) and proportion of urine samples positive for opiates or cocaine (qualitative). Group differences were assessed by use of mixed regression modeling., Results: The target dose of buprenorphine was achieved in 179 subjects. Subjects receiving 8 or 16 mg buprenorphine daily showed statistically significant decreases in urine morphine levels (P =.0135 for 8 mg and P <.001 for 16 mg) or benzoylecgonine concentrations (P =.0277 for 8 mg and P =.006 for 16 mg) during the maintenance phase of the study. For the 16-mg group, mean benzoylecgonine concentrations fell from 3715 ng/mL during baseline to 186 ng/mL during the withdrawal phase; mean morphine concentrations fell from 3311 ng/mL during baseline to 263 ng/mL during withdrawal. For the 8-mg group, mean benzoylecgonine concentrations fell from 6761 ng/mL during baseline to 676 ng/mL during withdrawal; mean morphine concentrations fell from 3890 ng/mL during baseline to 661 ng/mL during withdrawal. Qualitative urinalysis showed a similar pattern of results. Subjects receiving the highest dose showed concomitant decreases in both urine morphine and benzoylecgonine concentrations. There were no significant group differences in treatment retention or adverse events., Conclusions: A sublingual buprenorphine solution at 16 mg daily is well tolerated and effective in reducing concomitant opiate and cocaine use. The therapeutic effect on cocaine use appears independent of that on opiate use.

The use of bleach (hypochlorite) as a disinfectant for drug injection equipment in the intravenous-drug-using population was recommended early in the HIV-1/AIDS epidemic. Epidemiological studies have challenged the use of bleach as an effective measure to prevent HIV-1 transmission. However, in vitro HIV-1 coculture studies have shown that a high concentration of bleach is an effective cytotoxic and potentially virucidal agent. In this study, we demonstrate that HIV-1 peripheral blood mononuclear cell cocultures containing low concentrations of hypochlorite in the media showed earlier conversion to HIV-1 positivity, as measured by the presence of p24 antigen. HIV-1 cocultures with high concentrations of hypochlorite in the culture media, which appeared to be highly cytotoxic, and HIV-1 cocultures without bleach in the media did not exhibit this early p24 antigen positivity. Hypochlorite chemically disinfects by releasing free chlorine that is a potent oxidant. In injection drug equipment, a low residual concentration of bleach is likely to remain in cleaned equipment despite rinsing with water. Low concentrations of oxidants have been shown to enhance tissue inflammation, in vivo, as well as HIV-1 replication in vitro. Previous studies have shown that despite vigorous cleaning of blood-contaminated injection syringes with bleach followed by water, microaggregates of residual blood remained in bleach-cleaned blood-contaminated syringes. Hypothetically, oxidant effects of the residual bleach in the bleach-cleaned syringes could enhance the possibility of infection by remaining HIV-1 contained in a contaminated syringe. We suggest that the likelihood of an injection drug user contracting HIV-1 through the sharing of a bleach-cleaned blood-contaminated syringe may be increased by the cotransmission of residual bleach and its localized tissue-inflammatory effects; however, this has not been statistically proven in epidemiological studies., (Copyright 2000 S. Karger AG, Basel.)

The diagnosis and management of infectious complications associated with injection drug use (IDU) are among some of the more challenging aspects of working with substance abusing populations. As the population of injection drug users age, we expect the number and severity of these complications to increase. Commonly seen infections, such as bacterial endocarditis and bacterial infections of bones, joints, and soft tissue, are now frequently complicated by concurrent immunodeficiency. Parenterally and sexually transmitted viral hepatitis is responsible for significant IDU morbidity and mortality. The human leukemia/lymphoma virus types I and II are increasing in prevalence in the IDU with uncertain long-term clinical effects. Immune dysfunction has been described in the IDU for decades, but the impact of host immune compromise on the transmission and the course of HIV-1 has yet to be fully appreciated. The integration of the treatment of substance abuse and its concurrent psychiatric disorders with the management of infectious complications, including immunodeficiency, promises to improve patient compliance with possible savings of overall medical costs.

To determine whether a central nervous system marker of cocaine dependence might exist, the resting electroencephalogram (EEG) of 33 drug-free, cocaine-dependent men (DSM-III-R criteria) was compared with two control groups [nondrug group (n = 10) and drug group who abused drugs, but were not cocaine dependent (n = 20)]. The EEG was recorded from eight sites after about 10 days of monitored abstinence (range 4-15 days) on a closed research ward for the drug-using individuals. The EEG was recorded for the nondrug control group as outpatients. The drug history was determined by the drug history questionnaire and a medical screening interview. The percent of EEG beta activity for the cocaine-dependent subjects was greater than that of both control groups (p < .05) as well as a normative database (HZI: Tarrytown, NY). The percent of EEG beta in frontal and central areas of the cocaine-dependent individuals was correlated with the frequency of cocaine use during the last 30 days. High levels of EEG beta may be a neurophysiological withdrawal sign in cocaine-dependent men.

A small cohort of high-risk intravenous drug users (IVDU) from the Baltimore, MD, area was evaluated for HIV1 infection status and viral load. Quantitative dilution endpoint HIV1 DNA polymerase chain reaction (PCR) results, from HIV proviral DNA from quantitated peripheral blood mononuclear cell (PBMC) lysates, were compared to the dilution endpoint results for HIV PBMC micrococulture. The quantitative dilution endpoint HIV1 PCR was more rapid, sensitive and reproducible. In addition, an HIV1 capture RT-PCR technique was used to qualitatively detect the presence or absence of intact HIV1 virus in IVDU plasma and was compared with plasma culture detection, for HIV1 viraemia. Using the results of the PCR techniques, a rapid molecular assessment of the HIV1 infection status can be attained, which is important, as the IVDU population can be difficult to study prospectively. The PCR techniques can also be used to assess HIV1 burden as well as the potential effectiveness of antiviral therapies. These molecular techniques can be used to monitor the progression of HIV in patients and to evaluate the clinical effects of concurrent substance abuse.

Cocaine abusers have increased EEG beta and areas of reduced cortical blood flow. Since, nimodipine has neuroprotective effects and increases blood flow, we investigated the efficacy of single and multiple doses of the nimodipine in normalizing the EEG of substance abusers. Fourteen subjects received single (0, 30, 60 mg) and eleven received multiple daily (up to 150 mg in 12 hours) doses of nimodipine to determine whether this drug would increase EEG alpha and decrease beta in substance abusers. The EEG was recorded from eight scalp locations (F3, C3, P3, O1, F4, C4, P4 and O2) for three minutes during eyes closed, and eyes open conditions. Single and multiple doses of nimodipine produced significant increases in EEG alpha and decreases in EEG beta in the eyes open condition. Thus, nimodipine may have potential therapeutic implications in the treatment of cocaine dependence. Chronic nimodipine dosing in cocaine-dependent individuals is now needed to confirm its efficacy in the treatment of cocaine dependence.

We examined whether nimodipine can improve information processing in healthy drug abusers using cognitive event-related potential (ERP) methodology. Placebo and 30- and 60-mg doses of nimodipine were administered on separate days in a random double-blind design to twelve male subjects, who used cocaine and/or opiates as well as alcohol and marijuana. The subjects performed the auditory rare event monitoring (AREM) task and the paired letter version of the visual continuous performance task (CPT) before oral drug administration as well as one and two hours after drug ingestion. The EEG was recorded from 7 scalp locations. The P3 component of the ERPs to the target stimulus was reduced with repeated testing on the placebo day. The 30-mg dose of nimodipine blocked the decrease in P3, which reflects stimulus evaluation in both tasks. Chronic administration of nimodipine may alleviate the cognitive deficits observed in substance abusers during abstinence and prevent treatment relapse.

The seroprevalence and incidence of hepatitis A, B, C, and E virus infection were determined among North American missionaries (n = 328) serving in various geographic locations between 1967 and 1984. The mean age of subjects at entry into the study was 39.7 years (range 5-73 years); 65% were female; 89% had lived outside the United States before the study began. Seventy-eight percent of subjects served in sub-Saharan Africa during the study. At initial evaluation, 50.9% of the subjects had antibodies to hepatitis A virus (total anti-HAV), 8.5% to hepatitis B virus core antigen (total anti-HBc), 0.6% to hepatitis C virus (total anti-HCV by second-generation immunoblot assay), and 0% to hepatitis E virus (IgG anti-HEV). After an average period of service of 7.3 years (2,396 person-years total), 5.8% of the missionaries seroconverted to anti-HAV, 5.5% to anti-HBc, 0.6% to anti-HCV, and 0% to anti-HEV. This study indicates a relatively low risk of hepatitis C and E virus infection among missionaries while confirming the previously reported high risk of hepatitis A and B virus infection. Hepatitis A and B vaccination is recommended for long-term travelers to developing countries.

To delineate baseline seroprevalence rates before job placement, applicants for employment (n = 300) at a large urban medical center were screened for serologic markers to the hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) during a 15-week period in 1992. Eighteen applicants (6%) were positive for antibodies to HBV, nine (3%) for HCV, and 3 (1%) for HIV. There was no association by gender for any of these viral markers; however, both HBV and HCV were significantly more often detected in persons applying for hourly positions who were black. In an urban setting, preemployment screening of health care workers for HBV and HCV markers appears warranted, and serum banking for later HIV analysis, should a claim arise, is suggested.

Chloroquine continues to have a limited role in the chemoprophylaxis against malaria. Although periodic ophthalmologic examinations are recommended with weekly suppressive dosing, the occurrence of retinopathy associated with this regimen is unproven. Surveillance of career missionaries was conducted to explore the association between total body burden of chloroquine and the development of retinopathy. Five hundred eighty-eight missionaries, reflecting 6,250 person-years of chloroquine exposure were surveyed; 53 persons reflecting 560 person-years exposure with a median cumulative chloroquine dose in excess of 300 g were examined. Only one case of chloroquine-induced retinopathy was detected. This occurred in a missionary who had inappropriately taken chloroquine daily for at least six years as an anti-inflammatory agent for a connective tissue disorder. We also observed that expatriates often overused chloroquine because of apprehension about malaria and used the drug for unrelated conditions. Our results failed to demonstrate an association between a weekly chloroquine dosing regimen and drug-induced retinopathy.

Ciguatera fish poisoning is the most common foodborne illness related to fin fish consumption and is endemic throughout the Caribbean and Indo-Pacific regions. The clinical picture is characterized by a variety of gastrointestinal, neurologic and, occasionally, cardiovascular symptoms. Patients with bradycardia and/or hypotension may require urgent care. Neurologic symptoms tend to be the most distinctive and enduring and include sensory changes such as generalized pruritus, circumoral numbness and reversal of hot and cold sensation. Intravenous mannitol has evolved as a unique remedy for patients with acute poisoning, but management of chronic symptoms continues to be problematic. Though difficult to implement, preventive strategies remain the best defense.

This study examined current and proposed drug testing policies from a stratified random sample of colleges and universities in the United States. Two-hundred forty-five of the 288 athletic directors surveyed responded, and 29% reported drug testing of their student athletes. Testing was most commonly conducted on a random basis, with cocaine and amphetamines the most frequently screened drugs, 85% and 83%, respectively. Only 56% tested for other specific performance-enhancing drugs such as steroids. Referral for treatment was the most common consequence of testing positive. Among schools conducting testing, the majority of students supported the program, whereas in schools without a testing program, it was anticipated that the majority of students would be opposed. It is suspected that more schools will initiate testing over the short term.

Administrators at 400 colleges and universities were surveyed for information regarding their schools' current or proposed policies for the urine drug testing of faculty, nonfaculty employees, and students. Three hundred seven schools (77%) responded regarding their testing policies for employees and applicants for employment, including faculty and nonfaculty; 332 (83%) responded with respect to students. Twenty-five schools reported testing one or more of these groups. None of the schools reported randomly testing applicants for either faculty or nonfaculty positions, and none tested all applicants for all positions. Fewer than 7% of the colleges and universities surveyed reported that they tested urine of employees and applicants for employment to detect drug use. In those institutions that carried out tests, the tests were most often directed toward particular types of workers. Student testing was limited to approximately 2% of the 332 responding institutions.

A retrospective Medical Examiner case review of all deaths in Maryland where either fluoxetine or tricyclic antidepressant (TCA) use was forensically detected was conducted for the time period January 1987-July 1991. Case records and toxicology reports from the Office of the Chief Medical Examiner were reviewed to determine cause and manner of death, circumstances of death, demographic information on the decedent, prior medical history of the decedent, and presence and level of either fluoxetine or TCA in various body fluids/tissues. Suicide was the manner of death most frequently associated with TCA and fluoxetine detection. Violent methods were more often associated with fluoxetine suicides than with TCA suicides (65% v. 23%, P < 0.001). Demographic characteristics of antidepressant-related deaths in Maryland were similar to those of the entire USA. Possible explanations for the results obtained include the inherent lower lethality of fluoxetine compared to the TCAs, necessitating the use of additional means to complete the act of suicide; that physicians may have switched more impulsive, high risk patients to this new agent as it became available, thus creating a selection bias for more violence-prone individuals in the fluoxetine group; or that fluoxetine may be associated with induction of violence and/or suicidal ideation. Further research examining the possible association of these agents with violent acts is warranted.

During identical 2-month periods in 1989 and 1991, all applicants for employment at a major teaching hospital participated in preemployment drug screening. In 1989, before establishment of a formal preemployment testing program, screening was conducted without identifying information. Of 593 applicants screened, 64 (10.8%) were confirmed positive for one or more drugs. Marijuana metabolites were detected with the greatest frequency (35 samples, 55% of positive screens), followed by cocaine (36%), then opiates (28%). In 1991, after a formal preemployment testing program was in place, 365 applicants were screened, and 21 (5.8%) were confirmed positive. Opiates were most often detected (48% of positive screens), followed by cocaine (38%), then marijuana metabolites (28%). During both periods, positive urine screens were associated with ethnicity (non-White) and occupational category (blue-collar). Whereas in 1989 positive screens were associated with male gender, in 1991, females were more likely to test positive. The decline in prevalence following implementation of a screening program supports the notion that preemployment testing can serve as a deterrent for drug-using persons in applying for employment.

Organic calcium (Ca++) channel antagonists enhance opiate-induced analgesia and antagonize respiratory depression produced by morphine in rodents. Our preliminary data indicated that verapamil reduces the subjective effects of morphine in humans. We therefore assessed morphine-verapamil interactions in 12 experienced, male polydrug users with histories of heroin abuse by using a double-blind, cross-over study design. Treatments consisted of two drug infusions. Either verapamil, 2.5 or 10 mg, or saline was infused, 30 ml i.v. over 2 min; half way through this infusion either 10 mg of morphine or saline was infused, 3 ml i.v. over 10 sec, via a second catheter. Autonomic parameters, responsiveness to pain and subjective self-reports of mood and feeling state were measured over 4 hr. Analgesia was measured using a finger pressure test and hand immersion in ice water. Respiration was measured by using respiratory inductive plethysmography and transcutaneous CO2 levels. The Addiction Research Center Inventory (ARCI) was used to measure the subjective effects. Morphine had a liminal effect on pain threshold, but verapamil potentiated this effect to elevate pain threshold significantly. Verapamil did not affect the ability of morphine to increase pain endurance or to produce respiratory depression. Morphine produced positive affective responses, as demonstrated by elevated scores on the Morphine-Benzedrine Group subscale of the ARCI. Verapamil alone produced no effects on any ARCI subscales; however, 10 mg of verapamil significantly reduced morphine-elevated MBG scores over a 3-hr period. The results suggest the euphorigenic and analgesic effects of opioids may be differentiated by using Ca++ channel blockers.

Background: Ciguatera fish poisoning is a distinctive clinical syndrome associated with the consumption of contaminated marine fish. It is endemic in many popular travel destinations, including the Caribbean and Pacific Islands, where travelers are at risk., Methods: Clinical review of 23 patients (60% were travelers) with ciguatera fish poisoning in whom consultation was provided between 1987 and 1990., Results: Seven patients acquired ciguatera fish poisoning during international travel to the following destinations: Bahamas (n = 4), Dominican Republic (n = 1), British Virgin Islands (n = 1), and United States (n = 1). Suspected fish included grouper, red snapper, and amberjack. Two patients required emergency care, and four patients developed chronic symptoms. Severity was associated with chronicity, duration of peak symptoms, and worsening of symptoms with sexual activity. Chronicity was associated with severity, long latency period, and duration of peak symptoms. The three patients with complete resolution were scuba divers. Amitriptyline was the drug most often providing benefit for chronic symptoms., Conclusions: Ciguatera fish poisoning is a health risk to travelers to endemic regions, and their risk likely equals that of indigenous population groups. Barracuda should never be eaten, and travelers should exercise caution when considering other fish dishes, notably, grouper and red snapper.

Mortality trends of missionary staff serving in sub-Saharan Africa were tracked for the period 1945-1985. For 1945-1970, when more complete incidence data were available, the missionary death rate was approximately 40% lower, after adjustment, than would be expected in a comparable US population. This trend persisted through 1985. Between 1945 and 1970, the largest number of fatalities was attributable to malignancy, atherosclerosis, accidents, and infectious disease, and the greatest mortality risks, compared with the US experience, were from homicides, the complications of pregnancy, and infections, notably malaria, hepatitis, and polio. Beginning in the late 1950s, motor vehicle accidents became the leading cause of death. Since the 1960s, accidental causes of death have been approximately 50% higher than in the US, and homicides have been four times higher. During this same period, the infectious disease death rate decreased to approximately that within the US. Currently, the leading causes of mortality are motor vehicle accidents, malignancy, and atherosclerosis, followed by other accidental causes, notably aircraft mishaps and drownings. Viral hepatitis is presently the leading infectious disease cause of death. Other contemporary lethal infections include malaria, rabies, typhoid, Lassa fever, and retroviral infection. It was concluded that missionaries in sub-Saharan Africa had a death rate approximately half that expected in a comparable domestic control population. Preventive strategies, particularly relative to accident and infectious disease prevention, could effectively reduce mortality risk further.

The incidence of dengue fever, an acute febrile illness transmitted by the Aedes aegypti mosquito, is on the rise. High fever, severe headache, skin rash and a variety of constitutional symptoms are hallmarks of classic dengue fever. Dengue hemorrhagic fever, a severe manifestation associated with secondary infection, most often occurs in children. Treatment of classic dengue fever is supportive, whereas urgent rehydration therapy is often required in more severe forms. Community-based and personal strategies for avoiding the mosquito vector represent the best methods of prevention, although vaccine development programs are under way.

The U.S. Public Health Service Commissioned Corps performs health promotion and disease prevention activities and provides clinical care. The authors examined the epidemiology of deaths among active duty personnel and the hypothesis that, based on the mission, mortality would be less than in the general population, and that deaths would reflect nonpreventable causes. A retrospective record review for the period 1965-89 showed 118 active duty deaths, 26 percent of the number anticipated in a general population group adjusted for age, sex, and race or ethnicity. The five major causes of death were coronary heart disease, suicide, motor vehicle crash, malignant neoplasm, and drowning. Beginning with the mid-1980s, infectious disease became a principal cause of death, the only cause for which the rate trended upward. Among professionals, death rates were highest among sanitarians and veterinarians, and lowest among pharmacists. The only causes for which deaths exceeded the expected number involved suicides and possibly deaths related to acquired immunodeficiency syndrome. Active duty status in the Commissioned Corps was associated with a death rate less than that of comparable groups in the general population. Many of the premature deaths were attributable to preventable causes.

The disease, destruction, and destitution created by the recent conflicts in the Persian Gulf have resulted in increased international travel to affected countries for relief and reconstruction. Such travel involves more than minimal health risks, but effective preparation of travelers by primary care physicians can help, as discussed by the authors.

Serum specimens obtained from a nationwide sample of parenteral drug abusers (PDAs) during the period 1971-72 had previously been screened for human immunodeficiency virus (HIV) antibodies. Some specimens were considered to be positive to both ELISA and Western blot (WB) analysis. These findings have been a topic of controversy, since HIV was not thought to have penetrated at-risk populations at such an early date. This study was a followup of those PDAs with apparent seropositivity to WB analysis. Of 10 persons followed, only one death (in 1985) was documented, and postmortem findings were inconsistent with HIV infection. Eight of the remaining PDAs were traced and found to be alive and well in 1989. Fresh specimens were obtained from the two persons with the strongest 1971-72 WB staining and were found to be both ELISA and WB negative on retesting. Their T-cell parameters were within normal limits. We concluded that the earlier WB results were most likely false positives and that definitive evidence of HIV infection in the U.S. addict population as early as 1971-72 is still lacking.

We report the case of a Protestant missionary who contracted tick-borne relapsing fever in 1979 while serving in the Sudan. Despite tetracycline treatment, his acute illness ran a protracted course, with migratory polyarthralgias lasting approximately 10 months. Symptoms recurred in 1984 and have persisted. At regular intervals, the patient has experienced recurrent episodes of fever, generalized fatigue, bilateral upper and lower extremity muscle weakness, and asymetric large joint polyarthralgia. Indirect fluorescent antibody testing of sera demonstrated titers of 1:16 for B. burgdorferi and 1:64 for B. hermsii, and immunoblotting confirmed past exposure to relapsing fever, but not Lyme disease. It is hypothesized that this individual's chronic symptoms have been related to relapsing fever, and that in certain situations or in select individuals, relapsing fever can be capable of producing a chronic clinical picture analogous to Lyme disease.

Effects on the human immune system of volatile nitrite inhalation were studied in 18 male volunteers. While nitrite inhalation decreased the absolute number of CD3+ T lymphocytes during the period of inhalation, cell numbers returned to pre-treatment levels within one week after cessation of the drug. Nitrite inhalation did not alter the percentage of CD3+, CD4+, CD8+ or CD19+ lymphocytes. Natural killer (NK) cell activity against K562 target cells was depressed by nitrite administration but returned to pre-inhalation or greater levels after nitrite discontinuation. Cell proliferation following cell activation by PHA, ConA and PWM was unaffected by amyl nitrite inhalation. We conclude that in humans inhalation of volatile nitrites causes cycles of modest immunosuppression, particularly in NK activity, followed by gradual recovery when the drug is not inhaled for several days.