Herbal medicine development: a plea for a rigorous scientific foundation.

Science, including rigorous basic scientific research and rigorous clinical research, must underlie both the development and the clinical use of herbal medicines. Yet almost none of the hundreds or thousands of articles that are published each year on some aspect of herbal medicines, adheres to 3 simple but profound scientific principles must underlie all of herbal drug development or clinical use. Three fundamental principles that should underlie everyone's thinking about the development and/or clinical use of any herbal medicine.

Induction of chemoprotective phase 2 enzymes by ginseng and its components.

Phase 2 detoxification enzymes protect against carcinogenesis and oxidative stress. Ginseng ( PANAX spp.) extracts and components were assayed for inducer activity of NQO1 (quinone reductase), a phase 2 enzyme, in Hepa1c1c7 cells.

Possible differential induction of phase 2 enzyme and antioxidant pathways by american ginseng, Panax quinquefolius.

Human immunodeficiency virus (HIV)-infected patients often take herbal medicines, which may interact with antiretrovirals. American ginseng induces phase 2 and antioxidant enzymes in vitro and might increase the clearance of zidovudine and/or enhance antioxidant activity. Ten healthy volunteers received 300 mg of zidovudine orally before and after 2 weeks of treatment with a ginsenoside-enriched American ginseng extract 200 mg twice daily.

Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production.

Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0-50 microM in vitro, on normal human CD34+ haematopoietic progenitor cells cultured ex vivo for up to 12 days.

A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered- dose inhalers.

Background: With the expiration of the patent on albuterol metered-dose inhalers (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations required investigation.

Objective: In an effort to develop a sensitive method to document bioequivalence, bronchoprovocation with methacholine chloride was used to assess the dose-response relationship of albuterol as delivered by MDI. Sensitivity was assessed in terms of magnitudes of ED(50), the estimated albuterol dose required to achieve 50 % of the fitted maximal value of the pharmacodynamic effect above baseline, and change in response as a function of dose, with emphasis on 1 and 2 actuations.

Phase i/ii trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults.

Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period.

Clinical pharmacokinetics of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine in human immunodeficiency virus-infected patients.

The pharmacokinetics and bioavailability of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosi ne (cyclic HPMPC) were examined at four doses in 22 patients with human immunodeficiency virus infection. Two groups of six patients received a single dose of cyclic HPMPC at 1.5 or 3.

The effect of increasing gastric pH upon the bioavailability of orally-administered foscarnet.

For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals.

Safety, pharmacokinetics, and antiretroviral activity of intravenous 9-[2-(R)-(Phosphonomethoxy)propyl]adenine, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults.

9-[2-(R)-(Phosphonomethoxy)propyl]adenine (PMPA) is a nucleotide analogue with potent antiretroviral activity in vitro and in simian models. A randomized, double-blind, placebo-controlled, dose-escalation clinical trial of intravenous PMPA monotherapy was conducted in 20 human immunodeficiency virus (HIV)-infected adults with CD4 cell counts of >/=200 cells/mm3 and plasma HIV RNA levels of >/=10,000 copies/ml. Two dose levels were evaluated (1 and 3 mg/kg of body weight/day).

Two doses of PMPA protect newborn macaques against oral simian immunodeficiency virus infection.

Background: Simple and affordable intervention strategies are needed to reduce the rate of HIV transmission from mother to infant in developing countries. Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is considered to be a useful model of human pediatric HIV infection.

Objective: To investigate whether short-term 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) administration can protect newborn rhesus macaques against perinatal SIV infection.

A phase I/II evaluation of oral L-2-oxothiazolidine-4-carboxylic acid in asymptomatic patients infected with human immunodeficiency virus.

A randomized double-blind, placebo-controlled study was conducted in 37 asymptomatic HIV-infected individuals (mean CD4 count 707 cells/mm3) to characterize the safety, pharmacokinetics, and effect on blood thiols of three dosage levels of a cysteine prodrug, L-2-oxothiazolidine-4-carboxylic acid (OTC; Procysteine; Clintec Technologies, Deerfield, IL). Single-dose administration of OTC resulted in measurable plasma levels at all dosages, with a mean peak plasma concentration of 734 +/- 234 nmol/mL at the highest dosage studied. After 4 weeks of administration three times daily, a statistically significant increase was seen in whole blood glutathione in the 1,500 mg and 3,000 mg dose groups compared with the placebo group.

Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxil (9-[2-(bis-pivaloyloxymethyl)-phosphonylmethoxyethyl]adenine) in HIV-infected patients.

A randomized, double-blind, placebo-controlled, dose-escalation study of adefovir dipivoxil, an oral prodrug of adefovir, was conducted in 36 human immunodeficiency virus (HIV)-infected subjects to evaluate its anti-HIV activity, safety, and pharmacokinetics. Subjects received placebo or one of three dosages of adefovir dipivoxil daily for 14 days. Median decreases in serum p24 antigen of 31% (P = .

Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy.

Purpose: To compare the efficacy and safety of inpatient oral antibiotic treatment (oral) versus standard parenteral antibiotic treatment (intravenous) for right-sided staphylococcal endocarditis in injection drug users.

Patients And Methods: In a prospective, randomized, non-blinded trial, febrile injection drug users were assigned to begin oral or intravenous (IV) treatment on admission, before blood culture results were available. Oral therapy consisted of ciprofloxacin and rifampin.

Pharmacokinetics, safety and bioavailability of HPMPC (cidofovir) in human immunodeficiency virus-infected subjects.

We conducted a single-center, double-blind, placebo-controlled phase I study in HIV-positive subjects to ascertain the safety, tolerance, bioavailability, pharmacokinetics, and maximum tolerated dose of HPMPC (cidofovir). Five subjects were randomized to receive drug and two to receive placebo at each of three dosage tier (1, 3, and 10 mg/kg) with a 2-week washout period doses. Subjects at 1 and 3 mg/kg received single doses of HPMPC by subcutaneous (s.

Anticytomegaloviral activity of methotrexate associated with preferential accumulation of drug by cytomegalovirus-infected cells.

We extend the observation that inhibitors of pyrimidine biosynthesis are active against human cytomegalovirus by demonstrating that methotrexate (MTX) has preferential activity against cytomegalovirus replication. The 50% and 90% inhibitory concentrations of MTX for inhibition of cytomegaloviral DNA replication at 3 days postinfection in MRC-5 cells were 0.05 and 0.

A randomized trial of the activity and safety of Ro 24-7429 (Tat antagonist) versus nucleoside for human immunodeficiency virus infection. The AIDS Clinical Trials Group 213 Team.

Ro 24-7429, a Tat antagonist, dosed at 75, 150, or 300 mg/day, was compared with nucleoside analogue (zidovudine or didanosine) for 12 weeks in 96 human immunodeficiency virus (HIV)-infected patients to assess safety and activity. The primary adverse effect of Ro 24-7429 was rash, which necessitated treatment discontinuation in 6 of 71 patients. Nucleoside analogue treatment produced an average increase in CD4 cell count of 28 cells/mm3 at week 8 versus a decrease of 27 cells/mm3 in recipients of Ro 24-7429 (P < .

Modulation of alpha-interferon's antiviral and clinical effects by aspirin, acetaminophen, and prednisone in healthy volunteers.

The magnitude and duration of the antiviral and clinical effect of alpha-interferon was measured in healthy volunteers. A single 3 million unit intramuscular dose of interferon was given either alone (controls) or after 72 h of concomitant medications. These medications included either aspirin (650 mg every 4 h), acetaminophen (650 mg every 4 h), or prednisone (40 mg per day).

Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients.

The pharmacokinetics of cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.

Fluoroquinolone toxicities. An update.

The main types of adverse effects associated with quinolones are uncommon and reversible and vary in frequency among different agents. Phototoxicity appears more frequent with lomefloxacin than with some other quinolones. Three mechanisms have been proposed to explain the neurotoxic effects, including rare proconvulsant activity, associated with quinolone therapy.

Activity of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine against human cytomegalovirus when administered as single-bolus dose and continuous infusion in in vitro cell culture perfusion system.

HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] is a potent inhibitor of human cytomegalovirus (HCMV) replication as determined by conventional tissue culture methods in which the drug concentration remains constant over time. Previous studies have shown HPMPC to have a long intracellular half-life. Despite its relatively short extracellular half-life, HPMPC might provide significant anti-HCMV activity long after the elimination of the drug by first-order kinetics.

Effect of dipyridamole on zidovudine pharmacokinetics and short-term tolerance in asymptomatic human immunodeficiency virus-infected subjects.

Zidovudine delays the progression of infection and prolongs the survival of human immunodeficiency virus (HIV)-infected patients, but these benefits are limited by dose-related toxicity and the cost of the drug. Dipyridamole, in micromolar concentrations, acts synergistically with zidovudine, reducing the anti-HIV 95% inhibitory concentration of zidovudine 5- to 10-fold in vitro. We sought to establish a well-tolerated dose of dipyridamole for use in combination with zidovudine and to detect clinically significant pharmacokinetic interactions.