This report updates the 2002 recommendations by the Advisory Committee on Immunization Practices (ACIP) on the use of influenza vaccine and antiviral agents (CDC. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2002;51 [No. RR-3]:1-31). The 2003 recommendations include new or updated information regarding 1) the timing of influenza vaccination by age and risk group; 2) influenza vaccine for children aged 6-23 months; 3) the 2003-2004 trivalent inactivated vaccine virus strains: A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Hong Kong/330/2001-like antigens (for the A/Moscow/10/99 [H3N2]-like antigen, manufacturers will use the antigenically equivalent A/Panama/2007/99 [H3N2] virus, and for the B/Hong Kong/330/2001-like antigen, manufacturers will use either B/Hong Kong/330/2001 or the antigenically equivalent B/Hong Kong/1434/2002); 4) availability of certain influenza vaccine doses with reduced thimerosal content, including single 0.25 mL-dose syringes; and 5) manufacturers of influenza vaccine for the U.S. market. Although the optimal time to vaccinate against influenza is October and November, vaccination in December and later continues to be strongly recommended A link to this report and other information regarding influenza can be accessed at http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm.

https://stacks.cdc.gov/view/cdc/6625/cdc_6625_DS1.pdf

Prevention and control of influenza : recommendations of the Advisory Committee on Immunization Practices (ACIP)

The use of liposomal carriers and the modification of therapeutic molecules through the attachment of poly(ethylene glycol) [PEG] moieties ('pegylation') are the most common approaches for enhancing the delivery of parenteral agents Although 'classical' liposomes (ie phospholipid bilayer vehicles) have been effective in decreasing the clearance of encapsulated agents and in passively targeting specific tissues, they are associated with considerable limitations Pegylation may be an effective method of delivering therapeutic proteins and modifying their pharmacokinetic properties, in turn modifying pharmacodynamics, via a mechanism dependent on altered binding properties of the native protein Pegylation reduces renal clearance and, for some products, results in a more sustained absorption after subcutaneous administration as well as restricted distribution These pharmacokinetic changes may result in more constant and sustained plasma concentrations, which can lead to increases in clinical effectiveness when the desired effects are concentration-dependent Maintaining drug concentrations at or near a target concentration for an extended period of time is often clinically advantageous, and is particularly useful in antiviral therapy, since constant antiviral pressure should prevent replication and may thereby suppress the emergence of resistant variants Additionally, PEG modification may decrease adverse effects caused by the large variations in peak-to-trough plasma drug concentrations associated with frequent administration and by the immunogenicity of unmodified proteins Pegylated proteins may have reduced immunogenicity because PEG-induced steric hindrance can prevent immune recognition Two PEG-modified proteins are currently approved by the US Food and Drug Administration; several others, including cytokines such as interferon-alpha (IFNalpha), growth factors and free radical scavengers, are under development Careful assessment of various pegylated IFNalpha products suggests that pegylated molecules can be differentiated on the basis of their pharmacokinetic properties and related changes in pharmacodynamics Because the size, geometry and attachment site of the PEG moiety play a crucial role in determining these properties, therapeutically optimised agents must be designed on a protein-by-protein basis

Pegylation: a novel process for modifying pharmacokinetics

Pathogenesis of human immunodeficiency virus infection.

The development of antiretroviral therapy against acquired immunodeficiency syndrome (AIDS) has been an intense research effort since the discovery of the causative agent, human immunodeficiency virus (HIV). A large array of drugs and biologic substances can inhibit HIV replication in vitro. Nucleoside analogs--particularly those belonging to the dideoxynucleoside family--can inhibit reverse transcriptase after anabolic phosphorylation. 3'-Azido-2',3'-dideoxythymidine (AZT) was the first such drug tested in individuals with AIDS, and considerable knowledge of structure-activity relations has emerged for this class of drugs. However, virtually every step in the replication of HIV could serve as a target for a new therapeutic intervention. In the future, non-nucleoside-type drugs will likely become more important in the experimental therapy of AIDS, and antiretroviral therapy will exert major effects against the morbidity and mortality caused by HIV.

/pdf/molecular-targets-for-aids-therapy-26szl907hg.pdf

Molecular targets for AIDS therapy

Fatigue of voluntary muscular effort is a complex phenomenon. To date, relatively little attention has been placed on the role of the central nervous system (CNS) in fatigue during exercise despite the fact that the unwillingness to generate and maintain adequate CNS drive to the working muscle is the most likely explanation of fatigue for most people during normal activities. Several biological mechanisms have been proposed to explain CNS fatigue. Hypotheses have been developed for several neurotransmitters including serotonin (5-HT; 5-hydroxytryptamine), dopamine, and acetylcholine. The most prominent one involves an increase in 5-HT activity in various brain regions. Good evidence suggests that increases and decreases in brain 5-HT activity during prolonged exercise hasten and delay fatigue, respectively, and nutritional manipulations designed to attenuate brain 5-HT synthesis during prolonged exercise improve endurance performance. Other neuromodulators that may influence fatigue during exercise include cytokines and ammonia. Increases in several cytokines have been associated with reduced exercise tolerance associated with acute viral or bacterial infection. Accumulation of ammonia in the blood and brain during exercise could also negatively effect the CNS function and fatigue. Clearly fatigue during prolonged exercise is influenced by multiple CNS and peripheral factors. Further elucidation of how CNS influences affect fatigue is relevant for achieving optimal muscular performance in athletics as well as everyday life.

Possible mechanisms of central nervous system fatigue during exercise.

Phase i studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (azt)

Three groups of six subjects each received a single 36 X 10(6) U dose of recombinant leukocyte A interferon (rIFN-alpha A) as a 40-min infusion, an intramuscular injection, or a subcutaneous injection. Blood samples were collected at specific times after dosing for analysis of rIFN-alpha A serum concentrations by an enzyme immunoassay method, ELISA. The rIFN-alpha A was rapidly distributed and moderately eliminated (t 1/2 = 5.1 hr) after intravenous infusion. The maximum concentrations at the end of intravenous infusion were tenfold the maximum concentrations after intramuscular and subcutaneous injections. Renal tubular secretion or extrarenal elimination was suggested by clearance values of 1.8 times the glomerular filtration rate. After intramuscular and subcutaneous injection, rIFN-alpha A was absorbed slowly (time to reach maximum concentration ranged from 4 to 8 hr), which resulted in prolonged serum concentrations. Estimated bioavailability was more than 80% for both intramuscular and subcutaneous injection shares qualitatively the same adverse reactions, the reactions differ in severity and duration. The adverse effects appear to be related to route of administration of herpes labialis were also noted. There were no significant clinical laboratory abnormalities of medical concern. Although rIFN-alpha A injected by intravenous infusion or intramuscular or subcutaneous injection shares qualitatively the same adverse reactions, the reactions differ in severity and duration. The adverse effects appear to be related to route of administration.

Interferon kinetics and adverse reactions after intravenous, intramuscular, and subcutaneous injection.

The pharmacokinetics of recombinant alpha A interferon (rIFN-alpha A) were studied following an intravenous (iv) bolus, 60 min infusion, intramuscular (im), and oral administrations to four African Green monkeys. Each monkey received 3 X 10(6) units/kg of rIFN-alpha A parenterally and 6 X 10(6) units/kg orally. Blood samples were collected and the serum was separated and analyzed for rIFN-alpha A concentrations by an enzyme immunoassay, ELISA. No significant changes in clinical chemistry values resulted from rIFN-alpha A administration. There were no measurable rIFN-alpha A concentrations (less than 20 pg/ml) following oral administration. Serum rIFN-alpha A concentrations declined rapidly in a biphasic manner following iv bolus and infusion doses and were described by a single pharmacokinetic model. The volume of distribution at steady state (Vdss) ranged from 0.034 to 0.31 l/kg after iv infusion. Total clearance ranged from 4.5 to 19 ml/min, which is about 75% the estimated inulin clearance in monkeys, suggesting glomerular filtration without reabsorption. The elimination half-life ranged from 1.8 to 4.8 h. A prolonged absorption profile was seen following im administration and the systemic bioavailability was 93% when compared with intravenous infusion. The overall disposition of rIFN-alpha A is comparable to the disposition of other interferons in both animals and humans. The monkey appears to be a suitable pharmacokinetic model for the testing of rIFN-alpha A and could be useful in conjunction with a viral efficacy model.

Pharmacokinetics of recombinant alpha A interferon following I.V. infusion and bolus, I.M., and P.O. administrations to African green monkeys.

Interferon alfa-2a (Roferon-A, Hoffmann-La Roche Inc., Nutley, NJ) is identical to one of approximately 15 subtypes of interferon alpha made by human leukocytes and is produced in bacteria using recombinant DNA techniques. In its antiviral, antiproliferative, and immunomodulatory activities it is similar to leukocyte interferon alpha. These activities are species-restricted and have been demonstrable, thus far, only in humans, certain other primates, bovines, and guinea pigs or cells derived therefrom. The possibility that the toxicity of interferon alfa-2a would also be species-restricted appears to have been confirmed by results obtained thus far. Toxicological studies in rats, mice and several species of monkeys have failed to indicate the side effects that have been observed in humans. However, studies in species in which interferon alfa-2a is active and in others in which it is not, have revealed similar pharmacokinetics and elimination mechanisms.

The preclinical development of roferon®‐A

The pharmacokinetics and tissue distribution in mice of several recombinant human alpha-interferons [rHuIFN-alpha A, D, I, and A/D(Bgl)] as well as natural mouse alpha-interferon (MuIFN-alpha) were assessed following single intravenous injections. The serum profiles of rHuIFN-alpha A, rHuIFN-alpha D, rHuIFN-alpha A/D(Bgl), and MuIFN-alpha were similar, whereas those following rHuIFN-alpha I showed a much longer terminal elimination phase. Differences in elimination half-life, volume of distribution, and total body clearance between these IFNs were observed. There was appreciable uptake of IFN in the kidney: the amount of each interferon per gram of tissue in the kidney ranges from 1 to 9 times the amount found in the serum. The greatest uptake appeared with rHuIFN-alpha D, followed by rHuIFN-alpha A, rHuIFN-alpha A/D(Bgl), and MuIFN-alpha. The only exception was rHuIFN-alpha I which showed no uptake into the kidney.

Robert J. Wills

Papers

Phase i studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (azt)

Interferon kinetics and adverse reactions after intravenous, intramuscular, and subcutaneous injection.

Pharmacokinetics of recombinant alpha A interferon following I.V. infusion and bolus, I.M., and P.O. administrations to African green monkeys.

The preclinical development of roferon®‐A

Pharmacokinetics and tissue distribution of recombinant human alpha A, D, A/D(Bgl), and I interferons and mouse alpha-interferon in mice.