Recently, respiratory tract infection (RTI) such as pneumonia or lower respiratory tract infection (LRTI) is a serious problem. There is a risk of a rapid increase in RTI and with it the serious problem of drug resistant pathogens. Penicillin-resistant Streptococcus pneumoniae (PRSP) and methicillin resistant Staphylococcus aureus (MRSA) are the representative organisms in community clinics as well as in hospitals. The development of DDS with the aim of reducing the frequency of dosing and improving compliance is also suggestive of a new trend for DDS in the field of treating infectious diseases.
Meanwhile, research into gene therapy is also being pursued as a new, non-drug-based strategy. Therapeutic methods to stimulate the host's immune system by introducing genes for inflammatory cytokines such as IL-12 and IFN-γ—to act as immunomodulators for the human body—are being researched. Among gene therapies targeting causative microorganisms, new treatment approaches using antisense nucleotides or short-interfering RNA (siRNA) for the influenza virus, SARS virus, tubercle bacillus, and MRSA are being tested. Short-interfering RNA may be a new strategy against infectious diseases in the near future.

View full abstract

Recently, mucosal vaccine is paid to attention as a means that the immunization reaction is made to activate from the mucosa and the infection is prevented and a total body inflammatory disease can treat through the inducement of an antigen peculiar immunological tolerance. It introduces the application of DDS to the mucosal vaccine.

View full abstract

In this study, we designed a peptide which is specifically cleaved by HIV protease as a gene/drug carrier. This is based on a new concept of a drug delivery system (DDS) responding to intracellular signals. We observed that this peptide was cleaved by recombinant HIV protease and HIV infected cells. In this system, the gene/drug can be released only in HIV infected cells. Since drugs could be activated only in infected cells, this system has a potential to raise the efficacy of drugs and reduce their side effects. As a biological signal, nitric oxide (NO) has aroused much attention. NO is a promising biological signal as well as a HIV protease in the new concept of DDS. However, it is extremely difficult to measure directly because of extreme short half-life time. We will introduce our system to measure NO directly by an electrode method.

View full abstract

Amphotericin B (AmB), polyene macrolide antibiotics, has been used for the treatment of systemic fungal infections. It is necessary to administer at higher dosage to treat pulmonary aspergillosis, however, its clinical use is limited by toxic side effects. Liposomal formulation of AmB make it possible to reduce its toxicity and improve the therapeutic efficacy and recently, liposomal and lipid formulation of AmB have been developed and now on the market in USA, Europe and Japan. But, further improvements of the encapsulation of AmB into liposomes and therapeutic efficacy have still been required. Enhanced encapsulation of AmB in liposomes by complex formation between AmB and polyethylene glycol-lipid derivatives, DSPE-PEG, has clearly solved the problems, which have been investigated by us. Hydration by 9% sucrose solution and incorporation of DSPE-PEG were required for the high encapsulation efficacy. AmB-PEG liposomes showed not only high encapsulation of AmB but also high retention of AmB in liposomes in vitro and long-circulation property in vivo.
We also prepared the novel AmB encapsulating PEG-immunoliposomes carrying monoclonal antibodies at the distal ends of the PEG chains. AmB-PEG-immunoliposomes and AmB-encapsulating PEG liposomes also showed the higher therapeutic effects on murine model of pulmonary aspergillosis than that of commercially used liposomes.

View full abstract

Recent alarming increases of drug resistant pathogens have been serious problems causing parallel increases of intractable cases in acute otitis media and rhinosinusitis among Japanese children. For developing effective antimicrobial treatments against such intractable bacterial infectious diseases, physician should pay much attention to appropriate selection of antibiotics and administrative routes concerning pharmacokinetics and pharmacodynamics (PK/PD) of antibiotics and attractive drug delivery systems (DDS).
In the current study, we investigated two types of newly developed controlled-release antibiotics for the treatment of experimental otitis media caused by nontypeable Haemophilus influenzae in chinchillas. The controlled-release antibiotics showed better bactericidal effect rather than systemic administration or topical use of antibiotics. The controlled-release antibiotics by use of DDS will be attractive new procedures for the antimicrobial treatment against intractable bacterial infections.

View full abstract

AMPH-B has excellent profiles such as a broad spectrum and fungicidal activities. However, it has faults which cause various and crucial side effects in the high frequency. AMPH-B lipid formulations have been developed in an attempt to reduce the toxicities of AMPH-B while retaining its therapeutic efficacy. This review focuses on the characteristic of AMPH-B lipid formulations.

View full abstract

Permeation of meloxicam (MEL) through excised hairless mouse skin under the influence of various additives was investigated with respect to mechanisms of action. Of a total of 23 additives, such as alcohols, fatty acids, esters, terpenes, amines and surfactants. 12 were found to enhance the skin permeation of MEL, and these could be classified into three groups that are influencing diffusion in the skin, partition to the skin and solubility of the drug. Combination of additives enhancing diffusion and partition resulted in approximately 6-fold increase in permeation as compared to the water control case, whereas diisopropanolamine enhancing solubility combined with 1-menthol enhancing diffusion or glycerin monocaprylate enhancing partition caused 500-fold elevation. Therefore, to achieve high enhancement with combinations having differing mechanisms of action, use of an additive enhancing solubility with either of the other two types may have advantages.
With tape type patches containing diisopropanolamine to increase solubility of MEL with 1-menthol to increase diffusion in the skin or glycerin monocaprylate to increase partition to the skin, permeation was well enhanced, but this was not the case with poultice type patches. With these latter, improvement was obtained on substitution of polyoxyethylene oleylamine (5E.O.), a hydrophobic solvent, for the hydrophilic diisopropanolamine.
These results suggest that combinations of enhancers and confirmation of the miscibility of additives enhancing solubility with the base is important for achieving high permeation of drugs from transdermal patches.

View full abstract