A novel chemical delivery system for brain targeting

Yoshikawa, Tomohiro; Sakaeda, Toshiyuki; Sugawara, Tamio; Hirano, Koichiro; Stella, Valentino J.

doi:10.1016/s0169-409x(98)00091-x

Cited by 41 publications

(17 citation statements)

References 75 publications

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“…However, the oral antimalarial ED 50 for T3 could not be determined because it was Ͼ10 mg͞kg (data not shown). Nevertheless, this design gave a platform from which we attempted to overcome the low bioavailability of these drugs when delivered orally by creating prodrugs with a hydrolyzable thioester bond that could be bioconverted to the active form in the blood (26,27). One compound (TM1) lacking this hydrolyzable thioester, is devoid of antimalarial activity.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Prodrugs of bisthiazolium salts are orally potent antimalarials

Vial

Wein

Farenc

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

105

151

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We created neutral antimalarial prodrugs that deliver bisthiazolium compounds with antimalarial activity in the nanomolar range. These drugs primarily affect early intraerythrocytic stages through rapid, nonreversible cytotoxicity. The compounds are suitable for both parenteral and oral use and plasma promotes rapid conversion of the prodrug into the drug. We demonstrate that very low doses offer protection in a murine model of malaria. The drugs show great potential for curing high parasitemia with short-course treatments. Oral administration of the TE3 prodrug completely cures Plasmodium cynomolgi infection in rhesus monkeys. The drugs specifically accumulate inside infected erythrocytes, block phosphatidylcholine biosynthesis, and interact with hemozoin. To our knowledge, this class of compounds represents one of the most potent antimalarials tested to date. These unique properties signal a promising future for this class of antimalarial.M alaria is a public health problem affecting Ͼ40% of the world's population. It causes up to 2 million deaths, mostly young children, in Africa, and Ͼ300 million clinical cases each year (1), with major consequent impact on economic productivity and livelihood (2). Currently, there are no licensed vaccines and the spread of drug-resistant parasites and insecticideresistant mosquitoes is an increasing problem. New antimalarial compounds, particularly those based on compounds structurally unrelated to existing antimalarial drugs with new mechanisms of action, are urgently needed (3-5).We have developed classes of antimalarial drugs targeting membrane biogenesis during intraerythrocytic Plasmodium falciparum development. We have focused on mono-and bisquaternary ammonium compounds for their potent antimalarial activity in vitro and in vivo (6, 7). These compounds mimic choline structure; they potently inhibit the low-affinity choline carrier related to phospholipid biosynthesis in eukaryotic cells and the high-affinity carrier involved in biosynthesis of the neurotransmitter acetylcholine in the CNS (8, 9). These compounds have exceptional in vitro and in vivo antimalarial properties devoid of mutagenic activity (10 -12).G25 [1,16-hexadecamethylenebis(N-methylpyrrolidinium) dibromide] and other drugs in this class possess a permanently charged cationic group (7, 13) that is essential for activity but detrimental to oral absorption. This action prejudiced development for the clinic. Oral administration is essential for treatment in dispensaries in endemic countries and for prophylactic or curative treatment for travelers. A targeting carrier system is unsuitable because, in the absence of carrier-mediated specific processes, quaternary ammonium compounds are intrinsically incapable of crossing bilayered cellular membranes. Designing drugs that mask the ionizable groups was therefore the most attractive solution. This was the rationale behind development of a chemically modified form of drug that is converted into an active ionized form by enzymes present in plasma. Here, we repo...

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Section: Discussionmentioning

confidence: 99%

“…Oral dosages (27,9, and 3 mg͞kg once a day for 4 consecutive days) were based on ED 50 values obtained in mice (5 mg͞kg). Parasite development (an initial increase in parasite numbers followed by a decrease and subsequent recrudescence) was similar to that previously reported (10).…”

Section: Figmentioning

confidence: 99%

Prodrugs of bisthiazolium salts are orally potent antimalarials

Vial

Wein

Farenc

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

105

151

View full text Add to dashboard Cite

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“…Once in the brain, the prodrug undergoes an enzymatic reaction that returns the drug to its active state and with reduced BBB permeability (Sherman et al, 1991;Yoshikawa et al, 1999). These approaches, which have not yet been used for brain tumor chemotherapeutic drugs, offer an advantage by increasing K 1 in Equation 3 while k 2 and k 3 remain unchanged.…”

Section: Prodrug Therapymentioning

confidence: 99%

The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery

Groothuis¹

2000

Neuro-Oncol

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Drug delivery to brain tumors has been a controversial subject. Some believe the blood-brain barrier is not important, while others believe it is the major obstacle in treatment and have devised innovative approaches to circumvent it. These approaches can be divided into two categories: those that attempt to increase drug delivery of intravascularly administered drugs by manipulating either the drugs or capillary permeability, and those that attempt to increase drug delivery by local administration. Several strategies have been developed to increase the fraction of intravascular drug reaching the tumor, including intraarterial administration, barrier disruption, new ways of packaging drugs, and, most recently, inhibiting drug ef ux from tumor. When given intravascularly, all drugs have a common drawback: the body acts as a sink, and, even in the best situations, only a small fraction of administered drug actually reaches the tumor. A consequence is that systemic toxicity is usually the dose-limiting factor. When given locally, such as into the cerebrospinal uid or directly into the tumor, 100% of an administered dose is delivered to the target site. However, local delivery is associated with variable and unpredictable spatial distribution and variation in drug concentration. The major dose-limiting factor of most local delivery methods will be neurotoxicity. The relative advantages and disadvantages of the different methods of circumventing the blood-brain barrier are presented in this review, and special attention is given to convection-enhanced delivery, which has particular promise for the local delivery of large therapeutic agents such as monoclonal antibodies, antisense oligonucleotides, or viral vectors. Neuro-Oncology 2, 45-59, 2000 (Posted to Neuro-Oncology [serial online], Doc. 99-30, December 14, 1999 IntroductionThe delivery of drugs to brain tumors has long been a controversial problem. In 1977, Vick et al. wrote in an editorial: "We believe that there is compelling evidence to suggest that the 'blood-brain barrier,' as it is generally conceived, is not one of the factors impeding the success of brain tumor chemotherapy." They went on to say that "dosage, route of administration, tumor cell uptake, metabolic fate within tumor cells, and the washout or sink effect of the extracellular space and CSF are the issues that will have to be studied" (Vick et al., 1977). Some clinicians have agreed with Vick et al. (Donelli et al., 1992;Stewart, 1994); however, on the whole, the belief that the BBB 3 and BTB prevent drugs from reaching brain tumors in suf cient concentrations to kill the tumor cells has motivated numerous attempts to increase the amount of drug that reaches the tumor. Many innovative methods have been used to try to increase drug delivery including, most recently, a method in which drugs are infused directly into brain tumors, a method referred to as convection-enhanced delivery (CED) Laske et al., 1997a;Lieberman et al., 1995). This review Neuro-Oncology n J AN UA RY 2 0 00 45Neuro-Oncology

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“…In addition to the trigonelline targetor system, a system relying on the ring-closure reaction of cis-2-formylaminoethenylthio derivatives to quaternary thiazolium derivatives has also been explored for the brain delivery of DOPA (L-3,4-dihydroxyphenylalanine) [432], NMDA and AMPA receptor antagonists [436], and a-tocopherol analogs as free radical scavengers [436]. Selected brain-targeting CDS examples are summarized in the following chapters together with representative physicochemical properties, metabolic pathways, and pharmacological data.…”

Section: Brain-targeting (Enzymaticmentioning

confidence: 99%

Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

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A novel chemical delivery system for brain targeting

Cited by 41 publications

References 75 publications

Prodrugs of bisthiazolium salts are orally potent antimalarials

Prodrugs of bisthiazolium salts are orally potent antimalarials

The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery

Retrometabolism‐Based Drug Design and Targeting

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