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The eflornithine story
- ... Currently, the Food and Drug Administration (FDA) approves DFMO for female facial hirsutism and human African trypanosomiasis or sleeping sickness [10,[17][18][19][20][21][22]. Vaniqa (Allergan, Irvine, CA, US) is a 13.9% DFMO cream available for hirsutism with a prescription [10,18,20]. ...... Currently, the Food and Drug Administration (FDA) approves DFMO for female facial hirsutism and human African trypanosomiasis or sleeping sickness [10,[17][18][19][20][21][22]. Vaniqa (Allergan, Irvine, CA, US) is a 13.9% DFMO cream available for hirsutism with a prescription [10,18,20]. In addition, DFMO has orphan drug status for a variety of cancers including: neuroblastoma, colon, gastric, and pancreatic cancer. ...... This dosing scheme is notably labor intensive, costly, and difficult to administer in developing countries with limited health care resources. In addition, although DFMO is tolerated well, some dose-dependent side effects were noted, such as reversible ototoxicity [18]. Attempts to make the dosing regimen shorter or to administer oral DFMO were not efficacious [17]. ...The fluorinated ornithine analog α-difluoromethylornithine (DFMO, eflornithine, ornidyl) is an irreversible suicide inhibitor of ornithine decarboxylase (ODC), the first and rate-limiting enzyme of polyamine biosynthesis. The ubiquitous and essential polyamines have many functions, but are primarily important for rapidly proliferating cells. Thus, ODC is potentially a drug target for any disease state where rapid growth is a key process leading to pathology. The compound was originally discovered as an anticancer drug, but its effectiveness was disappointing. However, DFMO was successfully developed to treat African sleeping sickness and is currently one of few clinically used drugs to combat this neglected tropical disease. The other Food and Drug Administration (FDA) approved application for DFMO is as an active ingredient in the hair removal cream Vaniqa. In recent years, renewed interest in DFMO for hyperproliferative diseases has led to increased research and promising preclinical and clinical trials. This review explores the use of DFMO for the treatment of African sleeping sickness and hirsutism, as well as its potential as a chemopreventive and chemotherapeutic agent against colorectal cancer and neuroblastoma.
- ... Eflornithine had a life that lasted only nine years [16]. When it was licensed and approved for treatment for trypanosomiasis in 1990 it seemed like a solution-less toxic than melarsoprol [17]. ...... In 2000, eflornithine was given a new lease of life when it was approved by the FDA for use as a topical cream to control the growth of facial hair. Vaniqa was the name of the marketed cream, and eflornithine was its active ingredient [16]. ...In his own words, it was the most dramatic moment of his scientific career. At the back of an auditorium in Nairobi, Kenya, Cyrus Bacchi met Simon Van Nieuwenhove. Bacchi, at the time, was essentially a biochemist whose interest was the African trypanosome. Van Nieuwenhove was a clinician who had worked for many years in the field in Africa. The topic of their conversation was eflornithine—a small and simple compound that would eventually make a big impact. Bacchi had shown that the compound had an effect on the parasite that causes Human African Trypanosomiasis. Van Nieuwenhove was dosing patients with it. The story of eflornithine did not start with eflornithine.It started because no one knew how to purify an enzyme. Bacchi was working on his thesis, which centred on the α-glycerophosphate shuttle in hemoflagellates. The shuttle acts as a way to transport reducing equivalents from the cytosol to the mitochondrion. α-glycerophosphate dehydrogenase was the enzyme he spent much of his time trying to purify. The reason he could not purify it was it was hidden within another compartment of the trypanosome. It would not be until several years later, and published in 1977, that Fred Opperdoes discovered the glycosome [1]: the organelle that encapsulates glycolysis in trypanosomes, and the organelle that was hiding the enzyme. At every step of the purification process Bacchi lost activity in his enzyme extracts. Magnesium chloride, surprisingly, managed to boost activity. Bacchi looked into other nonmetallic compounds that would act as cations and eventually chose the polyamines: naturally occurring, nitrogen-containing cations whose concentration is closely controlled by the cell. Spermidine and spermine were found to be the best replacements for magnesium, yielding higher activities. With evidence that the enzyme he was trying to purify was most likely locked within the glycosome, Bacchi moved his attention to how the polyamines were made within the trypanosome. This was an area that had amassed a lot of knowledge everywhere apart from in trypanosomes. It was in 1677 that Anton van Leeuwenhoek first observed spermatozoa in humans, dogs, and a host of other organisms, and he later discovered crystals of spermine phosphate in human semen. Modern research had identified the biologically active polyamines—spermidine and spermine—in plants and many types of mammalian cells. The biochemical pathways that make and degrade the polyamines, along with some of their enzymes, had also been identified. At the time, nothing was known about polyamines in protozoa, and in trypanosomes in particular. Did these parasites contain polyamines? Could polyamine metabolism be a useful chemotherapeutic target?
- ... WHO estimates that 300,000-500,000 people are now infected and up to 60 million people in 36 countries are at risk of contracting the disease [2]. There are two forms of African sleeping sickness, Trypanosoma brucei gambiense and Trypanosoma brucei rhodiense [3]. There are drugs to treat sleeping sickness, but serious side effects are a problem with all of them, and also resistance is increasing. ...... DFMO was synthesized in the 1970s as a potential anticancer drug. It works by inhibiting ornithine decarboxylase (ODC), a key enzyme involved in polyamine biosynthesis, and the inhibition leads to impairment of cellular division [3]. DFMO is the only registered drug available when patients do not respond to melarsoprol and this drug is becoming less and less effective [1]. ...A bioanalytical method for determination of eflornithine (DFMO) in 1000 microL human plasma has been developed and validated. DFMO and the internal standard (IS) were analysed by liquid chromatography with evaporative light-scattering detection (ELSD). Separation was performed on a Chirobiotic TAG (250 mm x 4.6 mm) column with ethanol (99.5%):0.01 mol/L acetic acid-triethylamine buffer at the rate of 25:75% (v/v) with flow rate of 1.0 mL/min. For d-DFMO in plasma the inter-assay precision was 6.5% at 75 micromol/L, 6.6% at 375 micromol/L and 5.8% at 750 micromol/L. For l-DFMO in plasma the inter-assay precision was 10.4% at 75 micromol/L, 6.5% at 375 micromol/L and 5.0% at 750 micromol/L. The lower limit of quantification (LLOQ) was determined to 25 micromol/L where the precision was 4.3% and 5.7%, respectively.
- ... Repurposing of existing drugs has been successful in treating other medical conditions. For example, eflornithine is an ornithine decarboxylase inhibitor used to treat African sleeping sickness that was repurposed to treat female facial hirsutism (97). Thalidomide, an anti-inflammatory medication for treatment of leprosy, has recently been approved for treatment of multiple myeloma (98). ...Viruses commandeer host cell 26S proteasome activity to promote viral entry, gene expression, replication, assembly, and egress. Proteasomal degradation activity is critical for herpes simplex virus (HSV) infection. The proteasome inhibitor bortezomib (also known as Velcade and PS-341) is a clinically effective antineoplastic drug that is FDA approved for treatment of hematologic malignancies such as multiple myeloma and mantle cell lymphoma. Low nanomolar concentrations of bortezomib inhibited infection by HSV-1, HSV-2, and acyclovir-resistant strains. Inhibition coincided with minimal cytotoxicity. Bortezomib did not affect attachment of HSV to cells or inactivate the virus directly. Bortezomib acted early in HSV infection by perturbing two distinct proteasome-dependent steps that occur within the initial hours of infection: the transport of incoming viral nucleocapsids to the nucleus and the virus-induced disruption of host nuclear domain 10 (ND10) structures. The combination of bortezomib with acyclovir demonstrated synergistic inhibitory effects on HSV infection. Thus, bortezomib is a novel potential therapeutic for HSV with a defined mechanism of action. IMPORTANCE Viruses usurp host cell functions to advance their replicative agenda. HSV relies on cellular proteasome activity for successful infection. Proteasome inhibitors, such as MG132, block HSV infection at multiple stages of the infectious cycle. Targeting host cell processes for antiviral intervention is an unconventional approach that might limit antiviral resistance. Here we demonstrated that the proteasome inhibitor bortezomib, which is a clinically effective cancer drug, has the in vitro features of a promising anti-HSV therapeutic. Bortezomib inhibited HSV infection during the first hours of infection at nanomolar concentrations that were minimally cytotoxic. The mechanism of bortezomib’s inhibition of early HSV infection was to halt nucleocapsid transport to the nucleus and to stabilize the ND10 cellular defense complex. Bortezomib and acyclovir acted synergistically to inhibit HSV infection. Overall, we present evidence for the repurposing of bortezomib as a novel antiherpesviral agent and describe specific mechanisms of action.
- In the 10 last years, the increase of international travels and immigration from low income countries to Spain was related with an increased of prevalence of parasitic diseases. Critical review of the literature. STRUCTURE: Firstly, several general considerations were made on the antiparasitic drugs revised in this paper. Chemical structures and mechanisms of action of the main drugs with antiparasitic effect were considered in the second part of the review. Further, antiparasitic spectrum of selected drugs, main pharmacokinetical characteristics, usual posology, possible side effects and contraindications were detailed. Finally, some practical aspects, such as interactions and the methods for practical obtention of these drugs are indicated. This information is relevant because in Spain many anti-parasitic drugs may be obtained using non conventional methods. In Spain, the increase of parasitic diseases necessitates an update on antiparasitics drugs for their treatment.
- The development of new drugs against Human African Trypanosomiasis is much needed due to toxicity, efficacy and availability problems with current drug treatments for this resurgent parasitic disease. Delivery of drugs into cells is an important determinant of therapeutic efficacy of drugs. An effective means of selective drug delivery is to use plasma membrane transport systems to mediate the entry of drugs into the cell. Some amino acid transporters fulfil the criteria needed for successful exploitation of nutrient transport systems for drug delivery. The Trypanosoma brucei genomic database was screened to identify the full gene repertoire of amino acid transporters. From this, candidate genes were selected and functional genetic approaches were employed to characterise candidate amino acid transporter genes. Further characterisation of TbAATP1, a RNAi cell line shown to be a transporter of small neutral amino acids (serine, glycine, cysteine, asparagine and alanine), showed a role in threonine uptake. Amino acid analogues were tested for trypanocidal activity. Of the 96 tested, two (Azaserine and Levodopa) were investigated in more detail, paying special attention to the nature of their trypanocidal action and possible route of entry through an amino acid transporter. Azaserine showed a trypanostatic action as well multiple routes of entry into the protozoan interior (as shown by inhibition of glutamine, phenylalanine and tyrosine uptake). The trypanocidal Levodopa showed entry through a tyrosine specific transporter. However, it is possible that Levodopa’s trypanocidal activity may not be as a result of the analogue itself, but secondary products of the analogue. Amino acids are important for protozoa as energy sources as well as forming pools of soluble osmolites. Amino acid usage in trypanosomes was investigated. Upregulation of proline transport and catabolism in response to reduced glucose availability was exhibited by the genome strain of T. brucei. Moreover, this metabolic shift could be mimicked by addition of GlcNAc to the medium, which blocks the hexose transporter limiting glucose entry to the cell. Systems biology approaches were initiated to investigate the undergoing metabolic changes. More specifically, mass spectrometry methodologies were employed to investigate underlying metabolite changes in procyclic form trypanosomes grown in differing medium.
- Hirsutism, the appearance of facial hair on women in a male pattern distribution, is a problem with potential medical, social, and psychological implications for millions of women. Hirsutism can reflect the presence of an underlying systemic disease, namely one that results in hyperandrogenic states, or it may seem to be idiopathic. Many methods of treatment have been used over the years, from pharmacological and surgical treatment for underlying disease to mechanical means of hair removal. We discuss hirsutism and review the clinical experience with a topical cream approved for facial hair removal, called eflornithine (Vaniqa), which acts by inhibiting new growth by an enzyme inhibition mechanism. Therapeutic trials and our clinical experience have shown promising results with this agent in diminishing unwanted facial hair in women.
- Anatomy and physiologyAlopeciaAbnormalities of hair shaftExcessive growth of hairHair pigmentationHair cosmetics
- Treatment of second-stage gambiense human African trypanosomiasis relied on toxic arsenic-based derivatives for over 50 years. The availability and subsequent use of eflornithine, initially in monotherapy and more recently in combination with nifurtimox (NECT), has drastically improved the prognosis of treated patients. However, NECT logistic and nursing requirements remain obstacles to its deployment and use in peripheral health structures in rural sub-Saharan Africa. Two oral compounds, fexinidazole and SCYX-7158, are currently in clinical development. The main scope of this article is to discuss the potential impact of new oral therapies to improve diagnosis-treatment algorithms and patients' access to treatment, and to contribute to reach the objectives of the recently launched gambiense human African trypanosomiasis elimination program.
- Although the loss of scalp hair is distressing and many medical treatments focus on its restoration, the removal of body hair has been adopted since ancient times. Beauty standards, which r eflect the culture of each society, have been presenting the depilated body as absolutely desirable. Through the ages various methods of hair removal have been used depending on the requirements of the individuals. In recent years, Laser and Intense Pulse Light devices have been considered as the most promising solution for excess hair growth, without excluding the efficacy of other methods to induce satisfactory epilatory results. The enzyme-based hair removal method has received little recognition even though experimental and clinical data support its efficacy to provide long term or even permanent epilation. The present review presents these data and examines the likelihood of considering the aforementioned method as ideal.
- Introduction. Excessive hair may present as hirsutism or hypertrichosis. Hirsutism is defined as the occurrence of excessive hair growth in women in localizations specific for men such as the chin, upper lip, abdomen, chest and thighs. Hypertrichosis is excessive hair growth associated with the transformation of the follicular hair into keratinized structure. Hirsutismmay be amanifestation ofmany systemic diseases. Treatment of hirsutism comprises pharmacological and mechanical methods. Drugs used for the therapy of hirsutism can be divided into inhibitors of androgens, antiandrogens and oral hypoglycemic agents that reduce insulin resistance. Mechanical methods include shaving, bleaching, waxing, hair removal using creams, electrolysis and laser depilation. Recently in the literature there have been reports on a new substance - eflornithine - in the treatment of hirsutism in women. Objective. Presentation of a 24-year-old woman with hirsutism, treated with eflornithine cream. Case report. The patient has a history of irregular menstrual cycles, Hashimoto's disease, hyperprolactinemia since 2004, with hypertrichosis on the face, neck, linea alba and nipples for 9 years. She was hospitalized in the Department of Endocrinology and Internal Medicine, Medical University of Gdańsk with a diagnosis of idiopathic hirsutism. She consulted a dermatologist due to severe hirsutism affecting her mental state. In the past, the patient was treated with laser therapy and electrocoagulation with no effect. Due to the patient's reluctance to undergo previous treatments and the presence of dark, heavy hair in prominent places, we decided to introduce therapy with eflornithine cream applied 2 times a day for selected areas. Treatment was continued up to 8 weeks with a recommendation for further therapy, but the patient stopped it for financial reasons (the high cost of the product). Conclusions. Treatment with eflornithine cream 2 times a day within 8 weeks caused reduction of 60% of hair on the face, nipples and abdomen, and 30% on the neck.
- Hair removal practice for cosmetic or therapy purpose has been always in existence. Humanity is constantly searching for new methods which are less painful or easier for getting clear of hair, witness animality. Eight traditional or more modern methods are chronogically studied; razor, grips, waxing strips, chemical depilatories, X-rays, electrolysis, laser epilation, inhibitors of hair growth.
- Women throughout the U.S. are trying VANIQA™ to help manage unwanted facial hair [press release
- Bristol-Myers
- Squibb
Bristol-Myers Squibb Company.Women throughout the U.S. are trying VANIQA™ to help manage unwanted facial hair [press release]. http://www.bms.com/news/press/data/fg_press_ release_1388.html. Accessed Feb 14 2001. - Cosmetic saves a cure for sleeping sickness
- Mcneil
- Jr
McNeil DG Jr. Cosmetic saves a cure for sleeping sickness. New York Times Section A, p. 1, col. 1, Friday Feb 9, 2001. - New lease on life for resurrection drug
- Tdr
TDR. New lease on life for resurrection drug [news report]. http://www.who.int/tdr/publications/tdrnews/news64/ eflornithine.htm. Accessed Feb 14, 2001. 11. Merck. http://www.merck.com/overview/philanthropy/ mectizan/contents.htm. Accessed March 21, 2001. - The purpose of this study was to determine whether the rate of DNA synthesis in human skin could be increased by UVB radiation and to determine the potential for reversing the stimulatory effects of UVB radiation by alpha-difluoromethylornithine (DFMO). Split-thickness facial skin was grafted onto athymic CD-1 Nu/Nu mice on the anterolateral dorsal surface. Following graft healing for 6 weeks, grafts were treated with 0%, 2%, or 5% DFMO (a potent inhibitor of polyamine biosynthesis) and subsequently irradiated with 0.15 J/cm2 of UVB light. Two days after UVB exposure, [3H]thymidine was injected and the grafts were dissected and counted. Ultraviolet radiation significantly increased thymidine incorporation, indicating increased DNA synthesis. The stimulatory effects of UV radiation were significantly reduced by topical application of 5% DFMO. Thus administration of DFMO most likely decreased the polyamine level and decreased the rate of DNA synthesis, which may have caused a decreased rate of epidermal proliferation. Thus the topical application of DFMO may prove beneficial for UVB exposure and other hyperproliferative states where a decrease in the rate of cell turnover might be desirable.
- Alpha-difluoromethylornithine (DFMO) inhibits polyamine synthesis and is used as an antineoplastic and antiparasitic drug. In early human trials DFMO unexpectedly caused a sensorineural hearing loss. In the current study DFMO was administered to guinea pigs to investigate its effects on organ of Corti histology and on auditory thresholds. Histologic examination revealed that DFMO caused greatest damage in the hook and first turn. Damage in the second and third turns was minimal. Animals treated for 12 weeks with DFMO differed significantly (P less than 0.05) from controls in the hook and first turn in that: 1) DFMO caused a loss of hair cells in all rows. Loss of inner hair cells was greater than that of outer hair cells. 2) The remaining outer hair cells were shorter and contained a greater number of Hensen bodies. 3) The Deiters' cell bodies were longer and this increased length was associated with the decreased length of the corresponding outer hair cells. Brainstem audiometry showed that DFMO produced a hearing loss and the magnitude of this loss increased over twelve weeks of DFMO administration.
- • α-Difluoromethylornithine is a new antineoplastic and antiparasitic drug that inhibits the synthesis of polyamines. It causes a sensorineural hearing loss in humans. We have established an animal model for α-difluoromethylornithine-induced hearing loss. The time course for onset and recovery of the hearing loss in animals was similar to that seen in humans. Electrophysiologic and histologic data suggest that the anatomic site of α-difluoromethylornithine-induced hearing loss is the organ of Corti. Unlike other drugs with ototoxic effects, the specific enzymatic site of action of α-difluoromethylornithine is known, making it a potentially important tool in auditory research. (Arch Otolaryngol Head Neck Surg. 1989;115:1234-1237)
- 26 patients with arseno-resistant Trypanosoma brucei gambiense trypanosomiasis were treated with difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, given intravenously, then orally. There was rapid disappearance of trypanosomes in the cerebrospinal fluid (CSF), gradual decrease of CSF lymphocytosis, and parallel improvement in central nervous system status. Side-effects, including diarrhoea, anaemia, and hair loss, were common but tolerable and reversible. 5 patients died during or shortly after treatment. None of the 21 patients who completed therapy has had a relapse during the 6-30 month follow-up.
- alpha-Difluoromethylornithine (RMI 71,782), a specific irreversible inhibitor of the first step in polyamine biosynthesis, that is, the formation of putrescine from ornithine by ornithine decarboxylase, cures mice infected with a virulent, rodent-passaged strain of Trypanosoma brucei brucei. This parasite is closely related to the trypanosomes that cause human sleeping sickness. The drug, which is remarkably nontoxic, was effective when administered in drinking water or by intubation. The ability of the compound to inhibit ornithine decarboxylase in vitro was demonstrated by the reduced amounts of putrescine synthesized from tritiated ornithine in Trypanosoma brucei suspensions. These observations direct attention to polyamine metabolism as a target for chemotherapy of parasitic diseases.
