Thursday, 17 January 2013

Nicotinamide: An Oral Antimicrobial Agent with Activity against Both Mycobacterium tuberculosis and Human Immunodeficiency Virus

Coinfection with Mycobacterium tuberculosis and human immunodeficiency virus (HIV) is responsible for one-third of all deaths due to acquired immunodeficiency syndrome. More than 99% of cases of HIV-M. tuberculosis coinfection occur in the developing world, where limited resources add urgency to the search for effective and affordable therapies. Although antimicrobial agents against each of these infections are available, single agents that have activity against both M. tuberculosis and HIV are uncommon. The activity of nicotinamide has been evaluated in 2 different eras: in anti-M. tuberculosis studies performed during 1945–1961 and in anti-HIV studies performed from 1991 to the present. This review brings together these 2 bodies of inquiry and raises the possibility that, with more study, this small molecule could emerge at the beginning of the 21st century either as a therapeutic agent in itself or as the lead compound for a new class of agents with activity against both M. tuberculosis and HIV.

The story of nicotinamide's antimycobacterial capacity is unknown to many, because the literature predates the careers of most people currently involved in the treatment of these infections as well as the National Institutes of Health PubMed database [1]. In 1945, the first trials of streptomycin that involved humans were taking place in the United States [2], and a worldwide search for other effective anti-Mycobacterium tuberculosis therapies was underway. That year, in Paris, Ernst Huant [3] reported a serendipitous discovery regarding the use of nicotinamide for the treatment of patients undergoing radiation therapy for “lung tumors.” He found that nicotinamide therapy, which he had initiated in an attempt to protect patients' mucous membranes from the effects of radiation, shrunk those lung infiltrates that were caused by M. tuberculosis. This report complemented another report from France by Chorine [4], who suggested a new role for nicotinamide, distinct from its known vitamin effect, as an anti-M. tuberculosis therapy. McKenzie et al. [5], who apparently were screening compounds without knowledge of either Huant or Chorine's work, independently confirmed these findings.

Two structurally related compounds, pyrazinamide and isoniazid, were found to be effective anti-M. tuberculosis therapies in the period from 1945 through 1951; these discoveries were made, in part, through the use of nicotinamide as a lead compound (figure 1) [67]. Nicotinamide monotherapy resulted in clinical improvement for up to 64% of M. tuberculosis–infected patients described in published reports [8]. However, interest in nicotinamide as a treatment for M. tuberculosisfaded rapidly when one of the foremost research groups of the day reported antagonism between nicotinamide and isoniazid when they were used together as a 2-drug therapeutic regimen [9].

By the 1990s, all of this information had fallen into relative obscurity. In fact, a comprehensive review of nicotinamide's pharmaceutical effects, published in 1991 (the year of the first reported use of nicotinamide in HIV research), makes no mention of its effects againstM. tuberculosis [10].

In the past decade, 3 different hypotheses have prompted the testing of nicotinamide for use as therapy for HIV. First, several groups studied the effects of treatment with nicotinamide for HIV, giving attention to its inhibitory activity against the nuclear enzyme poly-ADP ribose polymerase (PARP) [1112]. Second, in 1995, when we reported that nicotinamide was an inhibitor of HIV [13], our hypothesis was generated out of interest in potential correlations between pellagra and AIDS [14]. Third, Cossarizza et al. [15] pursued studies of nicotinamide in the context of its antioxidant properties, and they reported inhibition of HIV-induced cellular damage. Of interest, these hypotheses were all pursued without reference to the anti-M. tuberculosis data that preceded them by 30–50 years.

Single agents with activity against both HIV and M. tuberculosis are rare. Any such agent stirs interest both as a potential therapy and as a window on pathogenesis. Although some of the nucleoside reverse-transcriptase inhibitors have been shown to have antibacterial inhibitory effects in addition to their known antiretroviral effects, this antibacterial activity does not extend to mycobacteria [16]. A number of cytokines have been shown to be significant in both infections, and therapeutic cytokine delivery for these infectious diseases is an area of active investigation [1718]. Nicotinamide is neither a reverse-transcriptase inhibitor nor a cytokine. Although nicotinamide is an inexpensive and orally available agent without significant side effects that has been in use for 65 years, there remain many unanswered questions regarding its unusual antimicrobial spectrum.

Nicotinamide As A Drug
Niacin is the generic name for 2 compounds: nicotinamide and nicotinic acid. Both nicotinamide and nicotinic acid were first used clinically in 1937, when these newly purified compounds were each shown to act as “pellagra-preventive” factors [19]. Niacin, also known as vitamin B3, is considered part of the B vitamin complex. Niacin can either be synthesized in the body or acquired directly from dietary sources; in fact, by some definitions, niacin is not a vitamin, given that its synthesis in the human body is achievable. The majority of preformed dietary niacin is nicotinamide, not nicotinic acid, although both compounds are readily transported across the gastrointestinal epithelium [10]. In the body, nicotinic acid is converted to nicotinamide in hepatocytes and erythrocytes, and nicotinamide can then be transported in plasma to be used by all cells for the synthesis of nicotinamide nucleotides (i.e., nicotinamide adenine dinucleotide [NAD] and nicotinamide adenine dinucleotide phosphate) [20]. To fulfill routine dietary requirements, only 20 mg of niacin is required on a daily basis. When this dietary requirement is significantly exceeded, then niacin in either form is considered to be a pharmacological agent or drug. Although nicotinamide and nicotinic acid can be used interchangeably to treat diet-associated pellagra, their other pharmacological activities often differ (table 1) [10].

A recent study of the use of nicotinamide for the treatment of HIV-positive patients confirmed that dosages of 3 g/day could be well tolerated [22]. Studies of the use of nicotinamide for the treatment ofM. tuberculosis have used similar dosages (e.g., 50 mg/kg/day) without attributable toxicity [9]. The pharmacokinetics of nicotinamide have been studied in humans; a study of twice-daily administration of oral nicotinamide in a total daily dose of 25 mg/kg revealed a plasma half-life of 3.5 h, and the mean maximum plasma concentration was 42.1 μg/mL (0.3 mM) [24].

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