Antiretroviral activities of acyclic nucleoside phosphonates [9-(2-phosphonylmethoxyethyl)adenine, 9-(2-phosphonylmethoxyethyl)guanine, (R)-9-(2-phosphonylmethoxypropyl)adenine, and MDL 74,968] in cell cultures and murine sarcoma virus-infected newborn NMRI mice

Abstract

From a side-by-side comparative study, the acyclic nucleoside phosphonates (R)-9-(2-phosphonylmethoxypropyl)adenine [(R)-PMPA] and 9-(2-methylidene-3-phosphonomethoxypropyl)guanine (MDL 74,968) proved more selective in their inhibitory effect on human immunodeficiency virus types 1 and 2, feline immunodeficiency virus, and Moloney murine sarcoma virus (MSV) in cell cultures than the 9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA) and guanine (PMEG). In particular, PMEG proved quite toxic. PMEA, (R)-PMPA, and MDL 74,968 afforded a marked delay in MSV-induced tumor initiation in MSV-infected newborn NMRI mice and substantially delayed associated animal death at doses as low as 4 to 10 mg/kg of body weight. Treatment of the NMRI mice with PMEA, (R)-PMPA, and MDL 74,968 at 25 or 50 mg/kg resulted in a high percentage of long-term survivors.

Hydroxyurea Enhances the Activities of Didanosine, 9-[2-(Phosphonylmethoxy)ethyl]adenine, and 9-[2-(Phosphonylmethoxy)propyl]adenine against Drug-Susceptible and Drug-Resistant Human Immunodeficiency Virus Isolates

“…The experimental human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitors 9- [2-(phosphonylmethoxy) ethyl]adenine (PMEA) and 9-[2-(phosphonylmethoxy)propyl] adenine (PMPA) are acyclic phosphonate analogs of AMP (3,26,32). Although they already contain a single phosphate, PMEA and PMPA, like other nucleoside analogs, rely on intracellular kinases for phosphorylation to their active diphosphate forms (27,28).…”

Applications of the FIV Model to Study HIV Pathogenesis

“…Furthermore, opportunistic infections detected in HIV-positive individuals are paralleled in feline oral disease syndromes [35,[222][223][224][225][226][227][228][229][230][231], and feline tonsillar tissues (palatine, pharyngeal, and lingual tonsils) are analogous to those in humans [216]. Coupled with recent advances in new generation cART protocols available for use in cats [232][233][234][235], the domestic cat model of FIV presents an easily manipulated animal model to evaluate drivers of immune dysfunction and microbial dyscrasias during HIV infection using a controlled in vivo study design. [236], and animals did not have overt, visual signs of clinical periodontitis at the time of sampling.…”

Treatment of blood flow abnormality using mucosal delivery of nitric oxide

“…To date, diethylenetriamine diazeniumdiolate (DETA NONOate) and S-nitrosoglutathione (GSNO) have been widely used as NO donors since they spontaneously release two equivalents of NO at a reliable first-order rate through the hydrolysis process [51]. Since the decomposition of DETA NONOate or GSNO is nearly instantaneous at pH of 5.0 or less, the NO donor should be stabilized under acidic Drug concentrations in IVS 10 −9 -10 −6 mol/L The concentrations of drug within 2 min of initial application define the minimum effective concentration for cell migration [21,22] Loading weight of IVS 1.5, 3.0, and 4.5 g The loading weight of IVS determines the volume effects of IVS on the drug release rate [23] Flow rate of VFS 3, 4, and 5 ml/h The flow rate of VFS reflects the physiological secretion rate (30-60 mg/day) of vaginal mucus at the different phases of the menstrual cycle [24,25] pH of VFS 4.0, 5.5, and 7.4 Normal pH range of vaginal secretion is 3.0∼5.5. Menstrual and cervical secretions and semen act as alkalizing agents to increase the vaginal pH [26,27] Speed of rotation 0, 2.5, and 5 rpm The dynamic movement was added on the system by shaking and rotating from vertical to horizontal position at various speeds [28,29] Site of application 7.5, 10, and 15 cm The loaded position of IVS determines the time required to achieve the effective NO concentration at the application site [30] IVS intravaginal system (i.e., drug delivery system), SVS simulating vaginal system (i.e., simulated organ for in vitro study), VFS vaginal fluid stimulant (i.e., synthetic vaginal fluids) environment for a prolonged delivery of NO.…”