Novel adamantane derivatives as multifunctional neuroprotective agents

>Magister Scientiae - MScThe pathology of neurodegenerative disorders involves multiple steps, and it is probably for this reason that targeting one particular step in a multi-step process has only yielded limited results. Nitric oxide (NO) is synthesised from L-Arginine by an enzyme known as nitric oxide synthase (NOS). Three isoforms of NOS exist, including endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). In the central nervous system (CNS), nNOS is involved in the synthesis of NO, which is involved in various neurological functions. NO is a free radical and this probably explains why an excess amount of it has been implicated in the development of neurodegenerative disorders. In the CNS, the Nmethyl- D-aspartate (NMDA) receptor in its active state allows the influx of calcium ions which activate nNOS thus increasing the amount of NO and other detrimental reactive nitrogen species within neuronal cells. Calcium entry through voltage-gated calcium channels (VGCC) may also contribute to this. Although calcium ions are important for physiological functioning, an excess is responsible for excitotoxicity, which can ultimately lead to neurodegeneration. Our aim was to synthesise a series of adamantane-derived compounds that act at multiple target sites in the neurodegenerative pathway. By conjugating benzyl and phenylethyl moieties with different functional groups (-H, -NO2, -NH2, -NHC(NH)NH2, -OCH3) to the amantadine structure, we aimed to synthesise compounds that display calcium channel and NMDA receptor (NMDAR) channel inhibition, as well as selective inhibition of nNOS. A series of compounds (-H, -NO2, -NH2, -OCH3) were obtained in yields that varied between 16.5 % and 90.25 %. These novel compounds were tested for calcium influx through VGCC and NMDAR inhibition using synaptoneurosomes isolated from rat brain homogenate against the reference compounds MK-801, NGP1-01, amantadine, memantine and nimodipine. A lack of success with the synthesis of the guanidine compounds prevented the use of the oxyhemoglobin capture assay for the determination of nNOS inhibitory activity of these compounds. The novel synthesised compounds display inhibitory activity towards VGCC and the NMDAR in the micromolar range. Further tests are recommended on compounds SE-1, SE-4, SE-11 and SE-12 as they displayed good inhibitory activity against both NMDAR- as well as ii KCl-mediated calcium influx. These novel compounds may be better therapeutic options than amantadine and memantine as they inhibit both NMDAR and VGCC-mediated calcium influx, whereas amantadine and memantine only inhibit NMDA-mediated calcium influx. These novel adamantane derived compounds may possibly serve as novel leads or potential therapeutic agents for the treatment of neurodegenerative disorders

Study protocol for a phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis [LASER-TBM] [version 1; peer review: 2 approved]

Background: Tuberculous meningitis (TBM) is the most lethal form of tuberculosis with a mortality of ~50% in those co-infected with HIV-1. Current antibiotic regimens are based on those known to be effective in pulmonary TB and do not account for the differing ability of the drugs to penetrate the central nervous system (CNS). The host immune response drives pathology in TBM, yet effective host-directed therapies are scarce. There is sufficient data to suggest that higher doses of rifampicin (RIF), additional linezolid (LZD) and adjunctive aspirin (ASA) will be beneficial in TBM yet rigorous investigation of the safety of these interventions in the context of HIV associated TBM is required. We hypothesise that increased dose RIF, LZD and ASA used in combination and in addition to standard of care for the first 56 days of treatment with be safe and tolerated in HIV-1 infected people with TBM. Methods: In an open-label randomised parallel study, up to 100 participants will receive either; i) standard of care (n=40, control arm), ii) standard of care plus increased dose RIF (35mg/kg) and LZD (1200mg OD for 28 days, 600mg OD for 28 days) (n=30, experimental arm 1), or iii) as per experimental arm 1 plus additional ASA 1000mg OD (n=30, experimental arm 2). After 56 days participants will continue standard treatment as per national guidelines. The primary endpoint is death and the occurrence of solicited treatment-related adverse events at 56 days. In a planned pharmacokinetic (PK) sub-study we aim to assess PK/pharmacodynamic (PD) of oral vs IV rifampicin, describe LZD and RIF PK and cerebrospinal fluid concentrations, explore PK/PD relationships, and investigate drug-drug interactions between LZD and RIF. Safety and pharmacokinetic data from this study will inform a planned phase III study of intensified therapy in TBM. Clinicaltrials.gov registration: NCT03927313 (25/04/2019