Safety Study of the Effect of Scelectium Tortuosum (as Zembrin®)in Aged Normals
Condition: Adverse Mental/Physical Effects of Low Dose S. Tortuosum.
Study type: Interventional
Phase: Phase 1

Summary: 
      Phosphodiesterase is a candidate for the Rx & prevention of cognitive and psychotic
      disorders. Since caffeine targets primarily PDE4(Phosphodiesterase subtype 4), caffeine
      analogs have been developed to mimic the actions of caffeine's ability to inhibit PDE-a,
      PDE4, PDE5 and adenosine-2 (AD-2)but are limited by the side effects of insomnia and
      heightened anxiety. Sildenafil (PDE-5 inhibitor) fails to enhance cognition in schizophrenia.

      The study of PDE-4 in cognition in Alzheimer's dementia and schizophrenia has been done using
      the PDE-4 prototypal compound, rolipram, which improves cognition in rodents. Rolipram
      reverses the memory deficits induced by amyloid fragment Abeta25-35 and Abeta1-40 peptide. In
      humans the frequent side effect of vomiting hampers translational research. The clinical
      trial of rolipram in multiple sclerosis was terminated prematurely due to serious adverse
      events with paradoxical increases in MRI MS-specific brain lesions. However, PDE-4 remains
      paradigm for cognition.

      Another strategy is chemical moieties capable of antagonizing the PDE-4 through allosteric
      modulation, rather than direct competitive inhibition hoping to minimize adverse events while
      retaining the biological potencies and functional responses of PDE-4 Modulators. Dietary
      supplements with PDE-4 effects have advantages in that small investments are needed to
      adequately study them.

      Pharmacologically active chemicals of Sceletium species are mesembrine-type alkaloids that
      have proven PDE-4 activity. The PDE-4D knockout mice have enhanced memory function mediated
      through hippocampal neurogenesis via phosphorylated cAMP response element binding protein
      (pCREB) signaling.

      This study purpose is to delineate the relationship of PDE-4 and cognition in normals. pCREB
      is possibly the putative biomarker of PDE-4 response with CREB as effector signaling pathway
      of PDE-4. CREB is close to nuclear receptors represented by BDNF (Brain Derived Neurotrophic
      Factor) and PPAR (Peroxisome Proliferator Activating Receptor) complexes. CREB changes in
      neuronal plasticity are targets for pharmacological paradigms for cognitive enhancement. This
      study will use the scelectium tortuosum as manufactured as Zembrin®. The findings in control
      subjects will form the basis for designing future studies of Zembrin® in neurodegenerative
      disorders with marked cognitive impairment such as Alzheimer's Dementia and Parkinson's
      Disease.
    

Detailed description: 
      1. Contextual Background For the past decade, converging evidence suggests that targeting PD
      Phosphodiesterase for cognition represents novel heuristic approaches for development of
      dietary supplements and drug candidates for the treatment and prevention of cognitive and
      psychotic disorders.

        1. . The earlier findings on caffeine as the prototypal PD inhibitor targeting primarily
           PDE4 (Phosphodiesterase subtype 4) has stimulated synthesis of caffeine analogs to
           improve upon the pharmacokinetic profile and benefits/risk ratio.

        2. . The dual actions of caffeine as inhibitor of PDE-a, PDE4 and PDE5 and adenosine-2
           (AD-2) antagonist, exerts multiple brain-behavior functions including sleep, cognition,
           memory and learning. It remains to be seen whether caffeine analogues live up the
           therapeutic potential in neurodegenerative diseases while bypassing the side effects of
           insomnia and heightened anxiety. Sildenafil (Viagra R) PDE-5 inhibitor indicated for
           erectile dysfunction (ED) fails to enhance cognition in schizophrenia

        3. . The full dosage range may not have been explored in the study with sildenafil. It is
           noteworthy that PDE-5 inhibition is related to NMDA (N-methyl-d-aspartic acid)
           glutamatergic modulation.

           In conducting a Pub Med search of recent studies point to the role of PDE-4 in diverse
           domains of cognition: memory, attention, executive function, recall, visual-spatial
           tasks. We find converging evidence targeting PDE-4 as the novel approach towards
           treating the cognitive deficits in Alzheimer dementia and schizophrenia

        4. . Most of the preclinical studies focus exclusively on the PDE-4 prototypal compound,
           rolipram. Rolipram improves memory consolidation, working memory and information
           processing in rodent species subjected to a variety of cognitive tasks: radial arm maze,
           passive avoidance, delayed arm water maze

        5. . A very recent study found that rolipram, reverses deficits induced by amyloid fragment
           Abeta25-35 and Abeta1-40 peptide in the Morris water maze and passive avoidance task

        6. . In preclinical screening of PDE-4 inhibitors, vomiting mediated via activating the
           area postema has been consistently noted. Tolerability and safety has hampered
           significantly the translation research in PDE-4 inhibitors. The clinical trial of
           rolipram in multiple sclerosis was terminated prematurely due to serious adverse events
           with paradoxical increases in MS-specific brain lesions identified by MRI

        7. . Notwithstanding the challenges in translational research, the molecular template of
           PDE-4 remains a highly viable paradigm for cognition.

           Drug Design has adopted another strategy in developing chemical moieties capable of
           antagonizing the PDE-4 pharmacological effects. Through allosteric modulation, rather
           than direct competitive inhibition at the catalytic site domain of PDE-4, the hope is to
           minimize the adverse events while retaining the biological potencies and functional
           responses relevant to the pharmacological activities of PDE-4 compounds.

        8. . The emergence of PDE-4 Modulators (PDE-4M) has attracted attention. Dietary
           supplements possessing the molecular templates and requirements in PDE-4 design strategy
           have added advantages in that preliminary clinical studies can be undertaken with a
           disproportionately small investment. If the preliminary results are favorable, strategic
           advances to GMP patented drug candidates are more predictable and confer less fiscal and
           clinical risks without compromising the efficacy stipulation in satisfying FDA criteria
           for phase II and Phase III trials.

           Our study the Zembrin® formulation of Scelectium Toruosum in cognition expands on an
           earlier study protocol which investigated the effects of Zembrin® in Generalized Anxiety
           Disorder (GAD). The pharmacologically active chemicals from the Sceletium species belong
           to mesembrine-type alkaloids; the structures are well characterized. Structure-activity
           relationship of the mesembrine-derivative alkaloids has been delineated in in-vitro
           assay of recombinant PDE-4 regarding the relative potencies in producing the functional
           responses. The IC50 of mesembrine-HCL is determined to be 20 microM

        9. . The PDE-4D knockout mice model provides evidence of enhanced memory function is
           mediated through hippocampal neurogenesis via phosphorylated cAMP response element
           binding protein (pCREB) signaling.

       10. . Microinfusion of lentiviral vectors carrying micro RNAs targeting the long-form of
           PDE4D isoforms directly into bilateral dentate gyrus of the hippocampus in the mice
           resulted in improved performance scores in object recognition test, water maze and
           radial arm maze.

           These considerations lead us to organize a pilot "proof-of-concept study" to delineate
           the relationship of PDE-4 and cognition in normal control subjects to validate the
           target of PDE-4 in modulating cognition functions in normal control subjects. It is
           noteworthy that none of the preliminary studies include measure of cAMP signaling in
           clinical subjects to correlate with brain-behavior interactions. With the availability
           of sensitive, reliable and valid ELISA method of assaying for pCREB, we consider it
           important to examine pCREB as the putative biomarker of PDE-4 response in clinical
           subjects treated with Zembrin®. There is emerging an increase of evidence in support of
           the construct that CREB as the effector signaling pathway of PDE-4, is the target of
           diverse classes of antidepressants

       11. . CREB is the late molecular partner to the family of nuclear receptors represented by
           BDNF (Brain derived neurotrophic factor) and PPAR (Peroxisome Proliferator Activating
           Receptor) complex

       12. . CREB reflects changes in neuronal plasticity and is sensitive to pharmacological
           paradigms for cognitive enhancement. CREB signaling integrates signal transduction from
           related neurotransmitters and neuromodulators besides PDE-4. Neuronal alpha-7 nicotinic
           receptor agonist A-582941 exerts its cognitive effects through interacting with
           phosphorylation of CREB pathway (13). The findings in control subjects will form the
           rational basis for designing controlled studies of Zembrin® in neurodegenerative
           disorders with marked cognitive impairment such as Alzheimer's Dementia and Parkinson's
           Disease.
    

Intervention name(s): Scelectium Tortuosum
Intervention type(s): Dietary Supplement
Intervention description(s): One arm has subjects 3 weeks on Scelectium Tortuosum 25gm po/d then 3 weeks off and then 3 weeks on Placebo.
The other arm has subjects 3 weeks on placebo, then 3 weeks off and then 3 weeks on Scelectium Tortuosum 25mg po/d.
Other intervention name(s): Zembrin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Keywords: CNSVS; Tower of London; Letter-Number Test; Trail Making Test; Vital signs; Mood; Suicidal ideation; ECG; Physical exam; Blood; Urine (Including pregnancy and drug screen); Cytokines; Side effects; Brief Psychiatric Rating Scale; Positive and Negative Symptom Scale