Medical Research
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BIOHISTORY for Dr Ashraf Virmani from Uganda, UK, USA and ITALY
A number of techniques cab be used for pharmacological research and drug-development e.g. cell culture of pituitary cells, brain and ganglionic neurons, as well as endothelial cells and specific neuronal and muscle cell lines. Other methods include; immunostaining methods- NSE for neuronal or GFAP for glial; perifusion technique to measure neurotransmitter and hormone release; receptor binding and uptake assays for neurotransmitters, hormones and drugs; radioimmunoassays for hormones. The main projects undertaken were for discovering drugs for: 1. neuroprotection, 2. acting on the hypothalamo-pituitary-organ axis, 3. affecting the uptake and release of neurotransmitters and 4. drugs effective on differentiation and proliferation of neuronal and glial cells.
Presently as clinical regulatory, working on registration of derivatives of camptothecine as anticancer agents and biotechnology products e.g. monoclonal antibody-based cancer radiotherapy kits
As
Scientific Consultant and Researcher at Sigma Tau S.p.A., Rome, Italy, set up
labs and trained technicans to screen for effective agents for the
treatment of disorders of the central nervous system (CNS) and endocrine system.
These laboratories specialized in receptor pharmacology and neuroendocrinology
but were also involved in the overall drug development effort of the company.
As
Regulatory Manager involved in all aspects of registration pharmaceutical drugs
in USA, Europe and Far East (Japan, China, India) following critical reappraisal
of all application and scientific documentation. Liaison with the partner
(subsidiary) companies and the National and European (EMEA) and US (FDA)
authorities. Provide regulatory and scientific support World-wide to the
Business Development and R & D.
A
number of collaborative projects were maintained with researchers in the
company, as well as with Public and Private Institutions within Europe and in
USA between 1987-1997, details available on request.
In
collaboration between NIH and Assay Research Inc., Laurel, MD, an enzyme-linked
immunoassay kit was developed for assaying the hormone lutenizing hormone (LH)
in blood.
As
regulatory manager, participated in number of licencing agreements for
joint-ventures and product development with other pharmaceutical companies
world-wide.
As
president of the Association of Art and Science, Rome, Italy, involved in
publicizing and growth of the Association and its activities e.g. formation and
runing of site on the internet (www.sistema.co.uk).
As Regulatory Manager product summary (SmPC), leaflet and labelling in liaison with the partner (subsidiary) companies, regulatory authorities, Business Development and marketing departments (especially clinical). . On-hand experience of International project management, CRO contracts and negotiation of licencing agreements.
Collaborative projects:
1. The secretion of GnRH from hypothalamic neurones and GT1 cell line: Action of ALC (collaboration Dr Kevin Catt, NICHD, NIH, Bethesda).
2. Use of cell lines for evaluation of oxidative damage: Action of ALC (collaboration with Dr Gary Fiskum, George Washington Univ., Washington).
3. Use of primary cells for evaluation of neurotrophic action: Efficacy of ALC (collaboration with Dr Gianluigi Forloni, Inst. Ricerche Farmacologiche, Mario Negri, Milano).
4. Use of straital, hippocampal and cerebellar primary neurones in in vitro models of neuroprotection (collaboration with Dr Robert Balaz, Netherlands Inst. Brain Res., Amsterdam).
5. Perinatal model of hypoxia-ischemia damage in rats: Action of ALC. (collaboration with Dr Robert Balaz, Netherlands Inst. Brain Res. and Dr M.A. Stasi, CNS group).
6. Characterisation of the L-carnitine transporter protein in neuronal and other cell types (collaboration with Dr Yanos Kerner, Univ. of Michigan, Lansing; Dr Baruch Kanner, Hadassah Med. School, Jerusalem and Prof N. Siliprandi & Prof M. Ciman, Padova, Dr Susan Kentroti, Univ. Colorado, Denver).
7. Characterisation of the drug-neurotransmitter interactions and potential therapeutic implications (collaboration with Prof. Donald Eccleston and Dr Elizebeth Marshall, Psychiatry Research. Unit, Univ. of Newcastle, England).
8. Characterisation of acylation/deacylation processes and phospholipid interactions in neurones (collaboration with Dr A. Arduino, Univ degli Studi G.D. Anuncio", Chieti and Dr John Hardy, St Mary's Medical School, London).
9. Protection by L-C and derivatives in other cell types e.g. hepatocytes (collaboration with Dr F. Zezza, Dept. Biochem.).
10. Analytic and pharmacokinetic information ALC, L-C and ST derivatives active on neuroendocrine system (collaboration with Dr A. Longo, Dept.of Pharmacokinetics).
11. FEB94- The possible effects of AZT, role of mitochondria in neurone function. (Dr Roberto Bisselli, DASRS, Reparto Medi.Aerona.Milit., Practica di Mare and Prof DiSimone, Univ. Aquila).
12. Expression of immediate early genes following oxidative damage: Action of ALC (collaboration with Dr Timothy Murphy, Johns Hopkins Univ., Baltimore).
13. Role of Loewy bodies in the eitiology of Alzhiemers disease. Dr Elizebeth Marshall and Prof. I. McKeith, University of Newcastle and Newcastle General Hospital.
PUBLICATIONS:
B.Sc. (Hons) Thesis
Structural analysis of the stomach lining mucus glycoprotein: form and function.
University of Newcastle-upon-Tyne, Dept. of Physiological Science, Newcastle-upon-Tyne NE1 7RU. U.K. 1981.
Ph.D. Thesis
The effects of ions and drugs on the mechanism(s) of release of gamma aminobutyric acid from rat brain. University of Newcastle-upon-Tyne, Medical library, Newcastle-upon-Tyne NE1 7RU, U.K. 1985.
Articles
1. Hardy J.A., Boakes R.J, Thomas D.J.E., Kidd A.M., Edwardson J.A., Virmani M.A., Turner J. & Dodd P.R. Release of aspartate and glutamate caused by chloride reduction in synaptosomal incubation media. J. Neurochem. 42, 875-877, 1984.
2. McDermott J.R., Virmani M.A, Turner J.D. & Kidd A.M. Peptidases involved in the catabolism of neurotensin: inhibitor studies using superfused rat hypothalamic slices. Peptides. 7, 225-230, 1986.
3. Turner J.D., Boakes R.J., Hardy J.A. & Virmani M.A. Efflux of putative transmitters from superfused brain slices induced by low chloride ion concentrations. J. Neurochem. 48, 1060-1068, 1987.
4. Virmani M.A., Stojilkovic S.S. & Catt K.J. Stimulation of LH release by GABA agonists: mediation by GABAA receptors and activation of chloride channels and voltage-sensitive calcium channels. Endocrinology. 126, 2499-2505, 1990.
5. Stojilkovic S.S., Stutzin A., Izumi S-I., Dufour S., Torsello A., Virmani M.A., Rojas E & Catt K.J. Generation and amplification of the cytosolic calcium signal during secretory responses to gonadotropin-releasing hormone. The New Biologist. 2, 272-283, 1990.
6. Stojilkovic S.S., Toshihiko I, Virmani M.A., Izumi S-I., Rojas E & Catt K.J. Dependence of hormone secretion on activation-inactivation kinetics of voltage-sensitive Ca2+ channels in pituitary gonadotrophs. Proc. Natl. Acad. Sci. (USA) 87, 8855-8859, 1990.
7. Virmani M.A., Krsmanovic L.Z., Stojilkovic S.S. & Catt K.J. Stimulatory effects of l-acetylcarnitine on the pituitary-gonadal axis in female rats. In: Major Advances in Human Female Reproduction, Eds. E.Y. Adashi and S. Mancuso. Sereno Symposium Publication. Raven Press. 73, 291-296 1991.
8. Krsmanovic L., Virmani M.A., Stojilkovic S.S. & Catt K.J. Actions of acetyl-L-carnitine on the hypothalamo-pituitary-gonadal axis in female rats. J. Steroid. Biochem. Molec. Biol. 43, 351-358. 1992.
9. Virmani M.A, Corsico N. & Arrigoni-Martelli E. Tests for evaluating the potential toxic effects of compounds on the neuroendocrine system. Review. European Bulletin of Drug Research. 1, 53-62. 1992.
10. Krsmanovic L.Z., Stojilkovic S.S., Merelli F., Dufour S.M., Virmani M.A. & Catt K.J. Calcium signaling and episodic secretion of gonadotropin-releasing hormone in hypothalamic neurones. Proc. Natl. Acad. Sci. (USA), 89, 8462-8466. 1992.
11. Virmani M.A., Dufour S., Corsico N, Catt K.J., Krsmanovic Z. & Arrigoni-Martelli E. An in vitro method for examining the effects of pharmacologically active compounds on neuropeptide secretion. Pharmacological Research 27, 57-59. 1993.
12. Arduini A, Denisova N., Virmani M.A., Avrova N., Federici G. & Arrigoni-Martelli E. Evidence for the involvement of carnitine-dependent long-chain acyltransferases in neuronal triacylglycerol and phospholipid fatty acid turnover. J. Neurochem. 62 (4), 1530-1538. 1994.
13. Virmani M.A, Conti R, Spadoni A, Rossi S & E. Arrigoni-Martelli. L-carnitine uptake into primary rat cortical cultures: Interaction with GABA. Mol. Brain Res. 25 (1-2), 105-112. 1994.
14. Krsmanovic L., Virmani M.A., Stojilkovic S.S. & Catt K.J. Stimulation of gonadotropin-releasing hormone secretion by acetyl-L-carnitine in hypothalamic neurones and GT1 neuronal cells.
Neurosci. Let. 165, 33-36. 1994.
15. Virmani M.A., Conti R., Spadoni A., Rossi S. & Arrigoni-Martelli E. Inhibition of L-carnitine uptake into primary rat cortical cultures by GABA and GABA uptake blockers. Pharmac. Res. 31 (3:4), 211-215. 1995.
16. Virmani M.A., Bisselli R., Spadoni A., Rossi S., Corsico N., Calvani M., Fattorossi A., De Simone C. & Arrigoni-Martelli E. Protective actions of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors. Pharm Res. 32, 383-389. 1995.
17. Virmani M.A., Rossi S., Conti R., Spadoni A., Arrigoni-Martelli E. & Calvani M. Structural, metabolic and ionic requirements for the uptake of L-carnitine by primary rat cortical cells. Pharm Res 33, 19-27. 1996.
18. Virmani M.A & Arrigoni-Martelli E. Hypothesis for acetyl-L-carnitine actions on the neuroendocrine system. Review. submitted, J. Endocrin. Investig. 1994.
Others submitted or under preparation for publication.
1. Stojilkovic S.S, Stutzin A., Izumi S-I., Torsello A., Virmani M.A., Dufour S., Rojas E. & Catt K.J. Initiation and amplification of the [Ca2+]i and LH responses in agonist-stimulated pituitary gonadotrophs. Submitted Proc. Natl. Acad. Sci.
2. Stojilkovic S.S., Virmani M.A., Rojas E. & Catt K.J.. Correlation between activation-inactivation kinetics of dihydropyridine-sensitive calcium channels and LH secretion in pituitary gonadotrophs. Submitted. J.B.C.
3.. Dufour S., Virmani M.A., Krsmanovic L. & Catt K.J. Role of Na+ in stimulation by GnRH of LH release from cultured rat pituitary cells. under preparation.
4.. Virmani M.A., Conti R., Spadoni A., Rossi S. & Arrigoni-Martelli E. Uptake of L-carnitine into primary rat cortical cultures: Interaction with neurotransmitters. under preparation.
5. Virmani M.A., Spadoni A., Rossi S., Russo F:, Calvani M. Abstract: Action of acetyl-l-carnitine on the neurotoxicity evoked by amyloid fragments on primary rat cortical neurones. International Symposium on Signal Transduction”, organised in honour of Dr Kevin Catt.
6. Virmani M.A., Spadoni A., Rossi S., Russo F & Arrigoni-Martelli E. Abstract: Effects of acute cold stress on serum hormone levels of growth hormone and corticosterone in male and female rats. International Symposium on Signal Transduction”, organised in honour of Dr Kevin Catt.
Abstracts
1. Boakes R.J., Dodd P.R., Edwardson J.A., Hardy J.A., Kidd A., Thomas D.J.E. & Virmani M.A. Impermeant anions cause release of transmitter candidates from synaptosomes and brain slices. J. Physiol. 346, 38P, 1983.
2. McDermott J.R., Virmani M.A. & Turner J.D. Peptidases involved in the degradation of neurotensin by brain slices. Regul. Peptides. 7, p297, 1983.
3. Boakes R.J., Turner J.D. & Virmani M.A. Quantitative studies of transmitter release induced by impermeant anions from brain slices. J. Physiol. 353, 95P, 1984.
4. Boakes R.J., Turner J.D. & Virmani M.A. Modulation by convulsants of the release of 5-hydroxytryptamine induced by low chloride concentrations. Br. J. Pharmacol. 82, 256P, 1984.
5. Turner J.D., Boakes R.J. & Virmani M.A.. Comparison of the release of three different cortical transmitters by different stimuli. Electropharmacology of the in vitro synapse. Satellite symposium of the 9th IUPHAR, St. Andrews, Scotland, p160, 1984.
6. Hardy J.A., Boakes R.J., Turner J.D. & Virmani M.A. A method for the biochemical measurement of neuronal chloride permeability. Acta. Neurol. Scanda. 69, 359-360, 1984.
7. Boakes R.J., Turner J.D. & Virmani M.A. Effects of putative anion transport inhibitors on the release of 5-hydroxytryptamine induced by low chloride superfusion. Br. J. Pharmacol. 83, 349P, 1984.
8. Stojilkovic S.S., Torsello A., Dufour S., Virmani M.A., Stutzin A., Rojas E. & Catt. Biochemical, pharmacological and electrophysiological characterization of biphasic [Ca2+]i and gonadotroph response to GnRH. Biology of Cellular Transducing Signals '89, IXth International Washington Spring Symposium. May 1989.
9. Virmani M.A. & Stojilkovic S.S.. Activation of GABAA receptors stimulates LH release from cultured rat pituitary cells. The Endocrine Society Annual Meeting, Washington, USA, p959, June 1989.
10. Stojilkovic S.S., Virmani M.A., Izumi S-I, Stutzin A., Rojas E. & Catt K.J. Agonist-induced desensitization of gonadotropin secretion results from inactivation of voltage-sensitive calcium channels. The Endocrine Society Annual Meeting, Seattle, Washington, p1255, June 1989.
11. Virmani M.A., Dufour S., Hughes C., Omeljaniuk R., Stojilkovic S.S. & Catt K.J. Purification of gonadotrophs from castrated female rats by sedimentation on ficoll gradients. Clinical Research, Eastern Meeting. New York. NY. Sept 1989.
12. Stojilkovic S.S., Virmani M.A., Izumi S-I., Rojas E. & Catt K.J. Activation-inactivation kinetics of dihydropyridine-sensitive calcium channels and regulation of LH secretion in pituitary gonadotrophs. Clinical Research, Eastern Meeting. New York. NY. Sept 1989.
13. Dufour S., Virmani M.A., Krsmanovic L. & Catt K.J. Role of Na in stimulated LH secretion from cultured rat gonadotrophs. The Endocrine Society Annual Meeting, Atlanta, USA, June 1990.
14. Krsmanovic L.Z., Dufour S.M. & Virmani M.A.. Effects of dihydropyridine calcium agonist and antagonist analogs on GnRH secretion from rat hypothalamus slices and cultured neurones. The Endocrine Society Annual Meeting, Atlanta, USA, June 1990.
15. Virmani, L.Z. Krsmanovic, S.S. Stojilkovic & K.J. Catt. Effects of L-acetylcarnitine on the pituitary-gonadal axis in female rats. International Symposium on Major Advances in Human Female Reproduction, Universita Catolica, Rome, May 1990.
16. Virmani M.A., Krsmanovic L.Z., Stojilkovic S.S., Corsico N., Arrigoni-Martelli. E. & Catt K.J. Effects of L-carnitine on serum hormonal levels in the estrus and proestrus phase in female rats. XXV National Congress of the Italian Pharmacological Society. Toarmina, Italy, October 1990. Published: Pharmacological Research, 22, 499
17. Stasi M.A., Virmani M.A., Corsico N. & Arrigoni-Martelli E. ST 789, a new immunostimulant compound; studies on the interaction with the endocrine and central nervous systems. XXV National Congress of the Italian Pharmacological Society. Toarmina, Italy, October 1990. Published: Pharmacological Research, 22, 469
18. Virmani M.A., Dufour S., Corsico N., Catt K.J., Krsmanovic Z. & Arrigoni-Martelli E. An in vitro method for examining the effects of pharmacologically active compounds on neuropeptide secretion. VI Congresso Della Societa Italiana Di Farmacognosia. Sept 91, Rome.
19. Krsmanovic L.Z., Virmani M.A., Stojilkovic S.S. & Catt K.J. Action of acetyl-l-carnitine on gonadotrophin secretion. 'Third World Congress of Gynecological Endocrinology', Madonna di Campiglio (Trentino, Italy) 9-16 February 1992. published in Gynecological Endocrinology, Vol. 6, Suppl. 1, pg. 11, 1992.
20. Virmani M.A, Conti R., Spadoni A., Corsico N. & Arrigoni-Martelli E. Effects of acetyl-L-carnitine on the secretion of neurotransmitter from brain slices under acute in vitro conditions. 2nd International Conference, Neuroendocrine and peripheral disorders of female reproductive system: pathophysiology and therapies. Capri (Italy), May 22-26, 1992.
21. Krsmanovic L.Z., Stojilkovic S.S., Merelli F., Dufour S.M., Virmani M. A. & Catt K.J. Calcium signaling and secretory response of GnRH neurones. The Endocrine Society Annual Meeting, San Antonio, Texas, p828, June 1992.
22. Virmani M.A., Spadoni A. & Arrigoni-Martelli E Effects of L-carnitine and its derivatives on hormone secretion from cultured rat pituitary cells. The Endocrine Society Annual Meeting, Las Vegas, Nevada p193, June 1993.
23. Virmani M.A., Dufour S., Spadoni A. & Arrigoni-Martelli E. Effects of furosemide, SITS and low [Cl-] on in vitro luteinizing hormone secretion. 3rd Int. Pituitary Congress, Marina Del Rey, California, June 1993.
24. Virmani M.A., Conti R., Spadoni A., Rossi S. & Arrigoni-Martelli E. Uptake of L-carnitine into primary rat cortical cultures: Interaction with GABA. Neuropsychopharmacology 9, 144S, Abs 322. Rhodes, Greece. Sept 1993.
25. Virmani M.A., Conti R., Spadoni A., Rossi S. & Arrigoni-Martelli E. Specific inhibition of L-carnitine uptake into primary rat cortical cultures by GABA and GABA uptake blockers. Brit J Pharm 1994; 111: 333P.
26. Virmani M.A., Spadoni A., Rossi S. & Arrigoni-Martelli E. Effects of acetyl-L-carnitine on serum levels of Growth Hormone and Corticosterone in male and female rats following acute cold-stress. The Endocrine Society Annual Meeting, Anaheim, California, June 1994.
27. Virmani M.A., Spadoni A., Conti R., Rossi S. & Arrigoni-Martelli E. Action of L-carnitine and its L-isobutyrlcarnitine pivaloyl oxymethyl ester derivative (ST 812) on uptake and release of GABA by rat cortical cells. The Endocrine Society Annual Meeting, Anaheim, California , June 1994.
28. Virmani M.A., Bisselli R., Spadoni A., Rossi S., Corsico N., Calvani M., Fattorossi A., De Simone C. & Arrigoni-Martelli E. Protective actions of acetyl-L-carnitine on neurotoxicity evoked by mitochondrial uncoupling or inhibitors in primary rat cortical cultures, Abstract. Neurodegenerative Diseases 95, Molecular and cellular mechanisms and therapeutic advances, Washington May 15-17, 1995.
29. Bisselli R., Virmani M.A., De Simone C., Spadoni A., Rossi S., Corsico N., Calvani M., Arrigoni-Martelli E. & Fattorossi A. Effect of L-carnitine in preventing mitochondrial inhibitor-associated damage in neuronal cells, Abstract. Neurodegenerative Diseases 95, Molecular and cellular mechanisms and therapeutic advances, Washington May 15-17, 1995.
30. Virmani M.A., Denisova N., Russo F., Arduini A., Spadoni A., Arrigoni-Martelli E. & Calvani M. Endogenous carnitine levels and carnitine palmitoyl transferase (CPT) activity in cultured rat cortical neurones at different ages of development. 8th European College of Neuropsychopharmacology (ECNP) Congress, Venezia. Sept 30-Oct 4 1995.