Abstract:

The discovery of X-ray in 1895 was promptly followed by concerted efforts in developing contrast agents for pacification of blood vessels, hollow organs and delineation of tumors from normal tissues and diagnosis of other diseases. But these efforts have been met by challenges of adverse reactions due to mismatch of the biochemical characteristics of the contrast agents and the physiological medium of the human body.

However, research efforts have yielded remarkable progress in the quality of contrast agents in current use, while improved understanding of possible risk factors have equally necessitated procedural strategies aimed at mitigating the prevalence in medical imaging practice. Presently, the qualities of contrast media in use have drastically reduced the incidence of adverse reactions; but have not eliminated them.

This paper therefore reviews the early efforts in the development of suitable contrast media for medical imaging, identified risk factors for adverse reactions and research proven considerations for reducing the incidence in Radiography practice.

Keywords: Iodinated contrast agents, evolution, Toxicity, Radiography practice.

References:

[1.]      Almen, T. (1969). Contrast agent design: some aspects on the synthesis of water soluble contrast agents of low osmolality. J. Theor. Biol: 24,216-226.

[2.]      Almen, T. (1985). Development of nonionic contrast media. Invest. Radiol, 20: 52-59.

[3.]   American College of Radiology. (2010). Manual on contrast media version 7, (American college of Radiology, committee on Drugs and contrast media).

[4.]   Andrew, L., Robert, M.T., Richard, H., Andrew S., David, S., & Mark, D. (2013) Prevention of Contrast Induced Acute Kidney Injury (CI – AKI) in Adult Patients; Clinical Radiology of The Royal College of Radiologists.P.3.

[5.]      Ansell, G. (1990). Adverse reactions to contrast agents; Scope of problem. Invest Radiol 25: 381.

[6.]      Battaoglu, G., Balkenci, R., Tirnaksiz, B., (1994). Fatal reactions to Intra-arterial injection of non-ionic contrast medium (letter) AJR.; 162 – 231.

[7.]      Berberich, J., Hirsch, S. R. D. (1923). Roentenographische Durstellung de Arterien and Venenam Lebenden menschen. KLin Wochenschr; 2226-2228

[8.]      Brooks, B. (1923). Intra-arterial Injection of Sodium iodide, JAMA; 82: 1016-1019.

[9.]      Burd, D. A., Santis, G., Milward, T. M. (1985). Severe extravasation injury; an avoidable iotrogenic disaster? Br Med J (Clinical Res Ed); 290: 1579-1580.

[10.]   Cameron, D. (1917). Acqueous Solutions of potassium and sodium iodides as opaque media in roentgenography. JAMA, 70; 754 – 755.

[11.]   Cohan, R. H., Dunnick, N. R., Leder, R. A., Baker, M. E. (1990). Extravasation of non-ionic radiologic contrast media: Efficacy of Conservative treatment. Radiology; 176: 65-67

[12.]            Dawson, P. and Hemingway, A. P.(1987). Contrast agent’s doses in interventional radiology. J Intervent Radiol. 2: 145-146.

[13.]            Dawson, P. (1998). Contrast agents in Interventional radiography: In Advances in X-ray contrast; collection of papers. Pg. 52-56 Kluwer Academic publishers, Great Britain.

[14.]   Dickinson, M, and Kam, P. C. (2008). Intravenous contrast media and the anaesthetist; Journal of the association of Anaesthetist of Great Britain and Ireland, Wiley online library, , doi: 10.1111/j.1365-2044. 05479.

[15.]   Greenberger, F., Meyers, S., Karmer, B. (1987). Effects of beta-adrenergic and calcium antagonistson the development of anaphylactoid reactions from radiographic contrast media during cardiac angiography. J. Allergy cllnimmunol; 80:698-702

[16.]   Haschek, E., Lindenthal, T. O.(1896). EinBeitragzur Prakhschen Verwerthung der Photographic nach Rontgen Wien Klin Wochenschr; 9; 63-64.

[17.]   Katayama, H. Y., Kozuka, T., Takashima, T., Seez, P., Matsura, K. (1990). Adverse reactions to ionic and nonionic contrast media; a report from the Japanese committee on the safety of contrast media. Radiology; 175: 621 – 628.

[18.]   Lang, D., Allpern, M., Visintainer, P., Smith, S.(1991). Increased risk for anaphylactoid reactions from contrast media in patients on beta-adrenergic blocker or with asthma. Ann intern Med; 115: 270-276.

[19.]   Laroche, D., Aimon-Gastin, I., Dubois, F., et al. (1998). Mechanisms of severe, immediate reactions to iodinated contrast material, Radiology; 209: 183-190.

[20.]   Lasser, E. C., Berry, C. C., Talner, L. B., et al. (1987). Pre-treatment with corticosteroids to alleviate reactions to intravenous contrast material. N. Engl. J. Med. 317:845-819.

[21.]   Lasser, E. C. (2000). The Multipotential psuedoantigenicity of X-ray contrast media. Psuedo-antigen excess may down regulate the release of hypotensive mediators. Int. Arch Allergy Immunil. 123: 282-290

[22.]   Lautin, E. M., Freeman, N. J., Schoenfeld, A. H., et al.(1991). Radio-contrast Associated Renal Dysfunction; Incidence and Risk Factors. American journal of Roentgenology, 157, 49-58.

[23.]   Marcos, S. K, Thompsen, H. S. (2001). Adverse reactions to iodinated contrast media; European Radiology;11: 1267-75.

[24.]   McClennan, B. L. (1990). Ionic and Nonionic iodinated contrast media: Evolution and Strategies for use. AJR, 55:225-233.

[25.]   McClennan, B.. L. (1987). Low-osmolality contrast media: premises and promises Radiology, 162: 1-8

[26.]   Moniz, E. (1927). Arterial encephalography: Its Importance in the location of cerebral tumour. Rev. Neurol; 48: 72.

[27.]   Morcos, S. K.. (2005). Review Article: Acute, serious and fatal reactions to contrast media: our current understanding . Br J Radiol; 78;686-693.

[28.]   Osborne, E. D., Sulherland, C.. Scholl, A. J. Jr., Rowntree, L. G. (1980). Roentgens of the urinary tract during excretion of sodium iodide. JAMA; 368 – 373.

[29.]   Raiston, W.H Robbins, M.S., Coveney, J & Blair, M. (1989). Acute and subacute studies of Ioversol in experimental animals. Invest. Radiol, 24[suppl 1];S52-S59

[30.]   Ronald, G. G. (1998). Development of Intravascular Contrast agents; the first 100years: in Advances in x-ray contrast (collected papers), Kluwer Academic Publishers, 89-96.

[31.]            Ronald, J. Z.(1998). Iodinated contrast agents in neuro radiology: in Advances in X-ray contrast (collection of papers) P. Dawson and W. Clauss Kluwer Academic Publishers, Boston/London B.V (printed in Great Britain), pg 81-88

[32.]   Rowlands, S. (1896). Report on the application of the new photography to medicine and surgery. British J. Feb 22, 492-497.

[33.]   Sovak, M. (1984). Radiocontrast agents. Berlin , Springer-Verlag.

[34.]   Swick, M., Darstellung der N. and Harnwege. (1929). in Roentgenbilddurch Intravenose Einbringeinesneuen Kontrast Stottes:des uroselectans. KlinWochewnshar; 8: 2087-2089.

[35.]   Swick, M. (1978). Radiographic media in urology. The discovery of excretory urography: historical and developmental aspects of the organically bound urographic media and their role in the varied diagnostic angiographic areas. Surg. Clin North Am; 58: 977-994.

[36.]   Swick, M. ( 1974). Uroradiographic media. Urology. 4, 750-757

[37.]   Thosen, H. S. and Morcos, S. K. (2003). Contrast Media and Kidney; European Society of Urogenital Radiology (ESUR) Guidelines. The British journal of Radiology.76, 513-6.

[38.]   Thrall, J. (1990). Adverse reactions to contrast media; etiology, incidence, treatment, prevention. In: Swanson, D. P., Chilton, H. M., Thrall, J. H. eds, Pharmaceuticals in Medical Imaging. New York. Macmillian, 253-277.

[39.]   Veiga-Pires, J. A., Grainger, R. G. (1982). Pioneers in angiography; the Portuguese school of angiography. Lancaster, Boston. The Hague: MTP Press;.

[40.]   Wallingford, V.H. (1953). The development of organic iodine compounds as x-ray contrast media. J Am. Pharm. Assoc. 42:721-729

[41.]   Wolf, G., Arenson, R., Cross, A.(1989). A prospective trial of ionic VS non-ionic contrast agents in routine clinical practice; comparison of adverse effects. AJR; 152: 939-944.

[42.]   Yamaguchi, K., Katayama, H., Takashima, T., Kozuka, T., Seez, P. & Matsuur, K. (1991). Prediction of severe adverse reactions to ionic and non-ionic contrast media in Japan; evaluation of pretesting. Radiology; 178: 363-4.

Abstract:

Neonatal sepsis has been identified by World Health Organisation (WHO) as one of the major causes of high morbidity and mortality in neonates [1]. It is a clinical syndrome characterised by systemic signs of circulatory compromise which is usually as a result of the invasion of the blood stream by bacteria during the first month of life [2], [3]. In Ghana where most people are in the middle or low-income range and cannot afford the cost of a blood culture investigation and considering the fact that it takes a minimum of five days for one to receive a blood culture report, there is usually the approach of empirical management of most cases of neonatal sepsis in the hospital. A request is made for blood cultures usually after treatment failure. The incidence of neonatal sepsis in the Korle-Bu Teaching Hospital is very high and this is likely due to the occurrence of predisposing factors and lack of essential facilities for optimal hygiene in most of the primary health facilities from where the patients are referred.

OBJECTIVE: The aim of this study was to evaluate the empirical management of neonatal sepsis at the Children’s Department of Korle –Bu Teaching Hospital (KBTH).

METHODOLOGY: A prospective cohort study method was used. Patients diagnosed with Neonatal sepsis were identified from the admissions and discharge records. All neonates admitted to the pediatric ward with sepsis during the period was selected and followed up over the study period (15th November, 2015 – 15th December, 2015. There was no intervention made to the management approach to the subjects during the study. All the necessary data was taken from the patients’ folders and the care givers (Clinical staff and parents of the patient) where possible. The data was collected using a specially designed data collection tool which captured data on the following; Patient characteristics, Septic screen, Case fatality, Sensitivity patterns and Pattern of antibiotic usage . The results were analysed using SPSS for Microsoft version 20 and Excel spreadsheet and presented as bar charts, pie charts and percentages.

FINDINGS: A total of 271 neonates were admitted at the study site during the period. A third of all neonatal admissions during the period were diagnosed with neonatal sepsis. 55.4% of the cases were males and the rest females. More than half of the neonates diagnosed with neonatal sepsis had septic screen conducted on them. Most of the cases (58.33%) were screened for C - reactive protein whilst less than half (40.2%) of the septic screen was for organism culture. Over half of the samples sent for organism culture yielded no growth. 48.27% yielded growth out of which only 35.71% were micro - organisms. Most of the cousative organisms were gram-negative micro-organisms. The case fatality rate of neonatal sepsis for the period was 4.17%. E-coli infection was confirmed as a cause of more than a third of death from Neonatal Sepsis. Almost all (95.83%) of the neonates diagnosed with neonatal sepsis were given empirical antibiotics. Only 4.17% of the cases had their antibiotics changed in accordance with their culture and sensitivity results.

CONCLUSION: Neonatal sepsis diagnosis at the department was usually of early onset and empirical treatment used for its management appeared effective. Most of the subjects did not have septic screen done making it impossible for microbial sensitivity and resistance patterns to be studied.

Keywords: Neonatal Sepsis, Septic Screen, Empirical Antibiotics, Culture and Sensitivity

References:

[1.]   Al-Shamahy, H.A., Sabrah, A.A., Al-Robasi, A.B. & Naser, S.M. Types of bacteria associated with neonatal sepsis in Al-Thawra University Hospital, Sena’a

[2.]   Anderson-Berry, A. L., Bellig, L. L., & Ohning, B. L. (2006). Neonatal sepsis. University of Nebraska Medical Center, Omaha

[3.]   Aurangzeb, B., & Hameed, A. Neonatal sepsis in hospital-born babies: bacterial isolates and antibiotic susceptibility patterns. Journal of the College of Physicians and Surgeons--Pakistan: JCPSP, (2003)13(11), 629-632

[4.]   Bahl, R., Martines, J., Ali, N., BHAN, M.K., Carlo, W., Chan, K.Y., & Rudan I. Research priorities to reduce global mortality from newborn infections by 2015. The Paediatric infectious disease journal (2009). 28(1) S43 –S48

[5.]   Baltimore, R. S., Huie, S. M., Meek, J. I., Schuchat, A., & O'Brien, K. L. (2001). Early-onset neonatal sepsis in the era of group B streptococcal prevention. Pediatrics, 108(5), 1094-1098.

[6.]   Baltimore, R. S. (2003). Neonatal sepsis. Pediatric drugs, 5(11), 723-740.

[7.]   Benitz, W. E., Han, M. Y., Madan, A., & Ramachandra, P. Serial serum C-reactive protein levels in the diagnosis of neonatal infection. Pediatrics, (1998)102(4), e41-e41.

[8.]   Benjamin, D. K., Miller, W., Garges, H., McKinney, R. E., Cotton, M., Fisher, R. G., & Alexander, K. A. Bacteremia, central catheters, and neonates: when to pull the line. Pediatrics, (2001) 107(6), 1272-1276

[9.]   Bizzarro, M. J., Dembry, L. M., Baltimore, R. S., & Gallagher, P. G. (2008). Changing patterns in neonatal Escherichia coli sepsis and ampicillin resistance in the era of intrapartum antibiotic prophylaxis. Pediatrics, 121(4), 689-696.

[10.]      Bryce, J. Boschi- Pinto, C., Shibuya, K., Black, R.E, WHO child health Epidermiology reference Group. WHO estimates of the causes of death in children. The Lancet (2005), 365(9465) 1147-1152

[11.]      Calfee, D. P., & Farr, B. M. Comparison of four antiseptic preparations for skin in the prevention of contamination of percutaneously drawn blood cultures: a randomized trial. Journal of clinical microbiology (2002),40(5), 1660-1665

[12.]      Darmstadt, G.L. Bhutta, Z.A, Causes, S., Adam, T., Walker, N de Bemis, L., & Lancet Neonatal Survival Steering Team. Evidence- based, cost effective interventions: how many newborn babies can we save? The Lancet (2005)365 (9463), 977-988.

[13.]      Edmond, K. & Zaidi, A. New approaches to preventing, diagnosing and treating neonatal sepsis PLOS medicine, (2010) 7(3) 283

[14.]      Enguix, A., Rey, C., Concha, A., Medina, A., Coto, D., & Diéguez, M. A. (2001). Comparison of procalcitonin with C-reactive protein and serum amyloid for the early diagnosis of bacterial sepsis in critically ill neonates and children. Intensive care medicine, 27(1), 211-215.

[15.]      Hengst, J. M. (2003). The role of C-reactive protein in the evaluation and management of infants with suspected sepsis. Advances in Neonatal Care,3(1), 3-13.

[16.]      Iregbu, K.C, Elegba, O.Y ., & Babaninyi, I.B, Bacteriological profile of Neonatal septicaemia in a tertiary hospital in Nigeria, African health sciences (2006) 6(3), 151-154

[17.]      Klein, J. O. (1990). Bacteriology of neonatal sepsis. Pediatr Infect Dis J, 9(10), 778.

[18.]      Krediet, T., Gerards, L., Fleer, A., & van Stekelenburg, G. (1992). The predictive value of CRP and I/T-ratio in neonatal infection. Journal of Perinatal Medicine-Official Journal of the WAPM, 20(6), 479-485.

[19.]      Kumhar, G.D., Ramachandran, V.G.& Gupta, P Bacteriological analysis of blood culture isolates from neonates in a tertiary care hospital in India, Journal of Health, Population and Nutrition (2002), 343-347

[20.]      Lanari, M, Lazzararotto, T., Pignatelli, S., Guerra, B., &Serra, L. Epidemiology of Neonatal infections. Journal of chemotherapy (Florence, Haly) (2007) 19,20-23.

[21.]      Lawn J.E. Cousens, S. Zupan., J., & Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: when? Where? Why? The Lancet (2005)365(9462), 891-900

[22.]      Mokoulu, O.A., Jiya N., & Adesiyun, O.O Neonatal Septicaemia in Ilorin: bacterial pathogens and antibiotic sensitivity pattern. Africa Journal of medicine and medical sciences (2002), 31(2)127-130

[23.]      Nizet, V., & Klein, J. O. (2011). Bacterial sepsis and meningitis. Infectious diseases of the fetus and newborn.

[24.]      Rahman, S., Hameed, A., Roghani, M. T., & Ullah, Z. Multidrug resistant neonatal sepsis in Peshawar, Pakistan. Archives of Disease in Childhood-Fetal and Neonatal Edition, (2002) 87(1), F52-F54

[25.]      Rodrigo, I. (2009). Changing patterns of neonatal sepsis. Sri Lanka journal of child health, 31(1).

[26.]      Seale, A. C., Blencowe, H., Manu, A. A., Nair, H., Bahl, R., Qazi, S. A., ... & Lawn, J. E. (2014). Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. The Lancet infectious diseases, 14(8), 731-741.

[27.]      Simon, L., Gauvin, F., Amre, D. K., Saint-Louis, P., & Lacroix, J. (2004). Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clinical Infectious Diseases, 39(2), 206-217.

[28.]      Simonsen, K. A., Anderson-Berry, A. L., Delair, S. F., & Davies, H. D. (2014). Early-onset neonatal sepsis. Clinical microbiology reviews, 27(1), 21-47.

[29.]      Sivanandan, S., Soraisham, A. S., & Swarnam, K. (2011). Choice and duration of antimicrobial therapy for neonatal sepsis and meningitis. International journal of pediatrics, 2011.

[30.]      Stoll B.Y., The global impact of neonatal infection. Clinics in perinatology (1997), 24(1), 1-21

[31.]      Tarlow, M.J, Epidemiology of Neonatal Infections Journal of Antimicrobial chemotherapy .(1994)34(suppl. A)43-52

[32.]   Thaver, D.,& Zaidi, A.K. Burden of neonatal infections in developing countries: a review of evidence from community –based studies. The paediatric Infectious disease journal (2009), 28(1), S3-S9

[33.]   Vergnano, S., Sharland, M., Kazembe, P., Mwansambo, C., & Heath, P. T. (2005). Neonatal sepsis: an international perspective. Archives of Disease in Childhood-Fetal and Neonatal Edition, 90(3), F220-FF224.

[34.]   Yemen and their antimicrobial profile, Sultan Qaboos University medical journal, (2012) 12(1),48

[35.]   Zaidi, A. K., Thaver, D., Ali, S. A., & Khan, T. A. (2009). Pathogens associated with sepsis in newborns and young infants in developing countries. The Pediatric infectious disease journal, 28(1), S10-S18.

Abstract:

We present a young female who developed bilateral cavernous sinus thrombophlebitis after a week’s history of a single acne-like lesion or furuncle over the right lateral ala of the nose which she had squeezed. She was managed aggressively with intravenous antibiotics, heparin and a sliding scale of insulin. Signs and symptoms improved after 2 weeks of treatment, and she was discharged from hospital on an oral anticoagulant.

Keywords: Bilateral Cavenous Sinus Thrombosis, Proptosis, Ophthalmoplegia, Nasal Furunculosis, Facial cellulitis

References:

[1.] Absoud M, Hikmet F, Dey P, Joffe M, Thambapillai E, ‘Bilateral cavernous sinus thrombosis complicating sinusitis’. J R Soc Med. (2006), 99, pp.474–476.

[2.] Baidya K. Bhaduri G, Mondal LK, ‘Atypical presentation of a unilateral septic thrombosis of cavernous sinus’. J. Indian Med Association. (2005), 103, pp.437-8.

[3.] Canon ML, Antonio BL, McCloskey JJ, ‘Cavernous sinus thrombosis complicating sinusitis’. Paiatr Crit Care Med. (2004), 5(1), pp.86-8.

[4.] Chacar-Rabay H, Hejeily RK, Aouad A, ‘Cavernous sinus thrombosis. Late diagnosis and complications’. JM ed Liban. (1998), 4, 6pp.218-21.

[5.] Hollinshead WH, ‘Anatomy of Surgeons’, The Head and Neck. New York, USA: Harper & Row. (1968).

[6.] Hom. Milton M, Bielory Leonard, ‘The anatomical and functional relationship between allergic conjunctivitis and allergic rhinitis. Allergy and Rhinology’. (2013), 4(3), pp.110-119.

[7.] Komatsu H, Matsumoto F, Kasai M, Kurano K, Sasaki D and Ikeda K, ‘Cavernous sinus thrombosis caused by contralateral sphenoid sinusitis: a case report’. Head & Face Medicine. ( 2013), pp. 9-9.

[8.] Okamoto H, Ogata A, Kosugi M, ‘Cavernous sinsus thrombophlebitis related to dental infection-two case reports’. Neurol Med Chir. (2012), 52(10), pp.757-60.

[9.] Osborn AG, ‘Craniofacial venous plexuses: Angiographic Study’. AJR. (1981), 136, pp.139-143.

[10.] Radulescu L, Poita I, Curca I A, ‘Thrombophlebitis of left cavernous sinus secondary to acute right sphenoid sinusitis’. Rev Med Chir Soc Med Nat lasi. (2005), 109, pp.573-6.

[11.] Rajesh V, Vivek J, Rakesh KS, Hari R, and Uma SPl, ‘Bilateral cavernous sinus thrombosis and facial palsy as complications of dental abscess’. Natl J Maxillofac Surg. (2013), 4(2), pp. 252–255.

[12.] Rohana AR, Rosli MK, Nik Rizal NY, Shatriah I and Wan Hazabbah WH, ‘Bilateral Ophthalmic Vein Thrombosis Secondary to Nasal Furunculosis’. Orbit. (2008), 27, pp.215-217.

[13.] Scheinfeld NS, ‘Obesity and dermatology’. Clin Dermatol. (2004)), 22(4), pp.303-9.

[14.] Sofferman RA, ‘Cavernous sinus thrombophlebitis secondary to sphenoid sinusitis’. Laryngosope. (1983), 93, pp.797-800.

[15.] Yarington CT, ‘Cavernous sinus thrombosis revisited’. Proc R Soc med. (1977), 70, pp.456-459.

[16.] Zetola N, Francis JS, Nuermberger EL, ‘Community-acquired meticillin-resistant Staphylococcus aureus: an emerging threat’. Lancet Infect Dis. (2005), 5(5), pp.275-86.

[17.] Zhang J, Stringer MD, ‘Opthalmic and facial veins are not valveless’. Clin Experiment Ophthalmology. (2010), 38(5), pp.502-10.

Abstract:

Background: Laryngomalacia is the commonest congenital abnormality of the larynx. It the most important cause of stridor in neonates and infants stridor in the main presenting symptoms. In majority of the patient seen especially in peripheral health centers clinical symptoms and signs are relied upon for the diagnosis of the condition. Flexible laryngoscopy is however the mainstay of diagnosis. Objective: The aim of this study is to compare clinical findings and endoscopic findings of laryngomalacia in department of Ear, Nose and Throat of Aminu Kano Teaching Hospital Northern Nigeria. Material and Methods: We undertook a prospective cross – sectional review of all patient with larynomalacia who presented at the department of ENT Aminu Kano Teaching Hospital between June 2012 to May 2014. Bio – data and clinical information were obtained and stridor graded. Then flexible fiber optic laryngoscopy was done on the entire patient and the stage of endoscopic grading documented. RESULT: A total of 35 children were seen during the study period and 26 met the inclusion criteria and were enrolled. There were 17 (65.4%) males and 9 (34.6%) females with a male female ratio of 2.1:1. There ages ranged from 1day to1year. The mean age at presentation was 5 ± 2.71 months. Twenty six (100%) of the children presented with different degrees of stridor. Based on, the clinical staging of stridor the degree of stridor found was 21(80.8%) had grade 1 to 2 stridor, and 5 (19.2%) had grade 3 none was found to have grade 4 stridor. Clinical assessment of the severity of the condition by the same investigators, 17 (65.4%) of the patients had mild laryngomalacia, 5 (19.2%) had moderate laryngomalacia and 4 (15.4%) had severe laryngomalacia. Objective endoscopic grading of findings in these patients showed 18 (69.2%) of the patients had grade 1 to 2, 3 (11.5%) had grade 3 and 5 (19.2%) had grade 4 to 5 laryngomalacia. Using the Spearman rho correlation coefficient test, we found a significant strong positive correlation between clinical assessment and endoscopic grading of laryngomalacia (r=0.860, P=0.000).Conclusion: clinical evaluation still has significant reliability in the diagnosis of laryngomalacia. But flexible laryngoscopy remains the mainstay of diagnosis and all patients with laryngomalacia should have flexible laryngoscopy.

Keywords: Laryngomalacia, Stridor, flexible laryngoscopy.

References:

1.Apley J: The Infant with Stridor: A follow – up Survey of 80 cases Arch Dis Child 1953; 28: 423 – 35.

2.April M. Landry and Dana M. Thompson: Laryngomalacia: - Disease presentation, Spectrum and Management; International Journal of Paediatric, Volume 2012(2012) Article ID 75356, 6 pages.

3.Bailey, Byron; Johnson, Jonas; Newlands, Shawn D: Title: Head &Neck Surgery – Otolaryngology, 4^th Edition volume one, Chapter 7, Congenital anomalities of aerodigestive tract page – 1126

4.Belmont JR, Grund fast K. Congenital Laryngeal Stridor (Laryngomalacia): Etiology Factors and Associated Disorders. Ann Otol Rhinol Laryngol 1984; 93:430 – 7.

5.Cotton RT, richson MA. Pediatric Otolaryngology. Philadelphia: WB Saunders; 1983.

6.Ferguson CF. Congenital abnormalies of the infant larynx. Otolaryngol Cli North Am 1970; 3: 185 – 200.

7.Ford GR, Irving RM, Jonas VS, Bailey CM: ENT Manifestation of Fraser Syndrome J Laryngol Otol 1992; 106:1 – 4

8.Haim Bib, MD; Ekaterina Khrolis MD; David Shoseyor, MD; MellyOhaly MD; David Ben Dor MD; Daniel London, MD; DoritAter, MD: The Prevalence of Gastroesophageal Reflux in Children with tracheosmalacia and Laryngomalacia. Chest 2001, 119 (2). 409 -413

9.Hawkins DB, Clark RW: Flexible Laryngoscopy in Neonates, Infants and Young Children. Ann Otol Rhinol Laryngol 1987; 69: 81 – 5.

10. Holinger LD, Konoir RJ: Surgical management of severe laryngomalacia. Laryngoscope 1989; 99:136 – 2.

11. Holinger PH, Johnson KC: The infant with Respiratory Stridor. Pediatr Chin North Am. 1955; 2: 4033 – 11.

12. Hollinger classification of Laryngomalacia: Classification system in paediatric ORL. www.orlforall.Com

13. Internet access: [PDF] STRIDOR www.medicine.vodiyala.edu.a//stridor. 546pm 24^th March, 2016

14.Lauren A, Kil Patrick, Jenings R Boyette , ladrry D. Hartzell, Jullen A. Norton. Prospectus quality of life assessment in laryngomalacia. International Journal of Pediatric ORL 2014 April 78(4): 583 - 7

15.Mancuso RF, Choiss, Zalzal GH, Grundfast KM. Laryngomalacia: the search for the second lesion. Arch Otolaryngol Head Neck Surgery 1996; 122:302 – 6.

16.McSwiney PF, Cavanagh NP, Languth P: Outcome in congenital Stridor (laryngomalacia).Arch Dis Child 1977; 52:215 – 8.

17. Nussbaun E, Maggi JC: Laryngomalacia in Children. Chest 1990; 98: 942.

18.Prasad J.T, Jeffrey P.S, Sukgi C, Raymond M, Deepak KM. Clinical relevance of quality of life in laryngomalacia. Laryngoscope 2015 Jul. 30.

19.Richter G.T and Thompson M.D: “The surgical management of laryngomalacia”, Otolaryngologic clinic of North America, Vol. 41, no. 5, pp 837 – 864. 2008.

20.Solomon MB, Prescott CA. Laryngomalacia: A review and surgical management for severe cases. Int J pediatrics Otoryngol 1987; 13:31 – 9.

21.Thompon D. M “Abnormal sensorimotor integrative function of the larynx in congenital laryngomalacia: a new theory of etiology”. Laryngoscope, vol. 117, no. 6, supplement pp 1 – 33, 2007

22.Zalzal GH, Anon JB, Cotton RT. Epiglohoplasty for treatment of laryngomalacia Ann Otol Rhinollaryngol 1987; 96:72

Abstract:

This review article presents the standard requirements and processes for activities which need attention during the collection of a Confidentiality agreement (CDA)/ Non-Disclosure Agreement (NDA) & Feasibility analysis from a potential investigator during the startup phase of the study. This article presents the roles and responsibilities of participants, and the importance of communication and flexibility during this phase of a study. This article is written in accordance with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonized Tripartite Guideline for Good Clinical Practice (ICH GCP Topic E6).

Keywords: Start-up, data, Protocol, Sponsor, Investigator, Site, Synopsis

References:

1. Andrea G. Procaccino. Managing Clinical Trials. New Drug Approval Process; Fourth Edition; 523-526

2. Carol Opalek & Joy Frestedt. 2009. Study Startup 101. The Monitor; Page 51 -55

3. Fundamentals of Clinical Research; SSV; Unit 5; Page 141

4. Dr. Julka. P. K. Becoming a Successful Clinical Trial Investigator; Introduction to Clinical Research;, Page 1

5. Karen E. Woodin. Coordinating Clinical Research; The Clinical Research Coordinator; Page 3-4’ 91-95

6. Karen E. Woodin & John C. Schneider. Monitoring Clinical Research; Second Edition; Page 106-111.

Abstract:

It is generally observed that triple negative breast cancer patients do not get benefited from endocrine targeted therapies. However, by a thorough Systematic review and critical analysis of the literature it could be depicted that a subset with Androgen Receptor expression could respond to anti-androgen therapies up to some extent. Presented here is a 65-years-old Postmenopausal female with a 5-year history of Carcinoma Right Breast (post-operative Chemotherapy and Radiotherapy) with bone and lung metastases, advanced, Grade III tumor diagnosed as Metastatic Adenocarcinoma on histology. This case had been presented to identify the role of Androgen Receptors in inhibiting and suppressing the tumor growth in breast oncology and to conclude that traditional Anti-Androgen therapy, that is, Bicalutamide could be considered as a differential diagnosis of Triple negative breast cancer metastatic tumors. Therefore, the present article represents some deeper insights regarding Androgen, Androgen-Receptor, Anti-Androgen drug-Bicalutamide and their role of action in the post-menopausal Triple Negative Breast cancer women with positive expression of Androgen Receptor.

Keywords: Breast, Lungs, Carcinoma, Metastasis, Bicalutamide, Androgen Receptor, Post-menopausal, Androgen, Estrogen, HER2, TNBC.

References:

1. ClinicalTrials.gov [Internet]. Xichun, Hu.: Fudan University (China). 2015 January 18- Identifier NCT02348281, Bicalutamide as A Treatment in AR-positive Metastatic Triple-Negative Breast Cancer (mTNBC) Patients; Accessed on: 2016 March 19; Available from:

https://clinicaltrials.gov/ct2/show/record/NCT02348281?term=androgen+receptor+and+bicalutamide&rank=1.

1. ClinicalTrials.gov [Internet]. Schroder, C.P.: University Medical Center Groningen (The Netherlands). 2015 August 25- Identifier NCT02697032, FDHT PET and Bicalutamide in Metastatic Breast Cancer; Accessed on: 2016 March 19; Available from:

https://clinicaltrials.gov/ct2/show/record/NCT02697032?term=androgen+receptor+and+bicalutamide&rank=2.

1. ClinicalTrials.gov [Internet]. Guan, X. : Jinling Hospital (China). 2015 January 26- Identifier NCT02353988, AR-inhibitor Bicalutamide in Treating Patients With TNBC (Arbre); Accessed on: 2016 March 19; Available from:

https://clinicaltrials.gov/ct2/show/record/NCT02353988?term=androgen+receptor+and+bicalutamide&rank=4.

1. ClinicalTrials.gov [Internet]. Memorial Sloan Kettering Cancer Center (United States). 2007 May 2- Identifier NCT00468715, Bicalutamide in Treating Patients With Metastatic Breast Cancer; Accessed on: 2016 March 19; Available from:

https://clinicaltrials.gov/ct2/show/study/NCT00468715?term=androgen+receptor+and+bicalutamide&rank=7.

1. ClinicalTrials.gov [Internet]. Memorial Sloan Kettering Cancer Center (United States). 2015 November 12- Identifier NCT02605486, Palbociclib in Combination With Bicalutamide for the Treatment of AR(+) Metastatic Breast Cancer (MBC); Accessed on: 2016 March 19; Available from:

https://clinicaltrials.gov/ct2/show/study/NCT02605486?term=androgen+receptor+and+bicalutamide&rank=14.

1. Cochrane, D.R., Bernales, S., Jacobsen, B.M., Cittelly, D.M., Howe, E.N., D’Amato, N.C., Spoelstra, N.S., Edgerton, S.M., Jean, A., Guerrero, J., Gómez, F., Medicherla, S., Alfaro, I.E., McCullagh, E., Jedlicka, P., Torkko, K.C., Thor, A.D., Elias, A.D., Protter, A.A., and Riche, J.K. (2014). Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Research, 16, R7. http://doi:10.1186/bcr3599.

2. Doane, A.S., Danso, M, Lal, P., Donaton, M., Zhang L., Hudis, C., and Gerald, W.L. (2006). An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene, 25, 3994–4008. http://doi:10.1038/sj.onc.1209415.

3. Garay, J. P., & Park, B. H. (2012). Androgen receptor as a targeted therapy for breast cancer. American Journal of Cancer Research, 2(4), 434–445. Available at:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410582/.

1. Gucalp, A., Tolaney, S., Isakoff, S.J., Ingle, J.N., Liu, M.C., Carey, L.A., Blackwell, K.., Rugo, H., Nabell, L., Forero, A., Stearns, V., Doane, A.S., Danso, M., Moynahan, M.E., Momen, L.F., Gonzalez, J.M., Akhtar, A., Giri, D.D., Patil, S., Feigin, K.N., Hudis, C.A., and Traina, T.A. (2013). Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Clin Cancer Res, 19, 5505–12. http://doi:10.1158/1078-0432.CCR-12-3327.

2. Kotsopoulos, J., Narod, S.A. (2012). Androgens and breast cancer. Steroids, 77, 1-9. http://:10.1016/j.steroids.2011.10.002.

3. Lehmann, B. D., Bauer, J. A., Chen, X., Sanders, M. E., Chakravarthy, A. B., Shyr, Y., & Pietenpol, J. A. (2011). Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. The Journal of Clinical Investigation, 121(7), 2750–2767. http://doi.org/10.1172/JCI45014.

4. Luo, X., Shi, Y.X., Li, Z.M., Jiang, W.Q. (2010). Expression and clinical significance of androgen receptor in triple negative breast cancer. Chin J Cancer, 29(6), 585-90. Available at: www.cjcsysu.cn.

5. Min Ni, M., Yiwen Chen, Y., Elgene Lim, E., Hallie Wimberly, H., Shannon, T., Bailey, S.T., Yuuki Imai, Y., David, L., Rimm, D.L., X. Shirley Liu, X.S., Myles Brown, M. (2011). Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer. Cancer Cell, 20, 119-131. http://dx.doi.org/10.1016/j.ccr.2011.05.026.

6. Rakha, E.A., El-Sayed, M.E., Green, A.R., Lee, A.H., Robertson, J.F., Ellis, I.O. (2007). Prognostic markers in triple-negative breast cancer. Cancer, 109(1):25-32. http://doi:10.1002/cncr.22381.

7. Shibahara, Y., Miki, Y., Sakurada, C., Uchida, K.., Hata, S., McNamara, K.., Yoda, T., Takagi, K.., Nakamura, Y., Suzuki, T., Ishida, T., Ohuchi, N., Sasano, H. (2013). Androgen and androgen-metabolizing enzymes in metastasized lymph nodes of breast cancer. Human Pathology, 44, 2338–2345. http://dx.doi.org/10.1016/j.humpath.2013.04.021.

8. Shipley, W.U., Hunt, D., Lukka, H.R., Major, P., Heney, N.M., Grignon, D., Patel, M., Bahary, J., Lawton, C.A., and Sandler, H.M. (2011). Journal of Clinical Oncology, 29 (7), 1. Available at: http://hwmaint.meeting.ascopubs.org/cgi/content/abstract/29/7_suppl/1.

9. Srikanth, M.V., Janaki Ram, B., Senthil Rajan, D.S., Adinarayana, G. and Ramana Murthy, K.V. (2013). Dissolution rate enhancement of bicalutamide by adsorption process. African Journal of Pharmacy and Pharmacology, 7 (21), 1357-1362. http://doi10.5897/AJPP10.073.

10. U.S. National Library of Medicine. (Updated 2016, February 24). Bicalutamide. Retrieved March 19, 2016, from Medline Plus:

https://www.nlm.nih.gov/medlineplus/druginfo/meds/a697047.html.

Abstract:

ITP scientifically known as ‘Idiopathic Thrombocytopenic Purpura’ is characterized as an uncommon benign acquired autoimmune hematologic disorder of unknown cause or etiology and normal bone marrow with acute condition in children and a chronic condition in adults which is often accompanied by symptoms such as, occasional Petechiae, Ecchymoses, excessive bleeding episodes in the form of Mucosal bleeding, spontaneous nosebleeds, bleeding from the gums, blood in the urine, blood in the stool, abnormally heavy menstruation, prolonged bleeding from cuts, and profused bleeding during surgery, with a platelet count of less than 100 × 109/L (100,000/μL). Chronic ITP was observed to be a rare disorder found to be associated with a loss of tolerance to platelet antigens and a phenotype of accelerated platelet destruction and impaired platelet production. According to the recent studies, prevalence of 1 in 5.000 was estimated with prevalence in adults and children ranging from 9.6 to 189 per 100 000 person ultimately leading ITP to be an orphan disease. Moreover, the increased risk of death was observed largely concentrated in patients 60 years of age or older. Mortality rate was observed to be very low with most of the outpatients being treated. ITP could present either alone (primary) or in the setting of other conditions (secondary) such as infections or altered immune states. This chapter of reviewed article highlighted the aspects of current understanding of definition of ITP, Pathophysiology of ITP, Diagnosis of ITP with considerable clues from genetic studies, treatment of Primary ITP with immunomodulatory mechanisms of action in ITP therapies (Evidence-based from clinical trials.gov) along with the Quality-of-Life of the ITP patients.

Keywords: ‘Immune Thrombocytopenic Purpura (ITP)’; ‘Mortality’; ‘Hemorrhage’; ‘Thrombocytopenia,’ ‘Platelet Count,’ ‘Autoimmune Thrombocytopenic Purpura,’ ‘Complete Blood Count,’ ‘Bone Marrow Examination,’ ‘Reticulocyte Count,’ ‘Antinuclear Antibody Test,’ ‘Pathophysiology,’ ‘Treatment,’ ‘Refractory disease,’ ‘Platelet response,’ ‘Thrombosis’.

References:

Abstract:

Background: Malaria continues to be a major health burden worldwide. In Ghana, Over-the-Counter (OTC) medicine sellers and community pharmacies are known private medicine outlets patients access for malaria treatment. The aim of this study was to assess the knowledge and practice on malaria control among OTC medicine sellers in the Pru, Sene West and East and Atebubu-Amantin districts in the Brong Ahafo region of Ghana. Method: A cross-sectional descriptive study was conducted using a structured questionnaire. Sixty-two (62) OTC medicine sellers were randomly selected, informed consent sought and interviewed on malaria transmission, symptoms, prevention, diagnosis and treatment, antimalarial medicine stock and malaria training participated in. Data entry, editing and analysis were done using SPSS. Results: The study revealed a high knowledge on malaria transmission vector, symptoms and prevention with 63% of the OTC medicine sellers have participated in at least one malaria training organized either by the Pharmacy council and/or partners within the past two years. Only 26.2% of OTC medicine sellers use the malaria rapid diagnostic test (RDT) kit to diagnosis and confirm suspected malaria. Majority (65.6%) of OTC medicine sellers often recommend Artemether Lumefantrine (AL) to patients to treat uncomplicated malaria, with between 26% to 43.5% of them haven herbal preparations, sulphadoxine pyrimethamine (SP), monotherapies (only artesunate, or only amodiaquine or only artemether or only lumefantrine) and quinine as the alternative antimalarial medicines at the shop. Most OTC medicine sellers do not comply with the national antimalarial drug treatment guidelines. There was a significant difference (p<0.05) between the malaria management knowledge and skills of a trained OTC medicine seller and a non trained one. Conclusion: Trained OTC medicine sellers have better malaria management knowledge and skills than the non -trained ones. Recommendation: Periodic malaria training of all OTC medicine sellers which focuses on effective diagnosis and treatment would significantly improve the knowledge and the skills in malaria management and control among OTC medicine sellers at the community level.

Keywords: Malaria, Knowledge, Practice, OTC medicine seller, Pru, Sene, Atebubu-Amantin

References:

[1.]               Addai-Mensah O,: Establishment of a phage display platform for the isolation of Plasmodium falcipurum, monoclonal antibodies, Research thesis, RWTH Aachen University: page 1, October, 2014

[2.]               Affordable Medicine Facility-malaria (AMFm) first-line buyers list, Global Fund, September, 2013.

[3.]               Ahorlu CK, Dunyo SK, Afari EA, Koram KA, Nkrumah FK: Malaria-related beliefs and behaviour in southern Ghana: implications for treatment, prevention and control. Trop Med Int Health 2: 488–499,1997

[4.]               Buabeng K.O, The Role of the Pharmaceutical Sector in malaria Control in Ghana, Faculty of Health Science, University of Eastern Finland 2010

[5.]               Cohen JC, Gyansa-Lutterodt M, Torpey K, Esmail LC, Kurokawa G: TRIPS, the Doha Declaration and increasing access to medicines: policy options for Ghana. Global Health 1: 17, 2005

[6.]               Danquah D.A , Evaluating Access to Anti-Malaria medicine and quality of Service delivery by Community Pharmacies and Licensed Chemical Shops in Ashanti Region, Ghana 2010

[7.]               FHI 360, OTC medicine sellers identification and selection exercise, Pru, Sene and Atebubu-Amantin districts, 2015, Ghana

[8.]               Gallup, JL; Sachs, JD. The economic burden of malaria. Am J Trop Med Hyg. 2001;64:85–96. [PubMed]

[9.]               Ghana district map -www.ghanadistricts.com/home) accessed on May 5^th, 2015

[10.]      Global Fund AMFm pricing , August 2010 report

[11.]      Goodman C, Brieger W, Unwin A, Mills A, Meek S, Greer G: Medicine sellers and malaria treatment in sub-Saharan Africa: what do they do and how can their practice be improved? Am J Trop Med Hyg 77 (Suppl 6): 203–218, 2007a

[12.]      Health Partners Ghana. Management of malaria by care givers and licensed chemical sellers in the Ashanti Region, Ghana. A baseline survey of the MAM Project October, 2008.

[13.]      Ministry of Health (GNDP) Ghana: Ghana national drug policy, second edition 2004. Accessed May 4^th 2015 from

http://who.int/countries/gha/publications/Ghana_National_DrugPolicy_2nd_Edition.pdf

[14.]      Pharmacy Council, Ghana: Practice standards for pharmacist and licensed chemical sellers, 2004.

[15.]      Republic of Ghana (Pharmacy ACT 489): Pharmacy Council ACT, 1994

[16.]      WHO The Roll Back Malaria strategy for improving access to treatment through home management of malaria. World Health Organization. 2005.

[17.]      World Health Organization: Guidelines for Treatment of Malaria, 2015

[18.]      World Health Organization: World Malaria Report 2015.

Abstract:

Introduction: Percutaneous injuries, caused by needle sticks and other sharps, are a serious concern for all health care workers (HCWs) and pose a significant risk of occupational transmission of blood borne pathogen. Two million injuries are believed to occur each year among HCWs. Methodology: The study group consisted of 249 HCWs of various categories of a tertiary care hospital in Khartoum, Sudan. Data collection was carried out using a standardized questionnaire. To measure knowledge, attitude and practices on needle stick injuries. Results:70% of respondents were females and around 47% of participants were nurses Half of participants attended a biosafety course, and around 90% of them followed what they was trained on in all or most of times. Most of respondents graded their knowledge about as good and the main source of knowledge was the university curriculum. In our study 46% had NSI with a mean of 6.1 injuries/year of 6.14 most of them were among nurses 40%. Almost thirty percent didn’t hear about the term post exposure prophylaxis more than 90% knew that HIV, HBV, and HIV can be transmitted through NSI. More than 83% of respondents were worried about NSI. Regarding the most recent NSI, Most of injuries occurred in the ward followed by emergency room, lab, and theatre. In half of cases the culprit was the victim himself during usage of syringe. The most common procedure associated with NSI was blood sampling. The frequent action was to wash the injury site using antiseptic solution. Almost two thirds of respondents who had NSI didn’t report it. Around 4.3% had NSI of HIV patient yet, the majority of them did not receive any medication. Out the 7 participants who had a NSI from a HBV positive patient, 5 were fully vaccinated all of which didn't check their vaccination status. Moreover, none of the 5 participants received PEP. Conclusion and recommendation: prevalence of NSI was relatively low but there were many deficient area such as checking immune status of HBV, knowledge about importance and methods of PEP, role of wearing gloves during handling needles, and procedure of reporting injuries.

HCW =health care worker NSI = needle stick injuries PEP= post exposure prophylaxis

References:

[1.]   Cullen, B.L., et al., Potential for reported needlestick injury prevention among healthcare workers through safety device usage and improvement of guideline adherence: expert panel assessment. J Hosp Infect, 2006. 63(4): p. 445-51.

[2.]   Departments, U.K.H., Guidelines on postexposure prophylaxis for healthcare workers occupationally exposed to HIV. 1997, Department of Health: London. p. 1-42.

[3.]   Desalegn, Z., Gebreselassie S, and. Asemamaw Y, Epidemiology of Needle Stick-Sharp Injuries (NSSIs) and Potential High Risk Exposures among Health Professionals in Ethiopia: Neglected Public Health Concern American Journal of Health Research, 2015. 3(5): p. 298-304.

[4.]   Gurubacharya, D. Mathura K, and. Karki D, Knowledge, attitude and practices among health care workers on needle-stick injuries. Kathmandu Univ Med J (KUMJ), 2003. 1(2): p. 91-94.

[5.]   Hauri, A.M., Armstrong G.L, and. Hutin Y.J, The global burden of disease attributable to contaminated injections given in health care settings. Int J STD AIDS, 2004. 15(1): p. 7-16.

[6.]   Ibekwe, R. and. Adam V, Injection safety practices among resident doctors in a tertiary health facility in Benin City. Nigerian journal of clinical practice, 2014. 17(4): p. 403-406.

[7.]   Kermode, M., et al., Occupational exposure to blood and risk of bloodborne virus infection among health care workers in rural north Indian health care settings. Am J Infect Control, 2005. 33(1): p. 34-41.

[8.]   Muralidhar, S., et al., Needle stick injuries among health care workers in a tertiary care hospital of India. Indian Journal of Medical Research, 2010. 131(3): p. 405.

[9.]   Osman, T., Epidemiology of sharp instruments injuries at a dental school in Sudan. International Journal of Infection Control, 2014. 10(4).

[10.]   Pruss-Ustun, A.,. Rapiti E, and. Hutin Y, Global burden of disease from sharps injuries to health-care workers. Geneva, Switzerland: WHO, 2003.

[11.]   Sari, S.Y.I., et al., Knowledge, attitude and perceived adherence with universal precautions among health care workers in the obstetrics and gynaecology department of an Indonesian teaching hospital. International Journal of Infection Control, 2011. 7(4).

[12.]   Sharma, S.,. Gupta A, and. Arora A, Knowledge, attitude and practices on needle-stick and sharps injuries in tertiary care cardiac hospital: a survey. Indian journal of medical sciences, 2010. 64(9): p. 396.

[13.]   Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis. MMWR Recomm Rep, 2001. 50(Rr-11): p. 1-52.

[14.]   (WHO), W.H.O., Standard supplies list. Universal Precautions, including Injection Safety. 2005.

Abstract:

Cancer is defined as a generic term for a large group of diseases that was observed to affect any part of the body, often characterized by abnormal rapid growth of abnormal cells. According to WHO report, Cancer was the leading cause of morbidity and mortality worldwide. The primary goal of the treatment is to cure cancer or to considerably prolong life, along with improved patient’s quality of life by palliative care, psychological support and alternative treatments. The present report focused on the use of Phytocannabis and its derivatives to alleviate the symptoms occurred due to cancer that included reduced appetite, chemotherapy-induced nausea and vomiting, radiotherapy-induced pain, nausea and vomiting in order to attenuate the disease process. Cancer, Chemotherapy and Radiotherapy-induced emesis and pain, all these mentioned factors led to the interrogation and investigation of the anti-emesis, pain relief, and mood stabilizing properties of Phytocannabis. This study presented the update on health and social consequences of Phytocannabis use, with a focus on the long-term and frequent use of medicinal Cannabis and its derivatives in alleviating the cancer related symptoms. It aimed to present the current knowledge on the impact of Phytocannabis use on health, from its impact on treating cancer related symptoms to its role in chemotherapy and Radiotherapy induced symptoms. This report evaluated the evidence on whether long-term Phytocannabis use is a contributory cause of the following health outcomes: relief from pain, nausea, vomiting, appetite, food taste, night sweats, and adverse physical and mental health effects such as mood swings, fatigue, hallucinations, postural hypotension, dizziness, mind alertness. Thus, the present paper reported of the use of Phytocannabis and its derivatives such as, Nabilone, Delta-9-THC, and Cannabis available in different forms (Oral, Inhaled, Sublingual) on the Quality of life of cancer patients who underwent Chemotherapy treatment and Radiotherapy treatment.

Keywords:‘cannabis’, ‘marijuana’, ‘cannabinoids’, ‘tetrahydrocannabinol’, ‘THC’, ‘dronabinol’, ‘cannabidiol’, ‘CBD’, ‘cannabidivarin’, ’nabilone’, ‘CBDV’, ‘cancer’, ‘chemotherapy’, ‘radiotherapy’ ,‘nausea’ ‘vomiting’, ‘pain’, ‘open-label studies’, Randomized controlled trials’.

References:

[1]     Abrahamov, A., Mechoulam, R. (1995). An efficient new cannabinoid antiemetic in pediatric oncology. Life Sciences, 56(23-24):2097-2102. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=7 .

[2]     Ahmedzai, S., Carlyle, D.L., Calder, I.T., Moran, F. (1983). Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. Br J Cancer, 48(5):657-63. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=119 .

[3]     Brisbois, T.D., de Kock, I.H., Watanabe, S.M., Mirhosseini, M., Lamoureux, D.C., Chasen, M., Macdonald, N., Baracos, V.E., Wismer, W.V. (2011). Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial. Ann Oncol., 22(9):2086-93. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=304

[4]     Cancer (Fact Sheets). Updated February 2015. Accessed on: 2016 June 1. Available from: http://www.who.int/mediacentre/factsheets/fs297/en/ .

[5]     Chang, A.E., Shiling, D.J., Stillman, R.C., Goldberg, N.H., Seipp, C.A., Barofsky, I., Rosenberg. (1981). A prospective evaluation of delta-9-tetrahydrocannabinol as an antiemetic in patients receiving adriamycin and cytoxan chemotherapy. Cancer, 47(7):1746-51. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=22 .

[6]     Chang, A.E., Shiling, D.J., Stillman, R.C., Goldberg, N.H., Seipp, C.A., Barofsky, I., Simon, R.M., Rosenberg, S.A. (1979). Delta-9-tetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. A prospective, randomized evaluation. Annals of Internal Medicine, 91:819-824. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=23 .

[7]     Chan, H.S., Correia, J.A., MacLeod, S.M. (1987). Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: a double-blind, crossover trial. Pediatrics, 79(6):946-52. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=120 .

[8]     Citron, M.L., Herman, T.S., Vreeland, F., Krasnow, S.H., Fossieck, B.E. Jr, Harwood, S., Franklin, R., Cohen, M.H. (1985). Antiemetic efficacy of levonantradol compared to delta-9-tetrahydrocannabinol for chemotherapy-induced nausea and vomiting. Cancer Treat Rep., 69(1):109-12. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=152.

[9]     Côté, M., Trudel, M., Wang, C., Fortin, A. (2015). Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial. Ann Otol Rhinol Laryngol, 125(4):317-24. doi: http://10.1177/0003489415612801. [ PubMed PMID: 26503964].

[10]  Cunningham, D., Bradley, C.J., Forrest, G.J., Hutcheon, A.W., Adams, L., Sneddon, M., Harding, M., Kerr, D.J., Soukop, M., Kaye, S.B. (1988). A randomized trial of oral nabilone and prochlorperazine compared to intravenous metoclopramide and dexamethasone in the treatment of nausea and vomiting induced by chemotherapy regimens containing cisplatin or cisplatin analogues. Eur J Cancer Clin Oncol., 24(4):685-9. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=122 .

[11]  Dalzell, A.M., Bartlett, H., Lilleyman, J.S. (1986). Nabilone: an alternative antiemetic for cancer chemotherapy. Arch Dis Child, 61(5):502-5. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=123 .

[12]  Duran, M., Pérez, E., Abanades, S., Vidal, X., Saura, C., Majem, M., Arriola, E., Rabanal, M., Pastor, A., Farré, M., Rams, N., Laporte, J.R., Capellà, D. (2010). Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. Br J Clin Pharmacol., 70(5):656-63. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=312 .

[13]  Einhorn, L.H., Nagy, C., Furnas, B., Williams, S.D. (1981). Nabilone: an effective antiemetic in patients receiving cancer chemotherapy. J Clin Pharmacol, 21(8-9 Suppl):64S-69S. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=124 .

[14]  Engels, F.K., de Jong, F.A., Sparreboom, A., Mathot, R.A., Loos, W.J., Kitzen, J.J., de Bruijn, P., Verweij, J., Mathijssen, R.H. (2007). Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel. Oncologist, 12(3):291-300. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=246 .

[15]  Epidemiology of cannabis use, disorders and treatment. Updated February 2015. Accessed on: 2016 June 1. Available from:

http://www.who.int/substance_abuse/publications/cannabis_report/en/index5.html .

[16]  Frytak, S., Moertel, C.G., O'Fallon, J.R., Rubin, J., Creagan, E.T., O'Connell, M.J., Schutt, A.J., Schwartau, N.W. (1979). Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. A comparison with prochlorperazine and a placebo. Annals of Internal Medicine, 91(6):825-830. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=5 .

[17]  George, M., Pejovic, M.H., Thuaire, M., Kramar, A., Wolff, J.P. (1983). Randomized comparative trial of a new anti-emetic: nabilone, in cancer patients treated with cisplatin. Biomed Pharmacother, 37(1):24-7. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=125 .

[18]  Gonzalez-Rosales, F., Walsh, D. (1997). Intractable nausea and vomiting due to gastrointestinal mucosal metastases relieved by tetrahydrocannabinol (dronabinol). Journal of Pain and Symptom Management, 14(5):311-314. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=35 .

[19]  Gottschling, S. (2011). Cannabinoids in children. Applied pain management and palliative care, 1:55-57. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=295.

[20]  Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence. (2009). Available from:

http://www.who.int/substance_abuse/publications/opioid_dependence_guidelines.pdf?ua=1 .

[21]  Guzman, M., Duarte, M.J., Blazquez, C., Ravina, J., Rosa, M.C., Galve-Roperh, I., Sanchez, C., Velasco, G., Gonzalez-Feria, L. (2006). A pilot clinical study of Delta(9)-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer, 95(2):197-203. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=193 .

[22]  Herman, T.S., Einhorn, L.H., Jones, S.E., Nagy, C., Chester, A.B., Dean, J.C., Furnas, B., Williams, S.D., Leigh, S.A., Dorr, R.T., Moon, T. E. (1979). Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy. N Engl J Med., 300(23):1295-7. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=126 .

[23]  Hutcheon, A.W., Palmer, J.B., Soukop, M., Cunningham, D., McArdle, C., Welsh, J., Stuart, F., Sangster, G., Kaye, S., Charlton, D. (1983). A randomised multicentre single blind comparison of a cannabinoid anti-emetic (levonantradol) with chlorpromazine in patients receiving their first cytotoxic chemotherapy. European Journal for Cancer and Clinical Oncology, 19(8):1087-90. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=132 .

[24]  Jatoi, A., Windschitl, H.E., Loprinzi, C.L., Sloan, J.A., Dakhil, S.R., Mailliard, J.A., Pundaleeka, S., Kardinal, C.G., Fitch, T.R., Krook, J.E., Novotny, P.J., Christensen, B. (2002). Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. Journal of Clinical Oncology, 20(2):567-573. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=49 .

[25]  Johansson, R., Kilkku, P., Groenroos, M. (1982). A double-blind, controlled trial of nabilone vs. prochlorperazine for refractory emesis induced by cancer chemotherapy. Cancer Treat Rev., 9 Suppl B: 25-33. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=146 .

[26]  Johnson, J.R., Burnell-Nugent, M., Lossignol, D., Ganae-Motan, E.D., Potts, R., Fallon, M.T. (2010). Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study of the Efficacy, Safety, and Tolerability of THC: CBD Extract and THC Extract in Patients With Intractable Cancer-Related Pain. J Pain Symptom Manage, 39(2):167-79. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=368 .

[27]  Johnson, J.R., Lossignol, D., Burnell-Nugent, M., Fallon, M.T. (2013). An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. J Pain Symptom Manage, 46(2):207-18. doi: http://10.1016/j. [PubMed PMID: 23141881].

[28]  Jones, S.E., Durant, J.R., Greco, F.A., Robertone, A. (1982). A multi-institutional Phase III study of nabilone vs. placebo in chemotherapy-induced nausea and vomiting. Cancer Treat Rev., 9 Suppl B: 45-8. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=156 .

[29]  Lane, M., Vogel, C.L., Ferguson, J., Krasnow, S., Saiers, J.L., Hamm, J. (1991). Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. Journal of Pain and Symptom Management,6:352-359. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=28 .

[30]  Levitt, M., Faiman, C., Hawks, R., Wilson, A. (1984). Randomized double blind comparison of delta-9-tetrahydroicannabinol (THC) and marijuana as chemotherapy antiemetics. Proceedings of the American Society for Clinical Oncology,3:91. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=29 .

[31]  Lynch, M.E., Cesar-Rittenberg, P., Hohmann, A.G. (2014). A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage, 47(1):166-73. doi: http://10.1016/j. [PubMed PMID: 23742737].

[32]  Madras, B.K. (2015). Update of Cannabis and its medical use. 37th ECDD (2015) Agenda item 6.2, available from:

http://www.who.int/medicines/access/controlled-substances/6_2_cannabis_update.pdf?ua=1&ua=1 .

[33]  Maida, V., Ennis, M., Irani, S., Corbo, M., Dolzhykov, M. (2008). Adjunctive nabilone in cancer pain and symptom management: a prospective observational study using propensity scoring. J Support Oncol., 6(3):119-24. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=176 .

[34]  Maida, V. (2008). Nabilone for the treatment of paraneoplastic night sweats: a report of four cases. J Palliat Med., 11(6):929-34. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=282 .

[35]  Maida, V. (2006). The synthetic cannabinoid nabilone improves pain and symptom management in cancer patients. Abstract presented at the San Antonio Breast Cancer Symposium on 15 December 2006, Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=177 .

[36]  McCabe, M., Smith, F.P., Goldberg, D., Macdonald, J., Woolley, P.V., Warren, R. (1988). Efficacy of tetrahydrocannabinol in patients refractory to standard anti-emetic therapy. Investigational New Drugs, 6:243-246. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=31 .

[37]  Meiri, E., Jhangiani, H., Vredenburgh, J.J., Barbato, L.M., Carter, F.J., Yang, H.M., Baranowski, V. (2007). Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin, 23(3):533-43. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=191 .

[38]  Musty, R.E., Rossi, R. (2001). Effects of smoked cannabis and oral delta-9-tetrahydrocannabinol on nausea and emesis after cancer chemotherapy: A review of state clinical trials. J Cannabis Ther, 1(1):29-42. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=256 .

[39]  Neidhart, J.A., Gagen, M.M., Wilson, H.E., Young, D.C. (1981). Comparative trial of the antiemetic effects of THC and haloperidol. International Journal of Clinical Pharmacology Research, 21: 38-42S. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=64 .

[40]  Nelson, K., Walsh, D., Deeter, P., Sheehan, F. (1994). A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia. Journal of Palliative Care, 10(1):14-18. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=52 .

[41]  Niederle, N., Schutte, J., Schmidt, C.G. (1986). Crossover comparison of the antiemetic efficacy of nabilone and alizapride in patients with nonseminomatous testicular cancer receiving cisplatin therapy. Klin Wochenschr, 64(8):362-5. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=127 .

[42]  Niiranen, A., Mattson, K. (1985). A cross-over comparison of nabilone and prochlorperazine for emesis induced by cancer chemotherapy. Amerícan Journal of Clinical Oncology, 8(4):336-40. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=128 .

[43]  Noyes, R. Jr, Brunk, S.F., Avery, D.A.H., Canter, A. C. (1975). The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clinical Pharmacology and Therapeutics, 18(1):84-89. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=17 .

[44]  Noyes, R. Jr, Brunk, S.F., Baram, D.A., Canter, A. (1975). Analgesic effect of delta-9-tetrahydrocannabinol. Journal of Clinical Pharmacology, 15(2-3):139-143. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=16 .

[45]  Orr, L.E., McKernan, J.F., Bloome, B. (1980). Antiemetic effect of tetrahydrocannabinol. Compared with placebo and prochlorperazine in chemotherapy-associated nausea and emesis. Annals of Internal Medicine, 140(11):1431-1433. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=6 .

[46]  Pomeroy, M., Fennelly, J.J., Towers, M. (1986). Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-induced emesis. Cancer Chemother Pharmacol, 17(3):285-8. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=129 .

[47]  Portenoy, R.K., Ganae-Motan, E.D., Allende, S., Yanagihara, R., Shaiova, L., Weinstein, S., McQuade, R., Wright, S., Fallon, M.T. (2012). Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain, 13(5):438-49. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=491 .

[48]  Priestman, T.J., Priestman, S.G. (1984). An initial evaluation of Nabilone in the control of radiotherapy-induced nausea and vomiting. Clin Radiol., 35(4):265-6. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=237 .

[49]  Sallan, S.E., Cronin, C., Zelen, M., Zinberg, N.E. (1980). Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. New England Journal of Medicine, 302(3):135-138. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=3 .

[50]  Sallan, S.E., Zinberg, N.E., Frei, E. (1975). Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. New England Journal of Medicine, 293(16):795-797. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=4 .

[51]  Steele, N., Gralla, R.J., Braun, D.W. Jr, Young, C.W. (1980). Double-blind comparison of the antiemetic effects of nabilone and prochlorperazine on chemotherapy-induced emesis. Cancer Treatment Report, 64(2-3):219-24. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=131 .

[52]  Strasser, F., Luftner, D., Possinger, K., Ernst, G., Ruhstaller, T., Meissner, W., Ko, Y.D., Schnelle, M., Reif, M., Cerny, T. (2006). Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-in-Cachexia-Study-Group. J Clin Oncol, 24(21):3394-400. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=195 .

[53]  Ungerleider, J.T., Andrysiak, T., Fairbanks, L., Goodnight, J., Sarna, G., Jamison, K. (1982). Cannabis and cancer chemotherapy: a comparison of oral delta-9-THC and prochlorperazine. Cancer, 50:636-645. Available from:

http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=65 .

[54]  Ungerleider JT, Sarna G, Fairbanks LA, Goodnight J, Andrysiak T, Jamison K. (1985). THC or Compazine for the cancer chemotherapy patient--the UCLA study. Part II: Patient drug preference. American Journal of Clinical Oncology, 8: 142-147. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=34 .

[55]  Vinciguerra, V., Moore, T., Brennan E. (1988). Inhalation marijuana as an antiemetic for cancer chemotherapy. New York State Journal of Medicine, 88:525-527. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=155 .

[56]  Wadleigh, R., Spaulding, G.M., Lumbersky, B., Zimmer, M., Shepard, K., Plasse, T. (1990). Dronabinol enhancement of appetite in cancer patients. Proc Am Soc Oncology, 9: 331. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=149 .

[57]  Waissengrin, B., Urban, D., Leshem, Y., Garty, M., Wolf, I. (2015). Patterns of use of medical cannabis among Israeli cancer patients: a single institution experience. J Pain Symptom Manage, 49(2):223-30. doi: http://10.1016/j. [PubMed PMID: 24937161].

[58]  Zutt, M., Hanssle, H., Emmert, S., Neumann, C., Kretschmer, L. (2006). Dronabinol for supportive therapy in patients with malignant melanoma and liver metastases. Hautarzt, 57(5):423-7. Available from: http://www.cannabis-med.org/studies/ww_en_db_study_show.php?s_id=180 .

Abstract:

The development of new drugs and medical devices takes many years and a lot of scientific research. After identifying a new molecule, which is likely to be beneficial in human disease, it must undergo rigorous trials to ensure its efficacy and safety. Regulatory bodies ensure that clinical trials are carried out in a uniformly acceptable manner, and that the results are reliable. Their main aim is to protect the individual from harm. The aim of this review article is to describe the process of drug development and clinical trials as well as the role(s) of the regulatory agencies involved. A MEDLINE search was conducted using relevant keywords to access published information on clinical trials. Other sources of information include relevant websites and publications of regulatory agencies and major textbooks. The development of a new drug or device starts from identification of the molecule in the laboratory, where it is postulated to have useful characteristics. Following rigorous animal tests, the drug is then entered into clinical trials using human subjects. Clinical trials are conducted in four phases. Regulatory agencies are involved at every stage to ensure compliance with guidelines. There are various designs of clinical trials that may be used and the appropriate design has to be chosen to produce reliable results. The appropriate statistics must also be chosen and the submission to regulatory bodies for approval must be done in a systematic and scientific manner. The International Conference on Harmonisation was convened in 1990 and has drafted good clinical practice (GCP) guidelines for clinical trials. Submission of the application for a new drug involves proper regulatory writing procedures and protocols.

Keywords: clinical trial, regulatory agencies, ICH

References:

[1.]   Bellary S, Krishnankutty B, Latha MS. Basics of case report form designing in clinical research. Perspect. Clin Res 2014; 5(4): 159-166.

[2.]   Bhatt A Quality of clinical trials: a moving target. Perspect. Clin Res 2011 ;2(4): 124-128.

[3.]   Chernick M R, Friis R H. Introductory biostatistics for the health sciences. Modern applications including bootstrap. John Wiley & Sons Inc. (2003).

[4.]   Chin, R. Y., & Lee, B. Y. (2008). Principles and practice of clinical trial medicine. Amsterdam: Elsevier/Academic Press.

[5.]   Code of Federal Regulations Annual Edition. Available from

https://www.gpo.gov/fdsys/browse/collectionCfr.action?collectionCode=CFR. Accessed 25^thMarch, 2016.

[6.]   Data and Safety Monitoring Board Guidelines. Available from

http://www.nidcr.nih.gov/Research/ToolsforResearchers/Toolkit/DSMBGuidelines.htm.

[7.]   Eypasch E, Lefering R, Kum CK, Troidl H. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ 1995; 311(7005): 619–620.

[8.]   Fleming T R. Current issues in non-inferiority trials. Stat Med 2008; 27(3): 317-332.

[9.]   Fontanarosa PB, Rennie D, DeAngelis CD. Post-marketing surveillance–lack of vigilance, lack of trust. JAMA. 2004; 292(21): 2647–2650.

[10.]   Golafshani M. Understanding reliability and validity in qualitative research. The Qualitative Report 2003; 8(4): 597 – 606.

[11.]   Guidance for industry E6 Good Clinical Practice: Consolidated Guidance. Available from

http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073122.pdf. Accessed 25th March, 2016.

[12.]   https://hub.ucsf.edu/protocol-development.

[13.]   Hulley SB, Cummings SR, Browner WS, Brady DG, Newman TB. Designing clinical research. Wolters Kluwer.

[14.]   ICH Topic E3. Structure and content of clinical study reports. Available from

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002832.pdf.

[15.]   Investigational New Drug (IND) Application. Available from

http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.htm. Accessed on 25^thJune, 2016.

[16.]   Johnson JJ, Gupta NV. Recent advances in quality management of clinical trials Int J Pharm PharmSci 2013:5(3): 34-38.

[17.]   Montgomery AA, Peters TJ, Little P. Design, analysis and presentation of factorial randomised controlled trials. BMC Med Res Method. 2003 DOI: 10.1186/1471-2288-3-26.

[18.]   Prentice R L. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 1989; 8(4): 431-440.

[19.]   Sibbald B, Roland M Understanding controlled trials; Why are randomised controlled trials important? BMJ 1998; 316(7126): 201.

[20.]   The ICH harmonised tripartite guidelines. Available from

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf.

[21.]   The Investigational Medicinal Products Dossier (IMPD). Available from http://www.impd.eu.

[22.]   Tobin John J. Walsh G. Medical product regulatory affairs. Pharmaceuticals, Diagnostics, Medical devices.Wiley-VchVerlag GmbH & Co. KGaA (2008).

[23.]   Umscheid CA, Margolis DJ, Grossman CE. Key concepts of clinical trials; a narrative review. Postgrad Med (2011) Vol 123, No 5, pp 194-204.

[24.]   Walker E. Nowacki AS. Understanding equivalence and non-inferiority testing. J Gen Intern Med 2011; 26(2): 192-196.

[25.]   Yang LJS, Chang KWC, Chung K C. Methodology rigors in clinical research. Plast Reconstr Surg 2010; 129(6): 979e-988e.

Abstract:

This review article presents an overview of the ‘site evaluation’ process, the roles and responsibilities of participants, the standard requirements and processes for activities which needs attention, and the importance of communication and flexibility during this startup phase of the study. This article is written in accordance with International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonized Tripartite Guideline for Good Clinical Practice (ICH GCP Topic E6).

Keywords: Protocol, Sponsor, Investigator, Site, Institutional Ethics Committee, Study team

References:

[1.]   Andrea G. Procaccino. Managing Clinical Trials. New Drug Approval Process

[2.]   Carol Opalek & Joy Frestedt. 2009. Study Startup 101. The Monitor

[3.]   Fundamentals of Clinical Research. 2007 edition.

[4.]   Dr. Julka P. K. Becoming a Successful Clinical Trial Investigator.

[5.]   Karen E. Woodin. Coordinating Clinical Research

[6.]   Karen E. Woodin & John C. Schneider. Monitoring Clinical Research; Second Edition.

[7.]   Dr. Umakant Sahoo. Monitoring Visits. Monitoring and Source Data Verification in Clinical Trial Management

Abstract:

The present study focused on the use of medicinal cannabis and its derivatives for the treatment of epileptic seizures in children, as well as, adults. “Epilepsy” defined as a chronic non-communicable disorder of the brain had shown to affect people of all age groups. There were many conventional treatments discovered up till date to minimize and alleviate the symptoms produced as a result of epilepsy, yet none among them could provide the long term safety and efficacy of the interventional drug. On the other hand, increased resistance to conventional drug therapy is another issue which has made researchers to think for the alternative treatment for the long run. On an average, it had been estimated that approximately, 50 million people worldwide were suffering from epilepsy, which thus made it one of the most common neurological diseases globally. Epilepsy accounted for 0. 75%, of the global burden of disease due to premature mortality, lost work productivity, health care needs and unhealthy quality of life. In 2012, epilepsy was responsible for approximately 20. 6 million disability-adjusted life years (DALYs) lost. According to WHO survey, it was estimated that about 80% of the people suffering from epilepsy resided in low- and middle-income countries in which three fourths of people could not access the treatment due to cost-effective or non-availability of the treatment in comparison to the people who availed the conventional treatment responded to only approximately 70% of the time. Besides, in many parts of the world, people with epilepsy and their families suffered a lot from stigma and discrimination therefore, making it a social economic burden for hampering the quality of life of the patient as well as, that of the patient caregivers. Several countries (including Canada, Netherlands, and Israel) and 23 of 50 states in the United States had permitted the use of cannabis for medicinal purposes, with or without undergoing a systematic medicines approval process. Epilepsy-related deaths are a significant public health problem, yet are poorly understood and often overlooked. Hence, people with epilepsy are two to three times more likely to die prematurely than people without the disease which is surely a matter of concern to both the health providers and the patient.

Keywords: ‘cannabis’, ‘marijuana’, ‘cannabinoids’, ‘tetrahydrocannabinol’, ‘THC’, ‘Pediatric’ ‘cannabidiol’, ‘CBD’, ‘cannabidivarin’, ‘CBDV’, ‘seizures’ and ‘epilepsy’

References:

[1.] Anbesaw, W. , Selassie, Dulaney, A. , Wilson, Angela, M. , Malek, Janelle, L. , Wagner, Smith, G. , Martz, G. , Edwards, J. , Wannamaker, B. , Zack, M. M. , Koba, R. (2014). Premature Deaths Among Children with Epilepsy — South Carolina, 2000–2011. Centers for disease Control and Prevention, 63(44). Available from:

http://www. cdc. gov/mmwr/pdf/wk/mm6344. pdf.

[2.] CANNABIS RESEARCH A – Z Open Source Health Cannabis Education [Internet]. Accessed on: 2016 May 26; Available at:

http://www. calgarycmmc.com/epilepsy. htm .

[3.] CDC Features: Epilepsy in Children, Citizens United for Research in Epilepsy (CURE) [Internet], 2016 April 27. Accessed on: 2016 May 27. Available from:

http://www. cureepilepsy. org/news/story. asp?id=129.

[4.] ClinicalTrials. gov [Internet]. University of Colorado, Denver (United States). 2016 February 22-Identifier NCT02523183, The Use of Medicinal Cannabinoids as Adjunctive Treatment for Medically Refractory Epilepsy; Accessed on: 2016 May 25; Available from:

https://clinicaltrials. gov/ct2/show/study/NCT02523183?term=Cannabis+and+epilepsy&rank=1.

[5.] ClinicalTrials. gov [Internet]. Georgia Regents University (United States). 2015 April 23- Identifier NCT02397863, Epidiolex and Drug Resistant Epilepsy in Children (CBD); Accessed on: 2016 May 25; Available from:

https://clinicaltrials. gov/ct2/show/NCT02397863?term=Cannabis+and+epilepsy&rank=2.

[6.] ClinicalTrials. gov [Internet]. University of Colorado, Denver (United States). 2016 February 29-Identifier NCT02447198, Cannabidiol (CBD) and Pediatric Epilepsy; Accessed on: 2016 May 25; Available from:

https://clinicaltrials. gov/ct2/show/NCT02447198?term=Cannabis+and+epilepsy&rank=3.

[7.] ClinicalTrials. gov [Internet]. University of Colorado, Denver (United States). 2016 March 18-Identifier NCT02229032, Genetic Analysis Between Charlotte's Web Responders Versus Non- Responders in a Dravet Population; Accessed on: 2016 May 25; Available from:

https://clinicaltrials. gov/ct2/show/record/NCT02229032?term=Cannabis+and+epilepsy&rank=4.

[8.] Consroe, P. , Benedito, M. A. , Leite, J. R. , Carlini, E. A. , Mechoulam, R. (1982). Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. Eur J Pharmacol, 24;83(3-4):293-8. Doi: doi: http://10. 1016/0014-2999(82)90264-3. [PubMed PMID: 6129147].

[9.] Consroe, P. F. , Wood, G. C. , Buchsbaum, H. (1975).      Anticonvulsant nature of marihuana smoking. Journal of the American Medical Association, 234(3):306-307. Available at: http://www. cannabis-med. org/studies/ww_en_db_study_show. php?s_id=39.

[10.]   Consroe, P., Wolkin, A. (1977). Cannabidiol--antiepileptic drug comparisons and interactions in experimentally induced seizures in rats. J PharmacolExpTher, 201(1):26-32. Available at:

http://www. ncbi. nlm. nih. gov/pubmed/850145?dopt=Abstract. [PubMed PMID: 850145].

[11.]   Cunha, J. M. , Carlini, E. A. , Pereira, A. E. , Ramos, O. L. , Pimentel, C. , Gagliardi, R. , Sanvito, W. L. , Lander, N. , Mechoulam, R. (1980). Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology, 21(3):175-185. Available at:

http://www. cannabis-med. org/studies/ww_en_db_study_show. php?s_id=42.

[12.]   Devinsky, O. , Marsh, E. , Friedman, D. , Thiele, E. , Laux, L. , Sullivan, J. , Miller, I. , Flamini, R. , Wilfong, A. , Filloux, F. , Wong, M. , Tilton, N. , Bruno, P. , Bluvstein, J. , Hedlund, J. , Kamens, R. , Maclean, J. , Nangia, S. , Singhal, N. S. , Wilson, C. A. , Patel, A. , Cilio, M. R. (2005). The Lancet Neurology, 15(3), 270 – 278. DOI: http://dx. doi. org/10. 1016/S1474-4422(15)00379-8 .

[13.]   Epilepsy, Fact sheet, Updated February 2016. [Internet], Accessed on: 2016 May 28; Available from: http://www. who. int/mediacentre/factsheets/fs999/en/.

[14.]   Families, Doctors, Advocates Urgently Seeking Answers in Epilepsy Deaths, Citizens United for Research in Epilepsy (CURE), [Internet], 2016 April 27. Accessed on: 2016 May 27. Available from: http://www. cureepilepsy. org/news/story. asp?id=151.

[15.]   Few Answers in Understanding Death from Epilepsy, Citizens United for Research in Epilepsy (CURE), [Internet], 2016 April 27. Accessed on: 2016 May 27. Available from: http://www. cureepilepsy. org/news/story. asp?id=150.

[16.]   Florek-Luszczki, M. , Wlaz, A. , Zagaja, M. , Andres-Mach, M. , Kondrat-Wrobel, M. W. , Luszczki, J. J. (2015). Effects of WIN 55, 212-2 (a synthetic cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant activity of various novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice. PharmacolBiochem Behav. , 130:53-8. doi: http://10. 1016/j. pbb. 2015. 01. 003. [PubMed PMID: 25592741].

[17.]   Gedde, M. , Maa, E. (2013). Whole Cannabis Extract of High Concentration Cannabidiol May Calm Seizures in Highly Refractory Pediatric Epilepsies. In Press with the American Epilepsy Society, 67th Annual Meeting, Available at:

https://www. thcint.com/uploads/1/9/3/7/19371199/2013_cannabidiol_may_calm_seizures. pdf.

[18.]   Gedde, M. M. (2014). Clinical Experience with Cannabis in Treatment-Resistant Pediatric Epilepsy. Presentation, [Internet], Available from:

http://www. theroc. us/images/gedde_presentation. pdf.

[19.]   Hadorn, D. (2003). Use of Cannabis Medicines in Clinical Practice. Internet Archive: Wayback Machine, Available from:

http://medicalmarijuana. procon. org/sourcefiles/use-of-cannabis-medicines-in-clinical-practice. pdf.

[20.]   Hellerman, C. “Federal marijuana bill would legalize some cannabis strains”. CNN. Cable News Network, 2015 April 15, Accessed on: 2016 May 25; Available from:

http://edition. cnn.com/2014/07/28/health/federal-marijuana-bill/index. html.

[21.]   Hamerle, M. , Ghaeni, L. , Kowski, A. , Weissinger, F. , Holtkamp, M. (2014). Cannabis and other illicit drug use in epilepsy patients. Eur J Neurol, 21(1):167-70. Available at:

http://www. cannabis-med. org/studies/ww_en_db_study_show. php?s_id=558.

[22.]   Hegde, M. , Santos-Sanchez, C. , Hess, C. P. , Kabir, A. A. , Garcia, P. A. (2012). Seizure exacerbation in two patients with focal epilepsy following marijuana cessation. Epilepsy Behav, 25(4):563-6. Available at:

http://www. cannabis-med. org/studies/ww_en_db_study_show. php?s_id=560 .

[23.]   Izquierdo, I. , Orsingher, O. A. , Berardi, A. C. (1973). Effect of cannabidiol and of other Cannabis sativa compounds on hippocampal seizure discharges. Psychopharmacologia, 28(1):95-102. Doi: http://link. springer.com/article/10. 1007%2FBF00413961.

[24.]   Johnson, D. D. , McNeill, J. R. , Crawford, R. D. , Wilcox, W. C. (1975). Epileptiform seizures in domestic fowl. V. The anticonvulsant activity of delta9-tetrahydrocannabinol. Can J Physiol Pharmacol. , 53(6):1007-13. Available at:

http://www. ncbi. nlm. nih. gov/pubmed/1222370. [PubMed PMID: 1222370].

[25.]   Jones, N. A. , Glyn, S. E. , Akiyama, S. , Hill, T. , Hill, A. J. , Weston, S. E. , Burnett, M. D. A. , Yamasaki, Y. Stephens, G. J. , Whalley, B. J. , Williams, C. M. (2012). Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures. European Journal of Epilepsy, 21(5), 344 – 352.

DOI: http://dx. doi. org/10. 1016/j. seizure. 2012. 03. 001 .

[26.]   Jones, N. A. , Hill, A. J. , Smith, I. , Bevan, S. A. , Williams, C. M. , Whalley, B. J. , Stephens, G. J. (2010). Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther, 332(2):569-77.

doi: http://10. 1124/jpet. 109. 159145. [PubMed PMID: 19906779]; [PubMed Central PMCID: PMC2819831].

[27.]   Liu, H. , Song, Z. , Liao, D. , Zhang, T. , Liu, F. , Zhuang, K. , Luo, K. , Yang, L. (2015). Neuroprotective effects of trans-caryophyllene against kainic acid induced seizure activity and oxidative stress in mice. Neurochem Res, 40(1):118-23. doi: http://10. 1007/s11064-014-1474-0. [PubMed PMID: 25417010].

[28.]   Megiddo, I., Colson, A. , Chisholm, D. , Dua, T. , Nandi, A. , and Laxminarayan, R. (2016). Health and economic benefits of public financing of epilepsy treatment in India: An agent-based simulation model. Epilepsia Official Journal of the International League Against Epilepsy, 57(3): 464-474. doi: http://10. 1111/epi. 13294.

[29.]   Mortati, K. , Dworetzky, B. , Devinsky, O. (2007). Marijuana: an effective antiepileptic treatment in partial epilepsy? A case report and review of the literature. Rev Neurol Dis, 4(2):103-6. Available at:

http://www. cannabis-med. org/studies/ww_en_db_study_show. php?s_id=157.

[30.]   Pelliccia, A. , Grassi, G. , Romano, A. , Crocchialo, P. (2005). Treatment with CBD in oily solution of drug-resistant paediatric epilepsies. Congress on Cannabis and the Cannabinoids, Leiden, The Netherlands: International Association for Cannabis as Medicine, p. 14. http://www. cannabis-med. org/studies/ww_en_db_study_show. php?s_id=173.

[31.]   Philipsen, N., Butler, R. D. , Simon-Waterman, C. , Artis, J. (2014). Medical Marijuana: A Primer on Ethics, Evidence, and Politics. Journal for Nurse Practitioners, 10(9):633-640. Available at: http://www. medscape.com/viewarticle/833782_8.

[32.]   Press, C. A. , Knupp, K. G. , Chapman, K. E. (2015). Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. (2015). Epilepsy Behav, 45:49-52. Available at:http://doi:10. 1016/j. yebeh. 2015. 02. 043. [PubMed PMID: 25845492].

[33.]   Rush, I. R. (2015). Initiative seeks to uncover causes, develop treatments, design possible cures for epilepsies, [Internet], Accessed on: 2016 May 27. Available from: http://articles. philly.com/2015-05-31/news/62882680_1_patients-citizens-united-seizures.

[34.]   Saundra, Y. "Marijuana stops child's severe seizures. " CNN. Cable News Network. [Internet], 2013 August 7. Accessed on: 2016 May 25. Available from:

http://edition. cnn.com/2013/08/07/health/charlotte-child-medical-marijuana.

[35.]   Schachter, S. C. , Shafer, P. O. , Sirven, J. I. (2013). Treating Seizures and Epilepsy. Epilepsy Foundation, [Internet], Available at:

http://www.epilepsy.com/learn/treating-seizures-and-epilepsy/other-treatment-approaches/medical-marijuana-and-epilepsy%2024.

[36.]   Shirazi-zand, Z., Ahmad-Molaei, L., Motamedi, F., Naderi, N. (2013). The role of potassium BK channels in anticonvulsant effect of cannabidiol in pentylenetetrazole and maximal electroshock models of seizure in mice. Epilepsy Behav. 28(1):1-7. doi: http://10. 1016/j. yebeh. [PubMed PMID: 23644464]. 

Abstract:

Background: In Nigeria about 50,000 children are infected with HIV annually, mostly through mother to child transmission, thus making her the greatest contributor (30%) to the global paediatric HIV burden. Since the inception of the PMTCT programme in Nigeria in 2001, the number of HIV+ pregnant women that had accessed the service was more than 200,000. Some accessing the service more than one time during different pregnancies.

Objectives: The study was conducted primarily to determine, if there was any, the impact of maternal exposure to repeated PMTCT care on the rate of mother to child transmission of HIV infection. Other secondary objectives included calculating the proportion of PMTCT clients who are accessing the PMTCT service for the first time, the 2nd, 3rd or 4th time

Methods: This was a retrospective case-control multicenter study. PMTCT clients who have had repeated PMTCT services form the case while the control group consisted of first-timers PMTCT clients.

Results: The control group consists of 387 HIV positive nursing mothers who were assessing the PMTCT service for the first time while the case group consisted 116 who were repeated users of the PMTCT service. Of the repeated PMTCT clients (case group), 95% (n=110) were accessing the PMTCT service for the 2^nd time while 5%(n=6)were third time users of the PMTCT service. None had used the service for more than 3^rd time. HIV vertical transmission rate was 0% among babies of mothers who were having repeated PMTCT service(case group) while only 1.4% babies whose mothers were receiving PMTCT service for the first time(control) were vertically infected.

Conclusion: Though the vertical transmission of HIV was slightly higher among babies whose mothers were exposed to the PMTCT service for the first time. The difference in the transmission rates between the two groups was not statistically significant P>0.05, X² = 1.309, df=1) and there was no statistical association between the number of vertically HIV infected infants and the number of time the mother was exposed to PMTCT services.

Keywords: HIV (human immunodeficiency virus), Prevention of Mother To child Transmission of HIV (PMTCT), ARV (antiretroviral drugs), PCR (polymerase chain reaction), Seroconversion, HAART.

References:

[1]. A.S. Sagay, et al. Vertical transmission of HIV-1 infection in northern Nigeria. : AIDS 2006 - XVI International AIDS Conference: Abstract no. TUPE0345

[2] A review of HIV transmission through breastfeeding. Geneva: UNAIDS and WHO; 1998.

[3] Burgos-Soto J et al. Intimate partner sexual and physical violence among women in Togo, West Africa: prevalence, associated factors, and the specific role of HIV infection. Global Health Action. 2014; 7. doi: 10.3402/gha.v7.23456

[4] DITRAME STUDY GROUP. 6 month efficacy, tolerance and acceptability of a short regime of oral zidovudine to reduce vertical transmission of HIV in breastfed children in coted`Ivoire and Burkina Faso: a double –blind placebo-controlled metacentre trial. Lancet, 1999, 353(9155):786-792.

[5] Fitzpatrick, Fidelma, et al. "Use of a fourth generation HIV assay for routine screening–The first years’ experience." Journal of Infection 53.6 (2006): 415-416.

[6] Global AIDS Response Country Progress Report, Nigeria GARPR 2012

[7] Global Aids Response Country Progress Report, Nigeria GARPR 2015, National Agency for the Control of AIDS (NACA), Abuja, Nigeria

[8] Homsy J et al. Reproductive intentions and outcomes among women on antiretroviral therapy in rural Uganda: a prospective cohort study. PloS ONE. 2009; 4(1). doi: 10.1371/journal. pone.0004149

[9] Myer L et al. Impact of antiretroviral therapy on incidence of pregnancy among HIV-infected women in Sub- Saharan Africa: a cohort study. PLoS Medicine. 2010; 7.2: 194.

[10] Nigerian Integrated National Guidelines For HIV Prevention, Treatment And Care 2014

[11] Nigeria National Guidelines on Prevention of Mother-To-Child Transmission (PMTCT) of HIV, 2010

[12] Nigerian National guideline for HIV Counselling and Testing 2012 pg 35.

[13] Nigerian National Operational Plan for the Elimination of Mother to Child Transmission (eMTCT) of HIV in Nigeria 2015–2016, Federal Ministry of Health, Abuja, Nigeria.

[14] PETRA STUDY TEAM. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda(Petral study): a randomised, double-blind, placebo-controlled trial. Lancet, 2002, 359(9313):1178-1186

[15] Tonwe-Gold et al. Highly active antiretroviral therapy for the prevention of perinatal HIV transmission in Africa: mother-child-transmission HIV plus, Abidjan, Cote d’Ivoire, 2003-2004. 12^th Conference on Retroviruses and Opportunistic Infections, Boston, MA US, 22-25 Feb. 2005 (Abstract 785).

[16] The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity http://www.who.int/bulletin/volumes/88/1/08-062554-table-T3.html

[17] UNAIDS 2014 report

[18] UNAIDS 2014 estimates

[19] West and Central Africa Regional Stocktaking Meeting on the Global Plan for the Elimination of Mother-to-Child Transmission of HIV and Keeping Mothers Alive by 2015: The Last 600 Days: Challenges, Opportunities and the Way Forward.

[20] WHO validates elimination of mother-to-child transmission of HIV and syphilis in Cuba Http://www.who.int/mediacentre/news/releases/2015/mtct-hiv-cuba/en/?

[21] 2015 Progress report on the Global Plan UNAIDS / JC 2774/1/E