Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524131EnglishN-0001November30HealthcareCLINICAL PROFILE AND HAEMATOLOGICAL INDICES OF CLINICALLY DIAGNOSED EARLY NEONATAL
SEPTICAEMIA: A STUDY CONDUCTED IN TEACHING INSTITUTE ATTACHED TO RURAL HOSPITAL OF
WARDHA DISTRICT
English0410Gargi D. MudeyEnglish Neelima S. TankhiwaleEnglish Abhay MudeyEnglishIn India, neonatal infections occurs in 10.97 to 27 per thousand live births and is the leading cause of neonatal mortality accounting for one quarter to nearly half of all neonatal deaths. A detailed clinical profile of 155 early onset neonatal infections was carried out prospectively for 12 months. Almost 70% babies had associated risk factors. Refusal to feed, respiratory distress, lethargy, restlessness, irritability, hypothermia and fever were the most common presenting features in that order. Blood culture was positive in 71(68.93%) cases. Klebsiella pneumoniae was the most frequently isolated pathogen (61.97%). CRP positivity, increased micro-ESR concentration and associated thrombocytopenia were present in statistically significant number of cases. It can be concluded from the findings of the study that some routine inexpensive
laboratory tests will help in the early diagnosis of neonatal septicaemia.
EnglishEarly onset neonatal septicaemia, Clinical profile, Neonatal infections, Laboratory investigationsINTRODUCTION
Neonatal septicaemia is a clinical syndrome of bacteremia characterized by systemic signs and symptoms in the first month of life, it encompasses systemic infections of newborn including meningitis, pneumonia, arthritis, osteomyelitis and urinary tract infections[1] . In India, neonatal infections occurs in 10.97 to 27 per thousand live births and is the leading cause of neonatal mortality accounting for one quarter to nearly half of all neonatal deaths[2,3] . Early onset neonatal septicaemia (EOS) usually presents within the first 72 hours of life [4,5] . A remarkable feature of the clinical manifestations of early neonatal septicaemia is non-specificity of symptoms which creates difficulty in diagnosis of infections in the early stage [6] . The associated risk factors for earlyonset sepsis include low birth weight and prematurity. Resuscitation at birth, particularly if it involves endotracheal intubation, insertion of an umbilical vessel catheter, intravenous fluids,
blood products, and those babies who stay in hospital for more than 48 hours are at increased risk of bacterial infection [7,8] . Blood culture remains an important investigation in diagnosing neonatal septicaemia but it has its limitations. In routine practice minimum of 48 hours are required to isolate, identify and determine antimicrobial susceptibility of bacteria [1] . Changing pattern of organisms causing neonatal septicaemia and the frequent emergence of resistant bacteria are causing difficulty in the treatment [9]. The present study was carried out with objectives of finding out the foetal risk factors, common clinical presentations and laboratory findings in neonates those were admitted in NICU with suspected neonatal infections.
MATERIAL AND METHODS
This is a prospective study done at NICU of Acharya Vinoba Bhave rural hospital, Sawangi (M) Wardha. Study period was from September 2009 to August 2010. 155 neonates in whom clinical diagnosis of early neonatal infections was established were selected for the study. Details of these cases were recorded in a separate proforma including obstetric risk factors, history of labor, birth weight, gestational age, day of onset and subsiding of symptoms, presenting clinical features, complications and duration of hospital stay. Blood culture, C-reactive protein (CRP) estimation, micro-ESR(erythrocyte sedimentation rate), total leucocytes count, platelet count and peripheral blood smear for toxic granules, band cells, cytoplasmic vacuolations were done in all the cases. Statistical analysis was done using the statistical software SPSS 13.0
RESULTS
Among 155 neonates with early onset infections, 99 were males whereas 56 were females. Thus male to female ratio in this group was 1.7:1. Associated risk factors were studied in all the cases. Among 155 neonates 96(61.93%) were preterm, 102(65.81%) were low birth weight. 72(46.45%) neonates had mild to moderate birth asphyxia and required active resuscitation. In 15 (9.68%) cases there was history of instrumentation or invasive procedures. 9(5.81%) cases were on ventilator. Presenting sign and symptoms recorded in all the 155 cases are shown in Table I. Refusal to feed, respiratory distress, lethargy, restlessness, irritability, hypothermia and fever were the most common presenting features in that order. Blood culture was positive in 71(68.93%) cases. Among these Klebsiella pneumoniae was the most frequently isolated pathogen (61.97%), followed by Staphylococcus aureus (11.26%), Escherichia coli (8.45%), Enterobacter species (7.04%), Citrobacter freundii (4.23%), Acinetobacter species (4.23%) and Klebsiella oxytoca (2.82%). Blood count and peripheral blood smear findings recorded in all 155 cases are shown in Table II. CRP positivity, increased micro-ESR concentration and associated thrombocytopenia in early onset neonatal infections were statistically significant findings.
DISCUSSION
Early onset neonatal infections is observed more common in males with male/female ratio ranging from 1.4:1 to 3.1:1[5,7,10,11,12]. The male/female ratio in this study was 1.7:1. In the present study prematurity, low birth weight, birth asphyxia, history of instrumentation and ventilators were observed in neonates with early onset neonatal infections (EOS) whereas similar findings were quoted by I Roy et al, Shahsanam Gheibi et al and Meenu Singh et al in which they were reported prematurity, low birth weight and birth asphyxia to be the commonest risk factors associated with EOS [13,14,15] . The most common presenting features in the present study were refusal to feed, respiratory distress, lethargy, restlessness, irritability, hypothermia and fever in that order. The same findings were also observed by some researchers[2,8,15,16] . Blood culture positivity in EOS as reported by various reporters ranges from 22.9% to 85.99% [7,9,10,13,17,18,19,20,21] whereas in the present study blood culture positivity rate in EOS was observed in 68.93% cases, this finding correlates well with the findings of K. Chugh et al, Khanal B et al and Nalini Agnihotri et al. Various researchers have reported incidence of Klebsiella species between 13-60% in their studies [7,9,13,21]. In the present study Klebsiella pneumoniae was the most frequently isolated pathogen (61.97%) which is very close to the findings of K. Chugh et al where they reported Klebsiella sp. in 77.3% of EOS group [20] . Alistair G. S. Philip et al [22] in the study of 376 cases of neonatal septicaemia reported positive CRP in 64(17.02%) cases, Pradip Kumar Das et al [23] reported positive CRP in 251/310(80.9%) cases, R. S. Jaswal et al [2] in the study of 50 cases reported positive CRP in 50% cases of EOS, SS Ahmed et al [24] in the study of 60 neonates found that 70% cases of EOS were CRP positive, Mustafa S et al [25] in the study of 50 cases reported CRP positive in 58 % cases of EOS whereas CRP was positive in 99/210(47.14%) cases in the study of Reza Ghotaslou et al [26]. The present study finding of CRP positive in 75/155(48.39%) cases of EOS corroborates with the findings of R. S. Jaswal et al and Reza Ghotaslou et al. The present study finding of increased micro-ESR in 59(38.06%) in EOS cases correlates well with the finding of R. S. Jaswal et al where they reported increased microESR in 48% of cases of EOS. SS Ahmed et al reported thrombocytopenia in 63.3% cases, K.V Shyamala et al in the study of 103 cases reported thrombocytopenia in 72 (69.9%) cases. Torkaman M et al in the retrospective study observed in 56.6% EOS. Thrombocytopenia in the present study i.e. 42 (27.10%) in EOS was present in less number of cases when compared with other researchers. Leukocytosis observed in the present study i.e. 19(12.26%) cases in EOS was present in less number of cases when compared with other researchers like SS Ahmed et al (53.3%) and Archana Devi and Pushpa et al (50%). On the other hand present study finding of leucopenia in 13 (8.39%) EOS cases correlates with the finding of Alistair G. S. Philip et al (9.84%) and Jain NK et al (10%). Band cell count (>20%) or toxic granules or cytoplasmic vacuolation in the present study 11(7.10%) in EOS was present in less number of cases when compared with other researchers Alistair G. S. Philip et al (27.39%) and Jain NK et al (34.4%). The present study findings of CRP positivity, increased micro-ESR concentration and associated thrombocytopenia in cases of neonatal septicaemia were statistically significant findings.
SUMMARY AND CONCLUSION
Early onset neonatal septicaemia is more common among males. Prematurity, low birth weight, birth asphyxia was the common foetal risk factors found to be associated with EOS. Commonest clinical presentations were refusal to feed, respiratory distress and lethargy whereas commonest causative agent in the present study was Klebsiella pneumoniae. Positive CRP, increased micro-ESR and thrombocytopenia were found in statistically significant number in EOS. From the above summery it can be concluded that CRP, micro-ESR and platelet count estimations will help in the early diagnosis of neonatal septicaemia. These tests will be of great use in cases where antibiotics are started before collection of blood for blood culture. As these tests are inexpensive and readily available these can be of help in hospitals where blood culture facilities are not available.
Englishhttp://ijcrr.com/abstract.php?article_id=2200http://ijcrr.com/article_html.php?did=22001. John P. Cloherty, Eric C. Eichenwald, Ann R. Stark: Manual of neonatal care: Sixth edition : Lippincott Williams and Wilkins: 2007; Page No.274-300
2. R.S. Jaswal, R.K. Kaushal, Asha Goel and Kushla Pathania: Role of C-reactive protein in deciding duration of antibiotic therapy in neonatal septicaemia: Indian Pediatrics 2003; 40: Page 880-883.
3. David Osrin, Stefania Vergnano and Anthony Costello: Serious bacterial infections in newborn infants in developing countries: Current opinion in infectious diseases 2004; 17: 217-224.
4. Samuel P. Gotoff : Infections of the neonatal infants: Nelson's Textbook of Pediatrics: 16th edition: 2000; Chapter 105: Page No. 538-552
5. Jain NK, Jain VM, Maheshwari S: Clinical profile of neonatal sepsis: Kathmandu University Medical Journal: 2003; 1(2): 117-120.
6. Kenneth C. Iregbu, Olufumilayo Y. Elegba, Iretiola B. Babaniyi: Bacteriological profile of neonatal septicaemia in a tertiary hospital in Nigeria: African Health Sciences 2006; 6(3): 151-154.
7. Kurien Anil Kuruvilla, Swati Pillai, Mary Jesudason and Atanu Kumar Jana: Bacterial profile of sepsis in a neonatal unit in south India: Indian Pediatrics 1998; 35:851-858
8. NNF: The National Neonatology Forum www.nnfi.org
9. Shashikala S. Tallur, A. V. Kasturi, Shobha D. Nagdir and B.V.S. Krishna: Clinico-bacteriological study of neonatal septicaemia in Hubli: Indian Journal of Pediatrics: 2000; 67(3): 169-174.
10. Jia-Horng Jiang, Nan-Chang Chiu, Fu-Yang Huang, Hsin-An Kao,Chyong-Hsin Hsu, Han-Yang Hung, Jui-Hsing Chang, ChunChih Peng: Neonatal sepsis in the neonatal intensive care unit: Characteristics of early versus late onset: The Journal of Microbiology, Immunolology and Infection: 2004; 37: 301-306.
11. AH Movahedian, R Moniri , Z Mosayebi: Bacterial culture of neonatal sepsis: Iranian Journal of Public Health, 2006; 35(4) : 84-89.
12. S. P. Khatua, A.K. Das, B.D. Chatterjee, S. Khatua, B. Ghose and A. Saha: Neonatal septicaemia: Indian J Pediatrics 1986; 53: 509-514.
13. I Roy, A Jain, M Kumar, S K Agarwal: Bacteriology of neonatal septicaemia in a tertiary care hospital of northern India: Indian Journal of Medical Microbiology: 2002; 20 (3):156-159.
14. Shahsanam Gheibi, Zahra Fakoor: Coagulase negative staphylococcus; The most common cause of neonatal septicemia in Urmia, Iran: Iran Journal of Pediatrics: Sep 2008; 18(3): 237- 243
. 15. Meenu Singh, Anil Narang, and O. N. Bhakoo: Predictive perinatal score in the diagnosis of neonatal sepsis: Journal of Tropical Pediatrics 1994; 40: 365-368.
16. Piyush Gupta, Murali M V, MMA Faridi Kaul P B, Ramachandran VG, Talwar : Clinical profile of Klebsiella septicemia in neonates: Indian Journal of Pediatrics: 1993; 60(4): 565-572.
17. Shrestha P, Das BK, Bhatta NK, Jha DK, Das B, Setia A, Tiwari A: Clinical and bacteriological profiles of blood culture positive sepsis in newborns: Journal Nepal Pediatric Society 2006; 27(2) : 64-67.
18. Nalini Agnihotri, Neelam Kaistha and Varsha Gupta: Antimicrobial susceptibility of isolates from neonatal septicemia: Jpn Journal of Infectious Diseases 2004; 57:273- 275.
19. Khanal B, Shariff M, Deb M :Neonatal septicaemia: A hospital based study in eastern Nepal: Journal of Nepal Medical Association 2004; 43: 231-234
20. K.Chugh, B. B. Agrawal, V.K. Kaul and S.C. Arya: Bacteriological profile of neonatal septicaemia: Indian Journal Pediatrics 1988; 55: 961-965
. 21. Dr. Rizwan Waseem, Dr. Muhammad Khan, Dr. Tahira S. Izhar, Prof. Dr. Abdul Waheed Qureshi: Neonatal Sepsis: Professional Medical Journal: December 2005; 12(4): 451-456 22. Allistair G. S. Philip and Jean R. Hewitt: Early diagnosis of neonatal sepsis: PEDIATRICS 1980; 65(5):1036-1041
23. Pradip Kumar Das, Kaberi Basu, P Chakraborty, P K Bhowmik: Clinical and bacteriological profile of neonatal infections in metropolitan city based medical college nursery: Journal Indian Medical Association 1999; 97(1): 3-5
24. SS Ahmed, Maka Chowdhury, MM Hoque, D Begum, Asmnu Ahmed: Role of intravenous immunoglobulin (IVIG) as an adjuvant in the treatment of neonatal sepsis in preterm babies: Journal of Bangladesh College of Physicians and Surgeons 2006; 24(3): 97-104.
25. Mustafa S, Farooqui S, Waheed S and
Mahmood K: Evaluation of Creactive protein as early indicator of blood culture positivity in neonates: Pak Journal Medical Science: January-March 2005; 21( 1): 69-73.
26. Reza Ghotaslou, Ziaadin Ghorashi and Mohammad-Reza Nahaei: Klebsiella pneumonia in neonatal sepsis: A 3-year-study in the pediatric hospital of Tabriz, Iran: Jpn. Journal of Infectious Diseases: 2007; 60: 126-128.
27. K.V. Shyamala, N.K. Sabbalakshmi, K. Raghuveera: Role of platelet count and CRP level in gram negative versus gram positive bacterial sepsis in low birth weight neonates: Journal of Chinese Clinical Medicine 2010; 5(8): 474-479.
28. Torkaman M, Afsharpaiman S H, Hoseini M J, Moradi M, Mazraati A, Amirsalari S, Kavehmanesh Z: Platelet count and neonatal sepsis: A high prevalence of Enterobacter spp.: Singapore Medical Journal 2009; 50(5) : 482-485.
29. Archana Devi and Pushpa: A comparative study in sepsis and normal neonates -A microbiological perspective: Journal Medical sciences 2008; 8: 515-518.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524131EnglishN-0001November30HealthcareCOMPARISON BETWEEN THE PAIN RELIEVING ACTION OF SERRATIOPEPTIDASE, NSAIDs AND
COMBINATION OF BOTH IN THE ROOT CANAL TREATMENT PATIENTS
English1117Prafulla ManeEnglish Kavita AtreEnglish Rahul MayeeEnglishA three arm observational study was conducted by SRM Clinical Research Services Pvt. Ltd. to compare the efficacy of NSAIDs, serratiopeptidase enzyme and the combination of the two in relieving of pain of the root canal patient in the Aurangabad (MS) region. The study was conducted on 45 patients who were provided with a pain scale to keep a record of their rate of pain at the dosing time as well as at an hour from dosing. The rate of pain for each day was recorded in the patient‘s diary provided to the patients. The data was recorded from the time the root canal was opened till it was operated which is usually about 4-5 days. The data was then analyzed using statistical method and was finally represented as a histogram for easy comparison. The comparison was done for all the three arms i.e., patients prescribed with only NSAIDs, only serratiopeptidase and a combination of both the drugs. The histogram clearly indicated the change in level of pain in the patients. It was observed that the pain decreased in level when the patients consumed only NSAIDs or only serratiopeptidase enzyme but the pain was found to have aggravated in some patients of Aurangabad region when combination of both NSAIDs and serratiopeptidase was prescribed to them, hinting at an antagonistic action of the two.
EnglishSerratiopeptidase, Pharmacovigilance, Root Canal Treatment.INTRODUCTION
Pharmacovigilance The word ?pharmacovigilance' has been derived from a Greek word -pharmakon? which means medicinal substance and a Latin word ?vigilare? which means to keep watch. In 2002, World Health Organization (WHO) defined Pharmacovigilance as ?The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems.?[1] The percentage of hospital admissions due to iatrogenic diseases (those caused by drugs) is as high as 3 to 5 % in USA alone. [2] Therefore, it is one of the most important pre-requisites for the progress of medicine that the new drug being introduced in the market should not cause many adverse drug reactions (ADRs). Studies directed at detecting and assessing safer use of medications, appear mandatory to prevent ADRs and achieve rational therapeutic practices. Such activity requires collective and coordinated efforts from all the healthcare professionals such as - doctors, nurses and pharmacists. In addition, distribution of ADR data among consumer groups and pharmaceutical firms also becomes necessary. [3] There is certainly a need to be ?vigilant' about Pharmacovigilance studies.
Serratiopeptidase
Pain is one of the most troubling aspects of inflammation. Acute pain produced by cellular chemical reactions is part of the body's natural inflammatory healing response. Chronic pain, though, can be detrimental to healing. Swelling caused by inflammation can cause tissue to press against sensitive nerves and cause pain. The conventional treatment for inflammation disorders has a dark side - serious side effects. The two most common treatments for inflammation are steroids such as Prednisone and non-steroidal anti-inflammatory drugs, called NSAIDs both of which are associated with serious side effects such as thinning of skin, slow wound healing, high blood pressure, lowered immune system, fluid retention, suppression of normal adrenal function ulcers, internal bleeding etc. [4] Fortunately, there is a natural alternative to steroids and NSAIDs that is effective without serious side effects - Serratiopeptidase or serrapeptase which is a protein (proteolytic) enzyme isolated from the non-pathogenic enterobacteria Serratia E15 found in silkworms. Serratiopeptidase's ability to reduce and drain fluid from the inflamed area can reduce swelling and pain. It also reduces pain through its ability to block the release of paininducing amines from inflamed tissues. [5] Unlike NSAID pain medications, serratiopeptidase does not cause dangerous internal bleeding, nor is it addictive like many pain medications. Hence, it is being widely used in treating various diseases such as, inflammation, sinusitis, bronchitis, infection, atherosclerosis, carpel tunnel syndrome and in reducing pain. [6-13]
Brainwave
Pharmacovigilance (PV) has now been established as an important part of research activities owing to the statistical observations of ADRs recorded in various countries. But, like every research activity, PV also needs generation of some idea or as it may be rightly called a ?brainwave' for the commencement of the study. Such a brainwave was generated by few dentists in Aurangabad (MS) region which are a part of the SRM Clinical Research Services Pvt. Ltd. database. It was regarding the above mentioned miracle enzyme - Serratiopeptidase. Given its anti-inflammatory capability, Serratiopeptidase is widely used by dentist during the root canal treatment (RCT). It is prescribed during the preRCT period from the time RC is opened till the time it is operated. It is either prescribed individually or in combination with NSAIDs. These conventional NSAIDs are used widely during the root canal treatment for dental patients. The NSAIDs are used as covering agents for pain before and after the root canal procedure. Now-adays, Serratiopeptidase and the combination of NSAIDs and Serratiopeptidase are also used for the same purpose. It was observed by few dentists that though Serratiopeptidase is an established anti-inflammatory agent, it was found to be aggravating the pain in the RCT patients when administered in combination with other NSAIDs. It was this observation that led us to propose the study to compare the efficacy of NSAIDs, Serratiopeptidase and combination of both in the pain relieving capacity.
MATERIALS AND METHODS
Protocol was generated for comparing the efficacy of NSAIDS, Serratiopeptidase and a combination of both in the pain relieving capacity in the root canal patients of the Aurangabad (MS) region. The protocol was submitted to the Institutional Review Board (IRB) of SRM Clinical Research Services Pvt. Ltd. Feasibility assessment was conducted for 20 dental sites after the protocol was approved by the IRB of SRM Clinical Research Services Pvt. Ltd. Only 14 sites were selected for the study as they provided us with patients undergoing RCT. Each of the sites was assigned a specific site number. Recruitment of the patients was done after their informed consent. Totally 45 patients were enrolled for the study, out of which 12 patients were prescribed NSAIDs, 10 patients were prescribed serratiopeptidase and 13 patients were prescribed combination. This being a pharmacovigilance observational study, the prescription of the drug was left to the sole decision of the dentist. A three arm study was conducted which comprised of patients being treated with only NSAIDs, only Serratiopeptidase and the combination of both. The case report form was duly filled which included patient's medical history and the drugs prescribed for RCT. The patients were provided with a patient diary which contained a pain rating scale ranging from 0 - 10 (Figure 1). Data was recorded at both dosing time as well as after one hour from dosing, from the time root canal was opened till it was operated which is usually about 4-5 days. Average of the rate of pain of both the timings was calculated for each patient. A gross average was calculated for both the timings for each of the patient of all the three arms. The final average value was calculated by taking the average of the gross values. These final average values were then used to plot the histogram to compare the efficacy of the three arms in the treatment of the RCT patients.
RESULT AND DISCUSSION
The average rate of pain for NSAIDs was found to have decreased from 5.72 at dosing time to 2.98 after one hour from dosing. A similar decrease in pain was also seen in patients administered with serratiopeptidase enzyme where the rate of pain at dosing time was 3.15 but after one hour from dosing it was reduced to 1.02. But, a similar pattern was not observed in case of combination drugs. Contrary to decrease in pain in case of NSAIDs and serratiopeptidase, the pain was found to have aggravated in the patients of Aurangabad (MS) region which were administered with a combination of the two drugs. The rate of pain increased from 5.63 at the dosing time to 8.22 after one hour from dosing.
CONCLUSION
This three arm study was conducted to compare the efficacy of NSAIDs, serratiopeptidase enzyme and combination of the two in the pain relieving capacity for root canal treatment. It was observed from the study that NSAIDs and serratiopeptidase were capable of reducing the pain whereas a combination of the two drugs exhibited aggravation of pain in the root canal patients. Hence, it can be concluded that there might be an antagonistic relationship between the two drugs. This was a pilot study conducted by SRM Clinical Research Services Pvt. Ltd. in the Aurangabad (MS) region. Thus, it clearly suggests that a similar pharmacovigilance study on a large population should be conducted for the benefits of the consumer groups and Pharmaceutical firms.
Englishhttp://ijcrr.com/abstract.php?article_id=2201http://ijcrr.com/article_html.php?did=22011. WHO - The importance of Pharmacovigilance, Safety Monitoring of medicinal Products, Geneva; 2002.
2. Das BP, Rauniar GP, Bhattacharya SK. Medical errors challenges for the health professionals: need of Pharmacovigilance to prevent. JNMA. 2006 Apr-Jun; 45(162): 273-8.
3. Kuruvilla A. Pharmacovigilance - Review Topic Rational Drugs. 2006 Oct - Dec; Issue 26. 4. Miyata K. Intestinal absorption of Serratia Peptidase. J Appl. Biochem. 1980; 2:111-16.
5. Mazzone A, et al. Evaluation of Serratia peptidase in acute or chronic inflammation of otorhinolaryngology pathogoly: a multicentre, double-blind, randomized trial versus placebo. J Int Med Res. 1990; 18(5):379-88.
6. Kakinuma A, Moriya N, Kawahara K, Sugino H. Repression of fibrinolysis in scalded rats by administration of Serratia protease. Biochem Pharmacol 1982; 31(18):2861-6.
7. Mazzone A, Catalani M, Costanzo M, Drusian A, Mandoli A, Russo S, Guarini E, Vesperini G. Evaluation of Serratia peptidase in acute or chronic inflammation of otorhinolaryngology pathology: a multicentre, double-blind, randomized trial versus placebo. J Int Med Res. 1990; 18(5):379-88.
8. Esch PM, Gemgross H, Fabian A. Reduction of postoperative swelling. Objective measurement of swelling of the upper ankle joint in treatment with serrapeptase-a prospective study (German) 2FortscherMed. 1989; 107(4):67-8, 71-2.
9. Kee WH, Tan SL, Lee V, Salmon YM. The treatment of breast engorgement with Serrapeptase (Danzen); a randomized doubleblind controlled trial. Singapore Med J. 1989; 30 (1):48-54.
10. Klein G, Kullich W. Short-term treatment of painful osteoarthritis of the knee with oral enzymes. A randomized, double-blind study versus diclofenac. Clin Drug Invest. 2000; 19 (1):15-23.
11. Majima Y, Inagaki M, Hirata K, Takeuchi K, Morishita A, Sakakura Y. The effect of an orally administered proteolytic enzyme on the elasticity and viscosity of nasal mucus. Arch otorhinolaryngol. 1988; 244(6):355-9.
12. Selan L et al. Proteolytic enzymes: a new treatment strategy for prosthetic infections? Antimicrob Agents Chemother. 1993; 37(12):2618-21.
13. Panagariya A, Sharma AK. A preliminary trial of serratiopeptidase in patients with carpal tunnel syndrome. J Assoc Physicians India; 1999; 47 (12); 1170-1172.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524131EnglishN-0001November30HealthcareEFFECT OF SUPERVISED EXERCISE PROGRAM AND HOME BASED EXERCISE PROGRAM IN
OSTEOARTHRITIS OF KNEE JOINT
English1827Vandana J. Rathod Jagatheesan AlagesanEnglish Parthipan RamasamyEnglishIntroduction: Osteoarthritis of knee is a most common degenerative joint disease. Exercise programmes have been shown to be effective when patients are closely supervised by physiotherapists; however, data are lacking on the efficacy of an unsupervised home based exercise regimen in subjects with osteoarthritis of knee.
Materials and Method: An experimental study was carried out to compare supervised exercise program and home based exercise program in osteoarthritis of knee joint. A convenient sample of 60 subjects with unilateral osteoarthritis of knee joint, age between 45 and 55 years of both sexes were divided in to supervised exercise group (Group-A) and home based exercise group (Group-B). Group-A was receiving exercises under the supervision of physiotherapist at outpatient department of Physiotherapy College and Group-B was doing exercises at home following a specially designed exercise pamphlet. Numeric Pain Rating Scale and Western Ontario and McMaster universities Index were used as outcome measure before and after two months of intervention.
Results: There was a significant decrease in pain and also significant improvement in physical function (pEnglishKnee osteoarthritis, supervised exercises, home based exercises, exercise pamphletINTRODUCTION
Osteoarthritis is a chronic joint disorder in which there is a progressive softening and disintegration of articular cartilage accompanied by new growth of cartilage and bone at the joint margins and capsular fibrosis.1 Disease resulting from uncoupling of the balance between the cartilage degeneration and regeneration. Osteoarthritis contributes greatly to disability in the general population, particularly in the elderly.2,3 World Health Organization estimated that it accounts for 14.8 million disability adjusted life years (DALYs) lost, with 80% percent of those afflicted having some degree of limitation of movement and 25% being unable to perform the major activities of daily living. As the incidence and prevalence of osteoarthritis increase with age, the DALYs lost due to this disease are expected to increase by 40% by 2030.4,5,6 Generally the process of clinically detectable osteoarthritis is irreversible and typical treatment consists of medication and other interventions includes physiotherapy in majority.7,8 Management of osteoarthritis is directed towards decreasing the symptoms. Physiotherapeutic treatment, particularly exercise, has been part of the management of knee osteoarthritis for nearly a century and is the second most frequently prescribed treatment after oral medication.9,10 There are many barriers to the uptake of exercises in population and two are of particular importance: (1) Failure in the part of medical practitioners to properly recommend exercises to patients and make appropriate referrals to exercise professionals and (2) failure of patients to comply with prescribed exercises programs. Exercises are underused by medical practitioners as a treatment strategy for osteoarthritis.11 Given the large number of patients who choose to exercise independently where many failed to consult a professional regarding the most appropriate exercise. Thus, it is important to understand prescribing exercises to patients and potential benefits such exercises. Recent researchs12,13,14,15,16 has provided a rationale for the use of muscle rehabilitation as part of overall treatment regimen for knee osteoarthritis. Regular knee strengthening and aerobic exercises shows improvement in functional ability, aerobic capacity and endurance and reduce knee pain. However, the most effective types and combinations of exercise and dosage are unclear. Various studies have examined the effect of different home based exercises in knee osteoarthritis.17,18,19,20 Exercises reduce pain and improve physical function in patient with osteoarthritis knee.17,21 The need for cost effectiveness throughout the health care system emphasizes the importance of knowing whether patients require numerous visits to a physical therapist or whether they might receive a similar benefit from a well-designed home program. The purpose of this study is to determine the effectiveness of a treatment that included exercise under supervision compared with an exercise program performed at home for osteoarthritis of the knee. Home based exercises training require participants to perform different exercises in home in guidance with exercises booklet. The effects of unsupervised exercises are still controversy and need to be proved.
MATERIALS AND METHODS
An experimental study was carried out to compare supervised exercise program and home based exercise program in osteoarthritis of knee joint at outpatient department of a physiotherapy college. Ethical clearance was obtained from institutional review board. A convenient sample of 60 subjects with unilateral osteoarthritis of knee joint, age ranging between 45 and 55 years of both sexes were included in the study after obtaining informed consent. Subjects with lower extremity joint replacement, post fracture stiffness, ligament injury of knee joint and secondary osteoarthritis were excluded. Subjects were consecutively assigned in to Group-A or Group-B i.e. first one to Group-A and second to Group-B and so on. The subjects of both groups were explained about the importance of exercise. Subjects of Group-A were put under supervision of therapist during exercises in physiotherapy outpatient department and also taught five joint protection techniques. Subjects of Group-B were advised to do the same exercises at home with the help of exercise pamphlet (Exercise Pamphlet is printed in two pages of standard A4 size paper in both Vernacular [Kannada] and English with diagrams prepared for this study vide Annexure). Exercises consist of Quadriceps strengthening exercise in lying and sitting, Hamstring and VMO Strengthening exercises and proprioceptive training exercises with five joint protection techniques as follows,
1. Quadriceps strengthening exercise in lying- Lie on your back with leg straight at knees and arms at sides. With a thick fold of 5-10? cotton towel roll, subject was advised to place under knee and to press it till 10 seconds. Relax. Repeat.
2. VMO strengthening exercise- Lie on your back with leg straight at knees and arms at sides. Rotate your one leg outside, maintain this position and receive your leg up without bending your knee up to 600 . Hold it for 10 seconds. Lower the leg as slowly as possible. Relax. Repeat.
3. Hamstring strengthening exerciseLie on your abdomen and place hands on your sides with knee straight. Try to bend your knee at a time as much as possible. Hold for 10 seconds. Straight the leg. Relax. Repeat.
4. Quadriceps strengthening exercise in sitting- Sit on chair or high stool. Sit straight and try to straighten your knee as high as possible. Hold for 10 seconds. Lower the leg to floor as slowly as possible. Relax. Repeat.
5. Proprioceptive training exercise- Sit on chair or high stool with leg above the ground. Place a soft ball under your feet and try to move the ball in all direction in circular and linear direction. Do it for 10 seconds. Relax. Repeat.
Joint protection techniques
1. Avoid crossed leg sitting.
2. Avoid squatting.
3. Avoid prolonged standing.
4. Avoid prolonged walking.
5. Avoid stair climbing.
Subjects of both the groups were advised to do each exercise 10 times with 10 seconds hold and 10 seconds relaxation, once a day for six days in a week for two months. The outcome measures used were Numeric Pain Rating Scale (NPRS) and Western Ontario and McMaster universities (WOMAC) Index; all subjects of both groups were assessed before and after two months of intervention.
RESULTS
The data collected were analyzed for demographic variables and significance by using SPSS-17 for windows. Significance was tested by independent t-test and paired t-test for NPRS and Mann Whitney U-test and Wilcoxon Signed Rank test for WOMAC index with p < 0.05. Table-1 shows age and sex distribution of both groups, the Mean SD for age in Group-A is 49.73 3.27 and group-B is 49.23 3.13. Inter group comparison at baseline was done by independent t-test for NPRS shown in table-2. The Mean SD for Group-A is 6.60 1.16 and Group-B is 6.28 1.07 with p=0.26 proves homogeneity of both groups before intervention. Intra group comparison was done by using Paired t-test shown in table-3, the Mean SD of post treatment for Group-A is 5.38 1.11 and Group-B is 5.01 1.06 with p value < 0.001 for both groups confirms that there is significant reduction of pain in both groups after intervention. Table-4 shows post treatment comparison between groups by independent t-test with t=1.31 and p=0.19 proves no significant difference between groups after intervention. WOMAC Index scores at baseline were compared by Mann Whitney U test for homogeneity shown in table-5. The median for Group-A is 50 and group-B is 52.5 before intervention in WOMAC Index with p=0.569 and z=0.570 proves the same. Intra group comparison was done by Wilcoxon Signed Rank test for both groups shown in table-6 with p value is Englishhttp://ijcrr.com/abstract.php?article_id=2202http://ijcrr.com/article_html.php?did=22021. Apley's system of orthopaedics and fractures, 7th edition, Butterworth - Heineman, Page 80-81.
2. Felson DT, Naimark A, Anderson JJ, Kazis L, Castelli W, Meenan RF. The prevalence of knee osteoarthritis in the elderly: the Framingham osteoarthritis study. Arthritis Rheum 1987; 30:914-918.
3. Badley EM, Tennant A. Disablement associated with rheumatic disorders in a British population: problems with activities of daily living and level of support. Br J Rheumatol 1993; 32: 601-608.
4. Clinical practice guidelines. Osteoarthritis of knee, MOH clinical practice guidelines. Singapore Society of Rheumatology, College of Family Physicians, Singapore, Ministry of Health, Singapore, Chapter of Rheumatologists, College of Physicians, Singapore. 4/May,2007
5. American College of Rheumatology. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines: recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000; 43:1905-1915
. 6. Thumboo J, Chew LH, Lewin-Koh SC. Socioeconomic and psychosocial factors influence pain and physical function in Asian patients with knee or hip osteoarthritis. Ann Rheum Dis 2002, 61:1017-20.
7. Felson D T, Lawrence R C, Hochberg M C, et al. Osteoarthritis: New insights. Part 2: Treatment approaches. Annals of Internal Medicine 2000;133:726-737.
8. Jordan K M, Arden N K, Doherty M, et al. EULAR Recommendations: an evidence based approach to the management of knee osteoarthritis: Report of a task force of the standing committee for international clinical studies including therapeutic trials (ESCISIT). Annals of the Rheumatic Diseases 2003;62:1145- 1155.
9. C. J. McCarthy, P. M. Mills1, R. Pullen, C. Roberts, A. Silman and. A. Oldham Supplementing a home exercise programme with a classbased exercise programme is more effective than home exercise alone in the treatment of knee osteoarthritis. Rheumatology 2004; 43:880-886.
10. Tallon D, Chard JA, Dieppe PA. Exploring the priorities of patients with osteoarthritis of the knee. Arthritis Care Res 2000;13:312-19.
11. DeHaan MN, Guzman J, Bayley MT, et al.Knee osteoarthritis clinical practice guidelines-how are we doing? J Rheumatol 2007;34(10):2099-105.
12. Roddy E, Zhang W and Doherty M. Aerobic walking or Strengthening Exercise for Osteoarthritis of the Knee? A Systematic Review. Annals of Rheumatic Disease 2005;64:544- 548.
13. Fransen M, McConnell S and Bell M. Exercise for osteoarthritis of the hip or knee. The Cochrane Database of Systematic Reviews 2005;4.
14. Thomas et al., Home based exercises programme for knee pain and knee osteoarthritis; Randomized controlled trial.BMJ oct.5,2002 ;325: 752-5.
15. Evick, D. Sonel B., Effectiveness of a home based exercises therapy and walking programme on osteoarthritis of knee.Rhematol.Int.2002, July:22(3) ; 103-06.
16. La Mantia K, Marks R. The efficacy of aerobic exercises for treating osteoarthritis of the knee. New Zealand Journal of Physiotherapy. 1995;23:23-30.
17. Christensen R, Astrup A and Bliddal H. Weight loss: the treatment of choice for knee osteoarthritis? A randomized trial. Osteoarthritis Cartilage 2005;13:20- 27.
18. Adedoyin R, Olaogun M O B and Fagbeja O O. Effect of Interferential Current Stimulation in Management of Osteo-arthritis Knee Pain. Physiotherapy 2002;88:493-499.
19. Deyle G D, Henderson N E, Matekel R L, et al. Effectiveness on manual physical therapy and exercise in osteoarthritis of the knee - A randomized controlled trial.Annals of Internal Medicine 2000;132:173-181
20. Maillefert J F, Hudry C, Baron G, et al. Laterally elevated wedge insole in the treatment of medial knee osteoarthritis: a prospective randomised controlled trial. Osteoarthritis and Cartilage 2001;9:738- 745.
21. P Ravaud, B Giraudeau, I Logeart, J Larguier, D Rolland, R Treves, L Euller-Ziegler, B Bannwarth, and M Dougados. Management of osteoarthritis (OA) with an unsupervised home based exercise programme and/or patient administered assessment tools. A cluster randomised controlled trial with a 2x2 factorial design. Ann Rheum Dis. 2004 June; 63(6): 703- 708.
22. Lin S Y, Davey R C and Cochrane T. Community rehabilitation for older adults with osteoarthritis of the lower limb: a controlled clinical trial. Clinical Rehabilitation 2004;18:92-101.
23. Brosseau L, Judd MG, Marchand S, et al. Thermotherapy for treatment of osteoarthritis. The Cochrane Database of Systematic Reviews 2005; 2.
Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524131EnglishN-0001November30HealthcareSELF EMULSIFYING FORMULATION, PLATFORM FOR SOLUBILITY ENHANCEMENT: A REVIEW
English2838Panner Selvam REnglish Kulkarni P.KEnglish Mudit DixitEnglishPoor drug solubility remains a significant and frequently encountered problem for pharmaceutical scientists. Lipid formulations are one of the approach to enhance rate and extent of oral absorption for poor drug soluble drugs, because along with drug solubility it enhances drug permeability. Self emulsifying drug delivery system (SEDDS) composed of oils, surfactants and cosolvents which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro-intestinal tract. But the solubility of the drugs in these medium and
the proportion of ingredients taken are the most important criteria to have a proper, stable SEDDS. Thus, only very specific pharmaceutical excipients combinations will lead to efficient self-emulsifying systems. This review provides a comprehensive summary of the mechanism, development, characterization of SEDDS. SEDDS appears to be a unique and industrially feasible approach to overcome the problem of low oral bioavailability associated with the lipophillic drugs.
EnglishSelf emulsifying drug delivery system, surfactants, bioavailability.INTRODUCTION
Although oral delivery is the most preferred method of drug administration, this is not possible for roughly 50% of currently marketed drug compounds due to their low solubility in water and low oral bioavailability1,2. In drug discovery, about 40% of new drug candidates display low solubility in water, which leads to poor bioavailability, high intrasubject/intersubject variability and lack of dose proportionality3,4. Thus, for such compounds, the absorption rate from the gastrointestinal (GI) lumen is controlled by dissolution5 .There are various techniques available to improve the solubility of poorly soluble drugs6,7. Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants, ideally isotropic, and sometimes containing co-solvents, which emulsify spontaneously to produce fine oil in-water emulsions when introduced into aqueous phase under gentle agitation8,9 . Therefore, an SEDDS can be an efficient vehicle for class II to IV molecules of the Biopharmaceutical Classification System (BCS) drugs10. Currently the market value of the lipid formulation comprises an estimated 2-4% of the commercially available drug products surveyed in three markets (UK- 2%, US- 3%, and Japan- 4%) worldwide11, 12. The concept of using these systems for pharmaceutical purpose was initially developed by group of Groves. Therefore aspect of formulation of the SEDDS is to improve the bioavailability of the pharmaceutical product13. In this article SEDDS is a general name that includes all self-emulsifying formulations regardless of size.
LIPID FORMULATION CLASSIFICATION SYSTEM (LFCS) 14, 15
LFCS was established by Pouton in 2000 and recently updated in 2006 to help stratify formulations into those with similar component parts. The LFCS briefly classifies lipid-based formulations into four types according to their composition and the possible effect of dilution and digestion on their ability to prevent drug precipitation and they are shown in Table I. Type I are Nondispersing systems, Type II lipid formulations, referred as a self-emulsifying drug delivery systems, Type III lipid-based formulations, commonly referred to as selfmicroemulsifying drug delivery systems. Type IV is dispersion systems: non-oil micellar Systems.
ADVANTAGES 16-20
1. Fine oil droplets formed will pass rapidly from the stomach and promote wide distribution of the drug throughout the GI tract, thereby reduces the irritation.
2. Bioavailability enhancement results from the increased surface area by finely dispersed state of the drug containing lipid globules which leads to increased dissolution. The emulsion globules are further solubilized in the gastrointestinal tract by bile fluids. The surfactants in the formulations enhance absorption by membrane induced permeation changes. The droplets formed are either positively charged or negatively charged. A cationic emulsion has greater bioavailability than an anionic emulsion. As the mucosal lining is negatively charged it was observed that positively charged particles penetrated deeper into the ileum.
3. Enhanced oral bioavailability enabling reduction in dose.
4. More consistent temporal profiles of drug absorption.
5. Selective targeting of drug(s) toward specific absorption window in GIT.
6. Protection of drug(s) from the hostile environment in gut
. 7. Control of delivery profiles.
8. Protective of sensitive drug substances.
9. High drug payloads.
10. Solid, semisolid or liquid dosage forms.
11. Thermodynamically stable when compared to the simple emulsions.
DISADVANTAGES
The main drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations. The large quantity of surfactant in self-emulsifying formulations (30-60%) irritates GIT. Consequently, the safety aspect of the surfactant vehicle had to be considered. Moreover, volatile cosolvents in the conventional self-emulsifying formulations are known to migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic drugs 21 . One of the another obstacles for the development of SEDDS is the lack of good predicative in vitro models for assessment of the formulations 22-25 .
MECHANISM OF SELF EMULSIFICATION
There are many mechanisms proposed in emulsion formation, are as follows Self emulsifying process are related to the free energy, ΔG given by
ΔG = Σ N π r2 σ
Here, N is the number of droplets with radius r and σ the interfacial energy 26. It is clear from the equation that the spontaneous formation of interface between the oil and water phase is energetically not favorable. The system commonly classified as SEDDS have not yet been shown to emulsify spontaneously in the thermodynamic sense. Mustafa and Groves developed a method using phosphated nonylphenoloxylate (PNE) and phosphated fatty alcohol ethoxylate (PFE) in n?hexane. The results suggested that the emulsification process may be associated with the ease with which water penetrates the oil?water interface, with formation of liquid crystalline phase resulting in swelling at the interface, thereby resulting in greater ease of emulsification27 . Consequently, the authors were able to relate the phase behavior to the spontaneity of emulsification, with liquid crystals formation, tending to form emulsion more readily, as indicated by the lower equilibration times28 . Pouton has argued that the emulsification properties of the surfactant may be related to phase inversion behaviour of the system29 . For example, if one increases the temperature of the oil in the water system stabilized by using non?ionic surfactants, the cloud point of the surfactant will be reached followed by phase inversion30. Pouton has suggested that the specificity of surfactant combination required to allow spontaneous emulsification is associated with a minimization of phase inversion temperature, there by increasing the ease of emulsification29
FORMULATION ASPECTS
Ideal properties of drug:
The poorly soluble drugs having high/low permeability, in association with low melting point, critical stability, and low dose (highly potent) are suitable candidates31, 32 .
Composition of SEDDS:
1. Oil: Both long and medium-chain triglyceride (MCT) oils with different degrees of saturation have been used for the design of SEDDS. Unmodified edible oils provide the most ?natural' basis for lipid vehicles, but their poor ability to dissolve large amounts of hydrophobic drugs and their relative difficulty in efficient self emulsification33, 34. MCT were preferred in the earlier SEDDS because of its higher fluidity, better solubility properties and self emulsification ability, but evidently, they are considered less attractive compared to the novel semi-synthetic medium chain derivatives which can be defined rather asamphiphilic compounds exhibiting surfactant properties. Polyglycolyzed glycerides (PGG) with varying fatty acid and polyethylene glycol (PEG) chain lengths giving them a varied hydrophile-lipophile balance (HLB) value, in combination with vegetable oils have been used to solubilise poorly water-soluble drugs and improve their bioavailability35 .
2. Surfactants: Non-ionic surfactants with a relatively high hydrophilic lipophilic balance (HLB) were advocated for the design of self dispersing systems, where the various liquid or solid ethoxylated polyglycolyzed glycerides and Tween 80 are the most frequently used excipients. Nonionic surfactants are known to be less toxic compared to ionic surface-active agents, but they may cause moderate reversible changes in intestinal wall permeability. The usual surfactant concentration in self-emulsifying formulations required to form and maintain an emulsion state in the GI tract ranged from 30 to 60% w/w of the formulation36 .
3. Co-solvents: Organic solvents, suitable for oral administration (ethanol, propylene glycol (PG), polyethylene glycol etc. may help to dissolve large amounts of either the hydrophilic surfactant or the drug in the lipid base37 . Example: Co-solvents like diethylene glycol monoethyl ether(transcutol), propylene glycol, polyethylene glycol, polyoxyethylene, propylene carbonate, tetrahydrofurfuryl alcohol polyethylene glycol ether (glycofurol) etc38
4. Consistency builder: Additional material can be added to alter the consistency of the emulsions; such materials include tragacanth, cetyl alcohol, stearic acids and /or beeswax. 5. Polymers: Inert polymer matrix representing from 5 to 40% of composition relative to the weight, which is not ionizable at physiological pH and being capable of forming matrix are used. Examples are hydroxy propyl methyl cellulose, ethyl cellulose, etc39
SOLIDIFICATION TECHNIQUES40, 41
Spray cooling, Spray drying, Adsorption to solid carriers, Melt granulation, Melt extrusion/extrusion spheronization, Supercritical fluid based methods, Solid lipid nanoparticles (SLN) and Nanostructured lipid carriers (NLC)
DOSAGE FORM DEVELOPMENT OF S-SEDDS42
Dry emulsions, Self-emulsifying capsules, Self-emulsifying sustained/controlledrelease pellets Self-emulsifying sustained/controlledrelease tablets, Self-emulsifying solid dispersions Self-emulsifying beads, Self-emulsifying sustained-release microspheres, Selfemulsifying nanoparticles, Self-emulsifying suppositories, Self-emulsifying implants
TERNARY DIAGRAM 43, 44
This technique was mainly used to map the micro emulsion areas (composition ranges). Ternary phase diagram is used to map the optimal composition range for three key excipients according to the resulting droplet size following self emulsification, stability upon dilution and viscosity.
CONSTRUCTION OF PHASE DIAGRAM 43, 44
A Titration method is employed to construct phase diagram. Mixture of oil with surfactant is prepared at different ratios (e.g. 10:0, 9:1, 8:2, 7:3,6:4, 5:5, 4:6, 3:7, 2:8, 1:9, 0:10) into different vials. A small amount of water in 5 % (w /w) increments is added into the vials. Following each water addition the mixture in vials is centrifuged for 2 to 3 minute and is incubated at 25?c for 48 hrs with gentle shaking. The resulting mixture is evaluated by visual and microscopy observation. For phase diagram the micro emulsion is the region of clear and isotropic solution. Coarse emulsion is the region of cloudy dispersion.
EVALUATION PARAMETERS
Turbid metric evaluation:
Nepheloturbidimetric evaluation was done to monitor the growth of emulsification. Self-emulsifying system was added to 0.1N hydrochloric acids under continuous stirring on magnetic plate at ambient temperature, and the increase in turbidity was measured using a turbid meter45, 46 .
Viscosity determination: Viscosities of the systems as such and after dilution with 5% v/v water were determined using Brookfield rheometer at ambient temperature. Under varying shear rate, viscosities were measured and the data obtained were further analyzed by regression treatments47 .
Droplet size analysis or particle size measurements: The droplet size of the emulsions is determined by microscopic techniques or Coulter Nanosizer or photon correlation spectroscopy 48. The nanometric size range of the particle is retained even after 100 times dilution with water which proves the system's compatibility with excess water49 .
Droplet polarity: Polarity of oil droplets is governed by the HLB value of oil, chain length and degree of unsaturation of the fatty acids, the molecular weight of the hydrophilic portion and concentration of the emulsifier. Polarity of the oil droplets is also estimated by the oil/water partition coefficient of the lipophillic drug50 .
Electrical Conductivity Measurement: Electrical conductivity of the samples was measured using a conductivity meter. Electrical conductivity of the formulations was determined to check the stability and assert the nature of the formulation51 .
Refractive index and percent transmission: Refractive index and percent transmittance proves the transparency of formulation. The refractive index of the system is measured by refractometer by placing drop of solution on slide and it is compared with water. If refractive index of system is similar to the refractive index of water and formulation has percent transmittance > 99 percent then formulation has transparent nature 52 .
Centrifugation: Microemulsion systems were subjected to centrifugation at 3000 rpm for 30 minutes and then examined for any phase separation This technique helps to determine behaviour of small particles in gravitational field53 .
Differential scanning calorimetry (DSC): Physical state of the drug in lipid carrier was analyze by DSC studies. Thermal analysis of drug, the physical mixture of drug and Lipid carrier were carried out using differential scanning calorimetry method54 .
X-ray diffraction studies:X-ray diffraction studies analyze the crystalline nature of the drug in the mixture. X-ray diffraction was performed using a diffractometer, with a monochromatics radiation having suitable voltage and current at an angle of 2θ over a range of 5 40. Diffraction patterns of pure drug and Lipid carrier were prepared at the suitable drug-to-lipid ratio for the determination55 .
In vitro diffusion study: In vitro diffusion studies were performed using dialysis technique/Dissolution apparatus56
Drug content: Drug from pre-weighed SEDDS is extracted by dissolving in suitable solvent. Drug content in the solvent extract was analyzed by suitable analytical method against the standard solvent solution of drug.
In vivo Characterization includes Nonclinical Evaluation, Choice of nonhuman Test Species, Lymphatic Transport57 .
CONCLUSION
Approximately 40% of new chemical drug moieties have poor aqueous solubility and it is a major challenge to modern drug delivery system. Self emulsifying drug delivery system are suited for BCS class 2 and class 4 drugs. The proper selection of the oil and surfactants are most important for successful development of SEDDS. Solidification techniques enhances the stability and easy handling. By exploiting studies about human bioavailability and in vitro methods for predicting the dynamic changes involving the drug in the gut in order to monitor the solubilisation state of the drug in vivo, open the gateway for the many drugs to enter market as SEDDS
Englishhttp://ijcrr.com/abstract.php?article_id=2203http://ijcrr.com/article_html.php?did=22031. Humberstone AJ, Charman WN. Lipidbased vehicles for the oral delivery of poorly water soluble drugs. Adv Drug Deliv Rev 1997;25(1):103-28.
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3. Lipinski C. Poor aqueous solubility-an industry wide problem in drug discovery. Am Pharm Rev 2002;5:82-5.
4. Palmer AM. New horizons in drug metabolism, pharmacokinetics and drug discovery. Drug News Perspect 2003;16:57-62.
5. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutical drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995;12:413-20.
6. Pinnamaneni S, Das NG, Das SK. Formulation approaches for orally administered poorly soluble drugs. Pharmazie 2002;57:291-300.
7. Kulkarni PK, Dixit M, Kini AG, Johri A. Spherical agglomerates of mefenamic acid by solvent change method. An int j pharma sci 2010;1:388-402,.
8. Wakerly MG, Pouton CW, Meakin BJ, Morton FS. Self-emulsification of vegetable oil-non-ionic surfactant mixtures. ACS Symp Ser 1986;311:242-55.
9. Sachan R, Khatri K, Kasture S. SelfEumlsifying Drug Delivery System: A Novel Approach for enhancement of Bioavalibility. Int J PharmTech Res 2010 July-Sept;2(3):1738-45,.
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11. Strickley RG. Oral Lipid-based Formulations: Enhancing the Bioavailability of Poorly Water-soluble Drugs. New York: Informa Healthcare; 2007, pp.221-238.
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16. Corbo DC, Liu JC, Chein YW. Characterization of the barrier properties of mucosal membranes. J Pharm Sci 1990;79:202-6
. 17. Gershanik T, Haltner E, Lehr CM, Benita S. Charge dependent interaction of self emulsifying oil formulation with CaCo-2 cell monolayers; binding effects on barrier function and cytotoxicity. Int J Pharm 2000;211(1- 2),29-36.
18. Gershanik T, Benzeno S, Benita S. Interactions of the SELDDS with mucosa of everted rat intestine as a function charge and particle size. Phar Res 1998;15:863-9.
19. Patil P, Joshi J, paradkar P. Effect of formulation variables on preparation and evaluation of gelled selfemulsifying drug delivery system(SEDDS)of ketoprofen. AAPS Pharm Sci Tech 2004;5(3):34-42 .
20. Pouton CW, Charman WN. The potential of oily formulations for drug delivery to the gastro-intestinal tract. Adv Drug Deliv Rev 1997;25:1-2.
21. Pathak A, Jain V, Nagariya AK, Singh R, Nayak S, Bansal P, Gupta V, Kumar S, Singh H. Recent advances in self emulsifying drug delivery system - A review. Drug Invention Today 2010;2(2):123-9.
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23. Patil P, Patil V, Paradkar A. Formulation of a self-emulsifying system for oral delivery of simvastatin: In vitro and in vivo evaluation: Acta Pharm 2007;57:111-22.
24. Tang B, Cheng G, Chun J. Development of solid self emulsifying drug delivery systems, preparation techniques and dosage forms: Drug Discovery Today 2008;13:606-11.
25. Zhang P, Liu Y, Xu J. Preparation and Evaluation of SEEDS. Int J Pharm 2008;355:269-76.
26. Reiss H. Entropy-induced dispersion of bulk liquid. Journal of colloidal interface Sciences 1975;53:61?70.
27. Groves MJ, Mustafa RMA. Measurement of -spontaneity? of self emulsifiable oils. J Pharm Pharmacol 1974;26:671?88.
28. Groves MJ, Mustafa RMA, Carless JE. Phase studies of mixed surfactants nhexane and water. J Pharm Pharmacol 1974;26:616-23.
29. Pouton CW. Formulation of selfemulsifying drug delivery system. Adv Drug Del Rev 1997;25:47-58.
30. Friedman D. Non-aqueous compositions for oral delivery of insoluble bioactive agents. US Patent 20070190080. 2005 july 21.
31. Charman SA, Charman WN, Rogge MC. Self-emulsifying drug delivery systems: formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharmacy Research 1992;9:87-93.
32. Serajuddin ATM. Solid dispersion of poorly water- soluble drug: early promises, subsequent problems, and recent breakthroughs. J Pharma Sci 1999;88:1058-66.
33. Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs: Euro J Pharm Biopharm 2000;50:179-88.
34. Aungst BJ. Novel formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or presystemic metabolism. J Pharm Sci 1993;82:979- 86.
35. Tang JL, Sun J, He ZG. SelfEmulsifying Drug Delivery Systems: Strategy for Improving Oral Delivery of Poorly Soluble Drugs. Curr Drug Theraphy 2007;2:85-93.
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Radiance Research AcademyInternational Journal of Current Research and Review2231-21960975-524131EnglishN-0001November30HealthcareMODULATION OF CNS ACTIVITY BY TRADITIONAL MEDICINES: A REVIEW ON NEURO PHARMACOGNOSY
English3948Vivek Kumar REnglish Satish KumarEnglish Shashidhara SEnglish Anitha SEnglishModulation of CNS Secretion may offer novel approaches in the treatment of a variety of
diseases. One strategy in the modulation of CNS may be through the use of herbal medicines.
This review aimed to provide information on herbal drugs acting on CNS such as, Anesthetics,
Sedative-Hypnotics, Spasmolytics, Anti-seizure, Opioid analgesics, Anti-parkinsonism, Antidepressant,
Anti-psychotic, Anti-Alzheimer and Immuno-modulators. Phytotherapy offers a potential therapeutic modality for the treatment of many differing conditions. Given the activity demonstrated by many of the reviewed herbal medicines and the increasing awareness of the broad-spectrum effects of herbal medicines on autoimmune conditions and chronic degenerative processes.
EnglishAnesthetics, Anti-seizure, Immunomodulators, Neuro pharmacognosy.INTRODUCTION
The central nervous system directs the functions of all tissues of the body. The peripheral nervous system receives thousands of sensory inputs and transmits them to the brain via the spinal cord. The brain processes this incoming information and discards 99% as unimportant. After sensory information has been evaluated, selected areas of the central nervous system initiate nerve impulses to organs or tissue to make an appropriate response. Chemicals exerting their effects in the central nervous system (brain and spinal cord) have been used since the most primitive times to the present. Today, in addition to many medical uses, drugs acting on the CNS are used worldwide (i.e., alcohol, caffeine, and nicotine) with various degrees of societal controls due to production of addiction and/or dysfunctional behaviors. The World Health Organization estimates that 65%-80% of the world's population use traditional medicine as their primary form of health care. The use of herbal medicine, the dominant form of medical treatment in developing countries, has been increasing in developed countries in recent years. About one third of the adult U.S. population uses medicinal herbs as some form of alternative therapy (Foster and Tyler, 2000; Miller and Murray, 1998). Sales of herbal products at the retail level increased from an estimate of 500 million dollars to approximately 5 billion dollars in 1999, more than double the amount compared to sales just two years before (Foster and Tyler 2000; Karch 1999). Herbal medicine accounted for approximately 26% of complementary and alternative medicine used by South Australians according to MacLennan et al survey.
All psychotropic medications such as Anesthetics, Sedative-Hypnotics, Spasmolytics, Anti-seizure, Opioid analgesics, Anti-parkinsonism, Antidepressant, Anti-psychotic, Anti-alzheimer and Immuno-modulators will have the potential to induce numerous and diverse unwanted effects. This article provides an informal review of the scientific literature regarding the effects of botanical medicines on CNS.
METHODOLOGY
1. Search Strategy: The databases MEDLINE, EBSCO, and BIOSIS were searched for appropriate studies. Titles were screened for all hits to the terms "herbs and CNS" and "Chinese medicine and CNS? and "Ayurveda and CNS." A language restriction of English was observed
2. Criteria for Inclusion:
The following parameters were necessary for study inclusion:
? Investigations on whole herbs (e.g., seed, leaf, root, stem, flower, or entire plant) standardized extracts, or extractions of whole herbs not reduced to one constituent were accepted. Research on isolated constituents or multiple herbal formulations were generally rejected. Fungi, although technically not plants, were included as they are commonly used in phytotherapy.
? Information on methods of herbal preparation, concentration of the plant preparation, and dose/exposure time were required.
? Only studies demonstrating activity with regard to CNS were included.
3. Herbal drugs
3.1 Herbal drugs as Anesthetics:
A substance that causes lack of feeling or awareness. A local anesthetic causes loss of feeling in a part of the body. A general anesthetic puts the person to sleep for example procaine, amethocaine, cocaine. Local anesthetic toxicity involves the nervous system, including agitation, confusion, dizziness, blurred vision, tinnitus, a metallic taste in the mouth, and nausea that can quickly progress to seizures and cardiovascular collapse. Intravenous agents (non-opioid) barbiturates, opioid analgesic agents produce side effects such as Hyperkalemia, Muscle aches, malignant hyperthermia, Anaphylaxis. So herbal drugs were consider as a safe anesthetic with out side effects listed in Tab.b
3.2 Herbal drugs as Sedative-Hypnotics
Sedative-hypnotics are drugs which depress or slow down the body's functions. Often these drugs are referred to as tranquilizers and sleeping pills or sometimes just as sedatives Barbiturates and benzodiazepines are the two major categories. All sedatives can cause physiological and psychological dependence Dependent users may get withdrawal symptoms ranging from restlessness and insomnia to convulsions and death. The Literature survey suggest that the use of Herbal drugs are free of side effects enlisted in Tab.b
3.3 Herbal drugs as Spasmolytics
muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. Spasmolytics, also known as "centrally-acting" muscle relaxants, are used to alleviate musculoskeletal pain and spasms and to reduce spasticity which shows side effects such as syndrome heart failure, paralysis lethargy, as well as anti cholinergic side effects. Herbal drugs such as-Tab.b
3.4 Herbal drugs as Anti-seizure: Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. About 50 million people worldwide have epilepsy, with almost 90% of these people being in developing countries. Currently there are 20 medications approved by the Food and Drug Administration for the use of treatment of epileptic seizures in the US. According to European survey, 88% of patients with epilepsy, reported at least one anticonvulsant related side effect Some examples include mood changes, sleepiness, or unsteadiness in gait, drug rashes, liver toxicity (hepatitis), or aplastic anemia. Natural treatment to seizures using following herbs as in Tab.c
3.5 Herbal drugs as Opioid analgesics: An Opioid is a chemical that works by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract. The side effects of opioids include sedation, respiratory depression, and constipation. Tab .c
3.6 Herbal drugs as Anti-parkinsonism: Parkinson disease is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills, speech, and other functions. But lost of side effect
Digestive Tract: Nausea; vomiting; diarrhea; Nervous System: Uncontrolled movement (twitching) of face, eyelids, mouth, hands, or legs; Circulatory System: Palpitations (pounding in the chest); irregular heartbeat; chest pain; changes in blood pressure. Skin: Flushing; rash; increased sweating; hives; itching; hair loss; a normal skin sensation. Other: Difficult urination; urinary incontinence; difficulty swallowing; numbness; increased salivation; dry mouth or nose; grinding of the teeth; difficulty opening mouth; taste changes; bitter taste; Devoid of side effect herbal such as Mucuna prurens was used. Tab .b
3.7 Herbal Antidepressants and Anxiolytics:
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. St. John's Wort is by far the most widely-used and well-studied herbal antidepressant. A number of other herbs have been used traditionally to treat depression and related ailments like anxiety, but the research on most of these treatments is sparse.Tab .d
3.8 Herbal drug as Anti-psychotic:
An antipsychotic (or neuroleptic) is a tranquilizing psychiatric medication primarily used to manage psychosis (including delusions or hallucinations, as well as disordered thought), particularly in schizophrenia and bipolar disorder.Antipsychotics are among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008. A number of harmful and undesired (adverse) effects have been observed, including lowered life expectancy, weight gain, enlarged breasts and milk discharge in men and women (hyperprolactinaemia), lowered white blood cell count (agranulocytosis), involuntary repetitive body movements (tardive dyskinesia), diabetes etc.Herbal drug such as Tab .d
3.9 Herbal drug as Anti-Alzheimer: Alzheimer's disease (AD) is the most common form of dementia in the elderly, accounting for 50% to 75% of patients with dementia.Dementia is characterized by memory impairment and at least one of the following: aphasia, apraxia, agnosia, or a disturbance in the ability to think abstractly and to plan, initiate, sequence, monitor, and stop complex behavior. More than four million people have AD in the United States.Vitamin E, withania somnifera, Ginkgo Biloba is the herbal drug most commonly used. Tab .d
3.10 Herbal Immunomodulators:
Immunomodulators alters the activity of immune function through the dynamic regulation of informational molecules such as cytokines. However, as with the development of many nascent pharmacological strategies, the occurrence of adverse events generates barriers to successful therapeutic applications. Such obstacles have delayed progress in the use of several synthetic cytokines.In order to maintain relevance for clinical phytotherapy, this informal survey was limited to herbal medicines available in the marketplace or preparations that represent multi-component botanical medicines. Tab .e
3.11 Complete Index of Ayurvedic Formulations For CNS.(Tab a)
CONCLUSION
Although many of the plants listed in this review appear to affect CNS, it is the lead author's opinion that future research will further demonstrate the broad-spectrum activity of herbal medicine. Currently, the research on the influence of botanical medicines on CNS and other messenger molecules is limited. Informational molecules and many of their receptors may likely turn out to be modulated by plants, both herbal medicines and foods, providing potential for future therapeutics.
Further research (particularly clinical studies) is indicated to elucidate the effects of botanical medicines and to support or refute the hypotheses presented in this article.
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