Efficacy and Safety of Bisoprolol plus Amlodipine Fixed Dose Combination in Essential Hypertension

ABSTRACT

Objective: Antihypertensive drug combinations are being increasingly used in the  man­ management of hypertension. This was an observational study to gather data about the real-world experience on the safety and efficacy of bisoprolol and amlodipine combination in the  treat­ment  of stage  2 essential hypertension.

Methods: 801  patients with stage  2 essential hypertension who fulfilled inclusion and ex­clusion   criteria were   enrolled   in  the   study.   They received   fixed  dose   combination  of AmJodipine (5 mg) and    Bisoprolol (5 mg) OD for a period of 4 weeks. Patients were termed as “responder”. if the diastolic BP and systolic BP was  < 90 mmHg and  < 140 mmHg. respectively at the end of the trial period. The global efficacy and global tolerability was judged at the end of

4-week  treatment period.  Adverse  events,  either  spontaneously  reported by the patient. or noticed by the physician during trial  period, were recorded. Statistical analysis was done us­ ing Paired test and  Me Nemar’s  test,  as applicable.

Results: Out of the  801  patients enrolled  in the study, 749  patients completed  the study (median age 53.6 yrs). The mean  systolic blood pressure at baseline was 171.9 ± 17.9 mm Hg. This reduced  significantly (p < 0.001)  to 152.9  ± 16.4 mmHg, 142.1 ± 13.1 mmHg and 134.3 ±

10.1 mmHg at the end of 1,2 and  4 weeks of treatment respectively. The mean diastolic blood pressure at baseline was 103.9 ± 9.6 mmHg. This reduced significantly (p < 0.001) to 93.5± 8.8 mmHg, 88 ± 7.3  mmHg and  83.4  ± 6.2  mmHg at the end  of 1.2  and 4 weeks of treatment respectively. The  mean  heart rate  at  baseline  was 83.3 ± 9.6  beats per  minute. It reduced significantly (p < 0.0001)  to 78.3 ± 7.2. 75.8 + 6.8 and 74.6 ±  6.8 beats per minute, at the end of the 1. 2 and 4 weeks of treatment respectively. The responder rate  at the end of 4 weeks of treatment was 82.5.  Excellent to good efficacy and  tolerability  was  observed  in 91.4%  and 90.3% of the subjects, respectively.

Conclusion: Once daily administration of the  ftxed dose combination of amlodipine 5 mg and  bisoprolol 5 mg is effective, safe and  well tolerated in treatment of patients suffering  from stage 2 essential hypertension. (The Ind.  Pract. 2008; 61(4):225–234)

KEYWORDS
fixed dose combination, Bisoprolol, Amlodipine, Essential Hypertension.

INTRODUCTION
The  recent  ESC/ESH guidelines for the management  of   hypertension state  that monotherapy allows to achieve  BP target  in only a limited  number of hypertensive pa­ tients’  and  that ‘use  of more  than  one agent Is necessary to achieve  target  BP in the ma­ jority of patients. 1 The JNC VU recommends that  when  the  blood  pressure is more than 0/10 mmHg  above  goal,  consideration should  be given to initiating therapy with 2 drugs,  either  as separate prescriptions or in fixed dose combination. 2

It has been well demonstrated in multiple studies that  the response rate  to any single class  of antihypertensive agent,  given as monotherapy, is approximately 45-55o/o. Thus,  in approximately half of the hyperten­ sive  population, a  second   drug will be  re­quired  the  randomized  trials of antihyperten­ sive  therapy conducted during  the  1970s and  1980s,  in which very large doses  of sin­gle drug were  employed as Initial  therapy, more than   50o/o  of patients required   treat­ment  with  combination therapy in order  to achieve the blood pressure goal indicated in the  trial protocol.  This  implies  that  an  in­ crease in the dose of the initial antihyper­ tensive agent does not usually significantly increase the  effectiveness of monotherapy. It is well known that high doses of almost all antihypertensive agents  increase  the   risk and th<.; severity of adverse effects.  Adverse effects  of drugs are  the  main  cause of the low compliance of patients with  antihyper­ tensive  therapy in practice. Essential hyper­ tension  has  multiple mechanisms, and  ra­ tional  combination therapy allows  interfer­ence  with  more  than   one  of these mecha­ nisms.   Rational   combination  therapy  not only reduces adverse effects  because of the use of low doses of each combined  agent,  but can  also  take  advantage of counteractions that each  of the combined agents can  exert on   the   undesirable  actions of  the   other agent.4

It has  been shown  that  simplification  of a drug  regimen  by using combination therapy in a single  pill for hypertension resulted in significant increases in persistence with prescribed  therapy.5

Both bisoprolol  and amlodipine are widely used  antihypertensive drugs. Bisoprolol  be­ing  a  beta-blocker (BB) Is  well  suited foe young patients who have a ‘vasoconstrictive’ type of hypertension with  high  renin  while amlodiplne,    a   calcium    channel   blocker (CCB) is suited for older  patients with ‘vol­ ume expanded’ type  of hypertension and  a low or suppressed renin  activity.  Hence,  the physiologically   and    pharmacologically  ra­ tional  for the  combination of these  drugs is that  they have complementary mechanisms of action  and   may  counteract each  others side-effects:  for instance, CCBs  tend  to in­ crease   heart rate   (reflex  tachycardia)  BBs tend  to lower the  heart rate.

There  is  a  clear paucity of scientific  lit­erature regarding the  use  of a combination of bisoprolol  and  amlodipine in the  treat­ment  of hypertension. The  present observa­tional  study aims  to gather data about  the real world experience on the safety  and effi­cacy of bisoprolol  and  amlodipine combination  in  the  treatment of stage  2  essential hypertension.

OBJECTIVE

1. To evaluate the efficacy of the fixed dose combination of bisoprolol  (5 mg) and amlodipine (5 mg) for the treatment of stage  2 essential hypertension.
2. To  evaluate  the   responder  rate  to  the fiXed dose combination of bisoprolol (5 mg) and amlodipine (5 mg) used  for the treat­ment  of stage  2 essential hypertension
3. To evaluate the  safety  and  tolerability of the fixed dose combination of bisoprolol (5 mg) and  amlodipine (5 mg) for the  treatment  of moderate to stage  2  hyperten­sion.

STUDY DESIGN

The study was an open, non-comparative, multicentric, and  prospective trial  con­ducted at  169   centres  after   obtaining  a clearance  from an independent ethics  com­mittee.

NUMBER OF PATIENTS

This study was conducted in 801 adult males and females newly diagnosed  with a clinically confirmed  stage  2 essential hyper­ tension  (based  on  average  of 2 or more  re­ cordings each  taken  at 2 or more visits) and aged between 18 and 70 years. Patients with stage 2 hypertension uncontrolled by monotherapy with amlodipine or ramipril  or atenolol were also recruited.

The  patients were  recruited after  fulfill­ ing the inclusion and  exclusion criteria mentioned  below and  after  obtaining in­ formed written  consent.

INCLUSION CRITERIA

1. Patients of either  sex aged  18 -70 yrs
2. Newly diagnosed   patients with  clinically confirmed stage 2 hypertension (based on average  of  2  or  more  recordings each taken  at 2 or more visits) as per the JNC VII (Annexure 1)
3. Patients with  stage  2  hypertension  un- controlled    by      monotherapy      with amlodipine   or   ramipril  or atenolol

EXCLUSION CRITERIA

1. History  of  hypersensitivity  to  either   of the components
2. General  contraindications of 13  – blockers and I or calcium  channel blockers
3. Concomitant illness    such  as    uncon­trolled  diabetes mellitus. liver and  I or kidney dysfunction, decompensated car­ diac  failure.
4. Alcohol and I or drug abuse.
5. Pregnancy  and  I or lactation.
6. Necessity  for  unavoidable concomitant drug therapy, which may vitiate interpre­tation  of the results.

DRUG AND DOSAGE

Fixed dose  combination of Amlodipine  (5 mg) and   Bisoprolol (5 mg).

1 tablet  once daily (0.0.) preferably  given in  the  morning.  In  case  of inadequate  BP control,  at the end of the  2nd  week of treat­ment. enalapril 5 mg can  be added.

DURATION OF TREATMENT

The study was conducted for a period of 4 weeks.

DATA COLLECTION

Patients agreeing  to participate in the survey  were required to visit the hospital  as per  the  4  scheduled  visits.  The  Physician had  to capture the  patient’s clinical  history and  perform  a general   examination (Pulse and  BP measu rement)  and  administer the study   medication during  initial  visit  (VO). The patient has  to continue the study medi­ cation  containing amlodipine 5 mg plus Bisoprolol  5 mg. 1 tablet once  daily  in  the morning during the  entire  study period  (4 Weeks) and also Pulse and  BP measurement will be recorded  during the 3 scheduled fol­ low up visits V1 (Week 1). V2 (Week 2) and V3 (Week 4) ). In case of inadequate BP control, at  the   end   of  2nd   Week   of  treatment, enalapril 5 mg can be added. The Global im­ pression after usage of the study drug wilJ be recorded  in  the  final  Visit  (V3).  Physicians had  to complete  a clinical  case  report  form for each  patient that included   information on the patient’s blood pressure, and  con­ comitant medication usage.

Occurrence of any  side  effect suffered    I reported   by  patient were  also  be  noted  at every  visit.

ENDPOINTS

Efficacy

Patient  were termed  as “responder”, if the diastolic BP (DBP) and systolic BP of< 90 mm Hg and   < 140 mmHg respectively  was re­ corded  at the end  of trial period. The global efficacy was judged  on a four point scale  i.e. Excellent. good. satisfactory and poor. by the investigator at the end  of 4 week treatment period based  on the overall reduction in the systolic and diastolic blood pressure and the overall improvement in  the  patient’s condi­ tion.

Tolerability

The adverse events. either  spontaneously reported   by the  patient, or  noticed  by  the physician during trial period, were recorded. The global tolerability was judged  on a four­ point  scale  i.e. excellent. good, satisfactory and poor, by the investigator at the end of 4- week treatment period.

Compliance

All medications were dispensed by the in­ vestigator to all eligible patients, during all visits.  At each  visit,  patients were  in­ structed to bring back  the empty  packs and all  the  unused medication,  with  a view to check  compliance.

STATISTICAL ANALYSIS

Data on a continuous scale was expressed as  Mean ± SD. while the  frequency  type  of data  was expressed as  percentage. The dif­ ference from baseline to following visit is compared  using  Paired   test.  Repeated measure analysis of variance was  used  to see overall effect during trial  period. All sta­tistical test applied  here were two tailed and p < 0.05 was considered as statistically sig­nificant.

Descriptive  statistics are  used   to  report the   Demographics,   Concomitant   medica­ tion, Vital signs,  Responder rate. Adverse Events  and  Global  Expressions.  Mean. Standard  deviation.   Minimum and   Maxi­mum  is used  for continuous variables and Frequency and  Percentage is used  for cat­egorical  variables. P-value  is calculated  by Comparing the  average  change of BP from Baseline  to end  of the study using  paired  t­ test  with  2-  tailed  and  5o/o  level of signifi­cance.  P-value  is  calculated by  Comparing the proportion  of responder rate  from Base­ line  to e.1d of the  study using  Me Nemar’s test  with  2-  tailed and  5o/o  level of significance.

RESULTS

A total of 801 patients were enrolled in the study and 749 patients completed the study. There were a total of 52 dropouts during the treatment. The final data  was evaluated on a total of 749 patients.

The demographic characteristics of patients are given in Table  1. The mean  age of the patients was  53.6  years  (range  26-82 years).   Of  the  total patients,  59.7o/o  were males  and  40.3o/o were  females.  The  mean weight  of the  patients were 68.2  Kg (range 35-102 Kg).

The  mean  heart rate  of the  patients was per minute). The mean systolic and diastolic blood pressure of the patients was 171.7 mm Hg (range,168- 240 mmHg) and 103.5 mm Hg (range 60-160 mmHg).

The mean systolic blood pressure at base­ line was 171.9 …± 17.9 mm Hg. This reduced significantly (p < 0.001)  to 152.9 ± 16.4 mmHg, 142.1± 13.1 mmHg and 134.3  ± 10.1 mmHg at the end of 1, 2 and 4 weeks of treat­ment  respectively  (Table 2, Graph  1).

A mean  fall of 21.8  o/o  from baseline  was recorded in the systolic blood pressure at the end of 4 weeks of treatment (Graph 2).

The  mean  diastolic blood  pressure at baseline was  103.9  ± 9.6  mm  Hg. This  re­duced  significantly (p < 0.001)  to 93.5 ± 8.8 mmHg, 88 ± 7.3 mmHg and 83.4 ± 6.2 mmHg at the end of 1, 2 and  4 weeks of treatment respectively  (Table 3., Graph  3).

A mean  fall of 19.7o/o  from baseline was recorded  in  the  diastolic blood  pressure at the end  of 4 weeks of treatment (Graph 4).

At the  end  of  the  treatment period  the mean  systolic  blood pressure and  mean diastolic  blood pressure was well below goal set by the JNC VII for hypertension.

The mean  heart rate at baseline was 83.3 ± 9.6 beats  per minute. This reduced signifi­ cantly  (p < 0.0001)  to 78.3 ± 7.2,  75.8 ± 6.8 and  74.6 ± 6.8 beats per minute, at the end of the 1, 2 and 4 weeks of treatment respec­ tively (Table 4, Graph  5).

A mean  fall of 10.4% from  baseline was recorded  in the  mean  heart rate  at the  end of 4 weeks of treatment (Graph  6).

The responder rate  which  was calculated as  the  percentage of patients achieving  the blood pressure of< 140/90 mmHg, at the end of 4 weeks of treatment was 82.5.

Adverse events

The   most   commonly  reported   adverse event  was  oedema  feet occurring in 8% patients.  Other  adverse events reported  were headache (4%), fatigue (3%), leg cramps (3o/o) and  dry  mouth  (1o/o)  (Table 5). All reported adverse events were mild in severity  and did not require hospitalization or discontinua­ tion of therapy.

GLOBAL  ASSESSMENT

Efficacy and tolerability

The  efficacy and  tolerability of the  treat­ ment  was  assessed by investigators at  the end of 4 week treatment period based on the overall  reduction  in  the  systolic  and diastolic  blood  pressure and  the overall im­ provement  in the  patient’s condition.

The investigators reported an  excellent  to good efficacy in 91.4% of the patients (Graph 7). In 7.8% patients the efficacy reported was satisfactory and  in  0.8%  patients the  effi­cacy reported was poor (Graph 7).

The  global  tolerability, at  the  end  of  8 we ks  of treatment, was  also  assessed  by the patients. The patients reported an excel­ lent to good tolerability  to the combination in 90.3% of the  patients. In 8.7% patients the tolerability reported was satisfactory and  in 0.7% as poor (Graph 8).

 

Discussion

Hypertension  affects  approximately 50 million individuals in the United States and approximately 1  billion  worldwide.  As  the population ages,  the  prevalence of hyperten­ sion  will increase even further unless broad and   effective  preventive   measures are  im­plemented. Recent data from the Framingham Heart  Study suggest that  indi­ viduals who are  normotensive at the  age 55 have a 90 per cent  lifetime  risk for developing  hypertension.2

For  individuals 40-70 years  of age,  each increment of 20  mmHg  in systolic  BP (SBP) or 10 mmHg in diastolic BP (DBP) doubles the risk of CVD  across the entire BP range  from 115/75 to 185/115 mmHg:2

Reduction in systolic blood pressure  to <140 mm Hg and diastolic blood pressure to < 90 mm  Hg is associated with  a decrease in the incidence of CVD  complications.6 Two thirds of hypertensive patients are  not being controlled  to BP levels less than 140/90 mm Hg.  It is therefore recommended that  when the   blood   pressure  is   more   than  20I 10 mmHg  above  goal,  consideration should   be given to initiating  therapy with  2 drugs, ei­ them as  separate  prescriptions or  in  fixed dose combination.2

It is noteworthy that, only approximately 50% of hypertensive patients respond  to monotherapy, and majority of this group (>2/ 3 rd) require the highest recommended dose to achieve  control.7

Five  major  class of anti-hypertensive agents – thiazide diuretics, calcium antago­ nists, ACE inhibitors, Angiotensin receptor antagonists and  beta  blockers are  suitable for  the  initiation and  maintenance of anti­ hypertensive treatment,  alone  or in  combi­ nation. 1

The  combination  of  amlodipine and bisoprolol   demonstrates an   additive   effect since both  the drugs have different and com­ plementary modes of actions to reduce  blood pressure: for example, a vascular selective calcium  antagonist like amlodipine lowers total  peripheral resistance and  a beta  1 se­ lective  blocker  like  bisoprolol  lowers  heart rate and.  thus, cardiac output. Additionally, since  both  the  drugs have  to  be  administered  once daily,  the  rationality of the com­bination  is further strengthened.

In the present study a once daily adminis­ tration of the fixed dose  combination of amlodipine 5 mg and bisoprolol 5 mg demon­ strated a significant lowering of both systolic and  diastolic  blood  pressure at the  end  of 4 weeks of treatment.

The mean  systolic blood  pressure signifi­cantly  reduced  from 171.7 ± 17.9  mm Hg to 134.3 ± 10.1  mmHg  by  the  end  of the  41h week of treatment.

A similar  decrease was  also  recorded  in the  diastolic  blood pressure, which  reduced from a baseline of 103.9 ± 8.6 mm Hg to 83.4 ± 6.2  mmHg at the  end  of 4 weeks of treat­ment.

Both the systolic  and diastolic blood pres­ sures reached  the  target  range  as early as 4 and  2 weeks of treatment respectively.  The investigators reported an  excellent to good efficacy in 91% of the patients.

82.5% of the patients achieved blood pres­ sure control  at values < 140/90 mm  Hg at the end of 4 weeks of treatment. This was in compliance  with   the   JNC   VII  guidelines which  mentions that the  treatment goal for individuals with  hypertension and  no other compelling conditions should be   < 140/90 mmHg.2

The fixed dose combination of amlodipine 5 mg and  bisoprolol  5 mg was generally  well tolerated.  90o/o of the  patients reported  an excellent- good tolerability to the combina­ tion.

The  most  commonly reported adverse event was oedema  feet occurring in 56 (7.48 o/o)   patients. The   adverse  events  reported were  mild  and  did  not  require hospitaliza­ tion or treatment.

SUMMARY

The present open,  prospective, non  com­ parative  study evaluated the  safety,  efficacy and  tolerability of the flxed dose combination of amlodipine 5 mg and  bisoprolol  5 mg in 749 adult patients with stage 2 essential hy­pertension.

Once daily dose of the study medication resulted in a significant reduction in the systolic and   diastolic blood  pressure to  <140/90 mmHg  with  investigators reporting an excellent  to good efficacy in 91% of the patients. A responder rate  of 82.5%  was re­ corded  at the  end  of 4 weeks  of treatment. The flxed dose  combination of amlodipine 5 mg and  bisoprolol  5 mg was well tolerated, with 90% of the patients reporting an excel­ lent -good  tolerability.

CONCLUSION

Once  daily   administration  of  the   fixed dose  combination of amlodipine 5 mg and bisoprolol  5 mg is effective, safe and well tol­ erated   in   treatment  of  patients  suffering from  moderate essential  hypertension.

REFERENCES

1. Joint Task   Force  of European and  other  Socie­ ties on  Cardiovascular Disease  Prevention  In Clinical  Practice.  European Guidelines on car­ diovascular disease  prevention   In  clinical  prac­ tice. Eur  Heart  J. 2007,  28,  1462-  1536
2. Chobanlan AV. Bakris  GL, Black  HR. et  al. The seventh   report  of  the  Joint National  Committee on  Prevention,     Detection.      Evaluation.   and  Treatment   of    High    Blood    Pressure.   JAMA. 2003;289:2560-2572
3. Neutel  JM.  Black  HR. Weber  MA. Combination therapy with diuretics: an  evolution  of under­ standing. Am  J Med.   1996;101(3A):61S-70S
4. Zanchetti A. Contribution  of  fixed  low-dose combinations   to   Initial    therapy    Ln   hyperten­ sion.  Eur.  Heart  J. suppl.   1999;  1:L5-L9
5. Dezu  CM. A  retrospective  study   of  persistence with  stngle-ptll  combination therapy vs.  con­ current two-pill  therapy   In  patients with  hyper­ tension.  Manag  Care.  2000;  9(9 Suppl):2-6
6. Hansson    L,  et   al.   Effects  of  Intensive   blood­ pressure  lowertng  and   low-dose  asplrtn   Ln  pa­ tients   with   hypertension:  principal    results  of the Hypertension Optimal Treatment (H011 randomlsed   trtal.    Lancet    1998;    351:    1755-1762.
7. Neutel  JM: Low-dose antihypertensive combin-ation therapy:  Its  rationale   and   role  In cardio-vascular  risk management. Am J Hypertens  1999;  12  (8 Pt  2): 73S – 79S.

ACKNOWLEDGEMENT

The   authors acknowledge with  thanks the  following physicians who  have  contrib­uted in the above study.

Dr.  H. Abdul Hamid, (Mysore); Dr. M. Arunachalam, (Madras); Dr. Anna Chhatre, (Pune);Dr. Ashiwini Patki Doshi (Mumbai); Dr. Ashutosh Singh, (Bhopal); Dr. Bhinay Kumar, Gaya; Dr. Bharat Kumrwat, Rattam; Dr. P.K. Bandari, Arunachal, Dr, Behram S.Pardiwala,  (Mumbai);  Dr.   B.S. Bhatia, (Chandigarh); Dr. M.P. Chandrakar; (Durg); D  R.J.S. Chabra, (Muzafamagar); Dr.  T. Dinakaran, (Madurai); Dr. Deepak Rastogi (Garhwal); Dr. Debashish  Choudhary, (Patna); Dr.  D.S. Goel, (Ambala); Dr.  B. Ghatak, (Assam); D. Gurunath,(Bhilai); Dr. O.K. Das Bhiswas, (Asansol); Dr. S.S. Dhillon, (Durg); Dr.  Gunasekar,(Madras); Dr. Ganpat  Devpura  (Jaipur);  Dr.  S.R. Gabhir, (Pune); Dr. Hemant  Shastri, (Baroda). D.Hariharan. (Chennai); Dr. Keshav Singh, (Chennai); Dr.  Krupandhi, (Nellur); Dr. A.K. Kulkarni, (Amaravathi); Dr. B.D. Kkarhade, (Nasik); Dr. Kiran Kumawat (Nasik); Dr. S.K. Kamboj. (Chandigargh) Dr. Krutesh Sha, (Vadodara); Dr. Hussain Khazani, (Hyderabad); Dr. R.C. Kumar, (Baroda); Dr. B.R.J. Kannan, (Madurai); Dr. Lewin Lukose, Quillon;  Dr.  Maytree  Bhanerjee, (Kolkata); Dr. Showkat Mufti (Srinagar); Dr. R.  Murali Babu Rao,  (Guntur); Dr. Manoj Sharma, (Gaziabad); Dr. P. Manoj Sharma, (Tellichery);   Dr. Mehrajudin sha, (Srinagar); Dr. AbdulMajeet.  (Srinagar); Dr. A.K. Mahapatra, (Howrah);Dr.R. Manjunath, (Mysore); Dr. Mohammad Ameen, (Vellore);Dr. Meenakshi Sundaram, (Chennai); Dr.  Murugesan,  (Chennai), D. Manoj Agarwal (Ambhala); Dr. V. Manakavala Perumal, (Tirunelveli). Dr.  G. Narender Reddy, (Alwal); Dr. S. Namachivayam,(Kanchipuram); Dr. K. Narasaram (Kumool);Dr.  Nitin  Sahul, (Indore); Dr. Naina Mohamad, (Madurai); Dr. Praven  Kumar, (Vadagara)  Dr.   Pradeep Mehta, (Indore); Dr. Narayana Swamy Reddy, (Anantapur); Dr. K.K. Pichumani, (T.richy), Dr.   S.K.   Panda,  (Gaya);   Dr. R.  Pargania, (Raipur), Dr. Naresh Shetty, (Mumbai); Dr. S.K. Patil,(Pune); Dr. H.            Prabukar, (Mangalore); Dr. Prakash Mehta, (Vadodara); Dr. Parvaz Hashni, (Bhopal), Dr. Nambiar, (kerala); Dr. Praveen, (Indore); Dr. Pramod Kulkarni, (Dhule); Dr. Parvaiz Shaheed, (Bandhipur); Dr. Paramaswari, (Trichy;) Dr. R.S. Choudari, (Akola); Dr. T.S. Ramaswamy, (Kerala). Dr.  Ramash Singhal,  (Rewa);  D. Rajiv  Khera,  (Indore); Dr.  Jyoti  Ranjan Pandey, (Patna); D. F. Jhohar, Mhow, Dr. V. Rajendran, (Trichy;) Dr. Jeffrey, Nagerkqil; Dr.  Ramesh Pawar,  (Nasik;) Dr.  Rakesh Talwar,  Chandikar,  Dr.   K.V.  Ramatake, (Chandrapur); Dr. Raja Rathnan, Pondichery;  Dr.   Jeevaraj,  (Madras); Dr. Jahannath Reddy, Karimanagar, Dr. Jaikumar, (Chennai); Dr. A.K. Jain (Dehradun); Dr.  Jaipal Chandru, (Sarangpur); D. S. Krishnakumar, Kuzhikode; Dr. V. Jayapal, trtvandrum; Dr. Vuran Rahu; Dr. Atis Basak, (Midnapur); Dr. M.C.  Agarwal,  (Bhopal);  Dr.   S.K.    Arul. Tirunelveli Dr,. AtulKumar, (Patna); Dr. D. Ambasta.(Dhanbag;) D. Alok Singhal, (Rampur); Dr. Ashok Shari Ali, (Perundurai), Dr.  Anil  Batra,  Bhopal; Dr.  Vimal  Rai, (Hyderabad); Dr. Vinu Goel. (Mangalore); Dr. Sunil Kumar, (Trivandrum); Dr. Bhatacharya, (Jamshedpur); Dr. Bhatacharya, Dr. A.B.Balsara, (Jamshedp.ur);Dr. R.N. Bhat,(Udupi); Dr.Somath  Mitra,   (Bangalore); Dr. S.G. Chavan, (Pune);Dr. Shyam Mathur, (Jodhpur); Dr. Sunil Singvi, (Chennai); Dr. Shyam  Prasad,  (Hyderabad); Dr.   Rajpal, Nagerkoil; Dr. Rajesh. Dr. Ravindran, (Chennai); Dr. Sandeep Tak, (Jothpur); Dr. Saxena, (Jaipur) D. Ravi Quillon;  Dr. Raj Kapoor, (Moradabad); Dr. Renu, Pratiba Jn; Dr. A.M. Rathor, (Asrinagar); Dr. Raveendra, (Bangalore); Dr. Renu, Pratiba Jn: Dr. A.M. Rathor, (Srinagar); Dr. Raveendra, (Bangalore); Dr. AbdulRahman, (Srinagar); Dr. K. Roy, (Kerala); Dr. B.Ramesh, (Erode); Dr.  K.C.    Ravi,  (Nasik);  Dr.   Ranganah, (Kumool); Dr. Shabnam Kumar, Kammam; Dr. Satish, (Bangalore); Dr. Hemant (Pune); Dr. Subash Jain (Delhi); D. Sunil Kumar, (Patna);  Dr. Srinivas Reddy, (Mehbunagar); Dr.  Sushil Jain,  (New   Delhi).  D.  Shyam Kumar, (Madurai); Dr. A.K.  Pa. Singha, Dr. B.K. P. Singha, (Jamshedpur); Dr. Sankar Das,  (West Bengal); D. H.M. Rastogi(Meerut); Dr. Sridhar,  Nellore, Dr. Saibhal  Guha, (Calicut); Dr. K.V. Sahasranam, (Kerala); D. Shaha;  Dr.   Sudarshan,  (Hydrabad); Dr. Shushil Nandan Sahay, (Jharkhand); Dr. M. (Patna);    Dr.  Sunil  Wadhwa, (Delhi); Dr. Yeli,    Devangir; Dr.  Vimal Srivastava, Srinivas, (Vishagapatnam); Dr. Showkaf; Dr. Smit,  (Raipur). Dr. Shashank; (Surat) Dr. Vivek   Dr.   G.  Shivalingapa, Devangiri; D. Surya Lakshmi,  (Vishagatnam); D. Sundar, (Nellore);D. Sunil Kumar, (Patna); Dr. Somasundaram,   (Chennai); Dr. Sanjeev,(Delhi); Dr. Vidyasar, Anantpur; Dr. Vivek, Akola); Dr.  Geetha Lakshmi,  (Bangalore); Dr.  D.  Suresh (Chennai); Dr.  Sushobit Verma, (Bareillei); D. Tiwari,  (Bhilai); Dr. A.P.  Thiyagarajan, (Madurai); Dr. Tripathy, (Jamshedpur).