681
independence assumption may be difficult to justify. Lack of independence can be taken into account, but only if three or more large samples of patients are available.1 Department of Epidemiology and Public Health, Queen’s University of Belfast, Belfast BT12 6BJ,UK 1.
C. C. PATTERSON
Bishop YMM, Fienberg SE, Holland PW. Discrete multivariate analysis: theory and practice, ch 6 Estimating the size of a closed population Cambridge, Massachussetts: MIT Press, 1975.
S( +) versus racemic ibuprofen
Nhn
tH
H5 5
Comparison of mean intracellular (RBC) Naj in normotensive and hypertensive Nigerians. Error bars indicate SE, HS = hypertensives, FH =family history of hypertension, NFH=no family history of hypertension, and RBC Na,Red cell sodium (mmol/I). but more importantly, the offspring of hypertensives had RBC Navalues intermediate between those of hypertensives and normotensives (figure).4 These data support the role of a hereditary factor in the regulation of RBC Na+ and possibly BP, though not necessarily a racial factor per se. With techniques of molecular medicine being applied to hypertension research, the effect of race on BP may be eliminated or
normotensives4,s
reaffirmed. Genetic loci that encode for the colour of the skin for instance, may be in strong linkage disequilibrium with BP regulating genetic loci (provided they are on the same chromosome), to give support to the racial susceptibility hypothesis. We will need to be more precise in our definition of the phenotype(s) of hypertension, if we are to find the human "blood pressure" genes. It may well be that what we are studying in Lagos is a completely different disease from that seen in Los Angeles. Renal Unit,
Department of Medicine, University College Hospital, Ibadan, Nigeria
AFOLABI O. OGUNLESI OLADIPO O. AKINKUGBE
1.
Tyroler HKA. Socio-economic status, age and sex m the prevalence and prognosis of hypertension in blacks and whites. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology, diagnosis and management. New York: Raven,
2
Akinkugbe OO. High Livingstone, 1972.
1990: 159-74. blood pressure
in
the African.
Edinburgh: Churchill
3. Osotimehin B, Erasmus RT, Iyun AO, Falase AO, Ahmad Z. Plasma renin activity and plasma aldosterone concentration in untreated Nigerians with essential hypertension. Afr J Med Sci 1984; 13: 139-43. 4. Ogunlesi AO, Osotimehin B, Akinkugbe OO. Intracellular sodium and blood pressure in Nigerians. Ethnicity Dis 1991, 1: 280-87. 5. Aderounmu AF, Salako LA. Abnormal canon composition and transport in erythrocytes from hypertensive patients. Eur J Clin Invest 1979; 9: 369-75. 6. Ogunlesi A, Osotimehin B, Abbiyessuku F, et al. Blood pressure and educational level among factory workers m Ibadan, Nigeria. J Hum Hypertens 1991; 5: 375-80. 7. Akinkugbe OO The rarity of severe hypertensive retinopathy in the African. Am J Med 1968; 45: 401-04. 8. Aviv A, Gardener J. Racial differences in ion regulation and their possible links to hypertension in blacks. Hypertension 1989; 14: 584-89.
Counting birds, bees, and NCDs SIR,-Dr LaPorte and colleagues (Feb 22, p 494) quite rightly draw attention to the relevance of capture-mark-recapture methods in estimating numbers of cases of non-communicable disease. However, in their description of the method they fail to mention the crucial assumption of independence of the samples. The method will give quite misleading results if, as can often be the case in medicine, some patients are more "visible" than others. This results in a tendency for the patients marked in the first sample also to be marked in the second sample, and, consequently, for the total number of patients to be underestimated. The corresponding behaviour in animals is called "trap fascination". In practice this
SiR,—Dr Kean and co-workers (Dec 21/28, p 1565) discuss individual enantiomers of chiral drugs. Ibuprofen has up to now been used as the racemate, equal parts of ( + ) and ( - ) ibuprofen. In in-vitro experiments, the dextrorotatory enantiomer S(+)ibuprofen has shown significantly greater anti-inflammatory, analgesic, and antipyretic action than R(-)-ibuprofen.1 By inhibiting cyclo-oxygenase, S( + )-ibuprofen reduces prostaglandin biosynthesis. Because there is partial, stereoselective inversion from the R( - ) to the S( + ) enantiomer one would assume that isolated S( + )-ibuprofen must be given in a dosage that is higher than that of the S( + )-ibuprofen part of the racemate. In an open, randomised crossover study we have investigated the efficacy and tolerance of isolated S( + )-ibuprofen and of racemate consisting of equal parts of S( + ) and R( - ) ibuprofen. 24 patients with chronically inflammatory and degenerative rheumatic diseases took part. Patients were treated for two periods of 8 days. The half-life of ibuprofen is only 1-2 h so no washout was required. The initial dose was 300 mg S( + )-ibuprofen or 600 mg racemate three times per day, and doses were adjusted to the complaints of the individual patient. At crossover to racemate, the final daily dose was doubled; at crossover to S( + ) ibuprofen it was halved. The main end-point was the amount of drug required to achieve a condition satisfactory to the patient. Range of motion, swelling, rest pain, and pain of movement were also used. Blood indices were checked several times, and adverse events were recorded. We found that, with reference to the initial dose of racemate, 52% of S( + )-ibuprofen and 99% racemate were sufficient to obtain the same results. S(+)-ibuprofen showed efficacy and duration of action of 8-10 h, similar to what was found with the racemate. Blood indices and range of motion, swelling, rest pain, and pain on movement were the same with the two treatments. 3 patients on racemate complained of gastrointestinal effects typical of nonsteroidal agents. Of the 5 patients who were considered drop-outs, 2 had leucopenia when on racemate, which improved when the drug was discontinued. In 1 patient S(+)-ibuprofen was stopped because of severe permanent vertigo, and 1 patient required special therapy due to an attack of rheumatoid arthritis. 1 patient withdrew informed consent before therapy began. Our results suggest that the additional administration of R( - ) ibuprofen in form of racemate does not have any therapeutic effect. When isolated active S( + ) ibuprofen is used in the treatment of patients with rheumatic disease, half the racemate dose is sufficient. These results contrast with those of Wagener et alwho pointed to a 20-25% worse oral bioavailability of S(+)-ibuprofen compared with R( - )-ibuprofen. Rehabilitation Centre for Rheumatic Disease and Ludwig Boltzmann Institute for Rehabilitation of Internal Disease, Saalfelden
G. KLEIN H. NEFF W. KULLICH
Medical Department, Gebro-Fieberbrunn, 6391 Fieberbrunn, Austria
W. PHLEPS CH. J. KOLLENZ
SS, Bresloff P, Mason CG Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of the ( -)-isomer. J Pharm Pharmacol 1976; 28: 256. Hutt AJ, Caldwell J. The metabolic chiral inversion of 2-arylpropionic acids—a novel route with pharmacological consequences. J Pharm Pharmacol 1983; 35: 693-704. Lee EJD, Williams K, Day R, Graham G, Champion D. Stereo-selective disposition of ibuprofen enantiomers in man. Br J Clin Pharmaol 1985; 19: 669-74. Evans AM, Nation RL, Sansom LN, Bochner F, Somogyi AA. The relationship between the pharmacokinetics of ibuprofen enantiomers and the dose of racemic ibuprofen m humans. Pharm Drug Dispos 1990; 11: 507-18. Wagener HH, Kalbhen DA, Bemer G, Vogtle-Junkert U. Ibuprofen. Racemat und Enantiomere. Aktuel Rheumatol 1991; 16: 65-69.
1. Adams
2
3. 4.
5.
independence assumption may be difficult to justify. Lack of independence can be taken into account, but only if three or more large samples of patients are available.1 Department of Epidemiology and Public Health, Queen’s University of Belfast, Belfast BT12 6BJ,UK 1.
C. C. PATTERSON
Bishop YMM, Fienberg SE, Holland PW. Discrete multivariate analysis: theory and practice, ch 6 Estimating the size of a closed population Cambridge, Massachussetts: MIT Press, 1975.
S( +) versus racemic ibuprofen
Nhn
tH
H5 5
Comparison of mean intracellular (RBC) Naj in normotensive and hypertensive Nigerians. Error bars indicate SE, HS = hypertensives, FH =family history of hypertension, NFH=no family history of hypertension, and RBC Na,Red cell sodium (mmol/I). but more importantly, the offspring of hypertensives had RBC Navalues intermediate between those of hypertensives and normotensives (figure).4 These data support the role of a hereditary factor in the regulation of RBC Na+ and possibly BP, though not necessarily a racial factor per se. With techniques of molecular medicine being applied to hypertension research, the effect of race on BP may be eliminated or
normotensives4,s
reaffirmed. Genetic loci that encode for the colour of the skin for instance, may be in strong linkage disequilibrium with BP regulating genetic loci (provided they are on the same chromosome), to give support to the racial susceptibility hypothesis. We will need to be more precise in our definition of the phenotype(s) of hypertension, if we are to find the human "blood pressure" genes. It may well be that what we are studying in Lagos is a completely different disease from that seen in Los Angeles. Renal Unit,
Department of Medicine, University College Hospital, Ibadan, Nigeria
AFOLABI O. OGUNLESI OLADIPO O. AKINKUGBE
1.
Tyroler HKA. Socio-economic status, age and sex m the prevalence and prognosis of hypertension in blacks and whites. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology, diagnosis and management. New York: Raven,
2
Akinkugbe OO. High Livingstone, 1972.
1990: 159-74. blood pressure
in
the African.
Edinburgh: Churchill
3. Osotimehin B, Erasmus RT, Iyun AO, Falase AO, Ahmad Z. Plasma renin activity and plasma aldosterone concentration in untreated Nigerians with essential hypertension. Afr J Med Sci 1984; 13: 139-43. 4. Ogunlesi AO, Osotimehin B, Akinkugbe OO. Intracellular sodium and blood pressure in Nigerians. Ethnicity Dis 1991, 1: 280-87. 5. Aderounmu AF, Salako LA. Abnormal canon composition and transport in erythrocytes from hypertensive patients. Eur J Clin Invest 1979; 9: 369-75. 6. Ogunlesi A, Osotimehin B, Abbiyessuku F, et al. Blood pressure and educational level among factory workers m Ibadan, Nigeria. J Hum Hypertens 1991; 5: 375-80. 7. Akinkugbe OO The rarity of severe hypertensive retinopathy in the African. Am J Med 1968; 45: 401-04. 8. Aviv A, Gardener J. Racial differences in ion regulation and their possible links to hypertension in blacks. Hypertension 1989; 14: 584-89.
Counting birds, bees, and NCDs SIR,-Dr LaPorte and colleagues (Feb 22, p 494) quite rightly draw attention to the relevance of capture-mark-recapture methods in estimating numbers of cases of non-communicable disease. However, in their description of the method they fail to mention the crucial assumption of independence of the samples. The method will give quite misleading results if, as can often be the case in medicine, some patients are more "visible" than others. This results in a tendency for the patients marked in the first sample also to be marked in the second sample, and, consequently, for the total number of patients to be underestimated. The corresponding behaviour in animals is called "trap fascination". In practice this
SiR,—Dr Kean and co-workers (Dec 21/28, p 1565) discuss individual enantiomers of chiral drugs. Ibuprofen has up to now been used as the racemate, equal parts of ( + ) and ( - ) ibuprofen. In in-vitro experiments, the dextrorotatory enantiomer S(+)ibuprofen has shown significantly greater anti-inflammatory, analgesic, and antipyretic action than R(-)-ibuprofen.1 By inhibiting cyclo-oxygenase, S( + )-ibuprofen reduces prostaglandin biosynthesis. Because there is partial, stereoselective inversion from the R( - ) to the S( + ) enantiomer one would assume that isolated S( + )-ibuprofen must be given in a dosage that is higher than that of the S( + )-ibuprofen part of the racemate. In an open, randomised crossover study we have investigated the efficacy and tolerance of isolated S( + )-ibuprofen and of racemate consisting of equal parts of S( + ) and R( - ) ibuprofen. 24 patients with chronically inflammatory and degenerative rheumatic diseases took part. Patients were treated for two periods of 8 days. The half-life of ibuprofen is only 1-2 h so no washout was required. The initial dose was 300 mg S( + )-ibuprofen or 600 mg racemate three times per day, and doses were adjusted to the complaints of the individual patient. At crossover to racemate, the final daily dose was doubled; at crossover to S( + ) ibuprofen it was halved. The main end-point was the amount of drug required to achieve a condition satisfactory to the patient. Range of motion, swelling, rest pain, and pain of movement were also used. Blood indices were checked several times, and adverse events were recorded. We found that, with reference to the initial dose of racemate, 52% of S( + )-ibuprofen and 99% racemate were sufficient to obtain the same results. S(+)-ibuprofen showed efficacy and duration of action of 8-10 h, similar to what was found with the racemate. Blood indices and range of motion, swelling, rest pain, and pain on movement were the same with the two treatments. 3 patients on racemate complained of gastrointestinal effects typical of nonsteroidal agents. Of the 5 patients who were considered drop-outs, 2 had leucopenia when on racemate, which improved when the drug was discontinued. In 1 patient S(+)-ibuprofen was stopped because of severe permanent vertigo, and 1 patient required special therapy due to an attack of rheumatoid arthritis. 1 patient withdrew informed consent before therapy began. Our results suggest that the additional administration of R( - ) ibuprofen in form of racemate does not have any therapeutic effect. When isolated active S( + ) ibuprofen is used in the treatment of patients with rheumatic disease, half the racemate dose is sufficient. These results contrast with those of Wagener et alwho pointed to a 20-25% worse oral bioavailability of S(+)-ibuprofen compared with R( - )-ibuprofen. Rehabilitation Centre for Rheumatic Disease and Ludwig Boltzmann Institute for Rehabilitation of Internal Disease, Saalfelden
G. KLEIN H. NEFF W. KULLICH
Medical Department, Gebro-Fieberbrunn, 6391 Fieberbrunn, Austria
W. PHLEPS CH. J. KOLLENZ
SS, Bresloff P, Mason CG Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of the ( -)-isomer. J Pharm Pharmacol 1976; 28: 256. Hutt AJ, Caldwell J. The metabolic chiral inversion of 2-arylpropionic acids—a novel route with pharmacological consequences. J Pharm Pharmacol 1983; 35: 693-704. Lee EJD, Williams K, Day R, Graham G, Champion D. Stereo-selective disposition of ibuprofen enantiomers in man. Br J Clin Pharmaol 1985; 19: 669-74. Evans AM, Nation RL, Sansom LN, Bochner F, Somogyi AA. The relationship between the pharmacokinetics of ibuprofen enantiomers and the dose of racemic ibuprofen m humans. Pharm Drug Dispos 1990; 11: 507-18. Wagener HH, Kalbhen DA, Bemer G, Vogtle-Junkert U. Ibuprofen. Racemat und Enantiomere. Aktuel Rheumatol 1991; 16: 65-69.
1. Adams
2
3. 4.
5.
