1539
Distribution of ivermectin by health workers SIR,-In 1987 the international health community was heartened to learn of the generous promise by Merck & Co, the developers of ivermectin (’Mectizan’), to supply the drug free to organisations interested in using it to combat river blindness. Merck set up the Mectizan Expert Committee (MEC) to screen applications for the
drug. MEC’s guidelines reflect Merck’s concern about product liability and diversion of the drug to the lucrative veterinary market, and access to the drug is restricted to organisations capable of delivering it responsibly and of preventing misappropriation. Governments and other organisations which receive the medicine free of charge are in turn encouraged to restrict access. These concerns, though understandable, have unfortunately created a climate in which most organisations, including ministries of health, are reluctant to permit village health workers to distribute the drug. Village health workers form the foundation of many successful primary health care programmes. They have proved themselves capable, when properly trained and supervised, of safely and effectively delivering a variety of health services (including oral contraception) and managing malaria, diarrhoea, and childbirth. No-one claims that they should work alone: a cornerstone of their training is the recognition of cases requiring referral. After listening to the concerns of some of the experts planning ivermectin distribution programmes one might think that the task is complex and that those who take the drug are at risk of life-threatening side-effects. Neither assertion is valid. Ivermectin is an oral medication, the dose of which depends upon body weight. Inexpensive "bathroom" scales are accurate enough for this purpose. In communities where onchocerciasis is a serious public health concern the drug should be dispensed to everyone except children weighing less than 15 kg, women who think they may be pregnant or who have been delivered of a baby in the previous week, and people who cannot walk or who otherwise appear seriously ill. The screening process thus comes down to a weighing, a quick visual assessment of general fitness, and, for women of childbearing age, two questions. In theory, the only record keeping essential to the distribution process is a tally of the people treated and the tablets dispensed. If village health workers distribute the drug house-to-house they can record the house number and the name and dose for every recipient. This permits supervisors to verify the accuracy of the records by visiting a sample of houses. Is ivermectin safe enough to be distributed by village health workers? The answer is "yes". Experts from the World Health Organisation and various research institutions have monitored community trials of the drug in West Africa in which over 100 000 people have been treated. Their conclusion was: "There are few, if any, drugs at present in use for the treatment of tropical diseases that have undergone the scrutiny that ivermectin has had. The drug is extremely safe, and is without known pharmacological side-effects in humans".1 Serious reactions to ivermectin have occurred to fewer than 1 in 1000 recipients (which is approximately a woman’s risk of stroke or thromboembolism while on oral contraceptives). These reactions have consisted of postural hypotension or of wheezing in people with a history of asthma.. All reactions seen thus far have evolved slowly over several hours and, according to a member of the MEC appointed to advise WHO: "It is probable that none of the reactions were life-threatening".2 The few serious reactions to ivermectin were easy to recognise (dizziness or shortness of breath) and evolved so slowly that a village health worker on a bicycle or motorcycle would have had plenty of time to seek help from a clinic within 20 km of the village. Merck has, in effect, set up a vertical hierarchy for distributing its drug. Every level in the hierarchy is reluctant to relinquish control over access to ivermectin. At the bottom are people living in villages hyperendemic for onchocerciasis. Such communities typically are tiny settlements of fewer than 500 people and are the very ones that seldom receive even the most basic of health and development services. The centralised hierarchies do not reach out that far, except piecemeal with shortlived pilot programmes. If ivermectin is to reach every one of the 50 000 or so mesoendemic or
hyperendemic communities in the world on a sustained annual basis, the controlling agencies (Merck, MEC, government health services, non-governmental organisations) must accept that tight control of the distribution process is unnecessary and impracticable. MEC has shown a commendable flexibility in its approval of alternative strategies of distribution and has permitted some programmes to hand over certain responsibilities to village health workers-but the perception remains amongst governments and other agencies that tight control is essential and is a prerequisite for receipt of the drug from Merck. More must be done to convince planners and administrators of a fundamental principle of the primary health care movement-namely, that Health for All depends upon community participation and community participation comes at the expense of tight central control. Kwara State Blindness Prevention Program, PO Box 52839, Falomo, Ikoyi, SW.
BOB POND
Lagos, Nigeria
Organisation. Report of a meeting of the TDR/OCP/OCT Subcommittee for Monitoring of Community Trials of Ivermectin (Ouagadougou, Burkina Faso, Jan 25-27, 1989). 2. Green B. Information and opinions to be conveyed by Dr Bruce Greene to the independent Mectizan Committee following the meeting of the Monitoring Sub-Group for Ivermectin Trials in Onchocerciasis (March 20, 1988). 1. World Health
Inhaled frusemide and asthma SIR,-We agree with your April 21 editorial that studies with frusemide may shed further light on the pathophysiology of asthma. We have evidence that one of the sites of action of frusemide is airway nerves. Investigations in healthy subjects show that inhaled frusemide inhibits cough responses induced by low chloride content solutions and prostaglandin F2, but not by capsaicin.1,2 We interpret these effects as probably being inhibition of the afferent limb of the cough reflex. In-vitro investigations with guineapig airways demonstrate that frusemide inhibits in a dose-dependent manner airway smooth-muscle contraction induced by stimulation of cholinergic and non-cholinergic, non-adrenergic nerves in tracheal and bronchial tissues, respectively.3 This effect was independent of airway epithelium and of cyclo-oxygenase production. Frusemide had no effect against direct activation of cholinergic or peptidergic receptors, and so clearly was inhibiting neural excitation. Bumetanide, another loop diuretic, was more potent than frusemide in these studies,3 which supports the view that such diuretics may + + act through inhibition of the Na /K 12Cl- co-transporter on airway nerves. National Heart & Lung Institute, London SW3 6LY, UK
K. F. CHUNG P. J. BARNES
P, Nichol GM, Barnes PJ, Chung KF. Inhaled frusemide inhibits cough induced by low chloride content solutions and not by capsaicin. Am Rev Respir Dis
1. Ventresca
(in press). P, Nichol GM, Barnes PJ, Chung KF. Inhibitory effects of inhaled frusemide against the induction and potentiation of cough responses in normal subjects. Am Rev Respir Dis 1990; 141: A361. 3. Elwood W, Barnes PJ, Chung KF. Frusemide and bumetanide loop diuretics inhibit neurally-mediated airway smooth muscle contraction in guinea-pig. Br J Pharmacol (in press). 2. Ventresca
Intrauterine devices and removal times SIR,-The advice given by manufacturers/distributors of intrauterine devices (IUDs) is that removal at the recommended time limit is to be preferred because of the possible increase in the likelihood of pregnancy and side-effects if the device is used for longer. Data collected in studies by the UK Family Planning Research Network suggest that this view may be incorrect. Pregnancy rates in a use-effectiveness study of 433 users of the ’Short Multiload’ IUD (recommended period of use 3 years) are
1540
available to 53 months of use. The gross cumulative pregnancy rate rises to 2-7 per 100 women at 24 months of use with no further rise through to 53 months. In a similar study of 438 ’Novagard’ users (recommended period of use 5 years) the gross cumulative pregnancy rate rises to 3-5 per 100 women at 48 months with no further rise through to 64 months. While the extended period of use is short for the novagard so far, the steady rate from 48 months and the fall-away which preceded these 4 years, suggest that no significant increase in the pregnancy rate in future months is likely. PREGNANCY RATES AFTER PHANTOM AND ACTUAL REFITTINGS AT 36 MONTHS (SHORT MULTILOAD) OR 60 MONTHS (NOVAGARD)
Diagrammatic representations of conventional primer-driven PCR of repeated units (A) and primer-independent extension after staggered annealing. bands after agarose gel electrophoresis. Initially, we assumed that all these bands were the results of conventional primer-driven amplification of ever-longer blocks of tandemly repeated sequence units (fig, A). However, now that the entire toxin A gene sequence is known,1,2 it is clear that this cannot be the correct explanation, since the longest block of repetitive sequence within the gene contains only three adjacent repeats. Instead, all except the two smallest PCR products can be explained by the same mechanism that underlies jumping PCR-namely, primerindependent extension of overlapping DNA fragments. In the early rounds of amplification, the concentrations of both the single unit sequence and the tandemly repeated sequences increase by conventional primer-driven PCR. Later, staggered annealing of tandemly repeated units, followed by primerindependent extension, takes place, generating a series of steadily longer DNA fragments as the number of PCR cycles increases (fig B). To confirm that this primer-independent process can generate the larger DNA fragments seen in our initial PCR reaction, we gel-purified DNA from the second band (126 bp) produced in our initial reaction. We then incorporated this as template in a second round of amplification under the same conditions as before, but without oligonucleotide primers. Multiple bands of the expected size were obtained, just as with our usual PCR procedure. Furthermore, the number of bands increased with the number of PCR cycles used. Many important eukaryotic and prokaryotic pathogens have or more
Figures in parentheses represent Pearl mdex rate per 100 woman-years P=phantom refit, A= actual refit *Insufflclent data for months 25-36 after actual
refitting
A separate study of these two devices is looking at the subsequent experience of satisfied users who, after discussion with the doctor, decided to continue using their IUD beyond the recommended time limit rather than have a routine refitting. This experience is being compared with that of women wearing a similar device who opt for a routine refitting of the IUD. Analysis is based on the experience of these IUD users after an actual or "phantom" refitting at the recommended time. So far 162 women continuing long-term use of these IUDs have been recruited. The likelihood of pregnancy is not increased among women experiencing a phantom refitting when compared with women who have an actual refitting (table). Use of these IUDs beyond their recommended "life" appears to have no disadvantages for the women. The above data support the view set out by Professor Newton and Dr Tacchi (June 2, p 1322) that "copper-bearing IUDs... should be assumed to have an active lifespan of five years or more". The UK
Family Planning Research Network tests IUDs and other family planning methods through the voluntary collaboration of medical teams in over forty clinics and general practices. Institute of Population Studies, University of Exeter, Exeter EX4 6DT, UK
genes
containing tandemly repeated
GILLIAN CARDY,
repeated
Chairperson, UK Family Planning
alternative
sequence may to
conventional
Research Network
"jumping PCR" in diagnostic procedures
SIR,-Dr Porter-Jordan and Dr Garrett report (May 19, p 1220) that "jumping PCR" (polymerase chain reaction) can give rise to troublesome false-positive signals in diagnostic PCR, especially if amplification is continued over many cycles. We have described (Feb 17, p 423) the rapid detection of toxigenic Clostridium difficile by PCR, with primers that amplify a repetitive sequence from within the toxin A gene. However, we have found that an occurrence akin to jumping PCR is, in this case, a valuable component of the assay. We obtained a series of amplification products from the toxin A gene, all of which are multiples of a 63 base pair (bp) repeat unit. This series of products gives an instantly recognisable ladder of five
Examples
range
provide a more easily interpretable single-product PCR.
Department of Medical Microbiology, St Bartholomew’s Hospital Medical College,
Beneficial effects of
sequences.
from the genes encoding the repetitive antigens of Plasmodium spp to the coagulase gene of Staphylococcus aureus. In any of these cases, staggered annealing with primer-independent extension is likely to generate characteristic ladder-like profiles of amplification products whenever primers binding to the repeat units of the genes are used in PCR. Your Feb 17 editorial (p 381) on DNA and the law highlighted the difficulties in the identification of single DNA fragments visualised after agarose gel electrophoresis. The distinctive profile of bands seen after amplification from a tandemly
London EC1A 7BE, UK
BRENDAN W. WREN
MARK J. PALLEN SOAD TABAQCHALI
S-Z, Price SB, et al. Molecular characterisation of the C difficile toxin A gene. Infect Immun 1990; 58: 480-88. 2. Sauerbom M, von Eichel-Streiber C Nucleotide sequence of the C difficile toxin A gene. Nucleic Acids Res 1990; 18: 1629-30. 1. Dove CH, Wang
CORRECTION Rabies In Dr K. G. Nicholson’s contribution to the series Modem Vaccines (May 19, p 1201),the figure legend should indicate that 21 of the 4535 dots in section C represent cases of bat rabies, the rest animal rabies.
Distribution of ivermectin by health workers SIR,-In 1987 the international health community was heartened to learn of the generous promise by Merck & Co, the developers of ivermectin (’Mectizan’), to supply the drug free to organisations interested in using it to combat river blindness. Merck set up the Mectizan Expert Committee (MEC) to screen applications for the
drug. MEC’s guidelines reflect Merck’s concern about product liability and diversion of the drug to the lucrative veterinary market, and access to the drug is restricted to organisations capable of delivering it responsibly and of preventing misappropriation. Governments and other organisations which receive the medicine free of charge are in turn encouraged to restrict access. These concerns, though understandable, have unfortunately created a climate in which most organisations, including ministries of health, are reluctant to permit village health workers to distribute the drug. Village health workers form the foundation of many successful primary health care programmes. They have proved themselves capable, when properly trained and supervised, of safely and effectively delivering a variety of health services (including oral contraception) and managing malaria, diarrhoea, and childbirth. No-one claims that they should work alone: a cornerstone of their training is the recognition of cases requiring referral. After listening to the concerns of some of the experts planning ivermectin distribution programmes one might think that the task is complex and that those who take the drug are at risk of life-threatening side-effects. Neither assertion is valid. Ivermectin is an oral medication, the dose of which depends upon body weight. Inexpensive "bathroom" scales are accurate enough for this purpose. In communities where onchocerciasis is a serious public health concern the drug should be dispensed to everyone except children weighing less than 15 kg, women who think they may be pregnant or who have been delivered of a baby in the previous week, and people who cannot walk or who otherwise appear seriously ill. The screening process thus comes down to a weighing, a quick visual assessment of general fitness, and, for women of childbearing age, two questions. In theory, the only record keeping essential to the distribution process is a tally of the people treated and the tablets dispensed. If village health workers distribute the drug house-to-house they can record the house number and the name and dose for every recipient. This permits supervisors to verify the accuracy of the records by visiting a sample of houses. Is ivermectin safe enough to be distributed by village health workers? The answer is "yes". Experts from the World Health Organisation and various research institutions have monitored community trials of the drug in West Africa in which over 100 000 people have been treated. Their conclusion was: "There are few, if any, drugs at present in use for the treatment of tropical diseases that have undergone the scrutiny that ivermectin has had. The drug is extremely safe, and is without known pharmacological side-effects in humans".1 Serious reactions to ivermectin have occurred to fewer than 1 in 1000 recipients (which is approximately a woman’s risk of stroke or thromboembolism while on oral contraceptives). These reactions have consisted of postural hypotension or of wheezing in people with a history of asthma.. All reactions seen thus far have evolved slowly over several hours and, according to a member of the MEC appointed to advise WHO: "It is probable that none of the reactions were life-threatening".2 The few serious reactions to ivermectin were easy to recognise (dizziness or shortness of breath) and evolved so slowly that a village health worker on a bicycle or motorcycle would have had plenty of time to seek help from a clinic within 20 km of the village. Merck has, in effect, set up a vertical hierarchy for distributing its drug. Every level in the hierarchy is reluctant to relinquish control over access to ivermectin. At the bottom are people living in villages hyperendemic for onchocerciasis. Such communities typically are tiny settlements of fewer than 500 people and are the very ones that seldom receive even the most basic of health and development services. The centralised hierarchies do not reach out that far, except piecemeal with shortlived pilot programmes. If ivermectin is to reach every one of the 50 000 or so mesoendemic or
hyperendemic communities in the world on a sustained annual basis, the controlling agencies (Merck, MEC, government health services, non-governmental organisations) must accept that tight control of the distribution process is unnecessary and impracticable. MEC has shown a commendable flexibility in its approval of alternative strategies of distribution and has permitted some programmes to hand over certain responsibilities to village health workers-but the perception remains amongst governments and other agencies that tight control is essential and is a prerequisite for receipt of the drug from Merck. More must be done to convince planners and administrators of a fundamental principle of the primary health care movement-namely, that Health for All depends upon community participation and community participation comes at the expense of tight central control. Kwara State Blindness Prevention Program, PO Box 52839, Falomo, Ikoyi, SW.
BOB POND
Lagos, Nigeria
Organisation. Report of a meeting of the TDR/OCP/OCT Subcommittee for Monitoring of Community Trials of Ivermectin (Ouagadougou, Burkina Faso, Jan 25-27, 1989). 2. Green B. Information and opinions to be conveyed by Dr Bruce Greene to the independent Mectizan Committee following the meeting of the Monitoring Sub-Group for Ivermectin Trials in Onchocerciasis (March 20, 1988). 1. World Health
Inhaled frusemide and asthma SIR,-We agree with your April 21 editorial that studies with frusemide may shed further light on the pathophysiology of asthma. We have evidence that one of the sites of action of frusemide is airway nerves. Investigations in healthy subjects show that inhaled frusemide inhibits cough responses induced by low chloride content solutions and prostaglandin F2, but not by capsaicin.1,2 We interpret these effects as probably being inhibition of the afferent limb of the cough reflex. In-vitro investigations with guineapig airways demonstrate that frusemide inhibits in a dose-dependent manner airway smooth-muscle contraction induced by stimulation of cholinergic and non-cholinergic, non-adrenergic nerves in tracheal and bronchial tissues, respectively.3 This effect was independent of airway epithelium and of cyclo-oxygenase production. Frusemide had no effect against direct activation of cholinergic or peptidergic receptors, and so clearly was inhibiting neural excitation. Bumetanide, another loop diuretic, was more potent than frusemide in these studies,3 which supports the view that such diuretics may + + act through inhibition of the Na /K 12Cl- co-transporter on airway nerves. National Heart & Lung Institute, London SW3 6LY, UK
K. F. CHUNG P. J. BARNES
P, Nichol GM, Barnes PJ, Chung KF. Inhaled frusemide inhibits cough induced by low chloride content solutions and not by capsaicin. Am Rev Respir Dis
1. Ventresca
(in press). P, Nichol GM, Barnes PJ, Chung KF. Inhibitory effects of inhaled frusemide against the induction and potentiation of cough responses in normal subjects. Am Rev Respir Dis 1990; 141: A361. 3. Elwood W, Barnes PJ, Chung KF. Frusemide and bumetanide loop diuretics inhibit neurally-mediated airway smooth muscle contraction in guinea-pig. Br J Pharmacol (in press). 2. Ventresca
Intrauterine devices and removal times SIR,-The advice given by manufacturers/distributors of intrauterine devices (IUDs) is that removal at the recommended time limit is to be preferred because of the possible increase in the likelihood of pregnancy and side-effects if the device is used for longer. Data collected in studies by the UK Family Planning Research Network suggest that this view may be incorrect. Pregnancy rates in a use-effectiveness study of 433 users of the ’Short Multiload’ IUD (recommended period of use 3 years) are
1540
available to 53 months of use. The gross cumulative pregnancy rate rises to 2-7 per 100 women at 24 months of use with no further rise through to 53 months. In a similar study of 438 ’Novagard’ users (recommended period of use 5 years) the gross cumulative pregnancy rate rises to 3-5 per 100 women at 48 months with no further rise through to 64 months. While the extended period of use is short for the novagard so far, the steady rate from 48 months and the fall-away which preceded these 4 years, suggest that no significant increase in the pregnancy rate in future months is likely. PREGNANCY RATES AFTER PHANTOM AND ACTUAL REFITTINGS AT 36 MONTHS (SHORT MULTILOAD) OR 60 MONTHS (NOVAGARD)
Diagrammatic representations of conventional primer-driven PCR of repeated units (A) and primer-independent extension after staggered annealing. bands after agarose gel electrophoresis. Initially, we assumed that all these bands were the results of conventional primer-driven amplification of ever-longer blocks of tandemly repeated sequence units (fig, A). However, now that the entire toxin A gene sequence is known,1,2 it is clear that this cannot be the correct explanation, since the longest block of repetitive sequence within the gene contains only three adjacent repeats. Instead, all except the two smallest PCR products can be explained by the same mechanism that underlies jumping PCR-namely, primerindependent extension of overlapping DNA fragments. In the early rounds of amplification, the concentrations of both the single unit sequence and the tandemly repeated sequences increase by conventional primer-driven PCR. Later, staggered annealing of tandemly repeated units, followed by primerindependent extension, takes place, generating a series of steadily longer DNA fragments as the number of PCR cycles increases (fig B). To confirm that this primer-independent process can generate the larger DNA fragments seen in our initial PCR reaction, we gel-purified DNA from the second band (126 bp) produced in our initial reaction. We then incorporated this as template in a second round of amplification under the same conditions as before, but without oligonucleotide primers. Multiple bands of the expected size were obtained, just as with our usual PCR procedure. Furthermore, the number of bands increased with the number of PCR cycles used. Many important eukaryotic and prokaryotic pathogens have or more
Figures in parentheses represent Pearl mdex rate per 100 woman-years P=phantom refit, A= actual refit *Insufflclent data for months 25-36 after actual
refitting
A separate study of these two devices is looking at the subsequent experience of satisfied users who, after discussion with the doctor, decided to continue using their IUD beyond the recommended time limit rather than have a routine refitting. This experience is being compared with that of women wearing a similar device who opt for a routine refitting of the IUD. Analysis is based on the experience of these IUD users after an actual or "phantom" refitting at the recommended time. So far 162 women continuing long-term use of these IUDs have been recruited. The likelihood of pregnancy is not increased among women experiencing a phantom refitting when compared with women who have an actual refitting (table). Use of these IUDs beyond their recommended "life" appears to have no disadvantages for the women. The above data support the view set out by Professor Newton and Dr Tacchi (June 2, p 1322) that "copper-bearing IUDs... should be assumed to have an active lifespan of five years or more". The UK
Family Planning Research Network tests IUDs and other family planning methods through the voluntary collaboration of medical teams in over forty clinics and general practices. Institute of Population Studies, University of Exeter, Exeter EX4 6DT, UK
genes
containing tandemly repeated
GILLIAN CARDY,
repeated
Chairperson, UK Family Planning
alternative
sequence may to
conventional
Research Network
"jumping PCR" in diagnostic procedures
SIR,-Dr Porter-Jordan and Dr Garrett report (May 19, p 1220) that "jumping PCR" (polymerase chain reaction) can give rise to troublesome false-positive signals in diagnostic PCR, especially if amplification is continued over many cycles. We have described (Feb 17, p 423) the rapid detection of toxigenic Clostridium difficile by PCR, with primers that amplify a repetitive sequence from within the toxin A gene. However, we have found that an occurrence akin to jumping PCR is, in this case, a valuable component of the assay. We obtained a series of amplification products from the toxin A gene, all of which are multiples of a 63 base pair (bp) repeat unit. This series of products gives an instantly recognisable ladder of five
Examples
range
provide a more easily interpretable single-product PCR.
Department of Medical Microbiology, St Bartholomew’s Hospital Medical College,
Beneficial effects of
sequences.
from the genes encoding the repetitive antigens of Plasmodium spp to the coagulase gene of Staphylococcus aureus. In any of these cases, staggered annealing with primer-independent extension is likely to generate characteristic ladder-like profiles of amplification products whenever primers binding to the repeat units of the genes are used in PCR. Your Feb 17 editorial (p 381) on DNA and the law highlighted the difficulties in the identification of single DNA fragments visualised after agarose gel electrophoresis. The distinctive profile of bands seen after amplification from a tandemly
London EC1A 7BE, UK
BRENDAN W. WREN
MARK J. PALLEN SOAD TABAQCHALI
S-Z, Price SB, et al. Molecular characterisation of the C difficile toxin A gene. Infect Immun 1990; 58: 480-88. 2. Sauerbom M, von Eichel-Streiber C Nucleotide sequence of the C difficile toxin A gene. Nucleic Acids Res 1990; 18: 1629-30. 1. Dove CH, Wang
CORRECTION Rabies In Dr K. G. Nicholson’s contribution to the series Modem Vaccines (May 19, p 1201),the figure legend should indicate that 21 of the 4535 dots in section C represent cases of bat rabies, the rest animal rabies.
