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Drug Research
Drug Research
Recombinant DNA-Derived Hormone May Help Treat Infertility
R
ecombinant DNA-human luteinizing hormone (rechLH), a genetically engineered version of a human hormone that induces ovulation, appears to be biologically identical to the natural hormone and may provide superior treatment for many female and male fertility problems, conclude investigators at the Jones Institute for Reproductive Medicine (JAMA, 259, 3290, 1988). They report animal study findings suggesting that the product of this genesplicing technique is identical to the natural human hormone that induces ovulation. Human luteinizing hormone (hLH) is now extracted from pituitary glands and from the urine of postmenopausal women. This impure preparation is used to treat infertility caused by hormonal abnormalities in both women and men. The therapeutic advantages of the commercially produced hormone include a more reliably available supply of hormone, as well as improved treatment flexibility in determining the optimal dose for individual patient management either by having pure rechLH to administer alone (as an alternative to human chorionic gonadotropin, hCG), or in various ratios with follicle-stimulating hormone (FSH) Some of the infertility problems now treated with the gonad-stimulating hormones are ovulatory disorders, endocrine disorders causing early pregnancy wastage, and, in men, androgen-deficient problems of libido and hormone-related failure to produce sperm. The hormones also have been helpful with in vitro fertilization for sterility caused by damaged fallopian tubes. Tests have not been conducted on humans, but studies with rats and monkeys indicate that the effects of the rechLH preparation are virtually identical to those of natural hormones from urine and the pituitary glands. Chemical analysis has yet to be conducted to determine whether the molecular structure of 10
the hormone is identical to the naturally occurring substance. The authors also speculate that reaction to rechLH may mimic the normal cycle more closely than the hormone mixture used now, which may lead to better timing in the development of the ovum and better embryo quality.
'As a result of the shorter biological half-life, we may be able to reduce the frequency of multiple pregnancy in women undergoing ovulation induction by truncating the duration of ovulatory stimulus.' "The availability of rechLH has theoretical advantages over hCG for ovulation induction," the authors conclude. '~sa result of the
shorter biological half-life of hLH (approximately 50 minutes) vs hCG (approximately 10 hours), we may be able to reduce the frequency of multiple pregnancy in women undergoing ovulation induction by truncating the duration of ovulatory stimulus. Both an improved source and reliability of product supply of rechLH are likely gains that will enhance physician skills in the management of infertile patients." In an accompanying editorial (JAMA, 259, 3313, 1988), Alan H. DeCherney writes that the new work on rechLH has opened exciting possibilities in the rapidly growing field of ovulation induction because it greatly increases therapeutic possibilities by increasing flexibility in treatments to induce ovulation. "Their work illustrates beautifully how the marriage of new technology and well-conceived and executed scientific experimentation and validation will result in clinical realities that improve the quality oflife," DeChemey says. "Read from a narrow perspective, this article merely documents the potential use of rechLH as a pharmacologic agent; but read with a wider vision, it illustrates the importance ofbasic science developments in the practice of modem-day medicine."®
Zidovudine Can Inhibit AIDS Virus Activity idovudine (formerly azidothymiZ dine, or AZT) found in the semen of patients taking the anti-AIDS drug can reach levels considered sufficient to inhibit in vitro activity of the AIDS-causing human immunodeficiency virus (HIV-1), according to a preliminary report in the May 27 JAMA (259, 3023, 1988). The report says the results "support the possibility that the presence of zidovudine in semen could decrease the amount of culturable HIV in that body fluid." The authors would not go so far as to say that the conclusions mean that the presence of zidovudine would decrease the infectivity of semen.
The test, conducted on six patients with AIDS or AIDS-related complex who were taking 200 mg of the drug orally every 4 to 6 hours, also found that levels of zidovudine in semen samples were higher than serum levels- findings the authors called unexpected but not unprecedented. A commentary in the same issue (p. 3037) suggests that antiviral drugs and vaccines to prevent transmission of HIV should be aimed at attacking HIV-infected cells and not just the virus. Until now, most approaches have concentrated on the retrovirus alone. However, biologic and epidemiologic studies
American Pharmacy, Vol. NS28, No. 9 September 1988/554
Drug Research indicate that cell-free virus in body fluids is unlikely to be a meaningful source of HIV transmission. Therefore, Levy contends, researchers should focus their attention on the role of virus-infected cells in the spread of AIDS. "Unlike strategies to fight other
human viruses, such as measles virus, poliovirus, and hepatitis virus," Levy says, "blocking freevirus entry into the host without removal of the infected cell would not lead to effective prevention. The control and cure of AIDS will result only when the infected cell itself is
eliminated." Until such antiviral approaches are available, he says, a decrease in sexual transmission of HIV can be achieved only by avoiding intimate sexual activity or by using barrier methods - such as condoms - that block contact with the virus-infected cell. ®
Thyroid Hormone Replacement May Decrease Hip Bone Density
C
areful monitoring of the dosage of long-term thyroid hormone replacement therapy is needed to avoid excessive dosages that may result in osteoporosis, report investigators from the University of Massachusetts Medical School (JAMA, 259, 3137' 1988).
·.- .
~
.
dosages that are excessive for the thyroid condition being treated." In an accompanying editorial (p. 3175), DavidS. Cooper of the Johns Hopkins University School of Medicine notes that the study subjects were taking thyroid hormone for well-accepted indications: hypothyroidism secondary to Hashimoto's thyroiditis, hypothyroidism following radioactive 1odine or surgical treatment for Graves' disease, thy-
·w1
. -~ .:< "'\:·:. ;b !.~ ~ --~~'-/• ~~~l \~~~· . .•
roidcancer after total thyroidectomy or primary hypothyroidism, and suppressiorJ. of other types of nontoxic goiter. Cooper raises the question, "Is it appropriate to treat a benign thyroid problem with a medication that potentially could cause osteoporosis?" and further suggests that "one must choose the dosage with great care. In light of the data in [this] study, the whole concept of suppression therapy for benign thyroid disease may need reevaluation, especially in older women, whose skeletons are the most likely to be in jeopardy." ®
...
.·.
-
.
Their study- examined 31 premenopausal women (aged 19-46) who had been on levothyroxine for at least 5 years. Many were on dosages of the hormone that would now be considered excessive. Bone densities in the hip and spine were compared with those of a control group of31 women with no thyroid or bone abnormalities whose age and weight were matched. The women treated with levothyroxine had 10% to 13% lower bone density in the hip compared with the controls. Lumbar spine density, however, was similar in the two groups. The results of the study suggest that long-term levothyroxine therapy may predispose patients to decreased bone density in the hip and may increase the risk of age-related bone loss. The authors urge physicians "to employ a dosage of levathyroxine that is carefully monitored to avoid the long-term use of
Patient Control Lessens Narcotic Use for Pain
A
patient's total narcotic use is likely to be reduced and optimal analgesia reached, with minimal sedation and side effects, if the patient is allowed to decide when to use a prescribed medication, according to Paul F. White (JAMA, 259, 243, 1988). In a review of patient-controlled analgesia (PCA) for the management of acute pain, White emphasizes the inexact nature of predicting analgesic requirements because they vary widely from patient to patient. In PCA, the patient is administered small amounts of narcotic intravenously upon request by a patient activated infusion pump. The risk of accidental or deliberate overdose is minimized because only a small amount of drug is delivered in each bolus and a lockout safety device controls the interval between doses. After a loading dose, sub-
American Pharmacy, Vol. NS28, No. 9 September 1988/555
1
sequent smaller intravenous doses can be administered when the patient wants them, instead of when a busy nurse or physician deems analgesia necessary. Most patients prefer PCA to intramuscular injections and have shown less daytime sedation, more restful sleep, and increased physical activity. A summary of the study in the April 15 Emergency Medicine . praises PCA as an "enlightened approach to analgesia" but notes that putting the patient in control is a concept difficult for nurses and physicians to accept. It goes on to say that "many physicians overestimate the potential for addiction and underprescribe narcotics for patients with legitimate pain. Limiting analgesia may, in fact, enhance addiction; pain medication should not be a hard-to-come-by rew~rd for enduring hours of agony."® 11
Recombinant DNA-Derived Hormone May Help Treat Infertility
R
ecombinant DNA-human luteinizing hormone (rechLH), a genetically engineered version of a human hormone that induces ovulation, appears to be biologically identical to the natural hormone and may provide superior treatment for many female and male fertility problems, conclude investigators at the Jones Institute for Reproductive Medicine (JAMA, 259, 3290, 1988). They report animal study findings suggesting that the product of this genesplicing technique is identical to the natural human hormone that induces ovulation. Human luteinizing hormone (hLH) is now extracted from pituitary glands and from the urine of postmenopausal women. This impure preparation is used to treat infertility caused by hormonal abnormalities in both women and men. The therapeutic advantages of the commercially produced hormone include a more reliably available supply of hormone, as well as improved treatment flexibility in determining the optimal dose for individual patient management either by having pure rechLH to administer alone (as an alternative to human chorionic gonadotropin, hCG), or in various ratios with follicle-stimulating hormone (FSH) Some of the infertility problems now treated with the gonad-stimulating hormones are ovulatory disorders, endocrine disorders causing early pregnancy wastage, and, in men, androgen-deficient problems of libido and hormone-related failure to produce sperm. The hormones also have been helpful with in vitro fertilization for sterility caused by damaged fallopian tubes. Tests have not been conducted on humans, but studies with rats and monkeys indicate that the effects of the rechLH preparation are virtually identical to those of natural hormones from urine and the pituitary glands. Chemical analysis has yet to be conducted to determine whether the molecular structure of 10
the hormone is identical to the naturally occurring substance. The authors also speculate that reaction to rechLH may mimic the normal cycle more closely than the hormone mixture used now, which may lead to better timing in the development of the ovum and better embryo quality.
'As a result of the shorter biological half-life, we may be able to reduce the frequency of multiple pregnancy in women undergoing ovulation induction by truncating the duration of ovulatory stimulus.' "The availability of rechLH has theoretical advantages over hCG for ovulation induction," the authors conclude. '~sa result of the
shorter biological half-life of hLH (approximately 50 minutes) vs hCG (approximately 10 hours), we may be able to reduce the frequency of multiple pregnancy in women undergoing ovulation induction by truncating the duration of ovulatory stimulus. Both an improved source and reliability of product supply of rechLH are likely gains that will enhance physician skills in the management of infertile patients." In an accompanying editorial (JAMA, 259, 3313, 1988), Alan H. DeCherney writes that the new work on rechLH has opened exciting possibilities in the rapidly growing field of ovulation induction because it greatly increases therapeutic possibilities by increasing flexibility in treatments to induce ovulation. "Their work illustrates beautifully how the marriage of new technology and well-conceived and executed scientific experimentation and validation will result in clinical realities that improve the quality oflife," DeChemey says. "Read from a narrow perspective, this article merely documents the potential use of rechLH as a pharmacologic agent; but read with a wider vision, it illustrates the importance ofbasic science developments in the practice of modem-day medicine."®
Zidovudine Can Inhibit AIDS Virus Activity idovudine (formerly azidothymiZ dine, or AZT) found in the semen of patients taking the anti-AIDS drug can reach levels considered sufficient to inhibit in vitro activity of the AIDS-causing human immunodeficiency virus (HIV-1), according to a preliminary report in the May 27 JAMA (259, 3023, 1988). The report says the results "support the possibility that the presence of zidovudine in semen could decrease the amount of culturable HIV in that body fluid." The authors would not go so far as to say that the conclusions mean that the presence of zidovudine would decrease the infectivity of semen.
The test, conducted on six patients with AIDS or AIDS-related complex who were taking 200 mg of the drug orally every 4 to 6 hours, also found that levels of zidovudine in semen samples were higher than serum levels- findings the authors called unexpected but not unprecedented. A commentary in the same issue (p. 3037) suggests that antiviral drugs and vaccines to prevent transmission of HIV should be aimed at attacking HIV-infected cells and not just the virus. Until now, most approaches have concentrated on the retrovirus alone. However, biologic and epidemiologic studies
American Pharmacy, Vol. NS28, No. 9 September 1988/554
Drug Research indicate that cell-free virus in body fluids is unlikely to be a meaningful source of HIV transmission. Therefore, Levy contends, researchers should focus their attention on the role of virus-infected cells in the spread of AIDS. "Unlike strategies to fight other
human viruses, such as measles virus, poliovirus, and hepatitis virus," Levy says, "blocking freevirus entry into the host without removal of the infected cell would not lead to effective prevention. The control and cure of AIDS will result only when the infected cell itself is
eliminated." Until such antiviral approaches are available, he says, a decrease in sexual transmission of HIV can be achieved only by avoiding intimate sexual activity or by using barrier methods - such as condoms - that block contact with the virus-infected cell. ®
Thyroid Hormone Replacement May Decrease Hip Bone Density
C
areful monitoring of the dosage of long-term thyroid hormone replacement therapy is needed to avoid excessive dosages that may result in osteoporosis, report investigators from the University of Massachusetts Medical School (JAMA, 259, 3137' 1988).
·.- .
~
.
dosages that are excessive for the thyroid condition being treated." In an accompanying editorial (p. 3175), DavidS. Cooper of the Johns Hopkins University School of Medicine notes that the study subjects were taking thyroid hormone for well-accepted indications: hypothyroidism secondary to Hashimoto's thyroiditis, hypothyroidism following radioactive 1odine or surgical treatment for Graves' disease, thy-
·w1
. -~ .:< "'\:·:. ;b !.~ ~ --~~'-/• ~~~l \~~~· . .•
roidcancer after total thyroidectomy or primary hypothyroidism, and suppressiorJ. of other types of nontoxic goiter. Cooper raises the question, "Is it appropriate to treat a benign thyroid problem with a medication that potentially could cause osteoporosis?" and further suggests that "one must choose the dosage with great care. In light of the data in [this] study, the whole concept of suppression therapy for benign thyroid disease may need reevaluation, especially in older women, whose skeletons are the most likely to be in jeopardy." ®
...
.·.
-
.
Their study- examined 31 premenopausal women (aged 19-46) who had been on levothyroxine for at least 5 years. Many were on dosages of the hormone that would now be considered excessive. Bone densities in the hip and spine were compared with those of a control group of31 women with no thyroid or bone abnormalities whose age and weight were matched. The women treated with levothyroxine had 10% to 13% lower bone density in the hip compared with the controls. Lumbar spine density, however, was similar in the two groups. The results of the study suggest that long-term levothyroxine therapy may predispose patients to decreased bone density in the hip and may increase the risk of age-related bone loss. The authors urge physicians "to employ a dosage of levathyroxine that is carefully monitored to avoid the long-term use of
Patient Control Lessens Narcotic Use for Pain
A
patient's total narcotic use is likely to be reduced and optimal analgesia reached, with minimal sedation and side effects, if the patient is allowed to decide when to use a prescribed medication, according to Paul F. White (JAMA, 259, 243, 1988). In a review of patient-controlled analgesia (PCA) for the management of acute pain, White emphasizes the inexact nature of predicting analgesic requirements because they vary widely from patient to patient. In PCA, the patient is administered small amounts of narcotic intravenously upon request by a patient activated infusion pump. The risk of accidental or deliberate overdose is minimized because only a small amount of drug is delivered in each bolus and a lockout safety device controls the interval between doses. After a loading dose, sub-
American Pharmacy, Vol. NS28, No. 9 September 1988/555
1
sequent smaller intravenous doses can be administered when the patient wants them, instead of when a busy nurse or physician deems analgesia necessary. Most patients prefer PCA to intramuscular injections and have shown less daytime sedation, more restful sleep, and increased physical activity. A summary of the study in the April 15 Emergency Medicine . praises PCA as an "enlightened approach to analgesia" but notes that putting the patient in control is a concept difficult for nurses and physicians to accept. It goes on to say that "many physicians overestimate the potential for addiction and underprescribe narcotics for patients with legitimate pain. Limiting analgesia may, in fact, enhance addiction; pain medication should not be a hard-to-come-by rew~rd for enduring hours of agony."® 11