Miscellaneous hormones and prostaglandins

R. Bouillon and F.A. van Assche

45

Miscellaneous hormones and prostaglandins

MISCELLANEOUS H O R M O N E S Cnicitonin and related peptides (SED-IO, 808;

SEDA-8, 384; SEDA-9, 355; SEDA-IO, 379) In a multicenter study of the effects of synthetic human calcitonin on pain relief, involving 530 patients with primary or secondary osteoporosis and Sudeck's disease, an improvement in different types of pain was noted in 60% of all patients at Day 15 and in 82% after 1 month of treatment (lCR). The local tolerability of calcitonin injection was good with a burning sensation occurring in less than 5% of the patients. Slight systemic side effects were noted by 13% of the patients (usually nausea, vomiting, cutaneous flush or headache) with more severe reactions of the same type in about 3.7%, necessitating withdrawal of calcitonin treatment in 2.8%. This report, sponsored and written by the drug company providing the human calcitonin, concluded that this therapy was highly effective in relieving pain and functional impairment in bone diseases (lC~). A review of the usefulness of calcitonin therapy for Paget's disease of bone has supported the conclusions drawn earlier in these volumes (SEDA-10,379) that calcitonin is usually a safe and effective treatment for the most active cases of this disease. Unlike the bisphosphonates, calcitonin needs to be injected and its effects are rapidly reversed after withdrawal of treatment. Combined therapy can be useful in some cases (2R). Mild but frequent side effects of calcitonin therapy are dose-dependent and more frequent after intramuscular than subcutaneous injection (2~). To avoid these complications, nasal application of calcitonin has been tried (SEDA-10, 379). Two small studies have further confirmed the efficacy and tolerance of Side Effects of Drugs Annual 11 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1987

nasal administration (3 c, 4c). The lack of significant side effects after nasal application was especially well documented in patients previously proving intolerant to intramuscular injection (3~).

Vasopressin, analogs and antagonists (SED-IO, 809; SEDA-8, 384; SEDA-9, 355; SEDA-IO, 380) The vasoconstrictor effect of vasopressin is probably responsible for the necroses of the skin (SED-10, 809) or internal organs which are occasionally encountered: A 79-year-old woman with primary biliary cirrhosis and bleeding who was treated with vasopressin to reduce pressure in the esophageal varices developed cutaneous reaction: 4 hours after starting vasopressin, a diffuse mottling of the abdominal wall, back and foot appeared, worsening to diffuse ecehymoses. The vasopressin infusion had to be stopped and an emergency portocaval shunt was created but the patient later died of sepsis (5c). A less easily" detectable vasoconstriction in the splanchnic circulation may result in intestinal infarction. Such a lethal complication was observed in a 77-year-old woman with bleeding esophageal varices, treated with vasopressin infusion (20 IU/h) because of unsuccessful local sclerotherapy. Postmortem a gangrenous small bowel segment of 1 m length was found (6c). The effects of intravenous desmopressin acetate (DDAVP), the synthetic analog of vasopressin with reduced pressor but enhanced antidiuretic effect, have been studied in 6 normal adult volunteers (7cR). Facialflushing, a small fall in blood pressure ( - 1 3 % ) and an increased pulse rate ( + 1 8 % ) as well as a concomitant reactive increase in plasma renin activity and cortisol were observed. Similar reactions were also observed in patients with central diabetes insipidus, indicating that these reactions are not due to blocking of the endoge-

Miscellaneous hormones and prostaglandins Chapter 45

nous vasopressin activity but are directly drug-related (7cx). The hemostatic effects of DDAVP, which are well known but poorly understood, were studied in 2 patients with vasopressin-resistant diabetes insipidus. The expected increase in Factor VIII coagulant activity and Factor VIII related antigen was not observed, indicating that the normal vasopressin receptor is necessary for this hemostatic reaction (8c). The beneficial effect of this D D A V P therapy has been exploited in patients needing large blood transfusions during cardiac surgery. In a double-blind prospective, randomized trial, intraoperative DDAVP (0.3 I~g/kg) significantly reduced blood loss (1317_486ml in the treated group vs 2210+ 1415 ml in the placebo group). This decreased blood loss was associated with an increased 'Von Willebrand' factor concentration (9cR). No untoward side effects of DDAVP nor even the expected antidiuretic effect were observed. The possible impact of such treatment on blood requirements for all patients needing cardiac surgery could be enormous, as is stressed in the accompanying editorial (10R), which, however, also underlines the need for further studies, especially since the hemostatic effects might increase the incidence of coronary graft occlusion in patients undergoing saphenous vein bypass operation (11R). New analogs of vasopressin which antagonize the effects of vasopressin might find application in the treatment of hyponatremia, but testing in human subjects is necessary to confirm preliminary beneficial effects reported in animals (1 IX). A general review of the therapeutic effects of DDAVP has been presented in an excellent paper by Richardson et al (12R). Despite its advantage over slow-acting vasopressin with the latter's potential hypertensive side effects, over pituitary snuff associated with allergy, and over vasopressin-potentiating drugs, some skill and practice is necessary if one is to calibrate its nasal application. The safety of DDAVP in pregnancy is also reviewed, especially its lack of uterotonic effect (in contrast to vasopressin). DDAVP is remarkably free of side effects even after intravenous administration. Rare instances of headache, abdominal pain, general sweating or facial flushing have been reported; hyponatremia is rare, but care should nevertheless be taken when the drug is used in association with other agents which can induce this complication (such as chlorpropamide, clofibrate or indometacin). Allergic reactions and a case of paranoid psychosis have also been reported.

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Human growth hormone (somatotrophin) (SED-IO, 808; SEDA-8, 385; SEDA-9, 356; SEDA-IO, 381)

Human growth hormone therapy and Creutzfeldt-Jakob disease As already briefly mentioned (SEDA-IO, 381) on the basis o f preliminary announcements, the use o f human growth hormone (HGH) produced from human pituitaries has been suspended worldwide because o f its possible contamination with a slow virus or prion responsible for slow and delayed induction o f a lethal central nervous system disease known as Creutzfeldt-Jakob disease. Detailed reports on the death o f 4 young persons due to a subacute dementia accompanied by pyramidal, extrapyramidal and cerebellar signs have been published. They were all treated with HGH, extracted from human pituitary glands obtained at autopsy. Large numbers of glands are usually collected and combined before extraction and initial procedures for purification had been less extensive with the batch in question, which contained many more impurities than did later batches o f HGH. The index case was a 20-year-old American man who developedprogressive instability of gait, instability, ataxia, increasing dementia and died 6 months after the onset of symptoms (13cR). He had suffered from insulin-deficiency diabetesfrom infancy together with multiple pituitary hormonal deficiencies and had been treatedfrom 1966-1980 with HGH. An autopsy, reported in detail, clearly demonstrated CreutzfeldtJakob disease as the cause of death, with identification (using immunoelectron microscopy and Westernimmunoblots) of scrapie-associatedfibrils (14c). Subsequently, 2 similarly fatal cases in American recipients of HGH therapy were published (15cR). Later a 23-year-old girl died of Creutzfeldt-Jakob disease in the United Kingdom after having been treatedfrom age 10 to 14 (16c~) with HGH prepared in the U.K. (initially with crude Raben technique). On necropsy of the brain, cerebellar atrophy and diffuse spongiform changes in the cerebral cortex werefound. Both these findings and the clinical course of the disease are typical of this viral disease. Four other patients who had received HGH therapy and died of chronic neurological diseases are currently under reinvestigation for possible Creutzfeldt-Jakob disease (17R). This rare disease has an incidence of about 1 case per million population and is exceptionally rare under 30 years o f age. Approximately 10,000 Americans, all under the age of 40, have received HGH; the occurrence o f 3 cases in a

372 single year among such patients was highly unlikely to be a coincidence, especially since transmission o f this disease by contaminated neurological material is known to be possible and has occurred before in man (17 ~, 19R). About 1 in 10,000 deaths in the general population are due to Creutzfeldt-Jakob disease and it is clear that, occasionally, a pituitary from such a patient may be used for extraction o f HGH. The trouble is that the batches used often contain thousands o f glands, so that contamination o f the whole batch is possible from a single infected gland. Prior exclusion o f suspected pituitaries is difficult to guarantee. The infectivity o f such batches is also difficult to assess. Using the extensive purification product currently employed in the U.K. and worldwide since the late 1970s, which involves Sephadex gel filtration glands intentionally infected with the animal model o f the human disease (scrapie virus) can be freed o f the virus. The older H G H preparations, however, were prepared without such procedures. It is therefore important to note that all the 4 deaths from this viral disease were treated with H G H in the 1960s, or early 1970s, and had received H G H from 6-22 batches (17R). No new cases have been reported since the initial reports, but some fear for a further epidemic among HGH recipients persists, especially as regards children treated with the earliest preparations. Meanwhile, most national agencies, including the FDA, the Common Market countries and New Zealand, have taken steps to stop further treatment with H G H o f human pituitary origin or have restricted its use to the exceptional cases o f pituitary dwarfism associated with severe hypoglycemic reactions. Some other countries (e.g. Japan, Israel and countries in Central Europe) have however continued to distribute the product on the basis o f (incomplete?) evidence that the extensive purification procedures currently used are capable o f eliminating possible contamination. The likely association o f the severe viral disease with human pituitary extract also has repercussions for future policies. Fortunately, biosynthetic HGH is now almost ready for widespread clinical use, although it is not yet fully proven to be safe on a long-term basis, has the disadvantage o f containing one additional amino acid (methionine), and seems to induce more antibodies in recipients than highly purified human gland extracts. In the meantime, work continues to determine whether existing or improved methods for the preparation o f HGH from pituitary glands can render it completely safe with regard to possible viral or prion contamination.

Chapter 45 R. Bouillon and F.A. van Assche Similar reservations hoM good for the use o f other hormones obtained from human pituitary glands (e.g. gonadotrophins) both as regards their therapeutic or diagnostic use in man and the handling o f such materials in the laboratory. It also seems important to warn all physicians encountering patients with progressive neurodegenerative disorders who might have been treated with hypophyseal hormones to report such cases to the National Drug Monitoring Agency (20 R, 21~). New data facilitating the earlier diagnosis o f Creutzfeldt-Jakob disease (22 ~) are also eagerly awaited so that there can be a more thorough follow-up o f patients receiving H G H preparations.

General side effects of human growth hormone Antibodies to H G H appear with variable frequency (SED-10, 808; SEDA-10, 380) but are only rarely associated with a decreased growth rate (23c). When different growth hormone (GH) preparations were compared, marked differences were observed in this respect; H G H from KabiVitrum (Crescormon) produced a lower frequency of antibodies (45%) than did growth hormone (GH) from Serono (78%) or that prepared in a research laboratory (100% of patients treated) (23c). The optimal approach to GH therapy has received much attention since one will necessarily seek to attain maximal growth rates while using minimal amounts of this expensive and scarce hormone. The change from the classical intrarquscular injection 3 times a week to a daily subcutaneous injection was unexpectedly associated with a marked catch-up growth spurt (24c). Indeed, a mean growth velocity increase from 4.8-6.9 cm per year was observed after switching to the new scheme. Moreover, most patients preferred the subcutaneous to the intramuscular injection. No side effects were observed, but the follow-up period was too short ( < 1 year) to allow valuable comparison of antibody titers (24c). Although all studies reported up to now have dealt with human extracted GH, it is to be expected that these observations will also apply to biosynthetic HGH, which has recently been approved for use in children with lack of endogenous G H secretion (25r). The availability of large amounts of biosynthetic G H will certainly soon create a resurgence of interest in G H therapy in short people who do not have a classic or complete deficiency of G H (26R).

Miscellaneous hormonesand prostaglandins Chapter45 Growth-hormone-releasing hormone (SEDA-8, 385; SEDA-9, 357; SEDA-IO, 381) The diagnostic and therapeutic possibilities of growth-hormone-releasing hormone (GHRH) continue to be explored. A continuous infusion of G H R H in normal subjects will, though, slowly and incompletely, desensitize the hypophyseal gland to a subsequent G H R H bolus injection but will render it suprareactive to other stimuli (27c). This pattern is important when selecting the best dose and mode of administration of G H R H for prolonged treatment, especially since existing experience with gonadotrophin-releasing hormone has already clearly demonstrated its potential for hypophyseal desensitization (SED-10,810). Indeed, many children with severe growth delay and an absent G H response to classical stimuli (e.g. hypoglycemia, levodopa) can still secrete GH when submitted to repeated injections of GHRH, indicating that suprahypophyseal deficiency or disturbances are more frequent than true deficiency of the anterior pituitary gland. Chronic therapy with G H R H thus could be a valuable alternative to classical G H treatment, especially in view of the associated costs and risks (see section on HGH above). Severe GH-deficient children were treated with an intravenous infusion of GHRH (l'lzg/kg every 3 h for 9-12 days) and the growth response, measured using a sensitive lower leg measurement, was compared with growth after placebo infusion or classical GH therapy. A marked growth effect after GHRH was only observed in children with a concomitant increase in endogenous GH secretion and increase in somatomedin C concentration. Their growth rate exceeded even that observed after GH therapy. No allergy or other side effects were observed during short-term therapy. Even the flushes frequently seen during bolus injections of GHRH in adults were not observed (28cR). Pulsatile G H R H therapy could thus become a valuable alternative to GH therapy if an alternative route of administration could be found for long-term use. A first report on subcutaneous injections of GHRH (1-3 ~tg/kg) (given every 3 hours by a pulsatile infusion pump) revealed the feasibility and safety of such procedure in 2 children: After 6 months of therapy, a marked catch-up growth was observed (7.1 and 13.7 cm after treatment vs 4.6 and 2.1 era/year before GHRH therapy). Their somatomedin C and GH secretion was also increased. Again no major side effects were observed, but the authors are cautious not to extrapolate their findings in 2 children to more prolonged use in more heterogeneous groups of GH-deficient children (29cR).

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Since, especially in children treated for many years even chronic subcutaneous pulsatile infusion could be troublesome, alternative routes of administration of G H R H have been sought. G H R H still releases GH when given intranasally, but it then requires a higher dose (> 10-fold) than via the intravenous or subcutaneous route (30c). Some growth-delayed children can secrete GH after pharmacological stimuli but do not actually secrete it during normal life; such cases will only be detected if one uses integrated (day and night) measurements of GH levels over a long period. Several trials to detect these abnormal children using G H R H tests failed. Again no adverse reactions were observed during G H R H testing (31c). A detailed pharmacological study of a new synthetic hp-GRF-1-44-NH2 preparation using a 2.5 and 80 lag bolus and measuring subsequent G H secretion, points to reliable dose-effect relation with no effect on prolactin secretion. The intersubject variation, however, is large, so that for diagnostic use rather high amounts (40-100 lag) are needed. No changes in the continuously recorded blood pressure or pulse rate were observed such as have been previously mentioned (SEDA-9, 357; SEDA10, 381). Mild flushing reactions were also absent except when even higher doses ( > 150 lag) were used (32c). The GH secretion after G H R H was found to be higher in young males than in young female subjects (33c). This difference is remarkable since classical testing has usually revealed a higher GH response in females. Mild flushing of the face and chest or a sense of warmth occurred in about half of the subjects, but no serious side effects were noted (33c).

Corticotrophin-releasing hormone (SEDA-9, 357," SEDA-IO, 381) Intravenous bolus injection of (ovine) corticotrophin-releasing hormone (CRH) (1 pg/kg) is useful and safe for distinguishing between Cushing's disease originating from pituitary adenoma and ectopic corticotrophin (ACTH) secretion (34c). No difference in ACTH or cortisol response was observed between normal adults and children or between boys and girls (350. No adverse reactions to the bolus injection were observed (34c, 35r Endogenous depression or anorexia nervosa may alter the ACTH response to CRH as both groups of patients are characterized by high basal cortisol levels and decreased ACTH response (36 ~,

374 37r The best results are obtained by testing at 8 p.m. when basal ACTH levels are usually low. Again the procedure was found to be safe (36 ~ 37~).

Gonadotrophin-releasing hormone (SED-IO, 810; SEDA-8, 385; SEDA-9, 358; SEDA-IO, 382) Gonadotrophin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) has been increasingly used both to stimulate and to suppress the pituitary-gonadal axis. Use as a stimulant requires pulsatile administration (a bolus every 90-180 min). This has been applied in the treatment of cryptorchidism and for the induction of puberty and fertility. The opinion that GnRH given intranasaUy is an efficient and side-effect-free treatment for cryptorchidism (38 R) has recently been challenged by a randomized, double-blind study (39c). Both GnRH and hCG (human chorionic gonadotrophin) had an extremely low success rate in true cryptorchidism, whereas side effects such as an increase in penile and testicular size, erections and aggressive behavior occurred in both forms of treatment. The authors suggest that only retractile testes are responsive. Hadziselimovic, on the other hand, concludes that the success rate in true cryptorchidism can be markedly increased by combining GnRH and hCG and that the side effects are negligible in comparison with those of orchidopexy (40~). Puberty can be successfully induced in patients with idiopathic and organic hypothalamic hypogonadism by prolonged subcutaneous pulsatile administration of GnRH (41 R, 42 c) and normal spermatogenesis (43 c) or ovulation and some pregnancies (41 R) have also been induced. The main problem is that of multiple ovulations, which occur especially during prolonged intravenous GnRH treatment (44c), although the incidence of ovarian hyperstimulation is still less than during gonadotrophin therapy. To avoid this problem, a dosage of less than 6 ~tg per intravenous pulse has been recommended (44~). In a study with subcutaneous GnRH, the optimal dosage for achieving 100% ovulation without overstimulation appeared to be between 25-100 ng/kg/ bolus (41R). However, in other indications such as luteal phase defect, disordered folliculogenesis or irregular ovulation, a higher dose pulsatile GnRH regimen (10-20 ~tg s.c. every 3 h) was needed to induce ovulation and some

Chapter 45 R. Bouillon and F.A. van Assche patients needed intravenous therapy (45c). Hyperstimulation occurred in 1 woman treated intravenously. Only 1 case of a serious allergic reaction during such pulsatile GnRH therapy has been reported (4@): a female patient with Kallman's syndrome had to discontinue a successful treatment after 200 days because of wheal and flare reactions at multiple old injection sites. A continuously elevated blood level of GnRH analogs, such as can be attained using various sex steroids, suppresses the pituitarygonadal axis. This phenomenon finds its application in the suppression of precocious puberty and in contraception, but also in controlling sex-hormone-sensitive diseases like breast and prostate cancer, endometriosis and leiomyoma. The very potent substance (D-Trp 6, Pro 9NEt)GnRH and its analogs can be used for the suppression of idiopathic or organic hypothalamic precocious puberty, usually employing daily subcutaneous injections of high doses (e.g. 8 ~tg/kg/d) (47R). To avoid these cumbersome frequent subcutaneous injections, Roger et al (48c) used GnRH-analog microcapsules in a polymeric matrix to be injected intramuscularly every 4 weeks; they noted apparently similar effects and no side effects, except for a transient withdrawal bleeding in some girls. One group of investigators, using daily subcutaneous injections, noted a high incidence of local erythematous reactions (6/19 patients), associated with histamine release and specific IgE antibodies (49c). Two of these patients had to discontinue therapy because of wheal formation. One year later, because of continuing precocious puberty, they were desensitized to GnRH and could be further treated without problems. Because it retards skeletal maturation, GnRH increases the predicted adult height in precocious puberty (47R). On the other hand, there is no influence on the adrenarche (47R, 50c), but the retardation of skeletal maturation is less evident in children with onset or progression of adrenarche during therapy than in those who remained preadrenarchic (50c). Since earlier reports on GnRH as a male contraceptive were discouraging either because of lack of effect (51 c) or because it induced impotence, Swerdloff and co-workers have tried using a combination of daily subcutaneous nafarelin [D(NaI2)GnRH] and monthly testosterone enantate intramuscularly (52c). Sperm count was reduced by 90% in most subjects, without side effects, but none really became azoospermic.

Miscellaneous hormones and prostaglandins Chapter45 Nafarelin as a nasal insufflation of 125 or 250 ~tg was also used as a female contraceptive in two studies (53 c, 54c). No pregnancies occurred, but ovulatory cycles were significantly more frequent with the lower dosage (54c). The first group of authors did not notice any serious side effect, except for the bleeding irregularities due to anovulation (53c). In the second study, however, 2 subjects did not complete the treatment, 1 because of excessive weight gain and the other because of heavy uterine bleeding (54c). Furthermore 2 subjects experienced galactorrhea. One o f them had a slightly elevated serum prolactin concentration during therapy. In both, the galactorrhea persisted after the end of treatment. Moreover, two-thirds of the women experienced one or more symptoms which could be due to hypogonadism. GnRH-analog therapy, given in the form of daily subcutaneous injections or using monthly intramuscular administration of a slow-release preparation, is just as effective in controlling advanced or metastatic prostatic cancer as is orchidectomy (55 c) or diethylstilboestrol (DES) (56Rc). All these therapies produce in fact the same castration effect but of course result also in hot flushes and loss of libido. Leuprorelin (a G n R H analogue) causes even more hot flushes than DES, b m DES produces more painful gynecomastia, nausea and vomiting, edema and thromboembolism than leuprorelin (56Rc). A matter of concern remains the tumor 'flare" phenomenon due to the transient stimulatory effect of G n R H on the pituitary-testicular axis. Seventeen of 32 patients, presenting with bone pain, experienced an increase in symptoms during the first week of treatment with subcutaneous buserelin or decapeptyl [D(Trpr)LHRH]. Other transiently worsening symptoms included lymphedema, a serious increase in creatinine and spinal cord compression. Nevertheless, these patients with an initial flare phenomenon later responded at least equally well as those without a 'flare' (57c). A 20% rise in serum prostate-specific phosphatase was noticed in 6 patients during the first few weeks of subcutaneous buserelin treatment (58c). On the other hand, Parmar et al, using a slow-release D(Trpr)LHRH in 50 patients, found evidence for only 1 tumor flare, whereas 2 of 4 patients treated with subcutaneous D(Trpr)LHRH, developed tumor flare (59c, 60c). Since in the subcutaneous leuprorelin study (56cR) a 7% tumor flare was reported, Parmar et al suggested that slow-release preparations may cause less flare incidence. This suggestion does not seem in agreement with the findings of Robinson et al, who describe exactly the

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same initial stimulation of luteinizing hormone (LH) and testosterone after subcutaneous or slowrelease Zoladex (61c). An interesting result was obtained by a combination therapy of G n R H analog with an antiandrogen (62R). The 2-year survival rate in 88 patients was 90%, as opposed to 40-60% after all previous hormonal therapies. The authors conclude that the residual stimulatory action of adrenal androgens on prostate cancer, which persists after surgical or medical castration (even with G n R H alone), should be antagonized by antiandrogens in order to optimalize the response. In one report, the G n R H agonist D(Trp) 6L H R H was found to blunt thyroid-stimulating hormone ( T S H ) response to thyrotrophinreleasing hormone (TRH) stimulation in 5/10 patients after 1 month of treatment (63c). The response normalized after 2 or 3 months of G n R H therapy. The same potent analogs have also been used in the treatment of metastatic breast carcinoma in premenopausal women, with the same success rate as tamoxifen or castration (64c, 65c). Leuprorelin given daily subcutaneously increased bone pain (flare?) in 2/25 patients (64c). Beside signs of hypogonadism, local reactions and hives were observed. One patient experienced an unexplained polyuria and polydipsia (64c). Subcutaneous or intranasal administration of buserelin led to similar therapeutic effects, but in this study only hypogonadism-related side effects were observed (65c). Nafarelin (2 x 500 ~tg/d intranasally) resuited in relief of symptoms in all of a series of 8 patients with endometriosis and in 5 of them complete resolution of active lesions occurred (66c). Dose reduction to 2 x 250 ~tg decreased the symptoms of hypoestrogenism without interfering with the therapeutic effects. One of these patients developed leukopenia (nadir 2500 white blood cell count with 55% polymorphonuclear neutrophil leukocytes). No underlying disease could be identified and the leukopenia persisted despite discontinuation of nafarelin. Ten women with 12 leiomyomas were treated with a daily dose of 500 ~tg buserelin subcutaneously for 6 months (67c). Seven leiomyomas showed a marked reduction in size. Beside the castration symptoms, serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, alkaline phosphatase and phosphorus were elevated and a reduced neutrophil concentration was observed after 6 months

376 of therapy. All these changes were statistically significant, but they were nevertheless slight and within normal ranges. Oxytocin (SED-IO, 810; SEDA-8, 387; SEDA-9, 361; SEDA-IO, 384) Oxytocin is still frequently used to induce or advance labor, and although its correct use is considered safe, accidents or side effects are still occasionally reported. Although there is no proof that oxytocin can cause the sudden infant death syndrome, some case-reports focus attention on a possible link (68 c, 69r Water intoxication leading to cerebral edema, which may manifest as a decreased level of consciousness, convulsions and even death, may be a complication when oxytocin is given in high doses and for prolonged periods (70c). Allergic anaphylactoid reactions to oxytocin are extremely rare, but must be borne in mind by those involved in obstetric practice (71~).

Somatostatin analogs ( SED A-9, 359; SEDA-IO, 382) The experience with a synthetic somatostatin analog is rapidly increasing and due to a large variety of unknown effects of somatostatin, a similarly large field of potential applications is being explored. Subcutaneous injection of 50 lag of the octapeptide SMS 201-995 (d-Phe-Cys-PhedTrp-Lys-Thr-Cys-Thr-ol), produced a long-lasting (6-12 h) and marked (64%) suppression of serum GH levels in 8 acromegalic patients without subsequent rebound phenomena (73c). The SMS administration was very well tolerated without changes in blood pressure, pulse rate or routine blood chemistry, but insulin secretion was inhibited for several hours so that postprandial blood glucose levels significantly increased for 2-4 h after SMS injection. A more prolonged treatment (8-24 weeks) of 4 patients with acromegaly (100-300 lag/d) caused a rapid amelioration of clinical signs and symptoms of acromegaly with much reduced serum GH levels. The only side effect was suppression of insulin secretion and a mild increase in postprandial blood glucose (73cR). A slight shrinkage of the primary tumor was observed in 3 of the 4 patients. An accompanying editorial (74R) also considers this new form of treatment of acromegaly to be more than welcome but calls for a better evaluation of possible long-term complications. In reaction to these publications, several letters to the

Chapter 45 R. Bouillon and F.A. van Assche editor have pointed to other side effects, such as an increase in hemoglobin Arc in a patient with acromegaly and diabetes (75 c) and increased stool-fat excretion due to impaired intestinal fat digestion (75r Moreover, patients with the highest pre-treatment GH levels (> 50 ng/ml) failed to respond to SMS therapy (76c). Hypersecretion of insulin (insuloma), glucagon (glucagonoma) and vasoactive intestinal peptide (vipoma or pancreatic cholera) have also been favorably influenced by somatostatin therapy, and occasional reports on the use of SMS in these same conditions are now appearing (77c-79c). In a case of malignant insuloma, SMS therapy was able to suppress insulin secretion by 50% so that hypoglycemia and the side effects of diazoxide could largely be avoided during prolonged SMS therapy (77c). A similarly positive effect was observed in a case of inoperable glucagonoma (78c). Indeed, biochemical normalization, disappearance of skin rashes and restoration of weight gain was observed during SMS therapy in a patient with a glucagon-producing cancer. Fecal fat excretion temporarily increased to 17 g/d but normalized during more prolonged therapy. Transient episodes of a metallic taste and mild diarrhea were also observed but only during the 1st week of treatment (73c). The insulin requirement of this diabetic patient remained unchanged during SMS therapy. A patient with a vasoactive intestinal polypeptide (VIP) producing pancreatic non-beta-cell tumor who had become resistant to existing therapy also showed a favorable response to SMS therapy (200 lag/d). High levels of VIP and other pancreatic hormones rapidly normalized during SMS therapy (70-94% suppression) with continuous control of pre-existing diarrhea for 3 months, until the patient died from generalized metastases and infection. No evidence for hematologic or biochemical toxicity of SMS was observed, but the primary abdominal tumor did not decrease in size during SMS therapy (79c). A 53-year-old woman with malignant carcinoid also responded favorably to SMS therapy during a carcinoid crisis occurring at the time of surgery (80r The natural somatostatin peptide is still frequently used in intravenous or intra-arterial perfusion for treatment of bleeding of esophageal varicose veins. During such a procedure 250 lag of somatostatin was given as an intravenous bolus instead of slow infusion with prompt respiratory arrest, but thanks to previ-

Miscellaneous hormones and prostaglandins Chapter45 ous intubation rapid resuscitation was possible. A repeat intravenous bolus was again followed by immediate respiratory arrest, while the same amount of somatostatin did not influence spontaneous respiration when given as a slow infusion (81 ~). PROSTAGLANDINS Prostaglandins in cardiovascular diseases (SED-IO, 814; SEDA-8, 387; SEDA-9, 360; SEDA-IO, 383) PGE1 and PGE2 are effective drugs in many cases of congenital cardiac malformations with reduced pulmonary blood flow. Cortical hyperosteostosis with swelling and tenderness of several bones is a well-documented side effect (SED-10), but these abnormalities disappear a few months after discontinuation of PGE therapy. Widening of the cranial sutures is rare (82cR). PGE1 (alprostadil) infusion had no better effect on Raynaud's syndrome than did placebo and it had no favorable effect on skin ulcer healing. The marked side effects observed during the PGE1 infusion, however, included flushing, headache, peripheral edema and inflammation us well us pain at the i~jection site (83c). Dermal application of PGE2 for 6 weeks, however, produced a significant subjective and objective improvement in patients with Raynaud's phenomenon with self-limiting and only relatively minor side effects (headache, flushing and diarrhea) (84c). Prastaglandins in gastrointestinal disease (SEDA-8, 388; SEDA-9, 360; SEDA-IO, 383) Misoprostol, a 15-desoxy-16-hydroxy-16methyl-PGEl-methylester, inhibits the gastric secretion of acid and pepsin and therefore possesses anti-ulcer activity in the upper gastrointestinal tract. The cure rate for duodenal (85r c) and gastric (90c-95 c) ulcers varies between 60-70% after 4 weeks of misoprostol treatment and is therefore comparable with the cure rate obtained with cimetidine (85c-90 c, 94 ~, 95~). Patients on cimetidine, however, were more rapidly asymptomatic than were patients on misoprostol treatment (89~). Misoprostol in low doses may also have a cytoprotective effect besides the well-documented antisecretory effect of high doses (96c), so that it was possible to use it in the prophylaxis and therapy of gastric erosions

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caused by alcohol, non-steroidal anti-inflammatory drugs or chemotherapy (90~-93 c, 96 c, 97"). In a placebo-controlled trial, the only significant complaint dearly associated with misoprostol treatment was diarrhea in about 10% of all patients. This side effect was usually self-limiting and only rarely led to drug withdrawal. No biochemical or hematological side effects were noted (85"-95 c, 98c-100"). Clinical use of prostacyclin (SEDA-9, 360) Epoprostenol (PGI2), a naturally occurring prostaglandin, is a potent inhibitor of platelet aggregation and induces relaxation of the smooth muscle cells and vascular tone. It is therefore potentially of benefit in cases of peripheral vascular disease, ischemic heart disease and extracorporeal circulation (101a). Favorable results were achieved in patients with peripheral vascular disease, in which prostacyclin appeared to promote healing of ischemic ulcers and alleviate resting pain. However, PGI2 is chemically unstable. Ciprostene is a recently synthetized stable derivative of prostacyclin with in-vitro plateletinhibiting properties. The most frequent adverse drug reactions comprised headache, restlessness, nausea, palpitation, flushing and jaw pain. Pre- versus post-infusion routine laboratory examinations, fibrinogen concentration, antiplasmin activity and plasminogen and template bleeding times remained unchanged

(lO1r

In patients with coronary artery disease, the use of prostacyclin (PGI2) or analogs may induce ischemia, probably because o f dilatation of small coronary vessels; this may result in decreased subendocardial perfusion pressure, and/or 'coronary steal' (102c). Prostaglandins in obstetrics (SED-IO, 812; SEDA-8, 388; SEDA-9, 360; SEDA-IO, 384) The most important therapeutic use of prostaglandins remains the induction of 1st and 2nd trimester abortion. PGE2 is the substance most commonly utilized, as a rule intracervically or intravaginally (103c-107r 9 although PGF2~ is also in use (108c). The vaginal administration of 16,16-dimethyltrans-A2-PGEl-methyl ester has proved effective in managing intrauterine fetal death, but pyrexia was a common side effect and vomiting and diarrhea occurred in about 20% of the women. Moreover, a dangerous rise in blood pressure occurred in a few cases where fetal

378 death was associated with unresolved preeclampsia (10r Preinduction o f cervical ripening with PGE2 appears to be another c o m m o n strategy in obstetrics, intended to avoid longstanding induction of labor. Systemic side effects are minimal and this therapeutic regimen is usually described as safe (ll0C), although 2 cases of uterine rupture in previously unscarred uteri have been described (111r Uterine rupture

Chapter 45 R. Bouillon and F.A. van/Issche might be prevented by using a low dose ( ~<5 mg) (112r The therapeutic use o f PGI2 in obstetrics is still in its early stages, probably due to the very short half-life and the supposed local action of this prostaglandin (113r Administration o f intravenous PGI2 seems to be useful in patients with severe hypertension; however, the appearance of vasodilatorrelated side effects may limit its wider application (114r

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Miscellaneous hormones and prostaglandins

Chapter 45

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Miscellaneous hormones and prostaglandins

Chapter 45

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