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Biomedical subjects

A Hurwitz

Publications and source records attributed to A Hurwitz.

At least 37 records · Page 2Linked to original sources
PubMed1997

In-vitro modulation of plasminogen activator activity, prostaglandin E and nitric oxide production by interleukin-1 in pregnant mare serum gonadotrophin-primed theca-interstitial cells.

To examine the participation of the theca-interstitial (TI) compartment in cytokine modulation of ovarian function, the effects of interleukin-1beta (IL-1) on plasminogen activator (PA) activity and on prostaglandin E (PGE) and nitric oxide (NO) production were examined in cultures of pregnant mare serum gonadotrophin (PMSG)-primed rat TI cells. Exposure to IL-1 (10 ng/ml) resulted in a 25% reduction (P < 0.001) in PA activity, concurrent with a 4.6-fold increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. IL-1 also produced a 4.7-fold increase in PGE content and a 2.8-fold increase in NO generation. These effects of IL-1 were abolished by the IL-1 receptor antagonist, suggesting specific IL-1 receptor-mediated effects. Transforming growth factor (TGF)-beta1 (10 ng/ml) significantly attenuated the IL-1-stimulated PGE production and NO generation but did not affect the ability of IL-1 to suppress PA activity and stimulate urokinase inhibitor production. The NO synthase inhibitor N-nitro-L-arginine attenuated the IL-1-induced NO generation but had no effect on PA activity or PGE production. Thus, NO is not an obligatory mediator of IL-1 effects on plasminogen activation and PGE generation in rat ovary. The present observations attest to a pleiotropic response of PMSG-primed TI cells to IL-1, and suggest a paracrine/autocrine function for the TI compartment in ovulation and corpus luteum formation.

Animals↗
PubMed1997

Interleukin (IL)-1beta increases glucose uptake and induces glycolysis in aerobically cultured rat ovarian cells: evidence that IL-1beta may mediate the gonadotropin-induced midcycle metabolic shift.

This communication explores the possibility that interleukin (IL)-1beta, a putative intermediary in the ovulatory process, may take part in the gonadotropin-driven midcycle diversion of ovarian carbohydrate metabolism toward glycolysis. We examined the effect of treatment with IL-1beta on glucose metabolism in aerobically cultured whole ovarian dispersates from immature rats. Treatment with IL-1beta increased cellular glucose consumption/uptake, stimulated extracellular lactate accumulation and media acidification, and decreased extracellular pyruvate accumulation in a receptor-mediated, time-, dose- and cell density-dependent manner. Endogenous IL-1beta-like bioactivity was shown to mediate the ability of gonadotropins to exert these same metabolic effects. The IL-1beta effect was also (1) apparent over a broad range of glucose concentrations, inclusive of the putative physiological window; (2) relatively specific, because tumor necrosis factor-alpha and insulin were inactive; (3) contingent upon cell-cell cooperation (4) and reliant on de novo protein synthesis. Comparison of the molar ratios of lactate accumulation to glucose consumption in IL-1beta-replete vs. IL-1beta-deplete cultures suggests that IL-beta promotes the conversion of all available glucose to lactate but that other substrates for lactate production may also exist. However, no lactate was generated by cells grown under glucose-free conditions. Taken together, our data suggest that IL-1beta may act as a metabolic hormone in the ovary. Subject to the limitations of the in vitro paradigm, our data also suggest that IL-1beta may mediate the gonadotropin-associated midcycle shift in ovarian carbohydrate metabolism. By converting the somatic ovarian cells into a glucose-consuming glycolytic machinery, IL-1beta may establish glycolysis as the main energy source of the relatively hypoxic preovulatory follicle and the resultant cumulus-oocyte complex. The consequent oxygen sparing may conserve the limited supply of oxygen needed for vital biosynthetic processes such as steroidogenesis. This adaptational response may also provide the glycolytically incompetent oocyte with the obligatory tricarboxylic cycle precursors it depends on to meet the increased energy demands imposed upon it by the resumption of meiosis.

Aerobiosis↗
PubMed1997

The molecular basis of partial penetrance of splicing mutations in cystic fibrosis.

The splicing variant, 5T allele, in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was shown to be associated with partial penetrance of the clinical expression. This splicing variant leads to two possible transcripts: one normal and the other aberrantly spliced that lacks exon 9. The aim of this study was to analyze the molecular basis of the partial penetrance in individuals carrying the 5T allele. We analyzed the level of the correctly spliced RNA transcribed from the 5T allele in nasal and epididymal epithelium and correlated it with disease expression. Semiquantitative nondifferential reverse-transcriptase-PCR showed a considerable variability (6%-37%) in the total level of correctly spliced RNA transcribed from the 5T allele in nasal epithelium from 11 patients. A significant nonlinear correlation (r = .82, P = .002) between the level of the normal CFTR transcripts and the severity of lung disease was shown. No individuals with normal lung function and minimal or no lung disease (FEV1 >80% predicted) had <25% of normal transcripts, and individuals with <15% of normal transcripts did not have FEV1 >80%. The level of normal transcripts in epididymal epithelial cells from four infertile males with congenital bilateral absence of the vas deferens was low (6%-24%). In infertile males with normal lung function the level of correctly spliced transcripts in the nasal epithelium was higher than the level in the epididymal epithelium. These results indicate that there is variability in the efficiency of the splicing mechanism, among different individuals and between different organs of the same individual. This variability provides the molecular basis of the partial penetrance of cystic fibrosis disease in patients carrying the 5T allele.

Adolescent↗
PubMed1996

Human follicular nitric oxide pathway: relationship to follicular size, oestradiol concentrations and ovarian blood flow.

Nitric oxide (NO) has been suggested to be involved in ovarian physiology. Our aim was to study follicular nitrite and nitrate (NO3/NO2) levels in women undergoing in-vitro fertilization (IVF), and to examine their relationship to follicular size, oestradiol concentrations, and ovarian artery and intra-ovarian blood flow as measured by Doppler ultrasound. A total of 15 patients from the IVF programme of Hadassah University Hospital, Mt Scopus, Israel, participated in the study. Detailed transvaginal ultrasonographic examination was performed before ovum collection, and ovarian artery and intra-ovarian blood flow were measured. While aspirating the follicles, the content of two to four of the follicles in each ovary was collected individually, the volume of follicular fluid measured, and NO3/NO2 concentrations were determined. A statistically significant positive correlation was found between follicular fluid NO3/NO2 concentrations and follicular volume (r = 0.76), as well as between NO3/NO2 concentrations and oestradiol concentrations (r = 0.63). A statistically significant negative correlation was found between follicular fluid NO3/NO2 concentrations and ovarian flow parameters as well as between NO3/NO2 concentrations in follicles containing 4-5 ml and ovarian artery pulsatility index.

Adult↗
PubMed1996

Cytokine-mediated regulation of type IV collagenase expression and production in human trophoblast cells.

The invasive property of trophoblast cells is dependent on the activity of proteolytic enzymes of the metallo- and serine proteases family. Interleukin-1 (IL-1) was found to be involved in the regulation of these proteases in various systems, serving as an important modulator in trophoblast physiology (e.g. induction of hCG beta, cytokines, and others). Therefore, consideration is given in this report to the role of IL-1 in the regulation of metalloprotease activity in human trophoblasts. Human trophoblast cells were isolated from first trimester placentas by trypsin degradation and Percoll fractionation. Primary cell cultures of first trimester trophoblasts constitutively elaborated two species of collagenase type IV (92 and 72 kDa), as assessed in gelatin matrix. Treatment with IL-1 further augmented the 92-kDa type IV collagenase secretion in a dose-dependent manner. Furthermore, IL-1 significantly (P < 0.01) increased 92-kDa collagenase gene expression by trophoblast cells, as determined by solution hybridization/ribonuclease protection assay. Both the increase in gene expression and protein biosynthesis of the 92-kDa collagenase type IV were neutralized by the soluble IL-1 receptor, indirectly suggesting a receptor-mediated response. Interestingly, transforming growth factor-beta a putative modulator of IL-1 induced effects, was shown to induce the 92-kDa collagenase type IV secretion as well. These results provide indirect evidence supporting the idea that IL-1 and transforming growth factor-beta may play an intermediary role in trophoblast invasion at the feto-maternal interface by regulating trophoblast expression of 92-kDa type IV collagenase, a protease of prime importance in trophoblast invasion.

Cells, Cultured↗
PubMed1996

Characterization of intraperitoneal cytokines and nitrites in women with severe ovarian hyperstimulation syndrome.

OBJECTIVE: To assess the potential involvement of cytokines and nitrites in the hyperpermeability characterizing the ovarian hyperstimulation syndrome (OHSS). DESIGN: A controlled clinical study comparing peritoneal fluid (PF) from patients with severe OHSS and from non-OHSS controls. SETTING: Women hospitalized with severe OHSS in three tertiary medical centers. PATIENTS: Twelve patients with severe OHSS necessitating paracentesis and 20 non-OHSS controls. INTERVENTIONS: The criteria for ultrasound-guided paracentesis were tense ascites, hydrothorax, hemoconcentration, or oliguria. MAIN OUTCOME MEASURES: Interleukin (IL) 1 beta IL-1 receptor agonist, IL-2, IL-6, IL-8, and tumor necrosis factor alpha (TNF alpha) levels in PF were assayed by ELISA; nitrites were measured by the "Griess" reaction. Estradiol and P were determined by RIA. RESULTS: Ovarian hyperstimulation syndrome patients had significantly higher PF IL-6 (3,523 versus 30 pg/mL), TNF alpha (14 versus 4.2 pg/mL), and IL-8 (1,695 versus 900 pg/mL). In the serum, only IL-6 levels were significantly higher (375 versus 11 pg/mL). Conversely, nitrite levels were significantly lower in PF of OHSS patients (0.5 versus 34 nmol/mL). Interleukin 1 levels were higher and IL-1 receptor antagonist levels were lower in OHSS patients, suggesting potentially increased biologic potency of IL-1. CONCLUSION: These findings suggest that these substances could be involved in mediating the capillary hyperpermeability characterizing this syndrome.

Ascitic Fluid↗
PubMed1995

Drug-induced hypergastrinemia: absence of trophic effects on colonic carcinoma in rats.

BACKGROUND/AIMS: Published studies suggest that hypergastrinemia stimulates growth of normal or malignant colon tissue. Other studies dispute these findings. This study was designed to test the hypothesis that hypergastrinemia enhances progression or invasiveness of colon cancer. METHODS: Colonic carcinomas were induced in male Sprague-Dawley rats by six weekly intraperitoneal injections of methylazoxymethanol. Four weeks after the last injection of carcinogen, the animals were randomized into four treatment groups, including vehicle control, low- and high-dose omeprazole, and ranitidine. After 10 weeks of treatment, the animals were bled, stomach weights were recorded, and colon tumors were mapped, enumerated, measured, and scored histopathologically by Dukes' classification. Crypt and mucosal heights were determined in colonic mucosa unaffected by tumor. RESULTS: Drug administration induced a sustained hypergastrinemia that did not enhance tumor burden or invasiveness or crypt height/mucosal height ratios. Ranitidine-treated rats consumed less food, weighed less, and developed fewer tumors. This group also had lower crypt and mucosal heights than rats in the vehicle- or omeprazole-treated rats. CONCLUSIONS: The results suggest that endogenous hypergastrinemia induced by these acid-suppressing drugs has no stimulatory effect on colon mucosal growth or progression or biological behavior of experimental rat colon cancer.

Analysis of Variance↗
PubMed1995

Reduction of an incisional hernia using the open laparoscopic technique.

Recently published cases of operative laparoscopy complicated by incisional hernia reemphasizes the potential hazard of the procedure. A new approach may be an alternative to traditional laparotomy for reducing small bowel herniation through the 12-mm cannula incision. Explorative laparoscopy by the open technique was performed and a loop of small bowel was reduced using an atraumatic grasping forceps. We find this approach safe and convenient.

Abdominal Muscles↗
PubMed1995

Effects of omeprazole on cell kinetics of carcinogen-induced colon tumours in rats.

This study was designed to evaluate the effects of hypergastrinaemia induced via suppression of gastric acid by omeprazole on carcinogen-induced colon cancer in rats. The carcinogen methylazoxymethanol (MAM), 30 mg/kg, was administered intraperitoneally at 6-weekly intervals to Sprague-Dawley rats. Four weeks after the last MAM injection, the first daily dose of omeprazole, 40 mg/kg, was given by gastric gavage to one group of rats, and the rest were given buffered methylcellulose vehicle. After 10 weeks of daily omeprazole or vehicle, the rats were anaesthetized with ether, blood samples obtained, and animals sacrificed. Gastrin levels in serum from omeprazole-treated rats were elevated nearly six-fold. DNA and RNA levels in gastric mucosa were unchanged by omeprazole, but protein content was somewhat reduced. No biochemical or histological changes related to omeprazole treatment were observed in normal colon. The number of tumours, tumour volumes, and total tumour burden were not significantly different in colons of vehicle- or omeprazole-treated rats. Analysis by flow cytometry revealed that the S phase fraction was lower in tumour cells from omeprazole-treated animals; and that the frequency of DNA aneuploidy was also reduced. The results indicate that while omeprazole-induced suppression of stomach acid in rats elevates levels of gastrin in serum, it does not substantially alter the biochemical or cellular characteristics of carcinogen-induced colon tumours.

Animals↗
PubMed1995

Interleukin-1-mediated stimulation of prostaglandin E production is without effect on plasminogen activator activity in human granulosa lutein cell cultures.

In continuation of earlier observations on the involvement of interleukin-1 (IL-1) in ovarian function, we examined the ability of IL-1 to modulate plasminogen activator (PA) activity and prostaglandin (PG) synthesis in human granulosa lutein cells (GLCs). Toward this goal, GLCs were obtained from women undergoing in vitro fertilization, preincubated with 10% fetal calf serum for 48 h, and subsequently cultured for 48 h in serum-free media in the absence or presence of IL-1 beta (10 ng/mL). Cellular PA activity was measured by plasminogen-dependent cleavage of the chromogenic substrate H-D-valyl-L-leucyl-L-lysine-p-nitroanilide (S-2251). Prostaglandin E (PGE) levels were assayed by conventional RIA. Exposure of GLCs to IL-1 resulted in a 50% increase in PGE production, a 33% suppression of PA activity, and a 75% increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. The inhibitory capacity was attributable to an IL-1-mediated increase in PA inhibitor type-1 (PAI-1) production, inasmuch as urokinase inhibition could be abolished by the administration of a polyclonal antihuman PAI-1 immunoglobulin G. IL-1 treatment had no effect on plasmin or trypsin inhibition. Exposure of GLCs to IL-1 receptor antagonist abolished the ability of IL-1 to enhance PA inhibitory activity and PGE production, thereby establishing specific IL-1 receptor-mediated effects. The ability of IL-1 to suppress PA activity and to produce PAI-1 persisted in the presence of indomethacin, a potent inhibitor of PG synthesis. Likewise, transforming growth factor-beta 1 suppressed the ability of IL-1 to stimulate PGE production without affecting the IL-1-induced effects on the PA system. The present findings suggest a pluripotent response of GLCs to IL-1, characterized by the induction of PAI-1 and the suppression of PA occurring concurrent with, but independent of, PG production. These observations support the potential involvement of IL-1 in the regulation of human ovulatory processes.

Amino Acid Sequence↗
PubMed1995

Interleukin-1 stimulates prostaglandin E production by human trophoblast cells from first and third trimesters.

Prostaglandins (PGs) play a major role during implantation and labor, and their level is regulated by various cytokines. Interleukin-1 (IL-1) is a known mediator of prostaglandin E (PGE) production in various cell types, including endothelial, amniotic, and endometrial cells; however, its role in the regulation of PGE production in the trophoblast cells is yet unknown. As IL-1 and PGE are both known to be synthesized in the human trophoblast cells, we examined the possibility that IL-1 regulates PG production in human trophoblast cells. To this end, use was made of first and third trimester trophoblast cells, obtained from first trimester terminations of pregnancies and elective cesarean sections. The trophoblast cells were separated by trypsin degradation and fractionation on Percoll gradients, and cultured for 18 h under serum-free conditions in the absence or presence of IL-1 (10 ng/mL). IL-1 induced a 5-fold increase in PGE production, a response that was cell density, time, and dose dependent. IL-1-induced PGE biosynthesis was prevented in the presence of either IL-1 receptor antagonist or the soluble IL-1 receptor, suggesting a receptor-mediated response. Significantly, de novo production of PGE by trophoblast cells in the absence of IL-1 was also markedly (50%) reduced by either the IL-1 receptor antagonist or the soluble IL-1 receptor, further supporting the notion that IL-1 is involved in PGE synthesis even under basal conditions. Transforming growth factor-beta 1, a putative modulator of the effects of IL-1, significantly attenuated IL-1-stimulated PGE production, supporting the possibility that transforming growth factor-beta 1 may serve as a regulator of the effects of IL-1 in trophoblast cells. These observations suggest a pivotal role of IL-1 in the regulation of PGE economy by trophoblast cells. As trophoblast cells are in intimate contact with maternal cells, understanding the regulation of PGE levels may explain crucial processes at the feto-maternal interface, including implantation of the developing blastocyst, immunosurveilance, and the initiation of labor.

Cell Count↗
PubMed1995

Erythrocyte thiolmethyltransferase: another failed marker for Alzheimer's and Parkinson's diseases.

There are reports that patients with Parkinson's disease (PD) and Alzheimer's disease (AD) have reduced levels of thiolmethyltransferase (TMT) in erythrocyte membranes. TMT methylates thiols and thiocarbamates, thereby reducing their toxicity. We examined TMT levels in erythrocytes from patients with PD and AD and from age-matched controls. Specific activities of TMT were 564 +/- 199 U/mg protein in PD (n = 32), 513 +/- 118 in AD (n = 13), and 565 +/- 183 in controls (n = 35). There was no difference between any of the groups (p = 0.64). We failed to confirm TMT as a marker for neurodegenerative diseases or for this metabolic defect predisposing to susceptibility to neurotoxins.

Aged↗
PubMed1994

Developmental regulation of the expression of 72 and 92 kd type IV collagenases in human trophoblasts: a possible mechanism for control of trophoblast invasion.

OBJECTIVE: During early pregnancy fetal cytotrophoblast cells invade the uterus and penetrate the basement membrane, a property that is characteristic of malignant cells. However, unlike tumor invasion, trophoblast invasion of the uterus is under strict control. This control limits invasion, so that it primarily remains confined to the endometrial aspect of the myometrium and continues only until midgestation. The invasive properties of the trophoblast cells are made possible by the activity of proteolytic enzymes that belong to the metalloproteinases and serine proteinases. Type IV collagenase (metalloproteinase) is considered crucial in the extracellular matrix remodeling that takes place during the invasion process. In this study we set out to characterize the invasive properties of trophoblast cells at different stages of pregnancy. STUDY DESIGN: Human trophoblast cells were isolated from first- and third-trimester placentas by trypsin digestion and Percoll fractionation and were then cultured under serum-free conditions. The invasive ability of trophoblast cells was determined by the in vitro invasion assay, in which the ability of cells to penetrate an artificial basement membrane was examined. Metalloproteinase activity was measured by zymography, and the expression of messenger ribonucleic acid transcripts of 72 and 92 kd type IV collagenases was examined by reverse transcriptase polymerase chain reaction. RESULTS: First-trimester trophoblasts were 3.5 time more invasive in vitro than were third-trimester trophoblast cells (p < 0.005). Although first-trimester trophoblasts secreted both species of type IV collagenase, 72 and 92 kd, in large amounts, third-trimester cells secreted the 92 kd and only minimal amounts of 72 kd type IV collagenase. Moreover, first-trimester trophoblasts secreted significantly more (p < 0.05) 92 kd type IV collagenase than did third-trimester trophoblast. The messenger ribonucleic acid transcript expression of 72 and 92 kd type IV collagenases correlated with the activity of these enzymes secreted by first- and third-trimester trophoblasts. CONCLUSION: The described high in situ invasive capacity of first-trimester trophoblast might be explained by the increased expression and production of 72 kd type IV collagenase and the higher expression of 92 kd type IV collagenase by first-trimester trophoblast cells.

Base Sequence↗
PubMed1994

Loperamide effects on hepatobiliary function, intestinal transit and analgesia in mice.

Loperamide effects on hepatobiliary function, analgesia and gut transit were studied in mice. Varying doses of the antidiarrheal drug, loperamide, were administered to mice by intracerebroventricular, intravenous, subcutaneous and intragastric routes. Gut motility was determined by intestinal transit of India ink, analgesia by warm water tail flick latency, and hepatobiliary function by retention of the anionic dye, sulfobromophthalein in plasma and liver. When given by all routes at modest doses, loperamide slowed intestinal transit. Analgesia, a centrally mediated opiate effect, was only detected after intracerebroventricular or subcutaneous loperamide at high, near-toxic doses. Elevations of plasma and liver sulfobromophthalein were noted at routes and doses which slowed gut transit, well below those needed for analgesia. Intragastric loperamide at one fortieth its LD50 caused marked elevation of sulfobromophthalein levels and gut slowing, but no analgesia. Sulfobromophthalein elevation and gut slowing by intragastric loperamide were not affected by spinal cord transection but were reversed by naltrexone, an opiate antagonist. Non-toxic doses of loperamide slow gut transit and modify hepatobiliary function in mice by opiate actions at peripheral sites.

Administration, Oral↗
PubMed1994

Cytokine-mediated regulation of rat ovarian function: interleukin-1 inhibits plasminogen activator activity through the induction of plasminogen activator inhibitor-1 (PAI-1).

Intraovarian IL-1 has recently been implicated as a mediator in the ovulatory process. Since PA activation is an established component of the ovulatory cascade, consideration was given in this report to the possibility that IL-1 may modulate ovarian PA economy. Whole ovarian dispersates from immature rats (25-27-days-old) were cultured under serum-free conditions for 48 h in the absence or presence of IL-1beta. Cellular PA activity was measured by plasminogen-dependent cleavage of 14C-labeled globin. Cells grown in the absence of IL-1 exhibited appreciable PA activity, as assessed by the cleavage of 0.074 +/- 0.026 mg [14C]-globin/5 x 10(5) cells (mean +/- SD). Exposure to IL-1 (10 ng/ml) led to a 30% reduction in cell-associated PA activity (p < 0.001). The IL-1-mediated inhibition occurred concurrently with a 10-fold increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. At similar cell densities of 5 x 10(5) cells/well, isolated cultures of theca and granulosa cells exhibited comparable PA activity in the absence of IL-1. However, only theca cells responded to IL-1 with inhibition of plasminogen activation and enhancement of urokinase inhibitory activity. Granulosa cells in turn failed to respond to IL-1. Both the inhibition of PA activity and the increase in urokinase inhibitory activity proved cell-density- and IL-1 dose-dependent. The IL-1-induced inhibition of urokinase was abolished by the administration of a polyclonal anti-rat PAI-1 IgG. Both effects of IL-1 were counteracted in a dose-dependent fashion by the soluble IL-1 receptor (which specifically complexes with IL-1), and by a highly-specific IL-1 receptor antagonist suggesting that the IL-1 effects are receptor-mediated. The present observations indicate that ovarian PA activity is subject to inhibition by IL-1 probably by way of PAI-1 of theca-interstitial origin. Inasmuch as IL-1 may be involved in initiating and maintaining the preovulatory cascade, the periovulatory activation of plasminogen must be accomplished by agents other than IL-1.

Animals↗
PubMed1994

Germ cell tumors of the ovary arising after dermoid cyst resection: a long-term follow-up study.

OBJECTIVE: To study the long-term ovarian neoplastic consequences of resection of a dermoid cyst. METHODS: The study population comprised 99 patients who were operated on for an ovarian dermoid cyst. Follow-up information was obtained for 91 women for a mean period of 5.06 +/- 2.46 years. RESULTS: Of the 99 women, 18 had bilateral dermoid cysts. Multiple dermoid cysts in a single ovary were found in nine of the women with bilateral cysts and in one of the remaining patients. Two patients developed malignant germ cell tumors, and three developed a recurrent dermoid cyst in an ovary from which a dermoid cyst had previously been extracted. Bilateral or multiple ovarian dermoid cysts were present at the initial operation in four (80%) of these patients. CONCLUSIONS: Women with bilateral or multiple dermoid cysts may include a subgroup of patients with a greater tendency to develop future ovarian germ cell neoplasms.

Adult↗
PubMed1993

Propranolol and amitriptyline in prophylaxis of migraine. Pharmacokinetic and therapeutic effects.

OBJECTIVES: To determine if the effectiveness of propranolol hydrochloride and amitriptyline hydrochloride are correlated with blood levels and/or with standardized test of pharmacologic effect and to determine which clinical variables are predictors of response to one or the other medication. DESIGN: Three-month modules of treatment with each drug and placebo in a randomized crossover design. Headache scores from daily diaries were calculated at monthly intervals, as were simultaneous blood levels of drug, supine and standing blood pressure, pulse rise with exercise, and salivary flow. SETTING: Outpatient headache clinic at the University of Kansas Medical Center, Kansas City. PATIENTS: Thirty consecutive patients with a history of frequent migraine. MAIN OUTCOME MEASUREMENTS: From headache scores, patients were classified as either propranolol responders, amitriptyline responders, or nonspecific responders. Clinical variables as predictors of response to medications were studied, as were effects on frequency, duration, and/or severity of headache. RESULTS AND CONCLUSIONS: No significant correlations were found between changes in headache score and blood level of drug or change in any of the physiologic measurements. Amitriptyline significantly reduced the severity, frequency, and duration of headache attacks; propranolol reduced the severity of attacks only. Amitriptyline response was correlated with female gender and baseline headaches of shortest duration and of highest frequency. Propranolol response was associated with attacks of greatest duration at baseline and with low pulse rise with exercise at baseline. Nonspecific response was associated with male gender and most frequent headaches by history.

Adolescent↗