Adverse event profile for immunotherapy agents compared with chemotherapy in solid organ tumors: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Immunotherapy agents are an innovative oncological treatment modality and as a result their use has expanded widely. Understanding the treatment-related adverse events (AEs) of these drugs compared with traditional chemotherapy is crucial for clinical practice. DESIGN: A systematic review of studies indexed in Medline (PubMed), Embase, Web of Science, and the Cochrane Databases from January 2000 to 14 February 2019 was conducted. Randomized clinical trials comparing immunotherapy [cytotoxic T-lymphocyte protein-4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1)] with standard-of-care chemotherapy in the treatment of advanced solid-organ neoplasms were included if AEs were reported as an outcome. Primary outcome was AEs ≥ grade 3 in severity. Secondary outcomes were proportion of overall AEs, treatment discontinuation due to AEs, deaths due to AEs, and specific AEs [fatigue, diarrhea, acute kidney injury (AKI), colitis, pneumonitis, and hypothyroidism]. Paule-Mandel pooling and a random effects model were used to produce odds ratios (ORs) for measures of effects. RESULTS: Among 10 598 abstracts screened, we included 22 studies involving 12 727 patients. In the immunotherapy group, 16.5% of patients developed an AE ≥ grade 3 in severity, compared with 41.09% in the chemotherapy arm [OR = 0.26, 95% confidence interval (CI) 0.19-0.35, I2 = 92%]. Patients receiving immunotherapy also had lower odds of developing an AE overall (OR = 0.35, 95% CI 0.28-0.44; I2 = 77%), terminating therapy due to an AE (OR = 0.55, 95% CI 0.39-0.78, I2 = 80%), or dying from a treatment-related AE (OR = 0.67, 95% CI 0.46-0.98, I2 = 0%). When treated with chemotherapy versus immunotherapy, patients more frequently experienced fatigue (25.10% versus 15.83%), diarrhea (14.97% versus 11.13%), and AKI (1.79% versus 1.31%). However, colitis (1.02% versus 0.26%), pneumonitis (3.36% versus 0.36%), and hypothyroidism (6.82% versus 0.37%) were more common in those treated with immunotherapy. CONCLUSIONS: Treatment of advanced solid-organ malignancies with immunotherapy compared with traditional chemotherapy is associated with a lower risk of AEs.

The cost of intraoperative adverse events in abdominal and pelvic surgery: A systematic review.

BACKGROUND: The assessment of intra-operative adverse events (iAEs) is a vastly under researched area with the potential to provide new methods on how to improve patient outcomes and hospital costs. Our objective was to determine the relationship between iAEs and total hospital costs in abdominal and pelvic surgery. DATA SOURCES: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework. Embase, MEDLINE and EBM Reviews online databases were searched to identify all studies that reported iAE rates and total hospital costs. We then analyzed the costing approach used in each article using the Drummond tool and evaluated articles quality using the GRADE method. CONCLUSIONS: In total, 1709 unique references were identified through our literature search. After review, 23 were included. All studies that reported iAE rates and cost as the primary outcome found that iAEs significantly increased total hospital costs. We identified a relationship between iAEs and increased hospital costs. Future studies need to be performed to further evaluate the relationship between iAEs and cost as current studies are of low quality.

Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer.

BACKGROUND: Men undergoing treatment of clinically localised prostate cancer may experience a number of treatment-related complications, which affect their quality of life. METHODS: On the basis of population-based retrospective cohort of men undergoing surgery, with or without subsequent radiotherapy, or radiotherapy alone for prostate cancer in Ontario, Canada, we measured the incidence of treatment-related complications using administrative and billing data. RESULTS: Of 36 984 patients, 15 870 (42.9%) underwent surgery alone, 4519 (12.2%) underwent surgery followed by radiotherapy, and 16 595 (44.9%) underwent radiotherapy alone. For all end points except urologic procedures, the 5-year cumulative incidence rates were lowest in the surgery only group and highest in the radiotherapy only group. Intermediary rates were seen in the surgery followed by radiotherapy group, except for urologic procedures where rates were the highest in this group. Although age and comorbidity were important predictors, radiotherapy as the primary treatment modality was associated with higher rates for all complications (adjusted hazard ratios 1.6-4.7, P=0.002 to <0.0001). CONCLUSIONS: In patients treated for prostate cancer, radiation after surgery increases the rate of complications compared with surgery alone, though these rates remain lower than patients treated with radiation alone. This information may inform patient and physician decision making in the treatment of prostate cancer.

The impact of a BRCA2 mutation on mortality from screen-detected prostate cancer.

BACKGROUND: Men with a BRCA2 mutation face an increased risk of prostate cancer. These cancers tend to have an aggressive nature and it has not yet been demonstrated that regular screening of BRCA2 carriers is associated with improved survival. METHODS: We identified 4187 men who underwent a prostate cancer biopsy for an elevated PSA or an abnormal digital rectal examination between 1998 and 2010. We screened the BRCA2 gene in its entirety for mutations and we followed the men for death from prostate cancer until December 2012. RESULTS: The 12-year prostate cancer-specific survival rate was 94.3% for men without a BRCA2 mutation and was 61.8% for men with a mutation (P<10(-4); log-rank test). CONCLUSIONS: The survival of men with screen-detected prostate cancer and a BRCA2 mutation is much poorer than expected.

Effects of calcium channel blockers on pentylenetetrazol drug discrimination in rats.

The effects of the dihydropyridine L-type calcium channel blockers nitrendipine and nimodipine on the pentylenetetrazol (PTZ) drug discrimination, an operant model of anxiety, were investigated. Male Long-Evans rats were trained to discriminate PTZ (16 mg/kg, i.p.) from saline. Both nitrendipine (5.0-25 mg/kg, i.p.) and nimodipine (5.0-25 mg/kg, i.p.) partially substituted for the PTZ discriminative stimulus. However, pretreatment with nitrendipine (25 mg/kg, i.p.) or nimodipine (25 mg/kg, i.p.) produced no change in the PTZ dose-effect function. Rats were given a nutritionally balanced liquid diet containing 6.5% ethanol for 10 days. Rats selected the PTZ drug lever during withdrawal. Subchronic coadministration of nitrendipine (1.25-5.0 mg/kg, i.p., b.i.d.) with ethanol failed to dose-dependently reduce PTZ-lever responding, but it did reverse withdrawal signs. Acute administration of nitrendipine (5, 10, and 20 mg/kg, i.p.) produced marked suppression of lever responding, but it failed to significantly reduce levels of PTZ-lever responding. Although calcium channel blockers reduce signs of ethanol withdrawal, they also markedly reduce rates of behavior and produce no clear effects on anxiety-like behaviors induced by ethanol withdrawal.

Abecarnil and alprazolam reverse anxiety-like behaviors induced by ethanol withdrawal.

This study investigated the effects of a benzodiazepine partial agonist, abecarnil, and a full agonist, alprazolam, on ethanol withdrawal-induced anxiety-like behaviors in rats. Anxiety was assessed in two models: elevated plus maze and pentylenetetrazol (GABA(A) antagonist) discrimination assay. Male rats received an ethanol-containing (4.5%) liquid diet for 7 to 10 days and were tested for withdrawal symptoms 12 h after termination of the diet. In the elevated plus maze, ethanol-withdrawn rats displayed less open arm activity and total arm entries than pair-fed rats. Abecarnil (0.08-0.32 mg/kg, IP) and alprazolam (0.08-1.25 mg/kg, IP) each produced a dose-dependent, full reversal of ethanol withdrawal-induced reduction of open arm activity, but only alprazolam increased the total arm entries. In the pentylenetetrazol assay, ethanol-withdrawn rats selected the pentylenetetrazol lever (100%) over the salin-lever. Abecarnil (0.04-0.32 mg/kg, IP) and alprazolam (0.08-0.32 mg/kg, IP) dose dependently reduced pentylenetetrazol-lever responding to control levels (10-20%). Alprazolam was more potent than abecarnil in reversing ethanol withdrawal-induced decrease in open arm activities, but showed comparable potency and efficacy to abecarnil in blocking the pentylenetetrazol-like ethanol withdrawal stimulus. These results suggest that abecarnil and alprazolam may have therapeutic potential for treatment of ethanol withdrawal-induced anxiety-like symptoms.

Effects of ritanserin on ethanol withdrawal-induced anxiety in rats.

This study investigated the ability of ritanserin, a 5-HT2 antagonist, to modify ethanol withdrawal (EW) symptoms in two animal models of anxiety: the elevated plus-maze (EPM) and the pentylenetetrazol (PTZ) discrimination assay. Long-Evans hooded rats were given a nutritionally balanced liquid diet containing 4.5% ethanol for 10 days. Twelve hours after removal of the ethanol diet, rats were tested in the EPM. A significant reduction in the open-arm activity and the number of total arm entries was observed, which is indicative of EW. Acute ritanserin (0.16-0.64 mg/kg, i.p., 60 min) had no effect on EW-induced anxiety-like behavior on the EPM. Ritanserin (0.08-0.64 mg/kg, i.p., b.i.d. 12 h) administered concurrently with the last 5 days of ethanol diet produced an increase in the time spent on the open arms of the EPM and reversed the EW-induced reduction in total arm entries. Rats trained to discriminate between saline and PTZ (an anxiogenic drug), selected the PTZ lever during EW. Chronic ritanserin (0.32 mg/kg, i.p., b.i.d. ) did not block PTZ lever responding during EW. On the rotorod, ritanserin (0.32 mg/kg, i.p.) increased the motor incoordination induced by ethanol. In conclusion, coadministration of ritanserin with ethanol prevented the development of EW-induced anxiety as measured by the EPM, but not in the PTZ drug discrimination.

Sex differences in nicotine substitution to a pentylenetetrazol discriminative stimulus during ethanol withdrawal in rats.

RATIONALE: Nicotine and ethanol are frequently co-abused in men and women, but few studies compare common stimulus effects produced by these substances between males and females. OBJECTIVES: This study compared the anxiety-like behavior induced by nicotine prior to and during ethanol withdrawal in intact male, sham-operated female, and ovariectomized (OVX) rats. METHODS: Using an animal model of anxiety, the pentylenetetrazol (PTZ) drug-discrimination assay, rats were trained to discriminate PTZ (16 mg/kg, i.p.) from saline and were subjected to the following tests: (1) PTZ-lever selection at 12 h after termination of ethanol diet (4.5% for 10 days); (2) dose-response tests for nicotine (0.08-1.3 mg/kg) prior to ethanol and 1.5, 6, and 7 days after ethanol withdrawal. RESULTS: (1) During acute ethanol withdrawal (12 h), more male rats (43.4%) responded on the PTZ lever than OVX (29%) or sham female (15.3%) rats. (2) For nicotine dose-response tests, more male rats (70%) selected the PTZ lever than OVX (37.5%) or sham female (50%) rats prior to ethanol. At 1.5 days, nicotine fully generalized to the PTZ stimulus in male (100%) and OVX (90%), but only partially in sham female (50%) rats. At 6 days and 7 days after ethanol withdrawal, the PTZ-lever selection decreased, but more male rats (78%) tended to respond on a PTZ lever than OVX (63.6%) or sham female rats (62.5%). CONCLUSIONS: Acute nicotine produces anxiety-like behavior similar to that of PTZ in male and female rats, and this effect of nicotine is intensified during ethanol withdrawal in male and OVX rats, but not in sham female rats.

Sex differences in the discriminative stimulus effects of m-chlorophenylpiperazine and ethanol withdrawal.

RATIONALE: The serotonergic system plays a role in regulation of anxiety and ethanol withdrawal (EW). Nevertheless, few studies have assessed sex differences in serotonergic effects on EW. OBJECTIVES: This study examined sex differences in the anxiogenic stimuli induced by a serotonin (5-HT)(1b,2) agonist, meta-chlorophenylpiperazine (mCPP), prior to ethanol and during EW. METHODS: Gonadectomized or sham-operated adult male and female rats and 17beta-estradiol (2.5 mg, 21-day release, s.c.) -replaced ovariectomized (OVX) rats were trained to discriminate mCPP (1.2 mg/kg, i.p.) from saline in a two-lever choice task for food. Latency to the first lever press and mCPP lever selection were measured following mCPP (0-1.2 mg/kg). Rats then received chronic ethanol-containing liquid diet (6.5%) for 10 days and were tested for mCPP lever selection 12 h and 36 h after removal of ethanol. RESULTS: Fewer sham female and beta-estradiol-replaced OVX rats selected the mCPP lever than male or OVX rats, and showed an increased initiation latency after mCPP injection. During EW (12 h and 36 h), fewer sham female and beta-estradiol-replaced OVX rats responded on the mCPP-lever after saline injection as well as after mCPP challenge than male or OVX rats. Castration did not alter any response of male rats to mCPP. CONCLUSIONS: (1) mCPP discrimination is a useful measure of EW in male and female rats; and (2) sham female and beta-estradiol-replaced OVX rats are less sensitive to the discriminative stimulus prior to and during EW, but more sensitive to impaired behavioral initiation induced by mCPP than male or OVX rats.

Effects of NMDA receptor blockers on cocaine-stimulated locomotor activity in mice.

Effects of MK-801 and ketamine, N-methyl-D-aspartate (NMDA) receptor blockers, on cocaine-stimulated locomotor activity were investigated in male Swiss-Webster mice. MK-801 (0.25, 0.5, 1.0 and 2.5 mg/kg), ketamine (10, 25 and 50 mg/kg) or saline was injected 20 min before cocaine (5, 10 and 20 mg/kg i.p.). Locomotor activity was measured for 30 min immediately following cocaine treatment. All doses of the drugs were also tested for ability to depress or stimulate locomotor activity in the naive (no cocaine-treated) mice. Cocaine produced a dose-dependent increase in locomotor activity that was blocked dose-dependently by MK-801 or ketamine. The blockade by MK-801 was more prominent than by ketamine. Our results may suggest that cocaine-induced locomotor stimulation in mice is modulated via NMDA receptor mediated mechanisms.

Effects of NMDA antagonists on ethanol-withdrawal induced "anxiety" in the elevated plus maze.

The anxiolytic effects of NMDA antagonists during ethanol withdrawal were assessed in Long-Evans rats. Anxiety was measured by the elevated plus maze. Male rats were exposed to ethanol (6.5%) in a liquid diet for 10 days. Behavioral testing took place 12 h after withdrawal of ethanol. The competitive NMDA antagonists, AP-7 (0.02-0.32 mg/kg) and CGP-37849 (0.64-10 mg/kg), at least partially reversed the anxiety-like effects induced by withdrawal from ethanol. Both drugs produced a small increase in total arm entries, and a much larger increase in the percentage of open arm entries. AP-7, but not CGP-37849, also increased the percentage of open arm time. In contrast, the NMDA channel blocker, dizocilpine (MK-801; 0.08-0.32 mg/kg), produced only a small increase in the percentage of open arm entries and of open arm time. HA-966, a glycine-site antagonist, also failed to produce changes in ethanol withdrawal induced changes in anxiety at the doses tested. These results suggest that competitive NMDA antagonists may be useful for reduction of signs of anxiety during ethanol withdrawal.

Sex differences in the pentylenetetrazol-like stimulus induced by ethanol withdrawal.

This study investigated sex differences in responding to the pentylenetetrazol (PTZ, a gamma-aminobutyric acid A antagonist) discriminative stimulus and to substitution to PTZ during ethanol withdrawal. The PTZ stimulus has served as an anxiogenic stimulus in numerous studies. Adult male and female rats were trained to discriminate PTZ (16 mg/kg i.p.) from saline in a two-lever food-reinforced task. They were then gonadectomized or sham-operated. Ovariectomized (OVX) rats were also tested during 17beta-estradiol (2.5 mg, 21 days release, s.c.) replacement. The PTZ dose response (0-16 mg/kg i.p.) was tested in all groups. In general, fewer females than males responded to PTZ. Diazepam (DZP; 0-10 mg/kg i.p.) injected before PTZ (16 mg/kg) decreased the number of rats selecting the PTZ lever. This effect was greater in sham female and estradiol-replaced-OVX rats than in male or OVX rats. Rats then received chronic ethanol diet (6.5%) for 10 days. During ethanol withdrawal (12 h after termination of the ethanol diet), they were tested for PTZ lever selection. PTZ lever selection differed between groups: sham or castrated male rats > OVX > sham female or estradiol-replaced-OVX rats. In sham female rats, estradiol concentrations showed a cyclic pattern with an estradiol surge that did not influence their PTZ discrimination performance. After i.p. injection of ethanol (2 g/kg), blood ethanol concentrations were not different in male and female rats. These findings suggest that 1) female rats are less sensitive to the anxiogenic effects of PTZ; 2) female rats are less sensitive to the anxiogenic effects of ethanol withdrawal; and 3) estrogen plays some role in mediation of these sex differences.

The effects of adenosine ligands R-PIA and CPT on ethanol withdrawal.

The potential anxiogenic or anxiolytic effects of R(-)-N6-(2-phenylisopropyl)adenosine (R-PIA), an adenosine agonist, and 8-cyclopentyl-1,3,dimethylxanthine (CPT), an adenosine antagonist, were tested during chronic exposure to ethanol and to ethanol-induced withdrawal in rats. Effects on anxiety were measured by the elevated plus maze and dark-light box. Ethanol consumption and preference was tested in an additional experiment. In testing of elevated plus maze performance during withdrawal from ethanol, R-PIA produced no change in the anxiety-related behaviors of total arm entries and percent open arm entries, but produced a significant decrease in percent open arm time. CPT produced at least partial recovery from the anxiogenic effects of ethanol withdrawal on all three measures of elevated plus maze performance, although peak effects were seen at the intermediate dose of CPT (0.08 mg/kg) for total arm entries and percent open arm time. CPT also showed anxiolytic effects at low to intermediate doses (0.04, 0.08 mg/kg) in the dark-light box. CPT did not reduce the preference for ethanol over water or the total consumption of ethanol over a range of ethanol doses. In summary, the adenosine agonist, R-PIA, exacerbated the effects of ethanol withdrawal, whereas the adenosine antagonist, CPT, at least partially blocked the anxiogenic effects produced by ethanol withdrawal. These results suggest that adenosine antagonists, at least at some doses, may be useful for ameliorating the anxiogenic effects produced by ethanol withdrawal, although it does not appear useful for reducing consumption.

Lack of tolerance to ethanol-induced motor impairment on accelerod performance in rats.

The effect of ethanol on rats was investigated at increasing rates of acceleration for bar rotation speed. Ethanol was given to rats by a liquid diet starting with 2.4% ethanol (v/v) for 3 days. Then the ethanol concentration was increased to 4.8% (v/v) for 3 days and finally to 7.2% (v/v) for 15 days. Accelerod performance was recorded before and throughout 20 days of ethanol intake. Mean blood ethanol levels were 266.34+/-13.11 and 285.20+/-9.77 mg/dl on the 7th and 15th days of ethanol (7.2% v/v) consumption, respectively, as measured in a parallel group of animals. Ethanol produced significant concentration-dependent impairments in the accelerod performance of rats. The motor impairment effect of ethanol was most prominent in the test using the greatest rate of acceleration (from 0 to 79 rpm within 2 min). The impairment effect of ethanol on accelerod performance occurred throughout the period of ethanol exposure. Our results indicate that motor impairment on the accelerod performance test produced by an ethanol liquid diet depends on the concentration of ethanol and the rate of acceleration. In addition, under free-access conditions accelerod performance may not be a suitable behavioral test for detecting tolerance development to ethanol in rats.

A discriminative stimulus produced by 1-(3-chlorophenyl)-piperazine (mCPP) as a putative animal model of anxiety.

1. This study compares behavioral responses to serotonergic (5HT) agonists and pentylenetetrazol (PTZ) in two behavioral paradigms used as animal models of anxiety. PTZ and mCPP were compared for behavioral effects in elevated plus-maze and interoceptive discriminative stimuli they produce. 2. PTZ is a known anxiogenic drug. The discriminative stimuli of mCPP were selected for comparison because this drug produces "anxiety" in human subjects and "anxiety-like" behaviors in rats, and is a potent agonist at 5HT1B/2C receptors and a partial agonist at 5HT2A receptors. 3. In rats trained to discriminate mCPP (1.4 mg/kg, training dose) from saline, PTZ substituted for the mCPP suggesting the "anxiety-like" properties of the mCPP stimulus. The mCPP stimulus was blocked in a dose-related manner by methysergide, a 5HT2A/2C antagonist but not by the anxiolytic diazepam. TFMPP (a 5HT agonist) and DOI (a 5HT2A/2C agonist) substituted for mCPP, but 1-NP (a 5HT1 agonist and 5HT2C/2A antagonist) did not. 4. In animals trained to discriminate PTZ (16 mg/kg) from saline, mCPP and DOI substituted for PTZ, while TFMPP and 1-NP do not. 5. In the elevated plus maze, time spent on the open arms was reduced by mCPP, DOI and PTZ but there was no significant dose effect of TFMPP, or 1-NP. 6. Methysergide blocked the "anxiety-like" behavior in the EPM. 7. These data suggest that the discriminative stimuli produced by mCPP are based upon its selective actions on 5HT receptors and their use in behavioral pharmacology may offer another tool in studying pharmacology of 5HT based anxiogenic and anxiolytic drugs.

GM1 ganglioside reduces ethanol intoxication and the development of ethanol dependence.

The monosialoganglioside, GM1, protects the nervous system against a variety of insults. In this study, we evaluated the protective properties of GM1 on ethanol intoxication and development of dependence. GM1 (20-40 mg/kg, IP) reduced the extent and duration of ataxia produced by ethanol (2 g/kg, IP, 15-95 min), and delayed the onset of loss and reduced the duration of the righting reflex (LORR) produced by ethanol (4.2 g/kg, IP). GM1 did not alter ethanol-induced hypothermia or the rate of ethanol clearance. Rather, GM1 increased the waking blood ethanol concentration. In animals fed a complete liquid diet containing 4.5% ethanol, concurrent administration of GM1 (40 mg/kg/day) blocked the tremors, hypolocomotion, and anxiety-like behavior associated with ethanol withdrawal. These findings demonstrate that GM1 reduces both ethanol's acute intoxication and the signs and symptoms of ethanol withdrawal by a mechanism not related to ethanol pharmacokinetics.

Divalent cation binding to erythrocyte spectrin.

Erythrocyte spectrin dimers and separated alpha- and beta-spectrin chains bound 45Ca2+ after electrophoresis on native or sodium dodecyl sulfate-polyacrylamide gels, blotting, and 45Ca2+ overlay. Flow dialysis and equilibrium dialysis revealed two binding components: high-affinity, Ca(2+)-specific sites with kd = 4 x 10(-7) M and n = 100 +/- 20 per dimer and a low-affinity (millimolar) divalent cation component. Whereas brain spectrin had only four high-affinity sites [Wallis, C. J., Wenegieme, E. F., & Babitch, J. A. (1992) J. Biol. Chem. 267, 4333-4337], erythrocyte spectrin had 25-fold more sites per dimer. In addition to possibly modifying spectrin interactions with calcium-dependent protease and actin, as suggested by previous work on the interaction of Ca2+ with brain spectrin, the approximately two high-affinity sites per repeating segment of erythrocyte spectrin appear to stabilize a folded conformation of repeat structures indicated by an entropy increase upon binding. These data support the hypothesis that divalent cation binding to erythrocyte spectrin has become specialized to stabilize the membrane skeletal network and the cell, making them flexible but resistant to shear under the stressful conditions of blood circulation.

Characterization of calcium binding to brain spectrin.

Brain spectrin alpha and beta chains bind 45Ca2+, as shown by the calcium overlay method. Flow dialysis measurements revealed eight high affinity binding sites/tetramer that comprise two binding components (determined by nonlinear regression analysis). The first component has one or two sites (kd = 2-30 x 10(-8) M), depending on the ionic strength of the binding buffer, with the remaining high affinity sites in the second component (kd = 1-3 x 10(-6) M). In addition, there is a variable, low affinity binding component (n = 100-400, kd = 1-2 x 10(-4) M). Magnesium inhibits calcium binding to the low affinity sites with a K1 = 1.21 mM. Proteolytic fragments from trypsin or chymotrypsin digests of brain spectrin bind 45Ca2+ if they include alpha domain IV, alpha domain III, or the amino-terminal half of the beta chain (but more than 25 kDa from the amino-terminal). These data suggest that calcium ions bind with high affinity to the putative EF-hands in alpha domain IV and to one site in the amino-terminal half of the beta chain that is associated with alpha domain IV in the native dimer. The localization is consistent with a direct calcium modulation of the spectrin-actin-protein 4.1 interaction. In addition, there appears to be one high affinity site near the hypersensitive region of alpha brain spectrin. All four proposed binding sites occur near probable calmodulin-binding or calcium-dependent protease cleavage sites.

Pathophysiological actions of thromboxane A2 and their pharmacological antagonism by thromboxane receptor blockade with GR32191.

With a growing general conviction that thromboxane A2 does have a pathological role in occlusive vascular disease, there is a current debate on the ideal type of drug treatment needed. The more widely accepted view now seems to be that drugs that antagonize the actions of thromboxane A2 by blocking its receptors have greater clinical potential than those that block its synthesis. However, this premise has yet to be proven clinically. The historical development of thromboxane receptor blockers as a new class of medicines and, in particular, that of GR32191, are described here. The clinical evaluation of GR32191 should determine the importance of thromboxane A2 in cardiovascular disease.

Hormonal evaluation in patients with osteosarcoma.

Aspects of growth regulation were studied in patients with osteosarcoma to ascertain if hormonal imbalance is associated with this disease. Thirty-nine evaluated patients were of normal height for their ages. During the oral glucose tolerance test, carbohydrate intolerance was demonstrated in seven of 18 patients, while growth hormone was slightly elevated in four of 17 patients. Serum somatomedin activity (SMA) was elevated in seven of nine patients. In one untreated patient in whom SMA was measured across the tumor bed, significant gradient of SMA was found; gel filtration of the sera at pH 2.4 revealed a typical SMA profile in the arterial serum and an additional high SMA peak in the venous serum. Among needle biopsy specimens incubated for 48 hours, SMA was released by the histologically viable tumors but not by the nonviable specimens. The data suggest that young patients with osteosarcoma have elevated SMA.