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Biomedical subjects

A G Harris

Publications and source records attributed to A G Harris.

At least 91 records · Page 5Linked to original sources
PubMed1993

Effects of leukocyte activation on capillary hemodynamics in skeletal muscle.

Leukocytes may be an important determinant of microvascular resistance, particularly during pathological states that cause cell activation and cytoplasmic stiffening. Significant mechanisms include capillary plugging and venular adhesion. Previous quantitative studies on leukocyte-capillary plugging focused solely on arteriolar-capillary branchpoints. There are no quantitative data on plugging throughout the capillary network either under normal conditions or after leukocyte activation. Plugging measurements were made throughout capillary networks at both arteriolar-capillary and capillary-capillary branchpoints in spinotrapezius muscle of anesthetized rats under normal physiological conditions and after leukocyte activation by superfusion with 1 x 10(-7) M N-formyl-methionyl-leucylphenylalanine (FMLP). These data were used to estimate the increase in microvascular flow resistance due to leukocyte plugging. The increase was 1.1% in control and 15.9% in the activated state. On an individual network basis, this represents an average 23-fold increase (P < 0.002) in network resistance, suggesting that leukocyte activation has a significant impact on microvascular blood flow.

Animals↗
PubMed1993

Leukocyte cytoskeletal structure determines capillary plugging and network resistance.

Leukocyte plugging in capillaries may play an important role in microvascular hemodynamics under pathological conditions that result in leukocyte activation. Previous studies have quantified the effects of transient capillary plugging on microvascular resistance for control and activated leukocytes, but have not focused on the intracellular mechanisms responsible. The frequency and duration of leukocyte-capillary plugging were measured throughout capillary networks in spinotrapezius muscle of anesthetized rats under normal physiological conditions and after leukocyte activation coupled with cytoskeletal F-actin depolymerization, using superfusion with 10(-7) M N-formyl-methionyl-leucyl-phenylalanine (FMLP) and 0.3 microM cytochalasin D (CD). These data were used to estimate the increase in microvascular flow resistance due to leukocyte plugging. The increase was 1.1% in control and 0.7% in the activated FMLP-CD state and was not significantly different. CD abolished the previously reported 16% resistance increase caused by FMLP activation [Harris and Skalak, Am. J. Physiol. 264 (Heart Circ. Physiol. 31): H909-H916, 1993.], suggesting that leukocyte plugging in capillaries is primarily determined by leukocyte cytoplasmic viscosity and is not significantly affected by cell adhesion. Thus F-actin-mediated cytoskeletal reorganization during leukocyte activation has significant impact on microvascular resistance.

Actins↗
PubMed1993

Prospective study of the long-term effects of somatostatin analog (octreotide) on gallbladder function and gallstone formation in Chinese acromegalic patients.

This article reports the changes in gallbladder function examined by ultrasonography in 20 Chinese patients with active acromegaly treated with sc injection of the somatostatin analog octreotide in dosages of 300-1500 micrograms/day for a mean of 24.2 +/- 13.9 months. During treatment with octreotide, 17 patients developed sludge, 10 had gallstones, and 1 developed acute cholecystitis requiring surgery. In all of 7 patients examined acutely, gallbladder contractility was inhibited after a single 100-micrograms injection. In 8 patients followed for 24 weeks, gallbladder contractility remained depressed throughout therapy. After withdrawal of octreotide in 10 patients without gallstones, 8 patients assessed had return of normal gallbladder contractility within 1 month. In 8 of the remaining 10 patients who developed gallstones during treatment, gallbladder contractility normalized in 5 patients (3 of whom has disappearance of their stones within 3 weeks), and remained depressed in 3 (2 of whom had stones present at 6 months). Our results suggest that the suppression of gallbladder contractility is the cause of the successive formation of bile sludge, gallstones, and cholecystitis during octreotide therapy in Chinese acromegalic patients. It is therefore very important to follow the changes of gallbladder function during long-term octreotide therapy of acromegalic patients.

Acromegaly↗
PubMed1993

Restoration of gallbladder contractility after withdrawal of long-term octreotide therapy in acromegalic patients.

We sought to examine how the discontinuation of octreotide in long-term octreotide-treated acromegalic patients affects the well-documented side-effect of cholelithiasis. In 14 acromegalic patients, serum growth hormone levels, insulin-like growth factor I levels and percentage of relative gallbladder contractility were measured prior to and after the discontinuation of octreotide. Compared to pretreatment values, the basal growth hormone and 5-h growth hormone profiles were 36% and 24%, and 60% and 56% at the end of 1 and 2 weeks, respectively. Octreotide was found to be eliminated completely from the serum within 3 days after its withdrawal. In all of six patients who did not develop gallstones, the percentage relative gallbladder contractility normalized within 1 week. In eight patients who developed gallstones, four of them had restoration of normal contractility within 2 weeks. Our results show that upon withdrawal of octreotide, gallbladder contractility returns to normal while growth hormone suppression persists for a longer period of time. Therefore, discontinuation of octreotide therapy may allow for the clearance of stagnated bile and hence decrease the incidence of cholelithiasis in acromegalic patients receiving long-term therapy.

Acromegaly↗
PubMed1993

Effects of octreotide on insulin-like growth factor I and metabolic indices in growth hormone-treated growth hormone-deficient patients.

Animals studies have demonstrated that in addition to inhibiting growth hormone (GH) secretion octreotide inhibits in a direct manner hepatic or peripheral insulin-like growth factor I (IGF-I) generation. To test this hypothesis in humans we studied ten GH-deficient patients with frequent blood sampling during 38 h on two occasions. Regular GH therapy was discontinued 72 h prior to each study period. At the start of each study a subcutaneous (sc) injection of GH (3 IU/m2) was given (at 18.00 h). In a single-blinded crossover design, patients received a continuous sc infusion of either octreotide (200 micrograms/24 h) or placebo (saline). The pharmacokinetics of GH were similar on the two occasions. The area under the curve +/- SEM of serum GH was 142.5 +/- 53.6 micrograms.l-1 x h-1 (octreotide) and 144.8 +/- 41.8 micrograms.l-1 x h-1 (placebo), (p = 0.73); Cmax (microgram/l) was 12.5 +/- 1.47 (octreotide) and 12.8 +/- 1.42 (placebo) (p = 0.83), and Tmax (h) was 6.1 +/- 0.97 (octreotide) and 5.2 +/- 0.65 (placebo) (p = 0.49). Growth hormone administration was associated with an increase in serum IGF-I (microgram/l), which was identical during the two studies, from 85.3 +/- 19.4 to 174.25 +/- 30.3 for octreotide and from 97.0 +/- 26.4 to 158.8 +/- 28.2 for placebo. Mean IGF-I levels (microgram/l) were 138.2 +/- 25.1 (octreotide) and 134.5 +/- 28.6 (placebo) (p = 0.78). Similarly, the increase in IGF binding protein 3 (IGFBP-3) levels was identical. Mean IGFBP-3 levels (microgram/l) were 2303 +/- 323 (octreotide) and 2200 +/- 361 (placebo) (p = 0.25).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Clinical pharmacokinetics of octreotide. Therapeutic applications in patients with pituitary tumours.

Among somatostatin analogues, octreotide is the most extensively studied. Its pharmacodynamic properties are similar to those of somatostatin, with a wide spectrum of inhibitory effects on anterior pituitary function, pancreas and gut endocrine secretions, and gastrointestinal functions. Compared with the somatostatin, octreotide is highly resistant to enzymatic degradation and has a prolonged plasma half-life of about 100 minutes in humans, allowing its use in the long term treatment of various pathological conditions. Differential effects of octreotide on endocrine secretions such as growth hormone (GH) and insulin in healthy volunteers, as well as variable efficacy in the treatment of endocrine tumours, may relate to the distribution of somatostatin receptor subtypes. The volume of distribution of octreotide ranges from 18 to 30L. Calculated serum distribution half-life ranges from 72 to 98 minutes. In blood, octreotide is mainly distributed in the plasma, 65% being bound to lipoproteins. After subcutaneous injection, absorption appears rapid and complete and bioavailability is about 100%. Mean peak plasma concentrations are between 2 and 4 micrograms/L in patients receiving 50 to 100 micrograms. Peak concentrations are reached within 20 to 30 minutes and are 20 to 40% of corresponding values after intravenous injection. Peak concentrations and values for areas under the plasma concentration-time curve linearly correlate with the dosage. The elimination half-life is about 90 to 110 minutes. Total clearance in healthy individuals is about 160 ml/min (9.6 L/h). Hepatic metabolism of octreotide is extensive (30 to 40%) and about 11 to 20% of the dose is excreted unchanged in the urine. Among pituitary tumours, GH- and thyrotrophin-secreting adenomas are the most sensitive to octreotide. Octreotide has been widely used in the treatment of acromegaly. 50 to 80% of the patients respond to daily multiple subcutaneous injections with insulin-like growth factor-1 (IGF1) levels being normalised in about 40 to 50% of them. Neither desensitisation with long term therapy nor rebound phenomena after octreotide withdrawal have been noticed in these studies. Even in patients with partial response, clinical symptoms improved. Octreotide daily dosages needed to achieve optimum responses may vary greatly from one patient to another. In a minority of patients complete resistance to octreotide was observed and was not always related to the absence of somatostatin receptors in the tumour. The wide spectrum of effects of octreotide in humans accounts for adverse effects seen during long term treatment, primarily cholelithiasis. Other modes of administration are efficient.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1992

Gallstones in acromegalic patients undergoing different treatment regimens.

The frequency of gallstones during long-term treatment with the somatostatin analogue octreotide reported in different studies varies from 0% to 50%, the reason for this variation being unknown. Therefore, we examined 58 acromegalic patients undergoing different treatment regimens for the frequency of gallstones. Thirteen were treated with octreotide, 20 with bromocriptine, and 25 had no medical treatment after successful neurosurgery. Also, 58 patients without known gallbladder disease served as controls. The postprandial gallbladder contraction was also investigated in 27 acromegalic patients (10 with octreotide, 10 with bromocriptine, and 7 with no medical therapy). Ten of the 58 acromegalic patients were found to have gallstones, 4 of 25 receiving no medical treatment, 4 of 20 treated with dopamine agonists, and 2 of 13 treated with octreotide. In 9 of the 58 control patients, gallstones were detected. Although in the octreotide group the gallstones were newly formed under therapy, there was no difference in gallstone prevalence between the different treatment regimens and the control group. However, the postprandial gallbladder contraction was significantly more often inhibited during octreotide therapy, and this effect was most pronounced during the first hours following injection. Differences in the timing of injections therefore may be an explanation of the variable incidence of cholelithiasis in the different studies.

Acromegaly↗
PubMed1992

Effect of somatostatin analog octreotide on human sphincter of Oddi.

The effect of the long-acting somatostatin analog octreotide on the sphincter of Oddi was investigated in seven subjects referred for endoscopic sphincter of Oddi manometry. Six patients had unexplained right upper quadrant pain and one had bile duct dilatation without evidence of fixed obstruction on endoscopic retrograde cholangiopancreatography. A triple-lumen low-compliance system was used to record the sphincter of Oddi basal pressure, phasic contraction frequency, amplitude, duration, and direction of wave propagation before and after intravenous administration of octreotide in a dose of 50 micrograms. After a mean latency period of 1 min, significant changes included increased basal pressure in all seven patients, increased frequency of wave contractions in six patients, and decreased wave amplitude in six patients. The median duration of wave contraction and wave propagation sequence were not significantly influenced. Thus, octreotide has a significant stimulatory affect on the sphincter of Oddi activity, which may impair biliary and pancreatic flow.

Adult↗
PubMed1992

Effect of small doses of somatostatin analog, octreotide, on gallbladder contractility in normal Chinese adults.

The acute effects of single different doses of the somatostatin analog octreotide on the contractility of the gallbladder stimulated by fatty meal were studied in six healthy Chinese volunteers. Gallbladder contraction after a fatty meal was significantly suppressed by octreotide at doses of 50, 25, 12.5, and 5 micrograms. Mean duration of suppression lasted for more than 10 hr at doses of 25 and 50 micrograms, after which the gallbladder contractility was restored at 24 hr in three and four, respectively, of the six subjects. The percentage of relative gallbladder contraction (PRGC) in all subjects receiving 12.5 and 5 micrograms octreotide returned to pretreatment values at 10 hr but had not returned to normal 6 hr after the injection of 5 micrograms octreotide. In summary, octreotide inhibits the contraction of the gallbladder even with a dose as low as 5 micrograms. It appears that it may not be possible to avoid gallbladder dysfunction during long-term octreotide therapy by decreasing the dose. Further studies including modalities to increase the contractility of the gallbladder are recommended.

Adult↗
PubMed1992

Long-term efficacy and tolerability of octreotide treatment in acromegaly.

Twenty-five acromegalic patients were studied during 6 years of treatment with octreotide, with a particular focus on the following parameters: (1) Administration schedule: in 10 patients, continuous subcutaneous (SC) octreotide infusion was compared with injections of octreotide at three dose levels (100, 250, and 1,500 micrograms/24 h) and was found to induce a greater and less-fluctuating 24-hour growth hormone (GH) suppression. (2) Carbohydrate tolerance: average 24-hour blood glucose levels were unaffected by octreotide, regardless of administration schedule. Oral carbohydrate tolerance and intravenous (IV) glucose tolerance were unaffected by continuous octreotide infusion. However, octreotide injection given shortly before the tests reduced carbohydrate tolerance. (3) Thyroid function: octreotide and somatostatin acutely reduce the response of thyroid-stimulating hormone (TSH) to thyrotropin-releasing hormone (TRH). After a few days of treatment, it was demonstrated that octreotide slightly inhibits iodothyronine deiodination and induces a transient reduction in serum triiodothyronine (T3), rapidly compensated for by a persistent slight elevation of serum TSH. (4) Fat absorption was estimated as 24-hour fecal fat content and found to be in the same high-normal range before and after octreotide treatment. Vitamin K and D absorption were unaffected by octreotide. The incidence of gallstone formation was not greater than in the general Danish population, possibly due to the schedule used for octreotide injections. (5) Foot volume was regularly estimated and found to decrease with time, on average by 12% during the first 18 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1992

Presurgical octreotide treatment in acromegaly.

The aim of this study was to determine the role of octreotide administration in acromegalic patients as a preparation for selective adenomectomy using transsphenoidal route. Octreotide was administered for 3 to 6 weeks before surgery in 12 patients and for 4 to 39 months in 25 patients. The clinical response was judged as excellent or good in 10 of 12 patients from group I and in 23 of 25 patients from group II. Marked reduction (ie, greater than 50% of initial values) in serum growth hormone (GH) levels was seen in all patients, with levels to less than 5 micrograms/L in 68% of patients and less than 2 micrograms/L in 27%. Insulin-like growth factor 1 (IGF-1) levels decreased to within normal limits in half the cases. During long-term treatment, an escape phenomenon could be seen. Varying degrees of tumor shrinkage were seen in more than 50% of cases. During surgery, with regard to the relative ease or difficulty in removing the tumor, the consistency of the tumor and the separation of normal from pathological tissue, no significant difference was observed between patients given octreotide and those from control series. Morphological changes in adenomatous tissue were rather small. The surgical outcome was similar in the pretreated series as in the control series, except in enclosed adenomas, which showed a tendency to a higher success rate. Since octreotide improves both the clinical condition and hormonal parameters and induces varying degrees of tumor shrinkage, it is potentially useful as an adjunct to surgery. Morphological data suggest that octreotide exercises a functional inhibitory effect on GH release.

Acromegaly↗
PubMed1992

Octreotide and diabetes: theoretical and experimental aspects.

Diabetes is characterized by paradoxical hypersomatotropinemia and hyperglucagonemia. The latter appears to enhance the tendency in imperfect metabolic control to reduce nitrogen balance, and the former appears to accelerate the deterioration of carbohydrate and lipid metabolism, and also to induce peripheral insulin resistance and hyperinsulinemia. In addition to direct metabolic effects, increasing evidence points to an association between hypersomatotropinemia and a number of metabolically dependent, characteristic functional abnormalities linked to the development of late diabetic manifestations. These include increased capillary fragility, lipid and hemostatic aberrations, tissue hyperperfusion, including increased cardiac output and renal plasma flow, and kidney hypertrophy. In theory, octreotide's actions could reduce these aberrations, and, in fact, this has been confirmed in recent experimental trials.

Animals↗
PubMed1992

Preliminary results with Sandostatin nasal powder in acromegalic patients.

This report details the first half of a double-blind, crossover sequence (Latin square) study of local and hormonal effects of nasally insufflated Sandostatin compared with those of subcutaneously injected Sandostatin. Nine of the planned 16 patients have been studied. They received a single application of 0.5, 1.0, and 2.0 mg Sandostatin as nasal powder and 0.1 mg by subcutaneous (SC) injection. The results indicate that absorption from the nasal epithelium occurs after approximately 10 minutes and comprises approximately 20% of the dose administered. This indicates that peak serum Sandostatin values occur very rapidly, ie, 10 minutes after application. After approximately 2 hours, the serum disappearance rates are similar to those obtained after SC injection. The suppressive effect on serum growth hormone (GH) levels is equal with the two forms of application and suggests that future clinical treatment with an intranasal application of 0.5 mg thrice daily is feasible. No side effects were noted apart from an immediate swelling of nasal mucosa, which receded gradually over the following 2 hours. This was either unnoticed or considered insignificant by the patients and will probably be deemed harmless by the rhinologist in eventual long-term clinical trials.

Absorption↗
PubMed1992

Octreotide administration in diabetic rats: effects on renal hypertrophy and urinary albumin excretion.

Initial renal hypertrophy in experimental diabetes is prevented by administration of a long-acting somatostatin analogue octreotide (SMS). To investigate the long-term effects of SMS on renal hypertrophy and urinary albumin excretion (UAE), streptozotocin-diabetic and non-diabetic rats were treated with two daily subcutaneous injections of SMS (100 micrograms x 2) for six months. Untreated diabetic and non-diabetic animals were used as reference groups. No differences were seen between the two diabetic groups in respect to body weight, food intake, blood glucose levels, urinary glucose output, hemoglobin A1C(HbA1C), fructosamine, serum growth hormone (rGH) or creatinine clearance, but kidney weight (896 +/- 36 vs. 1000 +/- 24 mg, P less than 0.02), UAE (417 +/- 131 vs. 1098 +/- 187 micrograms/24 hr, P less than 0.02), kidney insulin-like growth factor I (IGF-I) (167 +/- 16 vs. 239 +/- 17 ng/g, P less than 0.01) and serum IGF-I (301 +/- 26 vs. 407 +/- 17 micrograms/liter, P less than 0.01) were all reduced in the SMS-treated diabetic animals when compared to the untreated diabetic group. In non-diabetic rats SMS reduced body weight (274 +/- 3 vs. 293 +/- 5 g, P less than 0.01), kidney weight (695 +/- 9 vs. 764 +/- 17 mg, P less than 0.01), UAE (83 +/- 29 vs. 364 +/- 114 micrograms/24 hr, P less than 0.02), kidney IGF-I (202 +/- 12 vs. 280 +/- 12 ng/g, P less than 0.01), serum IGF-I (428 +/- 21 vs. 601 +/- 54 micrograms/liter, P less than 0.01) and serum rGH (67 +/- 6 vs. 126 +/- 27 micrograms/liter, P less than 0.05) when compared to untreated controls. When kidney weights were expressed in relation to body weight no difference was found between SMS-treated and untreated controls, while the difference between SMS-treated and untreated diabetic animals was still present (P less than 0.01). In conclusion, chronic administration of SMS has abating effects on diabetic renal hypertrophy and UAE, and thus indicates that SMS may reduce development of diabetic kidney lesions in experimental diabetes. The long-term suppressive effects of SMS on renal enlargement and UAE may in part be mediated through reduction in circulating and kidney IGF-I levels.

Albuminuria↗