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PubMed2002

Treatment satisfaction in type 2 diabetes: a comparison between an inhaled insulin regimen and a subcutaneous insulin regimen.

BACKGROUND: In patients with type 2 diabetes, published data suggest that glycemic control can be achieved as effectively with an inhaled insulin regimen (preprandial inhaled intrapulmonary insulin plus a single bedtime Ultralente injection) as with a conventional subcutaneous insulin regimen involving 2 to 3 injections per day. It is unknown whether inhalation delivery of insulin improves patient satisfaction. OBJECTIVE: Our objective was to compare patient satisfaction between an inhaled insulin regimen and a subcutaneous insulin regimen. METHODS: This was a 12-week randomized, open-label, parallel-group, controlled trial in patients with type 2 diabetes. They were randomized to receive either a subcutaneous insulin regimen (split/mixed insulin with 2 to 3 injections daily) or an inhaled insulin regimen (inhaled insulin before meals and a single Ultralente insulin injection at bedtime). Change in glycosylated hemoglobin (HbA1c) from baseline to week 12 was the study's primary end point. At baseline and week 12, patients completed a questionnaire (Patient Satisfaction with Insulin Therapy Questionnaire) covering attributes of patient satisfaction. Treatment regimens were compared on each item with the Wilcoxon rank sum test and on the overall score with a t test. RESULTS: Fifty-one patients (age range, 35-65 years) participated in the study, 26 receiving inhaled insulin and 25 receiving subcutaneous insulin. Forty-seven patients (22 inhaled insulin, 25 subcutaneous insulin) completed the satisfaction questionnaire. The mean percent improvement in overall satisfaction with an inhaled insulin regimen (31%; 95% CI, 14-50) was significantly greater (P < 0.05) than that with a subcutaneous insulin regimen (13%; 95% CI, 7-19). Increases in overall satisfaction correlated with improvements in glycemic control (r = 0.30; P < 0.05). Both treatment regimens experienced a mean HbA1c reduction of approximately 0.7%. Although patient satisfaction was the chief focus of this article, these results should be considered exploratory, as the trial was powered prospectively for HbA1c values (the primary end point) and not for patient satisfaction. CONCLUSIONS: Administration of an inhaled insulin regimen may offer the first practical, noninvasive alternative to insulin injections. In the patients with type 2 diabetes studied, an inhaled insulin regimen with the need for only 1 subcutaneous injection at bedtime appeared to offer more ease of use, comfort, and convenience, as well as greater overall satisfaction, than a subcutaneous insulin regimen of 2 to 3 injections daily.

Administration, Inhalation↗

PubMed2002

Subcutaneous microdialysis for metabolic monitoring in abdominal aortic surgery.

UNLABELLED: Microdialysis, that is the sampling of interstitial fluid via semi-permeable tubes, has been shown to be suitable for detecting ischemic changes e.g. in brain and heart tissue. The purpose of the present study was to investigate the possibility of monitoring with subcutaneous microdialysis peri-operative metabolic sequelac of elective abdominal aortic surgery. In 22 patients microdialysis catheters were inserted subcutaneously in the lower leg as well as the shoulder serving as a reference topographic region. Lactate, pyruvate and glycerol, which indicate ischemia or reperfusion, were measured. We observed severe metabolic changes within the interstitial fluid of the lower extremity during ischemia followed by normalization during reperfusion. Despite high interstitial concentrations of lactate and glycerol indicating severe ischemia during clamping of the abdominal aorta these parameters returned to pre-operative values within 2 hrs after declamping and all patients recovered completely. OBJECTIVE: Information about the metabolic state of the lower extremity during and after infrarenal aortic aneurysm repair should modify peri-operative treatment. The aim of the study was to evaluate whether microdialysis of the subcutaneous tissue reflects metabolic changes during ischemia and reperfusion. Lactate, pyruvate and glycerol concentrations were measured in the subcutaneous tissue of the lower extremity and compared to the microdialysis measurements from shoulder subcutaneous tissue. METHOD: In 22 patients microdialysis catheters were inserted preoperatively in the subcutaneous space of the left shoulder and the left calf. Samples were taken at timed intervals before, during and after clamping of the abdominal aorta. RESULTS: The subcutaneous glycerol concentration of the calf was increased during the clamping period from initially 68 +/- 11 microM up to 182 +/- 27 microM (p < 0.05); the lactate/pyruvate (L/P) ratio was increased eightfold. After declamping these values normalized to baseline. Microdialysis measurements of the shoulder showed no prominent changes during the entire course of observation. CONCLUSIONS: Subcutaneous microdialysis was able to detect metabolic changes due to ischemia during clamping of the abdominal aorta as well as reperfusion there after. It is a suitable technique to monitor the peri-operative course of the dependent tissue after abdominal aortic vascular surgery.

Aged↗

PubMed1997

Modeling of subcutaneous absorption kinetics of infusion solutions in the elderly using technetium.

Absorption kinetics of solutes given with the subcutaneous administration of fluids is ill-defined. The gamma emitter, technitium pertechnetate, enabled estimates of absorption rate to be estimated independently using two approaches. In the first approach, the counts remaining at the site were estimated by imaging above the subcutaneous administration site, whereas in the second approach, the plasma technetium concentration-time profiles were monitored up to 8 hr after technetium administration. Boluses of technetium pertechnetate were given both intravenously and subcutaneously on separate occasions with a multiple dosing regimen using three doses on each occasion. The disposition of technetium after i.v. administration was best described by biexponential kinetics with a Vss of 0.30 +/- 0.11 L/kg and a clearance of 30.0 +/- 13.1 ml/min. The subcutaneous absorption kinetics was best described as a single exponential process with a half-life of 18.16 +/- 3.97 min by image analysis and a half-life of 11.58 +/- 2.48 min using plasma technetium time data. The bioavailability of technetium by the subcutaneous route was estimated to be 0.96 +/- 0.12. The absorption half-life showed no consistent change with the duration of the subcutaneous infusion. The amount remaining at the absorption site with time was similar when analyzed using image analysis, and plasma concentrations assuming multiexponential disposition kinetics and a first-order absorption process. Profiles of fraction remaining at the absorption site generated by deconvolution analysis, image analysis, and assumption of a constant first-order absorption process were similar. Slowing of absorption from the subcutaneous administration site is apparent after the last bolus dose in three of the subjects and can be associated with the stopping of the infusion. In a fourth subject, the retention of technetium at the subcutaneous site is more consistent with accumulation of technetium near the absorption site as a result of systemic recirculation.

Absorption↗

PubMed1999

Comparison of monthly intramuscular injections of Sandostatin LAR with multiple subcutaneous injections of octreotide in the treatment of acromegaly; effects on growth hormone and other markers of growth hormone secretion.

OBJECTIVE: To compare the effects of monthly intra-muscular injections of a long acting preparation of octreotide, Sandostatin LAR, with multiple daily subcutaneous injections of octreotide and to study the interrelationships between mean 24 h growth hormone profile, serum total and free IGF-1 levels, 24 h urinary growth hormone levels and serum IGFBP-3. DESIGN: Patients were assessed by 24 h GH profile off octreotide or any other GH modifying drug therapy; on subcutaneous octreotide (200-600 micrograms daily in divided doses for six weeks); and 28 days after the second of two injections of Sandostatin LAR (20 mg by intra-muscular injection) administered 28 days apart. Serum total and free IGF-1, serum IGFBP-3 and 24 h urinary GH were also measured on each occasion. RESULTS: Sandostatin LAR was well tolerated. None of the patients reported any adverse effect and all completed the study uneventfully. Mean GH off treatment was 10.1 +/- 3.0 micrograms/l falling equally significantly (P < 0.05) during therapy with subcutaneous octreotide to 3.0 +/- 0.7 micrograms/l and Sandostatin LAR to 2.8 +/- 0.7 micrograms/l. Fasting 0900 h GH was significantly reduced (P < 0.05) on Sandostatin LAR (3.0 +/- 0.7 micrograms/l) compared with subcutaneous octreotide (5.1 +/- 1.2 micrograms/l). Mean total IGF-1 off treatment was 658.6 +/- 56.1 micrograms/l and was reduced to a comparable extent with subcutaneous octreotide and Sandostatin LAR (466.0 +/- 59.7 and 448.6 +/- 59.5 micrograms/l respectively; both P < 0.05). Free IGF-1 off treatment was 3.1 +/- 0.6 micrograms/l and was reduced equally by subcutaneous octreotide and Sandostatin LAR (1.2 +/- 0.2 and 1.2 +/- 0.2 micrograms/l; both P < 0.05). IGFBP-3 was reduced to a greater extent during Sandostatin LAR than during subcutaneous octreotide (4518.2 +/- 247.3 vs 5132.8 +/- 280.7 micrograms/l; P < 0.05). Twenty-four hour urinary GH excretion was reduced to a comparable extent with both therapies. Highly significant positive correlations were found between mean 24 h GH levels and free IGF-1 (r = 0.66, P < 0.0001) and 24 h urinary GH excretion (r = 0.94, P < 0.0001). The relationships between mean 24 h GH levels and total IGF-1 and IGFBP-3 although significant showed less powerful correlations. CONCLUSIONS: These results suggest that Sandostatin LAR is well tolerated and as effective as subcutaneous octreotide. In addition, urinary growth hormone and serum free IGF-1 may prove valuable for outpatient follow-up of acromegalic patients, as both correlate well with mean 24 h serum growth hormone levels.

Acromegaly↗

PubMed2001

Subcutaneous emphysema associated with chest tube drainage.

BACKGROUND: Subcutaneous emphysema may complicate a pneumothorax, but may also occur as a consequence of its treatment by chest tube drainage. The aim of this study was to evaluate the factors involved in the association between subcutaneous emphysema and chest tube drainage, and the clinical outcomes in these cases. METHODOLOGY: One hundred and sixty-seven patients undergoing chest tube drainage within a 12-month period were evaluated retrospectively. There were 30 reported cases of subcutaneous emphysema (SE). Comparisons were made between those with subcutaneous emphysema and those who did not develop this complication. RESULTS: A total of 134 patient notes were evaluated (25 SE and 109 non-SE). Subcutaneous emphysema was more commonly associated with trauma, bronchopleural fistulae, large and bilateral pneumothoraces, and mechanical ventilation. Subcutaneous emphysema was also associated with prolonged drainage, poor tube placement, tube blockage, side-port migration, and a greater number of chest tubes. Importantly, those with SE had a longer length of stay and increased mortality. CONCLUSION: Subcutaneous emphysema can be spontaneous or traumatic, but is associated with avoidable causes such as inadequate chest tube drainage, particularly due to poor tube placement, anchorage and blockage, and also with side-port migration into the subcutaneous tissue. It is associated with an increased morbidity and mortality, and may indicate the need for urgent chest tube replacement.

Adolescent↗

PubMed2006

Subcutaneous fat modulates insulin sensitivity in mice by regulating TNF-alpha expression in visceral fat.

The distribution of fat in obese persons is related to the risk of developing various metabolic disorders, such as glucose intolerance, dyslipidemia and hypertension, and the combination of these conditions is known as the metabolic syndrome. The aim of this study was to investigate the role of subcutaneous fat in regulating insulin resistance and its influence on TNF-alpha expression in visceral fat, by using mice that were subjected to subcutaneous lipectomy with or without subsequent fat transplantation. After partial subcutaneous lipectomy, mice showed significantly greater accumulation of visceral fat compared with sham-operated control mice. Lipectomy led to higher plasma insulin and lower plasma glucose levels after loading with glucose and insulin, respectively, compared with the levels in control mice. Insulin-induced phosphorylation of IRS-1 was decreased in the skeletal muscles of lipectomized mice. Subcutaneous transplantation of fat pads into lipectomized mice reversed the above-mentioned changes indicating insulin resistance in these animals. The fat storage area of adipocytes and TNF- alpha expression by adipocytes in visceral fat were significantly higher in the lipectomized mice than in controls, while subcutaneous transplantation of fat reduced both the fat storage area and TNF-alpha expression. The insulin resistance of lipectomized mice was also ameliorated by systemic neutralization of TNF-alpha activity using a specific antibody. These findings obtained in mice subjected to subcutaneous lipectomy with/without subsequent fat transplantation indicate that subcutaneous fat regulates systemic insulin sensitivity, possibly through altering fat storage and the expression of TNF-alpha by adipocytes in visceral fat. The balance between accumulation of subcutaneous fat and visceral fat may be important with respect to the occurrence of systemic insulin resistance in the metabolic syndrome.

Animals↗

PubMed2005

Intravenous versus subcutaneous morphine titration in patients with persisting exacerbation of cancer pain.

BACKGROUND: Patients with cancer pain with initially adequate analgesia under oral sustained-release opioid medication may suffer from persisting pain exacerbations. Sometimes even fast help is needed and then optimally performed by intravenous application (IVA) of immediate-release (IR) opioids. This IVA, however, may only be performed by physicians in Germany. OBJECTIVE: We wanted to find out if subcutaneous application of IR-opioids might be an adequate alternative to IVA in persisting pain exacerbations of patients with cancer pain because this could be performed by the nursing staff in Germany as well. DESIGN: An open randomized controlled trial was used to compare intravenous versus subcutaneous morphine titration in persisting pain exacerbations in patients with cancer pain. SETTING/SUBJECTS: Thirty-nine patients with cancer (21 intravenously, 18 subcutaneously) of the pain management department of the university hospital of Cologne, Germany were included into the study. MEASUREMENTS: Calculated from preexisting analgesic medication boli of morphine were given every 5 minutes (intravenously) or 30 minutes (subcutaneously) up to adequate analgesia or intolerable side effects. Pain intensity, nausea, sedation, and some vital parameters were documented before the start, after each application and at the end of titration. RESULTS: Thirty-five patients were pretreated with oral opioids, 4 patients with nonopioid analgesics. Six patients stopped titration because of intolerable side effects (sedation, vomiting). Thirty patients (77%) reported at least sufficient pain reduction, 3 patients were free of pain (intravenously). Mean pain intensity decreased on a visual analogue scale (VAS, 0-100) from 83 to 32 (intravenously) and from 68 to 42 (subcutaneously). Morphine doses ranged from 4 mg to 32 mg (intravenously; mean, 18.5 +/- 9.2 mg) and from 10 mg to 200 mg (subcutaneously mean, 57.9 +/- 59.6 mg). Mean time up to adequate analgesia was 53 (intravenously) 77 min (subcutaneously), respectively. There was no change in vital parameters but an increase of sedation in both groups. The adaptation of the continuous analgesic medication resulted in a stable and lasting pain relief after 4 days in both groups. CONCLUSIONS: Intravenous and subcutaneous-morphine titration are adequate to antagonize persisting pain exacerbations in cancer pain patients quickly and to adapt the continuous opioid analgesic medication.

Adult↗

PubMed1999

Subcutaneous administration of fentanyl and midazolam to prevent withdrawal after prolonged sedation in children.

OBJECTIVE: To determine the efficacy of switching to subcutaneous fentanyl with or without midazolam to prevent withdrawal after prolonged sedation in children in the pediatric intensive care unit (PICU). DESIGN: Retrospective review of hospital records. SETTING: Tertiary care center, PICU. PATIENTS: The cohort for the study included patients who had received subcutaneous fentanyl with or without midazolam to prevent withdrawal after prolonged sedation in the PICU. MEASUREMENTS AND MAIN RESULTS: Subcutaneous fentanyl with or without midazolam was administered to nine patients ranging in age from 3 to 7 yrs (mean, 4.4 +/- 1.8 yrs) and ranging in weight from 11 to 31 kg (mean, 20.1 +/- 6.8 kg). All patients required prolonged administration of fentanyl with or without midazolam during mechanical ventilation for respiratory failure. The starting infusion rate for subcutaneous fentanyl varied from 5 to 9 microg/kg/hr (mean, 7.1 +/- 1.4 microg/kg/hr). Four patients also received subcutaneous midazolam at a rate of 0.15 to 0.3 mg/kg/hr (mean, 0.24 mg/kg/hr). Subcutaneous access was maintained for 3-7 days (mean, 5.7 +/- 1.4 days) in the nine patients. No problems with the subcutaneous access were noted during treatment. The fentanyl infusion was decreased by 1 microg/kg/hr every 12-24 hrs and the midazolam infusion was decreased by 0.05 mg/kg/hr every 12-24 hrs. No patient demonstrated signs of symptoms of moderate to severe withdrawal. CONCLUSION: The subcutaneous route provides an effective alternative to intravenous administration. It allows for gradual weaning from sedative/analgesic agents after prolonged sedation while eliminating the need to maintain intravenous access.

Analgesics, Opioid↗

PubMed2001

Intratumoral injection of lipopolysaccharide causes regression of subcutaneously implanted mouse glioblastoma multiforme.

OBJECTIVE: Anecdotal reports documented extended survival times for patients who developed infections at the site of resection of malignant gliomas. Hypothesized mechanisms for this phenomenon include immune responses triggered by lipopolysaccharide (LPS). This investigation assessed whether LPS could produce tumor regression in an in vivo model of malignant glioma. METHODS: Delayed brain tumor cells (2 x 10(6)) were injected subcutaneously into female BALB/c mice. LPS (300-500 microg) was injected intratumorally or subcutaneously at a contralateral site on Days 10, 17, and 24. Control animals received phosphate-buffered saline intratumorally or subcutaneously. Mice were killed on Day 28, and tumors were removed. Mean tumor masses for control animals and the two LPS-treated groups (intratumoral or contralateral subcutaneous treatment) were compared. Histological assessments of treated and control tumors were performed. RESULTS: Complete or nearly total tumor regression was achieved in all 20 mice with subcutaneous delayed brain tumor cell tumors treated intratumorally with 400 microg of LPS (mean tumor mass of 0.09 +/- 0.38 g versus 2.42 +/- 2.46 g for control animals, P < 0.0001). Intratumoral administration of 300 microg of LPS or subcutaneous injection of 300 or 400 microg of LPS at a contralateral site resulted in less consistent regression of subcutaneous tumors. Administration of 500 microg of LPS resulted in tumor regression similar to that observed with lower doses but was limited by treatment-related deaths in 40% of animals. Histological assessment revealed lymphocytic infiltration of LPS-treated tumors. CONCLUSION: Intratumoral injections of LPS caused dramatic regression of subcutaneously implanted delayed brain tumor cell mouse gliomas. Investigation of this antitumoral effect may improve treatment responses for patients with malignant gliomas.

Animals↗

PubMed2006

Maintenance of subcutaneous cavities with CO2.

UNLABELLED: Since mechanical retractors in endoscopic plastic surgery cause certain drawbacks, we developed a model in dogs, which, by insufflating CO2 into a subcutaneous cavity, we were able to maintain. We evaluated the magnitude of subcutaneous emphysema and absorption of CO2 by insufflating different pressures and the efficacy of external pressure on the skin with the purpose of limiting the subcutaneous emphysema. Sixteen dogs were divided in 3 groups, A, B, and C. We controlled the pulmonary function by using a volume-cycle ventilator. In all groups, we maintained a subcutaneous cavity by insufflating CO2. Groups A and C were insufflated at 15 mm Hg; group B, at 8 mm Hg. We placed circumferential Esmarch bandages on the thorax of groups B and C to delimit superiorly and inferiorly the surgical area. Arterial blood gas analyses (ABGA) were taken from the femoral artery 60 minutes after intubation, 60 minutes after Esmarch bandage was placed and at the end of the CO2 insufflation. Statistically, results were analyzed by Wilcoxon test. P < 0.05 was considered statistically significant. Group A showed extensive subcutaneous emphysema. Two dogs died. The systemic increase of the CO2 showed a median of 9.6 mm Hg (P < 0.05). In Group B, Esmarch bandages caused increase in CO2, with a median of 1.65 mm Hg (P < 0.028). None of these dogs showed subcutaneous emphysema during the insufflation after CO2 insufflation pressure augmented with a median of 3.7 mm Hg (P < 0.028). In Group C, chest restriction increased CO2 median of 6.1 mm Hg (P < 0.043), and subcutaneous emphysema shown was less extensive than group A. The CO2 increased after insufflation a median of 16 mm Hg (P < 0.043). CONCLUSIONS: Subcutaneous cavities can be maintained open with CO2 insufflation at 8 mm Hg, limiting perfectly the surgical area; as done with Esmarch bandages, it reduces CO2 absorption and makes this procedure safe.

Animals↗

PubMed2006

The visceral and subcutaneous fat changes in type 1 diabetes: a pilot study.

OBJECTIVE: To evaluate the effects of improved glycaemic control on the abdominal visceral and subcutaneous fat in type 1 diabetes. RESEARCH DESIGN AND METHODS: Sixteen subjects were enrolled for this 6-month study. The goal was to achieve normal haemoglobin A1c (HbA1c <5.6% in our laboratory). T1-weighted magnetic resonance imaging was used to measure the abdominal subcutaneous and visceral fat areas at the L2-L3 disk level. Activity and energy intake were assessed using a weekly recall and food diary respectively. Plasma leptin, ghrelin and adiponectin levels were measured at baseline and at 6 months. RESULTS: Twelve subjects completed the study. HbA1c was 10.4 +/- 2.2% at baseline, and abdominal visceral to subcutaneous fat ratio was 0.29 +/- 0.15. HbA1c dropped to 8.0 +/- 1.4% at 6 months (p = 0.009). There was a +1.85 kg weight change in 6 months (p = 0.30), whereas the visceral to subcutaneous fat ratios changed to 0.36 +/- 0.18 (p = 0.22). Daily metabolic equivalents (METs) of activity at 6 months correlated with a decrease in the visceral to subcutaneous fat ratios (r = -0.80, p = 0.01). Ghrelin level changes correlated negatively with the changes in the visceral to subcutaneous fat ratio (p < 0.01). CONCLUSIONS: The visceral to subcutaneous fat changes had a negative correlation with the physical activity METs at 6 months but not with HbA1c changes in this study. The correlation between the changes in ghrelin and the visceral to subcutaneous fat ratios is intriguing, but a larger study may be needed to confirm this finding.

Adiponectin↗

PubMed2006

Comparison of the role of the subcutaneous tissues in cutaneous wound healing in the dog and cat.

OBJECTIVE: To describe and compare the contribution of the subcutaneous tissues to 1st and 2nd intention cutaneous wound healing in the dog and cat. STUDY DESIGN: Experimental study. ANIMALS: Domestic shorthaired cats (n=6) and 6 beagle dogs. METHODS: Paired wounds were created on either side of the dorsal midline; the subcutaneous tissue was removed on 1 side and left intact on the other. Square, open wounds of the dorsal aspect of the thorax were observed for 21 days to monitor granulation tissue formation, wound contraction, epithelialization, and total healing (contraction+epithelialization). Breaking strength of sutured linear wounds was measured 7 days after wounding. Laser-Doppler perfusion imaging (LDPI) was used to measure cutaneous perfusion. RESULTS: First intention healing: subcutaneous tissue removal had no consistent effect on sutured wound strength at 7 days in dogs or cats. Second intention healing: removal of subcutaneous tissue reduced wound perfusion, granulation, contraction, epithelialization, and total healing. Granulation tissue formation and wound contraction were delayed to a significantly greater degree in cats than in dogs (P<.05). Two dogs (33%) had minor wound infections. CONCLUSIONS: The subcutaneous tissues make an important contribution to 2nd intention cutaneous healing. Dog and cat wounds had delayed 2nd intention healing when subcutaneous tissues were removed; wounds in dogs, but not cats, had largely recovered from this delay by 21 days. CLINICAL RELEVANCE: Extensive debridement of subcutaneous tissue may delay wound healing particularly in feline patients. A higher risk for wound infections may accompany extensive removal of subcutaneous tissues in dogs.

Animals↗

PubMed2005

Performing subcutaneous injections: a literature review.

BACKGROUND: Persons using daily subcutaneous injections to administer medicine perform them in different ways and thereby increase the risk of skin complications related to the injection. It is often part of nurses' role to administer medicine and educate the patient in injection technique. Course literature in nursing education, commercial patient education pamphlets, and instructional leaflets do not give consistent advice regarding subcutaneous injection technique. AIM: The aim of this review was to identify the scientific foundation for the technical performance of subcutaneous injections. The question to be answered was: How should a subcutaneous injection be administered to achieve the right dose in the right place with minimum complications? METHOD: The review included a search in three databases, a screening process at abstract level, followed by a quality assessment of included articles. The quality assessment was done independently by two people and followed specific protocols. RESULT: A total of 38 articles were assessed for quality and covered information on dose, location, and complications of subcutaneous injection. The assessed studies are heterogeneous in design and describe different aspects of the subcutaneous injection technique. Therefore, the scientific foundation for technical performance is weak. However, several studies indicate that the amount of subcutaneous fat and appropriate needle length are of high importance for the drug to reach the target tissue. CONCLUSION: More research regarding effective subcutaneous injection technique needs to be done.

Adult↗

PubMed2004

Tissue levels of WR-1065, the active metabolite of amifostine (Ethyol), are equivalent following intravenous or subcutaneous administration in cynomolgus monkeys.

Amifostine (Ethyol) is a cytoprotective drug approved for the reduction of xerostomia in head and neck cancer when administered to patients receiving postoperative radiation therapy. Although amifostine is approved for intravenous infusion, the off-label subcutaneous route of administration has become more prevalent. Although human patient data indicate higher plasma bioavailability of the active metabolite (WR-1065) following intravenous compared to subcutaneous administration, there are no corresponding data showing human tissue levels of WR-1065 following either route of administration due to the difficulty in obtaining human specimens. In our study we compared plasma and tissue pharmacokinetics of WR-1065 in primates following both routes of administration. Monkeys received amifostine at a dose of 260 mg/m2 either intravenously or subcutaneously. Plasma samples were analyzed for total WR-1065 by reverse-phase high-pressure liquid chromatography (HPLC) and fluorescence detection up to 4 h after amifostine administration. Tissues were analyzed for free WR-1065 by reverse-phase HPLC and electrochemical detection 30 and 60 min after administration. Following intravenous administration, plasma WR-1065 levels peaked rapidly and showed a bi-exponential decline, while following subcutaneous administration WR-1065 levels rose slowly and declined exponentially. The relative plasma bioavailability of WR-1065 given subcutaneously was lower at 30 and 60 min. Interestingly, after 30 min, tissues showed equal or slightly greater concentrations of WR-1065 following subcutaneous administration. Levels following 60 min were comparable following both routes. The plasma bioavailability studies performed in primates confirm human plasma data. Expanding the study to evaluate primate tissue levels of WR-1065 revealed that despite lower plasma bioavailability following subcutaneous administration, tissue levels of the active metabolite were surprisingly greater than or equal to those measured in animals that received the drug intravenously. These studies strengthen the argument for subcutaneous administration of amifostine in radiation oncology.

Amifostine↗

PubMedDate not supplied

Pharmacokinetics of insulin. Implications for continuous subcutaneous insulin infusion therapy.

This review considers subcutaneous insulin pharmacokinetics, with emphasis on those aspects relevant to subcutaneous insulin infusion devices. These devices are in increasing use for diabetes therapy, although reliable data on subcutaneous insulin absorption is required to optimise their programming. Techniques for obtaining and interpreting pharmacokinetic data are considered. Recent studies would suggest that it is possible to simulate the major physiological fluctuations in blood insulin levels via continuous subcutaneous insulin infusion, combined with appropriate bolus insulin delivery. Most insulin infused subcutaneously will reach the systemic circulation, and in the majority of diabetics, subcutaneous insulin degradation is low. However, the absorption rate is slow and it may take 6 to 8 hours to reach a steady-state following a change in the subcutaneous infusion rate. Thus there is little to be gained from hour by hour adjustments to the basal insulin infusion rate. Basal rate supplementation, and meal insulin requirements, are best met by bolus delivery. It is particularly important to provide increased systemic delivery of insulin with the start of a meal. The most appropriate adjustment for additional exercise may be a small reduction in the preceding meal bolus, rather than a reduction in the basal rate. Studies of the pharmacokinetics of insulin are an important contributing factor to the optimisation of subcutaneous insulin infusion therapy.

Absorption↗

PubMed1991

Intravenous insulin infusion to simulate subcutaneous absorption. Bioavailability and metabolic sequelae.

OBJECTIVE: To determine the bioavailability and bioactivity of subcutaneously injected insulin. RESEARCH DESIGN AND METHODS: A randomized block design with six male mongrel dogs as subjects. In protocol 1, purified pork insulin was infused intravenously to simulate the pattern of appearance in the blood that would have been expected from subcutaneous injection. Three intravenous doses (0.05, 0.10, and 0.15 U/kg) were infused on separate days in a pattern (0-300 min) designed to approximately simulate the absorption rate of subcutaneously injected insulin. In protocol 2, interscapular subcutaneous injections of pork insulin at 0.10 U/kg were made. RESULTS: Integrated insulin, decrement in plasma glucose, and maximal glucose clearance for subcutaneous injection experiments were similar to intravenous infusion of equal dose (P greater than 0.10) but significantly different from low-dose infusions (P less than 0.025). Similar results were observed for hepatic glucose output and glucose uptake. Hypoglycemia elicited counterregulatory responses that appeared to be under a threshold differentiated at a plasma glucose of approximately 3 mM. Integrated insulin was plotted against insulin dose to create dose-response curves for intravenous data. The curve was then used to predict the actual appearance rate of insulin in plasma for subcutaneous injection. The estimated bioavailability of subcutaneous insulin was 103.0 +/- 10.5% of the injected dose. CONCLUSIONS: We concluded that, in dogs, insulin delivered subcutaneously in the interscapular area is not significantly degraded before absorption, resulting in metabolic effects equal to intravenous insulin infusion of equivalent dose.

Animals↗

PubMed1996

Acute effects of intraperitoneal versus subcutaneous insulin delivery on glucose homeostasis in patients with NIDDM. Veterans Affairs Implantable Insulin Pump Study Group.

OBJECTIVE: The objective of this study is to compare the effect of intraperitoneal versus subcutaneous insulin injection on hepatic glucose production (HGP) and systemic glucose utilization (Rd) in patients with NIDDM. RESEARCH DESIGN AND METHODS: Eight male volunteers with NIDDM, each of whom had a programmable-rate, implantable insulin pump, were given an injection of insulin (0.15 units/kg body wt) by intraperitoneal or subcutaneous injection on separate days in randomized order. Plasma glucose was kept constant for 5 h using the glucose clamp technique, and HGP and Rd were measured using isotope dilution. RESULTS: Intraperitoneal insulin injection resulted in higher and earlier peak systemic insulin concentrations (1,469 +/- 245 vs. 454 +/- 48 pmol/l, P < 0.01). Glucose Rd doubled within 1 h after intraperitoneal injection and was greater than that attained with subcutaneous injection (3.91 +/- 0.27 vs. 2.60 +/- 0.19 mg.kg-1.min-1, P < 0.01). Intraperitoneal and subcutaneous injections suppressed HGP and plasma free fatty acid to a similar extent during the first 3 h, effects tht persisted through 5 h after subcutaneous insulin injection but waned 3-4 h after intraperitoneal injection. CONCLUSIONS: In patients with NIDDM, intraperitoneal insulin injection achieves more rapid and greater peak values for stimulation of glucose Rd than subcutaneous insulin injection. With regard to HGP and lipolysis, intraperitoneal and subcutaneous injections achieve similar initial suppression but this is maintained for a more limited duration with intraperitoneal as compared with subcutaneous injection. These differences in insulin action seem directly related to the rapidity of insulin absorption with intraperitoneal injection.

Blood Glucose↗

PubMed2003

Dose-response relationships of inhaled insulin delivered via the Aerodose insulin inhaler and subcutaneously injected insulin in patients with type 2 diabetes.

OBJECTIVE: To compare the dose-response relationship following inhalation of regular insulin delivered via the Aerodose insulin inhaler with that following subcutaneously injected regular insulin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Twenty-four patients with type 2 diabetes (21 nonsmoking men, aged 36-80 years) each received two of three doses of 80, 160, or 240 units inhaled regular insulin, delivered via a clinical Aerodose insulin inhaler, and two of three corresponding doses of 8, 16, or 24 units by subcutaneous injection under isoglycemic clamp conditions on 4 separate study days in an incomplete block design study. Glucose infusion rates (GIRs) and serum insulin concentrations were monitored over the following 8 h. RESULTS: Inhaled insulin exhibited significantly shorter time-to-peak insulin levels (T(max) 77 +/- 66 vs. 193 +/- 104 min, P < 0.001) and time-to-peak metabolic effects (T(GIRmax) 240 +/- 94 vs. 353 +/- 60 min, P < 0.001) compared with subcutaneously injected insulin. Comparison of total insulin absorption (insulin area under the curve [AUC]) versus total metabolic effect (GIR-AUC) from 0 to 8 h (group means) revealed overlapping dose-response relationships for both inhaled and subcutaneous injection treatments. Comparison of slopes revealed no significant differences between the inhaled and subcutaneous injection treatment groups (P = 0.6). No significant differences in either relative bioavailability or relative biopotency were found among doses, indicating a consistent subcutaneous injection-to-inhaled dosing conversion ratio among doses. No serious adverse events or clinically relevant changes in lung function were observed. CONCLUSIONS: The overlapping dose-response curves of inhaled and subcutaneous treatments together with a consistent relative bioavailability and relative biopotency for inhaled insulin across doses suggest that the Aerodose insulin inhaler will deliver a pharmacologically predictable insulin dose to patients with diabetes similar to that observed following subcutaneous injection.

Administration, Inhalation↗