Absorption kinetics and biologic effects of subcutaneously injected insulin preparations

This paper describes systematic studies on the absorption kinetics of exogenous insulin from its subcutaneous tissue depot in 52 male nonobese volunteers (age 20-30 yr). Five experimental protocols were used: effect of changing injection site, effect of temperature change and local massage, effect of aprotinin and human serum, effect of mixing regular insulin with long-acting insulin preparations, and effect of temperature change, muscular exercise, and local massage on the absorption of long-acting insulin preparations. The fastest absorption of insulin occurred at the abdominal injection. Absorption after arm injection was faster than after thigh injection. A hot bath and local massage dramatically increased serum insulin levels in the first 90 min after injection; in contrast, a cold bath delayed absorption substantially. Both aprotinin and the subjects' own blood serum mixed with insulin caused a marked acceleration of the insulin absorption process. Absorption kinetics of two neutral regular insulins (Actrapid and Leo Regular) were virtually identical. Mixing Actrapid with Monotard caused higher serum insulin levels than the mixture of Leo Regular with NPH. A time lag of 5 min between the mixing of Actrapid and Monotard and the injection caused a delayed rise of serum insulin levels; in contrast, this delay could not be observed when Leo Regular and NPH were mixed. Volunteers performed bicycle exercise, applied a hot water bottle to the injection site, or rubbed the injection site 2 1/2 h after injection of long-acting insulin. Accelerated absorption of insulin was only observed after local massage of the injection site of Monotard, Leo NPH, and Mixtard. Local heat had no effect. Exercise caused only an increased absorption of insulin after the Mixtard injection but not after Monotard or NPH injection. These findings have clinical significance and should not be without potential benefit in the attempt to improve metabolic control in insulin-treated diabetic patients.     

Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin

OBJECTIVE: This study compares the time-action profile of inhaled insulin (INH; Exubera) with that of subcutaneously injected insulin lispro (ILP) or regular human insulin (RHI) in healthy volunteers. RESEARCH DESIGN AND METHODS: In this open-label, randomized, three-way, crossover study, 17 healthy male volunteers were given each of the following treatments in random order: INH (6 mg), ILP (18 units), or RHI (18 units). Glucose infusion rates and serum insulin concentrations were monitored over 10 h. RESULTS: INH had a faster onset of action than both RHI and ILP, as indicated by shorter time to early half-maximal effect (32 vs. 48 and 41 min, respectively; P < 0.001 for IHN vs. RHI and P < 0.05 for IHN vs. ILP). Time to maximal effect was comparable between INH and ILP (143 vs. 137 min; NS) but was shorter for INH than RHI (193 min; P < 0.01). The maximal metabolic effect of INH was comparable with RHI but lower than ILP (8.7 vs. 9.8 vs. 11.2 mg . kg(-1) . min(-1), respectively; P < 0.01 for INH vs. ILP). The duration of action of INH, indicated by time to late half-maximal effect (387 min), was longer than ILP (313 min; P < 0.01) and comparable to RHI (415 min; NS). Total glucodynamic effect after inhalation of INH was comparable to both ILP and RHI (NS). Relative bioefficacy of INH was 10% versus RHI and 11% versus ILP. No drug-related adverse events were observed. CONCLUSIONS: INH had a faster onset of action than RHI or ILP and a duration of action longer than ILP and comparable to RHI. These characteristics suggest that inhaled insulin is suitable for prandial insulin supplementation in patients with diabetes.     

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.     

Massage-induced release of subcutaneously injected liposome-encapsulated drugs to the blood

Liposome-based, externally regulated drug delivery system is described in which liposome-encapsulated bioactive molecules can be delivered into the blood in response to simple mechanical action. Without any mechanical stimulation, subcutaneously injected 200 nm liposomes are usually trapped in the interstitial space for prolonged time. However, upon lymphotropic stimulation (such as manual massage of the injection site), the liposomes can be mobilized into the blood via lymphatic pathway. Up to 40% of the injected dose can be delivered to the blood via lymphatic pathway from the injection site at the rabbit's front paw dorsum during 5 min manual massage cycle. Using vasoconstricting hormone angiotensin II as liposome-encapsulated pharmacological marker, we demonstrated that physiological response to encapsulated drug (average blood pressure increase) can also be induced and modulated by massage. Massage itself was found to have no effect on the blood pressure. Modification of liposome surface with polyethylene glycol was found to increase blood localization of the liposome-encapsulated drug presumably due to decreasing the uptake of the drug carrier by lymph node macrophages. Pressure-dependent gaps between lymphatic capillary endothelial cells are thought to play the role of the size discrimination device allowing larger particulates into the lymphatics and, eventually, into the blood after increase of interstitial pressure caused by injection site massage.     

Ataxia and cranial neuropathies from subcutaneously injected elemental mercury

CONTEXT.?Although neurological toxicity from elemental mercury vapor and organic mercury exposure has been commonly reported in the literature, it is rarely reported from soft tissue injection of elemental mercury. We present a case of neurological dysfunction from subcutaneous injection of elemental mercury. CASE DETAILS.?A 35-year-old Latin American man subacutely developed gait ataxia, diplopia, and vomiting 1 year after subcutaneous injection of elemental mercury, a practice common in Afro-Caribbean and Latin-American cultures. Physical examination showed an indurated plaque on his right shoulder at the injection site, left third nerve and bilateral sixth nerve palsies, nystagmus, dysarthria, and gait and limb ataxia. The patient's serum and 24-h urine mercury levels were significantly elevated; he underwent excision of the mercury reservoir and chelation with dimercaptosuccinic acid but experienced only mild improvement after 1 year. DISCUSSION.?Neurological sequelae from elemental mercury, specifically cognitive dysfunction, tremor, cortical myoclonus, and peripheral neuropathy, have been reported but cranial neuropathies, ataxia, cerebrospinal fluid pleocytosis, and the presence of anti-Purkinje cell type-Tr antibody have not. Treatment involves removal of any existing mercury reservoir and chelation; however, improvement in neurological dysfunction after treatment has rarely been reported in the literature.     

Absorption of subcutaneously infused insulin: influence of the basal rate pulse interval

Eight insulin-dependent diabetic patients were given two constant infusions (each 1 IU/h) of 125I-labeled insulin into the abdominal subcutaneous tissue for about 12 h. Insulin was infused in pulses into one side of the abdomen in 6-min intervals (by means of an Auto-Syringe pump) and in the other side of the abdomen, insulin was infused in 1-h intervals (by means of a Medix pump). The size of the subcutaneous depots was continuously measured by counting the radioactivity at the infusion sites. After starting the infusions, the two depots were built up to steady-state levels at the same time and of the same size (approximately 3 IU) and with similar absorption rates. Thus, during basal rate insulin infusion, identical insulin absorption kinetics was achieved, irrespective of a 10-fold difference in the pulse rate.     

经皮下注射超声造影剂在乳腺癌前哨淋巴结诊断中的价值

目的探讨采用经皮下注射超声造影剂声诺维（SonoVue）检测乳腺癌前哨淋巴结（SLNs）并判定其性质的可行性。方法经皮下注射SonoVue对22例乳腺癌患者进行超声造影检查，观察同侧腋窝SLNs的造影增强情况；然后经皮下注射美蓝后手术切除SLNs进行病理学检查。结果22例患者术前超声造影发现SLNs32个，其中29个超声造影对其转移与否进行了准确的判断。以手术切除为标准，超声造影对SLNs检出率为91．4％（32／35）。根据造影增强的特点判定SLNs转移与否的敏感性、特异性和准确性分别为90．9％、90．5％和91．0％。结论经皮下注射SonoVue可较好地检测出SLNs并准确地判断其转移与否，具有很高的临床应用价值。     

经皮下注射超声造影剂在乳腺肿块前哨淋巴结检测中的应用价值

目的 探讨经皮下注射超声造影剂(SonoVue)在检测乳腺癌患者前哨淋巴结(SLN)中的应用价值.方法 对常规超声检出的42例乳腺肿块患者经皮下肿块边缘3、6、9、12点各注射1.25 m1SonoVue,观察同侧腋窝SLN的造影增强情况,记录淋巴管开始增强时间、增强淋巴结个数、部位、淋巴结开始增强时间、消退时间.并与美兰染色及病理对照,比较造影对SLN检出的准确性.结果 42例乳腺肿块患者术前超声造影成功检出SLN 30例,检出率71.4%.良性肿块10例,检出SLN 5例,检出率50%;乳腺癌32例,检出SLN 25例,检出率78.1%;共检出SLN 40枚,良性5枚,乳腺癌转移淋巴结35枚.美兰染色后检出SLN 39例,检出率92.9%,其中良性肿块10例,检出SLN 7例;乳腺癌32例,美兰全部染色.共检出SLN 64枚,良性11枚,乳腺癌转移淋巴结53枚.结论 经皮下注射SonoVue可较好地检测出SLN,在预测乳腺癌淋巴结是否转移中有一定的应用价值.     

诺和笔注射胰岛素剂量准确性的影响因素研究

[目的]探讨应用诺和笔注射胰岛素时影响剂量准确性的因素,更好地保证注射剂量的准确性.[方法]随机抽取60例住院糖尿病病人,先后采用四种不同的方式注射胰岛素,分别对注射后停留时间,不同注射部位及局部皮肤是否捏起等方面进行观察.[结果]停留不同的时间及选择不同的注射部位所得结果之间的差异具有显著性,而局部皮肤是否捏起所得结果之间的差异无显著性.[结论]延长停留时间或者选择腹部注射能有效减少针头滴液,保证胰岛素注射剂量的准确性,而局部皮肤是否捏起对胰岛素注射剂量的影响不大.     

Nociceptive effect of subcutaneously injected interleukin-12 is mediated by endothelin (ET) acting on ETB receptors in rats

Interleukin-12 (IL-12) is an inflammatory Th1-driving cytokine that has been clinically used as immune therapy and vaccine adjuvant. Recently, it was reported that patients receiving IL-12 presented hyperalgesia. In the present study, we investigated the mechanical hyperalgesic effect of IL-12 in rats using two tests: 1) paw constant pressure and 2) electronic pressure-meter. In both tests, intraplantar administration of IL-12 (3-30 ng paw(-1)) caused a dose- and time-dependent mechanical hyperalgesia, which peaked between 3 to 5 h, remaining significantly different from control levels until 7 h and resolved 24 h postinjection. However, the same doses of IL-12 did not induce thermal hyperalgesia, determined using the Hargreaves test. Pretreatments with effective doses of indomethacin (2.5 mg kg(-1)), atenolol (1 mg kg(-1)), 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimethylpropanoic acid, sodium (MK886) (5-lipoxygenase activating protein inhibitor; 1 mg kg(-1)), or cyclo[(D)Trp-(D)Asp-Pro-(D)Val-Leu] (BQ123) [endothelin (ET)(A) receptor antagonist; 30 nmol paw(-1)] did not inhibit IL-12-evoked mechanical hyperalgesia (10 ng paw(-1)). However, dexamethasone (2 mg kg(-1)), morphine (3-12 microg paw(-1)), and N-cys-2,6 dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarboyl-d-norleucine (BQ788) (ET(B) receptor antagonist; 3-30 nmol paw(-1)) did inhibit IL-12 hyperalgesia. Furthermore, neither pretreatment with effective doses of antiserum against rat-TNF-alpha (50 microl paw(-1)) nor against IL-18 (10 microg paw(-1)) inhibited the IL-12-induced hyperalgesia. Likewise, antiserum against IL-12 (10 ng paw(-1)) did not alter IL-18-induced hyperalgesia. In conclusion, we demonstrated for the first time that IL-12 is a prohyperalgesic cytokine that induces mechanical hyperalgesia mediated by endothelin action on the ET(B) receptor. Therefore, endothelin receptor antagonism could be beneficial in controlling IL-12 therapy-induced pain or hyperalgesia.     

Combined inhibin and CA125 assays in the detection of ovarian cancer

BACKGROUND: The reproductive hormone inhibin has been used as a diagnostic marker of ovarian mucinous and granulosa cell cancers. The aims of this study were to develop a new inhibin immunofluorometric assay (alphaC IFMA) to replace an inhibin RIA as a diagnostic marker of these ovarian cancers and to assess whether the alphaC IFMA in combination with CA125, which detects serous cancers, leads to an improved biochemical diagnosis of all ovarian cancers. METHODS: Serum inhibin concentrations were determined in healthy postmenopausal women (n = 165) and women with ovarian cancers (n = 154), using an inhibin RIA and an alphaC IFMA, which detects inhibin forms containing the alphaC subunit as well as the free alphaC subunit. RESULTS: The alphaC IFMA gave a similar or better discrimination of mucinous (90% vs 71%) and granulosa cell (100% vs 100%) cancers compared with the inhibin RIA. Combination of CA125 and alphaC IFMA values by canonical variate analysis or by multiROC analysis showed that the percentage of all ovarian cancers detected was significantly increased compared with either CA125 or alphaC IFMA alone. CONCLUSIONS: The alphaC IFMA shows a similar or better specificity compared with the RIA, but with increased sensitivity. In combination with CA125, the alphaC IFMA provides an effective dual test for the detection of the majority (90%) of ovarian cancers.     

不同注射方法对胰岛素注射剂量准确性影响的研究

目前,糖尿病已经成为危害人类健康的第三大杀手[1],皮下注射胰岛素是治疗糖尿病的主要方法之一,而注射剂量的准确性是保证疗效的前提。临床经常使用的人型胰岛素一般为3mL含300U胰岛素,0.1mL含10U胰岛素,因此对注射剂量的准确性要求高,一般使用专用的注射用笔,如诺和灵笔等。但是临床操作中发现,使用诺和笔注射胰岛素时虽然按使用说明要求操作,拔针后针头滴液现象(注射针头有胰岛素药滴凝集或滴下)发生率很高。针头滴液的胰岛素量每滴约1U,有时可达3滴或4滴,每单位胰岛素能对抗葡萄糖6g,而且每次针头滴液量有差异,使血糖波动很明显。我科…     

不同注射方法对胰岛素注射剂量准确性影响的研究

目前，糖尿病已经成为危害人类健康的第三大杀手，皮下注射胰岛素是治疗糖尿病的主要方法之一，而注射剂量的准确性是保证疗效的前提。临床经常使用的人型胰岛素一般为3mL含300U胰岛素，0．1mL含10U胰岛素，因此对注射剂量的准确性要求高，一般使用专用的注射用笔，如诺和灵笔等。但是临床操作中发现，使用诺和笔注射胰岛素时虽然按使用说明要求操作，拔针后针头滴液现象（注射针头有胰岛素药滴凝集或滴下）发生率很高。     

B型钠尿肽和CA125联合检测在呼吸困难鉴别诊断中的临床价值

目的探讨B型钠尿肽(BNP)、糖链抗原125(CA125)联合检测在呼吸困难病因诊断中的临床价值。方法选择心源性呼吸困难患者106例、肺源性呼吸困难患者56例、健康者60例,在患者入院时检测血浆BNP、CA125水平。另比较心源性呼吸困难患者治疗前后血浆BNP、CA125水平。结果心源性呼吸困难患者BNP、CA125水平高于肺源性呼吸困难患者和健康者,呼吸困难患者明显高于健康者(P0.05);随着心力衰竭病情的加重,BNP与CA125水平逐渐升高;BNP、CA125联合检测对心源性、肺源性呼吸困难的鉴别诊断价值高于单独检测(P0.05);心源性呼吸困难患者治疗前后BNP和CA125水平比较差异有统计学意义(P0.05)。结论 BNP和CA125联合检测有较高的特异度和灵敏度,有助于鉴别心源性、肺源性呼吸困难,判断心力衰竭程度、动态观察病情,值得推广应用。     

CA125检测在妇科疾病诊断及鉴别诊断中的作用

目的探讨糖链抗原(CA)125在临床常见妇科疾病诊断中的应用价值。方法采用电化学发光免疫分析法检测821例女性血清CA125水平。结果体检健康者(对照组)血清CA125水平均小于临界值;卵巢癌组为(740.87±1 180.03)U/mL,高于对照组(P<0.05)。宫颈癌组、子宫内膜癌组、子宫肌瘤组、子宫腺肌症组、卵巢囊肿组血清CA125水平高于对照组(P<0.05),子宫内膜息肉组、宫颈炎组与对照组比较差异无统计学意义(P>0.05)。恶性病变中,卵巢癌组与宫颈癌组比较差异有统计学意义(P<0.05),与子宫内膜癌组比较差异有统计学意义(P<0.05);宫颈癌组与子宫内膜癌组比较差异无统计学意义(P>0.05)。良性病变中,子宫肌瘤组与宫颈炎组、子宫内膜息肉组与宫颈炎组比较差异无统计学意义(P>0.05),其余各组比较差异有统计学意义(P<0.05)。恶性病变与良性病变比较,卵巢癌组与子宫腺肌症组比较差异无统计学意义,宫颈癌组与子宫肌瘤组、宫颈炎组比较差异无统计学意义,子宫内膜癌组与卵巢囊肿组、宫颈炎组比较差异无统计学意义(P>0.05),其余各组比较差异有统计学意义(P<0.05)。结论 CA125检测在临床妇科疾病诊断和鉴别诊断中具有一定的价值。     

Spontaneous disappearance of gallstones

A case of spontaneous disappearance of gallstones in a 55-year-old woman is presented. Examination of biliary lipids after the stones had disappeared revealed supersaturated bile with cholesterol. This suggests that the stones migrated from the gallbladder to the small intestine via the biliary ductal system.     

Pattern of insulin delivery after intravenous glucose injection in man and its relation to plasma glucose disappearance.

Plasma insulin concentrations after pulse intravenous injection of glucose show an early rise, which declines towards the prestimulation level smoothly. This pattern is the effect of both continuing secretion and hormone disappearance from the plasma. To reconstruct the time-course of the acutal secretory response, we measured insulin disappearance from the plasma of 17 healthy volunteers by means of a bolus intravenous injection of 125I-insulin, and then performed an intravenous glucose tolerance test with frequent blood sampling. The data were analyzed by deconvolution, which made it possible to compute the glucose-induced posthepatic insulin delivery rate minute by minute. Under basal conditions, 2.64 +/- 0.28 (mean +/-SEM) mU/min.m2 reaches the systemic circulation. In the 90 min that follow acute glucose stimulation, 0.86 +/- 0.11 U/m2, a 270% increment over the basal production rate, is made available to the periphery. A wide individual variability was found to exist in both the basal and the glucose-stimulated delivery. They were strongly (P less than 0.001) related to each other in a direct fashion. A first spike of insulin release (107 +/- 12 mU/min) occurred in all the subjects at 2.2 +/- 0.2 min followed, in 16 subjects, by a second spike (38 +/- 6 mU/min), at 11.3 +/- 0.9 min. Two-thirds of the total postglucose insulin output were associated with the initial, oscillatory phase (from 0 to 25 min, on average), and one-third with the "tail" phase (from 25 to 90 min), during which the average delivery rate was 5.0 +/- 0.9 mU/min.m2. The delivery curves were closely (mean squared deviation of 4.5 +/- 0.5 mU/min) reproduced by computer stimulation upon assuming that insulin secretion is a function of both glucose concentration and glucose rate of change. Both the first and the second spike of insulin delivery, but not the total insulin output during the test, showed a significant, positive correlation with the plasma glucose disappearance rate computed between 10 and 60 min. Furthermore, with a time shift of approximately equal to 15 min, a significant relationship between the phases of insulin secretion and the glucose decay rates, computed over corresponding time intervals, was evident throughout the test.