Supramolecular approaches for insulin stabilization without prolonged duration of action

Aggregation represents a significant challenge for the long-term formulation stability of insulin therapeutics. The supramolecular PEGylation of insulin with conjugates of cucurbit[7]uril and polyethylene glycol (CB[7]‒PEG) has been shown to stabilize insulin formulations by reducing aggregation propensity. Yet prolonged in vivo duration of action, arising from sustained complex formation in the subcutaneous depot, limits the application scope for meal-time insulin uses and could increase hypoglycemic risk several hours after a meal. Supramolecular affinity of CB[7] in binding the B1-Phe residue on insulin is central to supramolecular PEGylation using this approach. Accordingly, here we synthesized N-terminal acid-modified insulin analogs to reduce CB[7] interaction affinity at physiological pH and reduce the duration of action by decreasing the subcutaneous depot effect of the formulation. These insulin analogs show weak to no interaction with CB[7]‒PEG at physiological pH but demonstrate high formulation stability at reduced pH. Accordingly, N-terminal modified analogs have in vitro and in vivo bioactivity comparable to native insulin. Furthermore, in a rat model of diabetes, the acid-modified insulin formulated with CB[7]‒PEG offers a reduced duration of action compared to native insulin formulated with CB[7]‒PEG. This work extends the application of supramolecular PEGylation of insulin to achieve enhanced stability while reducing the risks arising from a subcutaneous depot effect prolonging in vivo duration of action.

Custo-minimização da troca entre imunoglobulinas de diferentes vias e marcas: sustentabilidade relacionada ao tratamento na saúde suplementar / Cost minimizing the switching between immunoglobulin of different routes and brands: of treatment-related in the supplementary health

Objetivo: Avaliar custo-minimização da troca entre as versões intravenosa (IVIg) e subcutânea (SCIg) das imunoglobulinas (Ig) em operadora de saúde com mais de 500.000 vidas. Métodos: Estudo retrospectivo, transversal, descritivo, seguido de custo-minimização entre os pacientes que utilizaram IVIg, de 1º de outubro de 2018 a 30 de setembro de 2019. Simulou-se a troca entre as IVIg e SCIg, objetivando descrever a economia de uma hipotética substituição. Estabeleceram-se como critérios de exclusão: o não pagamento e a liberação com dose acima de 60.000 mg. Após exclusão, calcularam-se as despesas totais, somando-se os custos do produto e taxas de infusão. Resultados: Evidenciou-se que 133 pacientes, totalizando 1.175 liberações, utilizaram IVIg no período avaliado. Identificou-se a utilização de 34.797.500 mg de IVIg, por 10 especialidades, totalizando R$ 12.408.192,50 de despesas. Quando aplicada simulação, há uma potencial economia de recursos de até 29,83%, dependendo da SCIg escolhida. Conclusão: A análise econômica no tratamento com imunoglobulinas evidenciou significativa relevância, pois contribui com o uso adequado da terapêutica garantindo a sustentabilidade do sistema de saúde. Medicamentos subcutâneos apresentam-se como uma opção custo-minimizatória em comparação ao tratamento intravenoso para saúde suplementar brasileira.

Objective: Cost-minimization evaluation of the switch from intravenous (IVIg) to subcutaneous (SCIg) immunoglobulin (Ig) in a Brazilian Health Maintenance Organization (HMO), with more than 500.000 lives. Methods: This is a retrospective, transversal and descriptive study, followed by a cost-minimization analysis among patients using IVIg between 2018, October, 1st and 2019, September, 30th. The simulation was performed supposing the exchange from IVIg to SCIg, in order to calculate possible savings. Exclusion criteria: non-payment (gloss), and infusions with doses above 60.000 miligrams. After exclusion, total expenditures were calculated by summing product and infusion costs. Results: There were133 patients, with1,175 IVIg infusion events in the period evaluated. It was identified the use of 34,797,500 milligrams of IVIg, for 10 specialties, with R$ 12,408,192.50 of final expenditure. The simulation previews hypothetical reduction in the final cost of up to 29.83%, depending on the SCIg brand chosen. Conclusion: The economic analysis in the treatment with immunoglobulins showed significant relevance, as it contributes to the appropriate use of therapy ensuring the sustainability of the health system. Subcutaneous drugs are a cost-minimizing option compared to intravenous treatment for Brazilian HMOs.

Comparison of the Effects of 2 Kinds of Administration Routes of Insulin on Related Indexes of Advanced Age Patients with Gestational Diabetes Mellitus / 中国药房

OBJECTIVE:To compare the effects of repeated subcutaneous insulin administration vs. insulin pump continuous subcutaneous administration on related indexes of advanced age patients with gestational diabetes mellitus(GDM). METHODS:Inretrospective study,120 advanced age patients with GDM were randomly divided into group A(60 cases)and group B(60 cases). Group A was given Insulin aspart injection with initial dose of 0.5 U/(kg·d)subcutaneously before meal,adjusted according to fast-ing blood glucose(FPG)and postprandial 2 h blood glucose(2 hPG),and then given Isophane protamine biosynthetic human insu-lin injection with initial dose of 0.5 U/(kg·d)subcutaneously at bedtime,adjusted according to FPG and 2 hPG. Group B was giv-en Insulin aspart injection with initial dose of 0.5 U/(kg·d)added into insulin pump using 40% of total daily insulin as basic pump,increasing to 60% of total daily insulin if blood glucose control was poor,adjusted according to FPG and 2 hPG. Treatment course of 2 groups lasted for 4 weeks. The time of blood glucose reaching target,the amount of insulin were observed in 2 groups, and the levels of FPG,2 hPG,HbA1c,Hcy and Cys-C before and after treatment,the occurrence of patients and neonates compli-cations. RESULTS:The time of blood glucose reaching standard in group B was significantly shorter than group A;the amount of insulin,the incidence of hypoglycemia,premature birth,excessive amniotic fluid and gestational hypertension in group B were sig-nificantly lower than group A,with statistical significance(P0.05). After treatment,the levels of FPG,2 hPG,HbA1c,Hcy and Cys-C in 2 groups were significantly lower than before treatment,and the group B was significantly lower than the group A, with statistical significance(P<0.05). CONCLUSIONS:The insulin pump continuous subcutaneous administration is significantly better than repeated subcutaneous insulin administration in respects of controlling glucose level,reducing the amount of insulin,the levels of Cys-C and Hcy,maternal and neonatal complications.

Frequency of Serious Adverse Skin Reactions Caused by Continuous Subcutaneous Administration of Psychotropic Drugs

Continuous subcutaneous injections of medication are effective in controlling symptoms of the terminal stage of cancer. Chlorpromazine and levomepromazine occasionally cause skin irritation. We examined all patients who underwent continuous subcutaneous administration of psychotropic drugs (chlorpromazine, levomepromazine, midazolam) at the palliative care unit of our hospital from April 2010 to March 2013, the frequency of adverse skin reactions of Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade 3 or above. Of the 603 hospitalized patients, 389 (64.5%) underwent continuous subcutaneous administration of one of the three drugs. The frequency of grade 3 or above (ulceration or necrosis) adverse skin reactions was 4 out of 345 chlorpromazine cases (1.2%; 95% CI: 0.0-2.3%), 2 out of 90 levomepromazine cases (2.2%; 95% CI: −0.8-5.2%), and 0 out of 210 midazolam cases (0.0%; 95% CI: 0.0-0.0%). The frequency of serious adverse skin reactions caused by continuous subcutaneous administration of psychotropic drugs was low, suggesting that this treatment is relatively safe for the skin.

Comparison of the effect of ultrashort and short -acting insulin after subcutaneous insulin infusion pump un-der glucose monitoring in treatment of diabetes / 中国基层医药

Objective To investigate the efficacy of ultrashort and short-acting insulin after subcutaneous insulin infusion pump under glucose monitoring in treatment of diabetes.Methods 110 cases with type 2 diabetes were selected,they were randomly divided into two groups with a random number table:the study group and the control group,55 cases in each group.The study group was treated with short -acting insulin after subcutaneous injection of insulin pump,the control group was treated with short -acting subcutaneous insulin infusion by insulin pump therapy, glucose monitoring system was used to monitor glucose during treatment of the two groups.The clinical efficacy after a month of treatment was observed.Results Before treatment,fasting blood glucose(FPG),postprandial 2 h blood glucose(2h PG),bedtime blood glucose of the two groups had no statistically significant differences.After treatment, FPG and 2hPG,bedtime blood glucose in the study group were (6.01 ±1.06)mmol/L,(7.90 ±0.50)mmol/L, (7.13 ±0.95)mmol/L respectively,which of the control group were (5.98 ±1.04)mmol/L,(7.91 ±0.48)mmol/L, (7.14 ±0.94)mmol/L,which were significantly lower than before treatment (t =9.843,23.669,13.569,9.683, 22.881,13.710,P 0.05).The blood glucose time and insulin dosage in the study group were (5.59 ±1.30)d,(39.98 ±11.01)u/d,which of the control group were (6.98 ±1.40)d,(51.89 ±11.97)u/d,and there were significant differences between the two groups(t =1.825,5.431,P <0.05).The mean blood glucose,blood glucose standard deviation,time percentage of blood glucose≥10 mmol/L,time percentage of blood glucose≤3.9 mmol/L in the study group were (5.95 ±0.61 )mmol/L, (1.28 ±0.25)mmol/L,(14.16 ±2.13)%,(6.35 ±1.45)%,which in the control group were (6.59 ±0.94)mmol/L, (1.54 ±0.29)mmol/L,(15.15 ±2.14)%,(7.96 ±1.42)% respectively,and the differences were statistically significant between the two groups(t =4.236,503.6,2.432,5.883,P <0.05).Conclusion Glucose monitoring system in monitoring blood glucose is accurate and reliable,ultra -short -acting insulin after subcutaneous insulin pump infusion in treatment of diabetes is better than short -acting insulin.

Successful Pain Management for the Postherpetic Neuralgia of Ophthalmic Nerve by Continuous Subcutaneous Infusion of Ketamine: A case report / 대한마취과학회지

A 25-year-old woman transferred to pain clinic complaining of severe throbbing eye ball pain, eyelid edema and severe tearing in her left eye under the diagnosis of herpes zoster ophthalmicus that was developed 3months ago. In addtion to conventional medication, she had been taken stellate ganglion block, supraorbital and supratrochlear nerve block to contol of pain, but the response was poor. So we tried to administer ketamine subcutaneously, because not only ketamine, NMDA receptor antagonist, played a significant role to reduce neuropathic pain and pain caused by nerve injury, but also she wanted to work in her office during the treatment. We used subcutaneous ketamine 3 mg/hr (0.06 mg/kg/hr) in patient with postherpetic neuralgia of the ophthalmic nerve, and accomplished almost complete pain relief without any sign of side effect.

The Neuromuscular blocking Effect of Subcutaneous Administration of Succinylcholine / 대한마취과학회지

Succinylcholine is commonly administered intravenously, however sometimes it can be administered intramuscularly or sublingually when an intravenous line is not available. We investigated the neuromuscular blocking effect of subcutaneous injection of succinylcholine. The 60 adult patients (ASA 1 or 2) were randomly divided into two groups. After intravenous administration of propofol 3 mg/kg, succinylcholine 1 mg/kg was administered intravenously in one group (IV group, n=10) and subcutaneously in another (SQ group, n=50). Neuromuscular transmission was monitered continuously by the train-of-four (TOF) from response stimulated the ulnar nerve with 2Hz at wrist and the evoked compound action potential of hypothenar muscles was measured with Relaxograph (Datex Co.). We determined the maximum depressed the twitch height (T(TXD)), onset time from injection of succinylcholine to T(MXD), recovery time from T(MXD) to the recovery of 75%, and duration of action from injection of succinylcholine to the recovery of 75%. In the results, T(MXD) of SQ group varied from O% to over 75% compared with 0% in IV group. The onset time of SQ group were more delayed between 7.78+/-2.80 to 13.08+/-3.51 minutes compared with 1.08+/-0.16 minutes in IV group. The recovery time of SQ group were faster between 15.67+/-10.40 to 2.59+/-1.75 minutes compared with 18.68+/-3.68 minutes in IV group. The duration of action of SQ group were not significantly different compared with IV group. And in the SQ group, the lesser depression of twitch height the slower onset time and the faster recovery time was revealed. Conclusively, the subcutaneous administration of succinylcholine 1 mg/kg resulted that the magnitudes of neuromuscular blockade was variable and incomplete, and onset time were slower but recovery were faster than intravenous injection.