Substitution Therapy Research Articles

Barriers to management of opioid withdrawal in hospitals in England: a document analysis of hospital policies on the management of substance dependence

BackgroundPeople who use illicit opioids are more likely to be admitted to hospital than people of the same age in the general population. Many admissions end in discharge against medical advice, which is associated with readmission and all-cause mortality. Opioid withdrawal contributes to premature discharge. We sought to understand the barriers to timely provision of opioid substitution therapy (OST), which helps to prevent opioid withdrawal, in acute hospitals in England.MethodsWe requested policies on substance dependence management from 135 National Health Service trusts, which manage acute hospitals in England, and conducted a document content analysis. Additionally, we reviewed an Omitted and Delayed Medicines Tool (ODMT), one resource used to inform critical medicine categorisation in England. We worked closely with people with lived experience of OST and/or illicit opioid use, informed by principles of community-based participatory research.ResultsEighty-six (64%) trusts provided 101 relevant policies. An additional 44 (33%) responded but could not provide relevant policies, and five (4%) did not send a definitive response. Policies illustrate procedural barriers to OST provision, including inconsistent application of national guidelines across trusts. Continuing community OST prescriptions for people admitted in the evening, night-time, or weekend was often precluded by requirements to confirm doses with organisations that were closed during these hours. 42/101 trusts (42%) required or recommended a urine drug test positive for OST medications or opioids prior to OST prescription. The language used in many policies was stigmatising and characterised people who use drugs as untrustworthy. OST was not specifically mentioned in the reviewed ODMT, with ‘drugs used in substance dependence’ collectively categorised as posing low risk if delayed and moderate risk if omitted.ConclusionsMany hospitals in England have policies that likely prevent timely and effective OST. This was underpinned by the ‘low-risk’ categorisation of OST delay in the ODMT. Delays to continuity of OST between community and hospital settings may contribute to inpatient opioid withdrawal and increase the risk of discharge against medical advice. Acute hospitals in England require standardised best practice policies that account for the needs of this patient group.

Treatment of Acquired Hypothalamic Obesity: Now and the Future.

The hypothalamus is the centre of neuroendocrine regulation of energy homeostasis and appetite. Maldevelopment of, or damage to, the key hypothalamic nuclei disrupts the coordinated balance between energy intake and expenditure leading, to rapid and excessive weight gain. Hypothalamic obesity is compounded by a disruption of the hypothalamic-pituitary axis, sleep disruption, visual compromise, and neurological and vascular sequalae. Amongst suprasellar tumors, craniopharyngioma is the most common cause of acquired hypothalamic obesity, either directly or following surgical or radiotherapeutic intervention. At present, therapy is limited to strategies to manage obesity but with a modest and variable impact. Current approaches include optimizing pituitary hormone replacement, calorie restriction, increased energy expenditure through physical activity, behavioral interventions, pharmacotherapy and bariatric surgery. Current pharmacotherapeutic approaches include stimulants that increase energy consumption, anti-diabetic agents, hypothalamic–pituitary substitution therapy, octreotide, and methionine aminopeptidase 2 (MetAP2) inhibitors. Some pharmacological studies of hypothalamic obesity report weight loss or stabilization but reported intervention periods are short, and others report no effect. The impact of bariatric surgery on weight loss in hypothalamic obesity again is variable. Novel or combined approaches to manage hypothalamic obesity are thus required to achieve credible and sustained weight loss. Identifying etiological factors contributing hypothalamic obesity may lead to multi-faceted interventions targeting hyperphagia, insulin resistance, decreased energy expenditure, sleep disturbance, hypopituitarism and psychosocial morbidity. Placebo-controlled trials using current single, or combination therapies are required to determine the impact of therapeutic agents. A well-defined approach to defining the location of hypothalamic damage may support the use of future targeted therapies. Intranasal oxytocin is currently being investigated as an anorexogenic agent. Novel agents including those targeting pro-opimelanocortin-C and AgRP/NPY expressing neurons and the MC4 receptor may result in better outcomes. This article discusses the current challenges in the management of hypothalamic obesity in children and young people and future therapeutic approaches to increasing weight loss and quality of life in these patients.

Interventions to increase linkage to care and adherence to treatment for hepatitisC among people who inject drugs: A systematic review and practical considerations from an expert panel consultation.

Following advances in treatment for hepatitis C (HCV), optimizing linkage to care and adherence to treatment of people who inject drugs became of pivotal importance. An ECDC/EMCDDA stakeholders survey in 2018 indicated that two components of the cascade of care, linkage to care and adherence to treatment, were priority areas for inclusion in the updated guidance, planned for publication in 2022. This systematic review was commissioned with the aim to evaluate the effectiveness of interventions on HCV linkage to care and adherence to treatment among people who inject drugs. The full study protocol is available at PROSPERO (2020 CRD42020191116). We searched five databases to identify studies published between 2011 and 2020. Studies were included if they had a comparative study design and reported on the primary outcomes for linkage to care (visits, treatment initiation) and/or adherence to treatment (treatment adherence, treatment completion, SVR12) among people who inject drugs/people receiving opioid substitution therapy. Following the risk of bias (EPHPP) and quality of evidence assessment (GRADE), evidence to decision tables were produced and shared for critical review with an expert panel convened by ECDC and EMCDDA. The expert panel provided further considerations on the benefit, acceptability, and transferability of interventions. Fourteen studies (using DAA therapy as well as DAA plus interferon-based therapy) met eligibility criteria and were included in the analysis. Integrated care with case management, peer support, psychological interventions, contingency management, and cooperation between health care providers improved engagement in and adherence to HCV care in most studies. However, the quality of evidence was predominantly low to moderate. Available evidence suggests that integrated, people-centered approaches may improve engagement throughout the continuum of HCV care among people who inject drugs. For progressing HCV elimination efforts, interventions should be implemented in colocation with harm reduction and counselling activities and in combination with additional services, including opioid substitution treatment, directly observed therapy, peer support and/or contingency management.

Influence of psychiatric disorders and opioid substitution therapy on hepatitis C treatment with direct-acting antivirals in people who inject drugs

The effectiveness of the hepatitis C virus (HCV) treatment seems to be lower in people who inject drugs (PWID). We analyze the influence of various factors as psychiatric disorders and opioid substitution therapy (OST) on the treatment with direct-acting antivirals (DAA) in this collective. Three hundred thirty-two PWID patients were treated with DAA in 12 Spanish hospitals between 2004 and 2020. They were catalogued in recent and former consumers (if the last consumption was in the last 3 years) and several variables were included, evaluating the effectiveness of the treatment according to the viral load 12 weeks after the end of the treatment with the parameter “sustained viral response” (SVR12). 23.4% were recent consumers and 27,7% were on OST. 41.5% had any diagnosis of psychiatric disorder. SVR12 was 84.04%, ascending to 96.21% when excluded from the analyses the patients lost to follow-up (12,7%). SVR12 was lower due to an increase in the loss to follow-up in recent consumers and other factors like OST, being in prison the last 5 years, naïve patients, generalized anxiety disorder and benzodiazepine consumption. The effectiveness of the HCV treatment with DAA in PWID is similar than in general population in patients whit an appropriate follow-up. It is important to maintain a closer follow-up in patients on OST, recent consumers and those with psychiatric disorders. La efectividad del tratamiento del virus de la hepatitis C (VHC) parece ser menor en usuarios de drogas por vía parenteral (UDVP). Analizamos la influencia de diversos factores como los trastornos psiquiátricos y la terapia de sustitución con opiáceos (TSO) en el tratamiento con antivirales de acción directa (AAD) de este colectivo. Trescientos treinta y dos pacientes UDVP fueron tratados con AAD en 12 hospitales de España entre 2004 y 2020. Se catalogaron, si se disponía del dato, en consumidores recientes y pasados (según si el último consumo fue en los últimos 3 años) y se recogieron diversas variables, evaluándose la efectividad del tratamiento según la carga viral 12 semanas tras la finalización del tratamiento con el parámetro «respuesta viral sostenida» (RVS12). El 23,4% eran consumidores recientes y el 27,7% estaban en TSO. El 41,5% presentaban algún diagnóstico de enfermedad psiquiátrica. La RVS12 fue del 84,04%, ascendiendo a 96,21% al excluir del análisis a los pacientes que perdieron el seguimiento (12,7%). La RVS12 fue significativamente inferior debido a un aumento de la pérdida de seguimiento en consumidores recientes, aquellos en TSO, los que habían estado en prisión los últimos 5 años y pacientes naive, así como en el trastorno de ansiedad generalizada y consumidores de benzodiacepinas. La efectividad del tratamiento del VHC con AAD en UDVP es similar a la población general si se consigue un adecuado seguimiento. Es importante realizar un seguimiento más estrecho en pacientes en TSO, consumidores recientes y aquellos con patología psiquiátrica.

Efektivitas Antibiotik Inhalasi pada Pasien Ventilator Associated Pneumonia: Kajian Sistematis dan Meta-Analisis

Inhaled antibiotics are adjunct to ventilator-associated pneumonia (VAP) therapy because they are delivered directly to the infection site of the lungs, while intravenous (IV) antibiotics work systematically. The Food and Drug Administration (FDA) and the European Medicine Agency have approved several inhaled antibiotics for cystic fibrosis treatment. However, none have been approved for VAP use, even with supporting evidence. Therefore, this study aimed to evaluate the effect of inhaled antibiotics as adjuvant therapy with IV or substitute in the treatment of VAP. The effect was measured based on clinical cure, microbial cure, and mortality. This study is a literature review and meta-analysis using a randomized control trial (RCT) design. The parameters measured were a clinical cure, microbial cure, and mortality. Furthermore, the literature search was conducted using the PubMed database. The included articles’ quality was assessed using the Critical Appraisal Skill Program (CASP) checklist and the journal’s reputation. Furthermore, 7 studies were included in the final review and meta-analysis. The results showed that the meta-analysis of inhaled antibiotics as adjuvant or substitution therapy is negative on clinical cure rates (RR=1,07; 95% CI=0,86–1,32) and mortality (RR=1,09; 95% CI=0,83–1,43). The analysis of inhaled antibiotics as adjuvant therapy was positive in microbiological cure (RR=1,56; 95% CI=1,13–2,17) but has no benefit as substitution therapy (RR=1,21; 95% CI=0,86–1,71). It can be concluded that using inhaled antibiotics as adjuvant therapy or monotherapy is ineffective in improving the clinical cure rate and mortality of VAP patients while using it as an adjuvant alone can eradicate microbes better.

Protecting the health of people living in Ukrainian detention facilities

Protecting the health of people living in Ukrainian detention facilities

Subclinical hypothyroidism

Subclinical hypothyroidism is usually a laboratory diagnosis without significant symptoms and is defined by an elevated thyroid-stimulating hormone (thyrotropin, TSH) with normal thyroid hormone levels. On laboratory checks after two to three months, spontaneous normalization is found in 50 % of all cases in the sense of a transient elevation.With persistently elevated TSH levels, subclinical hypothyroidism is associated with evidence of thyroid-specific antibodies in the sense of autoimmune thyroiditis. Physiologically higher TSH levels are found in old age. It can therefore be assumed that the diagnosis of subclinical hypothyroidism is made and treated too frequently in older people over 70years of age.Studies have so far failed to show a positive effect of substitution therapy of subclinical hypothyroidism, especially in elderly patients. On the other hand, there is a not inconsiderable risk of overtreatment with the development of subclinical hyperthyroidism. Its negative consequences in the form of atrial fibrillation and osteoporosis impair the quality and duration of life. Therefore, the indication for substitution therapy of subclinical hypothyroidism should be made with caution.One group in which diagnosis and therapy require special sensitivity is pregnant women. Here, two individuals, mother and child, must be treated. Varying target values and dosages in relation to the gestational age must be taken into account.

Overdose prevention centres in the UK

Overdose prevention centres in the UK

Corticotroph pituitary carcinoma with skeletal metastases masquerading as ectopic ACTH syndrome: a long and winding road to diagnosis.

SummaryPituitary carcinoma is a rare type of malignancy and only accounts for 0.1–0.2% of all pituitary tumours. Most pituitary carcinomas are hormonally active and they are mostly represented by corticotroph and lactotroph carcinomas. Corticotroph carcinoma can present as symptomatic Cushing’s disease or can evolve from silent corticotroph adenoma which is not associated with clinical or biochemical evidence of hypercortisolism. We hereby present a case of a bone-metastasized corticotroph pituitary carcinoma masquerading as an ectopic adrenocorticotropic hormone (ACTH) syndrome in a patient with a history of a non-functioning pituitary macro-adenoma. Our patient underwent two transsphenoidal resections of the primary pituitary tumour followed by external beam radiation therapy. Under hydrocortisone substitution therapy she developed ACTH-dependent hypercortisolism without arguments for recurrence on pituitary MRI and without central-to-peripheral ACTH-gradient on inferior petrosal sinus sampling, both suggesting ectopic production. Ultimately, she was diagnosed with an ACTH-secreting vertebral metastasis originating from the primary pituitary tumour. This case report demonstrates the complex pathophysiology of pituitary carcinoma and the long diagnostic work-up. Certain features in pituitary adenoma should raise the suspicion of malignancy.Learning pointsThe diagnosis of pituitary carcinoma can only be made based on documented metastasis, therefore, due to the often long latency period between the detection of the primary tumour and the occurrence of metastasis, the diagnostic work-up most often spans over multiple years.Pituitary carcinoma including corticotroph carcinoma is very rare in contrast to pituitary adenoma and only accounts for 0.1–0.2% of all pituitary tumours.Histopathology in pituitary adenoma should certainly accomplish the following goals: accurate tumour subtyping and assessment of tumoural proliferative potential.Repeated recurrence of pituitary adenoma after surgical resection, a discrepancy between biochemical and radiological findings, resistance to medical and radiation therapy, and silent tumours becoming functional are all hallmarks of pituitary carcinoma.Silent corticotroph adenomas are non-functioning pituitary adenomas that arise from T-PIT lineage adenohypophyseal cells and that can express adrenocorticotropic hormone on immunohistochemistry, but are not associated with biochemical or clinical evidence of hypercortisolism. Silent corticotroph adenomas exhibit a more aggressive clinical behaviour than other non-functioning adenomas.Treatment options for corticotroph carcinoma include primary tumour resection, radiation therapy, medical therapy, and chemotherapy. Sometimes bilateral adrenalectomy is necessary to achieve sufficient control of the cortisol excess.

Association of polymorphisms in ARRB2 and clinical response to methadone for pain in advanced cancer.

Background: The prescription of methadone in advanced cancer poses multiple challenges due to the considerable interpatient variation seen in effective dose and toxicity. Previous reports have suggested that ARRB2 influences the response to methadone in opioid substitution therapy. Associations with opioid response for pain management in advanced cancer are conflicting, with no studies including methadone as the primary intervention. Methods: In a prospective, multicenter, open-label dose-individualization study, we investigated whether polymorphisms in ARRB2 were associated with methadone dose requirements and pain severity. Results: Significant associations were found for rs3786047, rs1045280, rs2036657 and pain score. Conclusion: While studies are few and the sample size small, ARRB2 genotyping may assist in individualized management of the most feared symptom in advanced cancer.

Neurohypophyseal Peptides from Prague and Swedish Laboratories Used as Pharmaceuticals. Part 2: Desmopressin, Terlipressin, Carbetocin – Pharmacology and Clinical Applications

Licence agreements between the Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, Prague (IOCB), and the pharmaceutical company Ferring AB Malmö enabled the Swedish company to produce and commercialize worldwide a number of neurohypophyseal peptides designed at the IOCB. Several of them found therapeutic applications.
 dDAVP: 1-deamino-8-ᴅ-arginine-vasopressin was designed in one of the IOCB peptide laboratories (M. Zaoral and F. Šorm) in 1967. It displayed an extremely high antidiuretic activity (various tests indicate a 2- to 50-fold increase, as compared to arginine vasopressin) and a very low pressor activity. The peptide (covered by the U.S. Patent No. 3,497,491, 1970) has been used as a preferred drug in the substitution therapy of the central form of diabetes insipidus (Minirin®, today as Desmopressin INN). Besides, as later discovered (Mannucci et al. 1977), dDAVP increases the plasma concentration of the blood-clotting factor VIII. This fact extended its clinical use as haemostatics in cases of milder forms of haemophilia A, von Willebrand-Jürgens syndrome and some thrombocyte dysfunctions. Despite of the clinical success of dDAVP, a closer look reveals certain inadequacies in the presently available pharmacological data: several reports declare activity values and the prolongation effect (index of persistence) in very broad ranges.
 Triglycyl-8-lysine-vasopressin (Terlipressin), a peptide with lysine vasopressin chain extended at the N‑terminal by a triglycine residue, acts mainly as a prodrug (releasing lysine vasopressin after aminopeptidase splitting at the Nα group). The analogue belongs to the so-called „synthetic hormonogens“; individual peptides carrying various acylating groups were synthesized in the mid-sixties at the IOCB and legally protected by U.S. Patent No. 3,558,590 (1968). It was a part of the licence agreements mentioned above. The activities of triglycyl-8-lysine-vasopressin (both antidiuretic and vasopressor) are about 100 times lower than those of lysine vasopressin, but its persistence is 5 times longer. As such, it is occasionally used in emergency medicine in cases of esophageal (and other gastroenteral) bleeding, traumatic or septic shock, in cirrhotic patients and patients with portal hypertension. Its use as an early abortion drug was discussed but not pursued.
 Carbetocin (deaminocarba1-2-O-methyltyrosin-oxytocin) was synthetized in the laboratory of Karel Jošt at the IOCB before 1971; its synthesis was covered by a Czechoslovak patent (CS-149,028 B1) in June 1973 (at that time, Czechoslovak patent law did not provide for the patentability of substances as such) and first published in a biophysical communication by Frič et al., 1974). As a part of the licence agreement, it was included in the production program of Ferring AB, but marketed later also by several other pharmaceutical companies due to an incomplete patent protection. The peptide is a moderately active uterotonic partial agonist and as such has been utilized in veterinary obstetrics for delivery induction in cows and (multiparous) pigs: its milder and better-controlled uterotonic action was found preferential as compared to oxytocin so far used for these purposes. In the last two decades, carbetocin has been commonly used also in the human obstetrics, especially to prevent the peri- and post-partum haemorrhage, from the maternal side the most frequent and most severe delivery complication. It became a life-saving drug in emergency obstetrics.

Assessing the feasibility, acceptability and accessibility of a peer-delivered intervention to reduce harm and improve the well-being of people who experience homelessness with problem substance use: the SHARPS study

BackgroundFor people experiencing homelessness and problem substance use, access to appropriate services can be challenging. There is evidence that the development of trusting relationships with non-judgemental staff can facilitate service engagement. Peer-delivered approaches show particular promise, but the evidence base is still developing.MethodsThe study used mixed methods to assess the feasibility, acceptability and accessibility of a peer-delivered, relational intervention to reduce harms and improve health/well-being, quality of life and social functioning, for people experiencing homelessness and problem substance use. Four Peer Navigators were employed to support individuals (n = 68 total, intervention participants). They were based in outreach services and hostels in Scotland and England. Qualitative interviews were conducted with intervention participants, Peer Navigators and staff in services, and observations were conducted in all settings. Quantitative outcomes relating to participants’ substance use, physical and mental health, and quality of the Peer Navigator relationship, were measured via a ‘holistic health check’ with six questionnaires completed at two time-points.ResultsThe intervention was found to be acceptable to, and feasible and accessible for, participants, Peer Navigators, and service staff. Participants reported improvements to service engagement, and feeling more equipped to access services independently. The lived experience of the Peer Navigators was highlighted as particularly helpful, enabling trusting, authentic, and meaningful relationships to be developed. Some challenges were experienced in relation to the ‘fit’ of the intervention within some settings. Among participants there were reductions in drug use and risky injecting practices. There were increases in the number of participants receiving opioid substitution therapy. Overall, the intervention was positively received, with collective recognition that the intervention was unique and highly valuable. While most of the measures chosen for the holistic health check were found to be suitable for this population, they should be streamlined to avoid duplication and participant burden.ConclusionsThe study established that a peer-delivered, relational harm reduction intervention is acceptable to, and feasible and accessible for, people experiencing homelessness and problem substance use. While the study was not outcomes-focused, participants did experience a range of positive outcomes. A full randomised controlled trial is now required to assess intervention effectiveness.Trial registrationStudy registered with ISRCTN: 15900054.

Pituitary deficiency after brain radiation therapy in childhood

Introduction: As part of an anticancer therapy, craniospinal radiotherapy causes variable degrees of hormonal deficiencies. The onset of hormonal deficiencies depends on the dose delivered to the pituitary –hypothalamic region while their incidence and severity depends on dose fractionating and follow up duration.
 Objectives: Analyzing the long –term endocrine complications in children treated with craniospinal radiotherapy.
 Material and methods: A prospective study; including 4 medical files collected over a period of 2 years.
 Results: The study includes 4 patients with a sex ratio of 3M/1F; and a mean age of 18, 62 years. The average age at the time of irradiation was 9, 12 years. The delay between the end of radiotherapy and the first consultation varied between 1 year and 21 years. The radiotherapy was administred for medulloblastoma (n=1), Burkitt lymphoma (n=1), cavum cancer (n=1), Posterior Cranial Fossa Tumor (n=1).
 The hormonal assessment revealed: a central hypothyroidism in 3 patients, corticotropin insufficiency in 2 cases, and gonadotropin deficiency associated with micropenis in one case. No cases of diabetes insipidus have been reported. Pituitary hypothalamic MRI objectified an atrophic anterior pituitary gland in two cases. Hormonal substitutive therapy was started in all patients. Recombined human GH treatment was introduced in one case, but omitted in two others cases for bad control of the cancerous disease and for an achieved puberty in the fourth patient.
 Conclusion: The search of the hormonal deficiencies is essential for any child treated by craniospinal radiotherapy in order to institute an early hormonal substitutive therapy.
 Keywords: Craniospinal radiotherapy, hormonal deficiencies, substitutive therapy

A peer-delivered intervention to reduce harm and improve the well-being of homeless people with problem substance use: the SHARPS feasibility mixed-methods study.

For people experiencing homelessness and problem substance use, access to appropriate services can be challenging. There is evidence that development of trusting relationships with non-judgemental staff can facilitate service engagement. Peer-delivered approaches show particular promise, but the evidence base is still developing. This study tested the feasibility and acceptability of a peer-delivered intervention, through 'Peer Navigators', to support people who are homeless with problem substance use to address a range of health and social issues. The study objectives were to design and implement a peer-delivered, relational intervention to reduce harms and improve health/well-being, quality of life and social functioning for people experiencing homelessness and problem substance use, and to conduct a concurrent process evaluation to inform a future randomised controlled trial. A mixed-methods feasibility study with concurrent process evaluation was conducted, involving qualitative interviews [staff interviews (one time point), n = 12; Peer Navigator interviews (three or four time points), n = 15; intervention participant interviews: first time point, n = 24, and second time point, n = 10], observations and quantitative outcome measures. The intervention was delivered in three outreach services for people who are homeless in Scotland, and three Salvation Army hostels in England; there were two standard care settings: an outreach service in Scotland and a hostel in England. Participants were people experiencing homelessness and problem substance use (n = 68) (intervention). This was a peer-delivered, relational intervention drawing on principles of psychologically informed environments, with Peer Navigators providing practical and emotional support. Outcomes relating to participants' substance use, participants' physical and mental health needs, and the quality of Peer Navigator relationships were measured via a 'holistic health check', with six questionnaires completed at two time points: a specially created sociodemographic, health and housing status questionnaire; the Patient Health Questionnaire-9 items plus the Generalised Anxiety Disorder-7; the Maudsley Addiction Profile; the Substance Use Recovery Evaluator; the RAND Corporation Short Form survey-36 items; and the Consultation and Relational Empathy Measure. The Supporting Harm Reduction through Peer Support (SHARPS) study was found to be acceptable to, and feasible for, intervention participants, staff and Peer Navigators. Among participants, there was reduced drug use and an increase in the number of prescriptions for opioid substitution therapy. There were reductions in risky injecting practice and risky sexual behaviour. Participants reported improvements to service engagement and felt more equipped to access services on their own. The lived experience of the Peer Navigators was highlighted as particularly helpful, enabling the development of trusting, authentic and meaningful relationships. The relationship with the Peer Navigator was measured as excellent at baseline and follow-up. Some challenges were experienced in relation to the 'fit' of the intervention within some settings and will inform future studies. Some participants did not complete the outcome measures, or did not complete both sets, meaning that we do not have baseline and/or follow-up data for all. The standard care data sample sizes make comparison between settings limited. A randomised controlled trial is recommended to assess the effectiveness of the Peer Navigator intervention. A definitive cluster randomised controlled trial should particularly consider setting selection, outcomes and quantitative data collection instruments. This trial is registered as ISRCTN15900054. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 14. See the NIHR Journals Library website for further project information.

Диабетическая кардиальная автономная нейропатия: каковы перспективы в лечении?

Кардиальная автономная нейропатия (КАН) является серьезным и частым осложнением сахарного диабета. Несмотря на ее связь с повышенным риском сердечно-сосудистой смертности и различными симптомами и нарушениями, значимость КАН сложно переоценить. Изменение образа жизни, интенсивный гликемический контроль позволяют предотвратить развитие или прогрессирование КАН. Патогенетическое лечение КАН включает: сбалансированную диету и физическую активность; оптимизацию гликемического контроля; лечение дислипопротеинемии; коррекцию метаболических нарушений в миокарде; профилактику и лечение тромбоза; применение ингибиторов альдозоредуктазы; применение дигомо-гамма-линоленовой кислоты (ДГЛК); применение ацетил-L-карнитина, антиоксидантов, в первую очередь α-липоевой кислоты (α-ЛК), применение ω-3 и ω-6 полиненасыщенных жирных кислот (ω-3 и ω-6 ПНЖК), вазодилататоров, жирорастворимого витамина B1, аминогуанидина; заместительную терапию ростовыми факторами, в тяжелых случаях — лечение ортостатической гипотензии. Многообещающим является применение средств, которые повышают кровоток в vasa vasorum, в том числе аналогов простациклина, блокаторов тромбоксана А2, а также препаратов, которые способствуют усилению и/или нормализации функции Na+-,К+-АТФазы (ингибиторы фосфодиэстеразы), α-ЛК, ДГЛК, ω-3 ПНЖК, а также одновременное назначение α-ЛК, ω-3 ПНЖК и ДГЛК.

Step-Up Approach for Sodium Butyrate Treatment in Children With Congenital Chloride Diarrhea.

ObjectivesOral salt substitutive therapy is pivotal for the survival of patients with congenital chloride diarrhea (CLD), however this therapy is unable to influence the symptoms severity. Butyrate has been proposed to limit diarrhea severity in CLD. Unfortunately, the optimal dose schedule is still largely undefined. In addition, butyrate seems not to be well-tolerated by all patients, with some subjects reporting diarrhea worsening. We investigated the efficacy of a step-up therapeutic approach with sodium butyrate in patients who experienced a diarrhea worsening or an absent improvement after the direct administration of 100 mg/kg/day of sodium butyrate.MethodsThe efficacy of a step-up therapeutic approach starting from 50 mg/Kg/day with a subsequent 25 mg/kg/day weekly increase up to 100 mg/kg/day of oral sodium butyrate was investigated in previously three unresponsive CLD children.ResultsThe step-up therapeutic approach resulted effective in limiting diarrhea severity in all our three previously unresponsive CLD patients.ConclusionsOur results suggest the efficacy of the step-up therapeutic approach in CLD children.

Neurohypophyseal Peptides from Prague and Swedish Laboratories Used as Medications: Desmopressin, Terlipressin, Carbetocin. Part 1: History of Research and Beginnings of Industrial Production

From the fifties to the seventies of the last century, the neurohypophyseal peptides oxytocin and vasopressin constituted one of the main research areas at the Institute of Organic Chemistry and Biochemistry in Prague (IOCB). A significant contribution to this area is associated with the names of František Šorm, director of the said institute, and Josef Rudinger, head of the institute's peptide laboratory. At that time, newly developed research tools enabled to synthesize structural analogues of these hormones in numerous laboratories worldwide and hence to investigate the structure-activity relationships within this peptide group. Contributions of single peptide-chain positions to the respective biological activities were identified which opened a possibility to rationalize a design of peptides with a combination of changes in several positions. Several clinically interesting peptides were synthesized in the late 1960s at the IOCB and employed as therapeutics: [(Gly)3-Cys1,Lys8]-vasopressin (Glypressin Ferring®, Terli­pressin INN), 1-deamino-8-ᴅ-arginine vasopressin (Desmopressin INN, dDAVP), and later the uterotonics carbetocin (INN), widely used in obstetrics to prevent postpartum haemorrhage. Since the industrial production of peptide therapeutics was scarcely possible under the conditions of socialist economy in Czechoslovakia as well as in other countries under the Soviet influence, F. Šorm agreed to use the already established scientific contacts of IOCB with the Swedish pharmaceutical company Ferring AB and to transfer the production licences to Sweden. The license agreements were signed in 1969 and led to a quick spread of dDAVP in the substitution therapy of the central form of diabetes insipidus and, moreover, contributed to a fast upsurge of the Ferring company. Somewhat later, Glypressin was produced as a therapeutic with a prolonged action in cases of cardiovascular collapse. Contacts between Prague peptide chemists and the Ferring company lasted on a rather informal base until the end of the 1980s. After the fall of the totalitarian regime in Czechoslovakia in 1990, Ferring started a joint-venture collaboration with the newly organized Czech company Léčiva st.p. Praha in a newly established group Prague Polypeptide Institute spol. s. r.o. (later Ferring-Léčiva A.S.). A substantial part of the peptide-production capacities was then transferred to new buildings in Prague.

Safe use of opioids

Background: Opioids are effective analgesics for cancer pain and refractory non-cancer pain. Although they are essential medication, problematic issues on aberrant behavior and adverse events have rapidly emerged as social problems in Korea. This study aimed to describe the mechanisms, efficacy, and adverse events, especially how to deal with opioid dependency.Current Concepts: Opioid-induced aberrant behavior includes physical and psychological dependences (addiction), abuse, and diversion (giving prescribed opioids to another person). Most physicians are unfamiliar with how to handle patients presenting these problematic issues. Physical and psychological dependences develop through different pathophysiologic mechanisms, i.e., noradrenergic and dopaminergic pathways, respectively. Motivational enhancement therapy, psychosocial support, substitution therapy with buprenorphine, and adjunctive medications, including alpha-2 adrenergic agonist, antidepressants, and non-steroidal antiinflammatory drugs, are the mainstay of treatment for opioid dependency. Constipation, nausea/vomiting, drowsiness/sedation, delirium, itching sensation, voiding difficulty, dry mouth, opioid-induced hyperalgesia, and respiratory depression are well-known physical side effects of opioid consumption.Discussion and Conclusion: Research on the development history, epidemiology of opioid dependency, and its treatment are warranted to avoid an opioid crisis in Korea. Above all, thorough knowledge for physicians and patients is urgently needed.

Molecular and Cellular Bases of Lipodystrophy Syndromes.

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

The Impact of the COVID-19 Pandemic on the Population of Addicts Undergoing Substitution Therapy

Background: The pandemic of the new corona virus has taken its toll on the mental health of entire humankind with special impact on vulnerable groups, such as drug users in substitution treatment. Objective: The aim of the study was to determine the impact of the COVID-19 pandemic on mental health in the population of opiate addicts who are on substitution therapy. Methods: The research was conducted in the Institute of Addiction Diseases of the ZE-DO canton on the population of patients addicted to opiates who are included in the substitution therapy program. The sample of 80 patients was randomly selected with respect to the inclusion criteria. An 8-parameter questionnaire with symptoms of anxiety and depressive disorder, ranked by intensity on the Likert scale from 0 to 4, was used as a measuring instrument. The change in these symptoms in the one-year period before the pandemic to the one-year period of the pandemic are compared. The results are analyzed in descriptive statistics using the SPSS program. The statistical significance was monitored by the χ2 test. Results: The results of this research show an apperent statistically significant increase in the symptoms of anxiety and depressive disorder, as well as an increase in drug abuse during the pandemic period compared to the period before it. Conclusion: Results imply the existence of a significant adverse effect of the COVID-19 pandemic on the mental health of treated opiate addicts. This research impose the need to affirm the prevention of further abuse of illegal substances, as well as the introduction of new customized programs through various psychosocial interventions and therapies carried out by psychiatrists and psychologists. Telemedicine presents itself as useful way of intervention and treatment.