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PubMed2002

Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors.

The HMG-CoA reductase inhibitors (statins) are effective in both the primary and secondary prevention of ischaemic heart disease. As a group, these drugs are well tolerated apart from two uncommon but potentially serious adverse effects: elevation of liver enzymes and skeletal muscle abnormalities, which range from benign myalgias to life-threatening rhabdomyolysis. Adverse effects with statins are frequently associated with drug interactions because of their long-term use in older patients who are likely to be exposed to polypharmacy. The recent withdrawal of cerivastatin as a result of deaths from rhabdomyolysis illustrates the clinical importance of such interactions. Drug interactions involving the statins may have either a pharmacodynamic or pharmacokinetic basis, or both. As these drugs are highly extracted by the liver, displacement interactions are of limited importance. The cytochrome P450 (CYP) enzyme system plays an important part in the metabolism of the statins, leading to clinically relevant interactions with other agents, particularly cyclosporin, erythromycin, itraconazole, ketoconazole and HIV protease inhibitors, that are also metabolised by this enzyme system. An additional complicating feature is that individual statins are metabolised to differing degrees, in some cases producing active metabolites. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. Cerivastatin is also metabolised by CYP2C8. Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter present in the small intestine that may influence their oral bioavailability. In clinical practice, the risk of a serious interaction causing myopathy is enhanced when statin metabolism is markedly inhibited. Thus, rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin. Itraconazole has been shown to increase exposure to simvastatin and its active metabolite by at least 10-fold. Pharmacodynamically, there is an increased risk of myopathy when statins are coprescribed with fibrates or nicotinic acid. This occurs relatively infrequently, but is particularly associated with the combination of cerivastatin and gemfibrozil. Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring. Knowledge of the pharmacokinetic properties of the statins should allow the avoidance of the majority of drug interactions. If concurrent therapy with known inhibitors of statin metabolism is necessary, the patient should be monitored for signs and symptoms of myopathy or rhabdomyolysis and the statin should be discontinued if necessary.

Animals↗

PubMed1996

Drug therapy of non-insulin-dependent diabetes mellitus in the elderly.

Non-insulin-dependent diabetes (NIDDM) is a common problem in the elderly. The discovery of several classes of oral antidiabetic agents has increased the prospects of achieving better control of hyperglycaemia with reduced risk of severe adverse events. Some of these agents, such as acarbose or miglitol, do not cause hypoglycaemia and act locally in the gut. As such they are safer agents. On the other hand, the low cost of some sulphonylurea agents and a once or twice daily administration schedule make them an attractive option. Metformin appears to be especially useful in obese insulin-resistant patients with NIDDM. However, obesity is not as much of a problem in the elderly as it is in middle-aged patients, and contraindications to the use of metformin are common in the elderly. The use of a combination of 2 or 3 oral antidiabetic agents to delay the need for insulin therapy is now possible. The long term effects of this approach are not known and the cost of polypharmacy is of concern.

Administration, Oral↗

PubMed1992

Utilisation of psychotropic drugs in patients of the long stay ward.

A survey of the prescribing of psychotropic drugs was carried out at the Psychiatric Hospital of Bahrain. This retrospective study on 60 inpatients of the Long Stay Ward revealed a man:woman ratio of 2.7. 91% of the men and 88% of the women were over 40 years old. 44 of the 60 patients had a diagnosis of schizophrenia, the rest had dementia, depression, schizoaffective disorders, drug-induced psychosis, general paralysis or Huntington's chorea. 95% of patients received antipsychotic drugs. Thioridazine was the most common drug followed by chlorpromazine. The mean number of drugs/patient was 1.7, with 41.7% of patients receiving only 1 drug. Tardive dyskinesia was observed in 11 patients and 9 experienced varying degrees of tremor. The findings confirm that psychiatric illness treated by psychiatrists need not lead to polypharmacy. As a consequence, its treatment may be less likely to result in adverse reactions than when patients are treated by general practitioners.

Adult↗

PubMed1994

Pharmaceutical prices, quantities and innovation. Comparing Japan with the US.

Per capita expenditure on pharmaceuticals is higher in Japan than in the US, despite a series of drug price reductions instigated by the Japanese Ministry of Health and Welfare that began in 1981. For some individual products, these price reductions cumulatively totalled more than 50%. This article argues that although the price of individual drugs is lower in Japan than in the US, aggregate expenditure is higher because of the greater use of newly-introduced original drugs and lower use of generics. Providers and consumers also tend to use drugs in larger quantities in Japan, because of polypharmacy and greater use of vitamins and nutrients, antihypertensives, cerebral metabolic activators (e.g. idebenone) and milder-acting drugs (i.e. drugs with low toxicity but unproven clinical efficacy). The level of expenditure is unlikely to decline, despite changes to pricing policy and ongoing efforts to improve the pharmaceutical distribution system and to discourage physician dispensing activities.

Cross-Cultural Comparison↗

PubMed2002

Potential savings from splitting newer antidepressant medications.

BACKGROUND: The newer antidepressants are among the most commonly prescribed classes of medications. A favourable adverse effect profile and approvals for a wider range of disorders than their predecessors have fostered the growth of these drugs. However, newer antidepressants are appreciably more expensive than older medications, and the annual prescription costs of newer drugs are expected to continue to rise at double-digit rates. The price structuring of these medications is largely independent of their pill strengths, and splitting higher strength pills may reduce the average cost per dose by nearly half. Therefore, various health organisations and consumers have been using pill splitting to reduce prescription costs. Antidepressants are well suited for pill splitting because their therapeutic effects depend upon long-term alterations in neurotransmitters, and small variations in dose are not critical. OBJECTIVE: To examine the potential savings for various purchasers - health organisations and consumers - that can be derived from pill splitting of newer antidepressants. DESIGN AND SETTING: Product review and simulation study in the US healthcare setting. METHODS: All new antidepressants with pill strengths that could be halved and were not in capsular or time-release forms were included. Expenditures for purchasers of these pills were calculated using a variety of factors, such as the level of discounting of official average wholesale costs, average retail costs and the site of prescription dispensing. RESULTS: Seven antidepressants were included. In 2000, 42% of the pills of these antidepressants were at strengths that permitted splitting. If all eligible prescriptions had utilised split doses, purchasers could have saved over dollars US1.7 billion. The bulk of the saving (dollars US1.5 billion) would have been realised by pill splitting of only three medications - sertraline, paroxetine and citalopram. DISCUSSION AND CONCLUSIONS: The economic rationale for pill splitting of antidepressants is compelling for both health organisations and individual consumers. The literature indicates that when pill-splitters are used or a pharmacy cuts the pills, patients are satisfied and compliance is not reduced. However, pill splitting may be inadvisable for some subgroups of patients with reduced cognition or sensory or motor impairment, or older persons on polypharmacy. Pill splitting can be facilitated by mandating manufacturers to score all tablets, requiring pharmacists to fill prescriptions for split doses, and giving pharmacists incentives for splitting pills for patients. Finally, large-scale studies should be undertaken to examine the clinical effectiveness of, and financial savings from, pill splitting.

Antidepressive Agents↗

PubMed2005

Augmentation strategies in clozapine-resistant schizophrenia.

The introduction of antipsychotics in the 1950s revolutionised the treatment of schizophrenia, but it soon became apparent that a substantial number of patients demonstrated a suboptimal response to these antipsychotics. Clozapine proved to be beneficial in patients whose symptoms were treatment resistant, but it too had limitations, with as many as 40-70% of those treated with clozapine demonstrating inadequate response to this drug as well. The availability of other 'atypical' antipsychotics offers options, but clozapine appears to remain the most effective option in treatment-resistant schizophrenia. This, of course, raises the question of what to do when clozapine is only partially effective. To address the issue of treatment in patients who have demonstrated a suboptimal response to clozapine, efforts have focused on a variety of augmentation strategies, including numerous medications and electroconvulsive therapy. The current body of evidence consists largely of data from smaller open trials and case series/reports, although data from a limited number of controlled studies are now available. Not surprisingly, the evidence drawn from the former is more supportive of augmentation strategies, although the controlled trials are not without positive findings. The available information is certainly not so overwhelming as to endorse any single augmentation approach. Indeed, it argues for more controlled data and cautions us regarding the cost-benefit ratio in adopting this strategy. Over and above the added adverse effects of another treatment, there is evidence to indicate that actual clinical worsening can occur. Without compelling evidence, clinicians must resort to guiding principles. The potential benefits of augmentation cannot be ruled out, but it should be approached with caution and in a systematic fashion. Factors compromising clozapine response should first be ruled out, and any augmentation trials should be guided by existing evidence and a treatment plan that incorporates a clear understanding of target symptoms. A means of evaluating outcome effectively needs to be in place, and the trial should be circumscribed to prevent needless polypharmacy. A priori, an endpoint needs to be established and the trial discontinued unless results firmly support added benefits.

Animals↗

PubMed2006

Polytherapy in bipolar disorder.

Bipolar disorder is a life-long condition that is associated with frequent recurrence/relapse of symptoms. Although putative mood stabilisers, such as lithium, are considered to improve the natural course of bipolar disorder, complete long-term remission is rarely achieved. In order to effectively control mood symptoms and to reduce relapse, clinicians often use polypharmacy to treat patients with bipolar disorder. In this article, we examine the recent literature on treatment strategies in bipolar disorder to determine if combination treatments provide additional benefit over monotherapy for the management of various phases of bipolar disorder. The evidence suggests that for acute mania a combination of lithium or valproate and an atypical antipsychotic is the most effective approach, with approximately 20% more patients responding to the combination than to monotherapy with any antimanic agent. Few studies have examined the use of combination therapy in comparison to monotherapy for bipolar depression. The limited evidence suggests that lithium plus an antidepressant appears to be more effective than lithium alone in those with lower serum lithium concentrations. Similarly, the combination of olanzapine plus fluoxetine is more effective than olanzapine alone. There is consensus that antidepressant monotherapy is not appropriate because of concerns of a manic switch, but monotherapy with lithium or lamotrigine may be adequate for mild to moderate bipolar depression. For maintenance treatment, commonly used agents, such as lithium, valproate or olanzapine appear to be most effective in preventing manic relapses, whereas lamotrigine is more effective in preventing depressive relapses. As a result of these findings, it makes intuitive sense to combine lamotrigine with lithium, valproate or an atypical antipsychotic to achieve better mood stability. However, the efficacy and safety of such combinations have not been systematically compared with monotherapy. Preliminary studies suggest that lithium plus valproate may be more effective than lithium alone in preventing affective relapses. Similarly, the combination of lithium or valproate plus olanzapine seems to be more effective than monotherapy with a mood stabiliser in preventing manic episodes.

Antidepressive Agents↗

PubMed2006

Long-term prophylaxis in bipolar disorder.

Bipolar disorder is a major cause of disability, and the prevention of relapse is a key management goal. Pharmacological interventions, effectively delivered through enhanced clinical care, are central to long-term management. This article summarises the available evidence for a range of pharmacological options, and provides guidance on common issues in clinical management in line with current practice guidelines. The use of medications for long-term prophylaxis should be considered in all patients meeting criteria for bipolar I disorder. Increasing high-quality evidence from randomised trials informs management decisions relating to both novel agents, such as lamotrigine and olanzapine, and longer-established therapies, such as lithium and valproate, in monotherapy. Medications taken long-term in bipolar disorder differ in the extent to which they protect against manic and depressive relapse. Consequently, the emerging challenge is to understand how combination treatments can enhance efficacy and effectiveness based on data from controlled trials rather than random polypharmacy. Clinical care can be enhanced with effective education about the illness, and the use of strategies to improve treatment adherence and the recognition and management of stressors or prodromal symptoms. Where available, a range of specific psychological interventions can be effective as an adjunct to medication. When discontinuation of prophylaxis is necessary, gradual tapering of dose over weeks or months is recommended.

Age Factors↗

PubMed2001

Do women have more adverse drug reactions?

Up to 5% of all hospital admissions are the result of adverse drug reactions (ADRs). Identifying those factors which may predispose to ADRs is essential for risk management. Amongst the known risk factors for adverse reactions are increasing age, polypharmacy, liver and renal disease as well as being female. Female patients have a 1.5- to 1.7-fold greater risk of developing an ADR, including adverse skin reactions, compared with male patients. The reasons for this increased risk are not entirely clear but include gender-related differences in pharmacokinetic, immunological and hormonal factors as well as differences in the use of medications by women compared with men. Women generally have a lower lean body mass, a reduced hepatic clearance, have differences in activity of cytochrome P450 (CYP) enzymes (40% increase in CYP3A4, varied decrease in CYP2D6, CYP2C19 and CYP1A2), and metabolize drugs at different rates compared with men. Other important factors include conjugation, absorption, protein binding and renal elimination, which may all have some gender-based differences. However, how these differences result in an increased risk of ADRs is not clear. There are pharmacodynamic differences between men and women, seen particularly with cardiac and psychotropic medications. There is no doubt that chlorpromazine, fluspirilene and various antipsychotics appear more effective in women than men for the same dosage and plasma concentration. Similarly, women are at increased risk of QT prolongation with certain anti-arrhythmic drugs compared with men even at equivalent serum concentrations. The mechanisms are unknown. Increasingly the evidence is that idiosyncratic drug reactions, particularly cutaneous reactions, appear to have an immunological etiology. It is possible that gender difference in T cell activation and proliferation account for this as well as the increased prevalence of skin diseases such as systemic lupus erythematosus and photosensitivity. Whatever the mechanism(s), it is important to be aware that gender is a significant factor in ADRs.

Adult↗

PubMed2003

HIV-associated pruritus: etiology and management.

With the advent of highly active antiretroviral therapy (HAART), life-threatening opportunistic infection has become less common in patients with HIV infection and longevity has increased dramatically. With increased longevity, the problems of living with a chronic disease have become more prominent in this patient population. Disorders such as fat redistribution and metabolic abnormalities can result from antiviral medications and from HIV disease itself. Pruritus is one of the most common symptoms encountered in patients with HIV. The spectrum of skin diseases in such patients encompasses dermatoses of diverse etiologies; a few are peculiar to patients with HIV while others are not. Some of these conditions may cause severe and sometimes intractable pruritus that provokes scratching, picking, disfigurement, sleep loss, and significant psychological stress. Moreover, the expense of ongoing medical treatments can be daunting. Skin rash can sometimes be the initial presentation of HIV infection or serve as a harbinger of disease progression. Causes of pruritus include skin infections, infestations, papulosquamous disorders, photodermatitis, xerosis, drug reactions, and occasionally lymphoproliferative disorders. Drug eruptions are particularly common in patients who are HIV positive, presumably as a result of immune dysregulation, altered drug metabolism, and polypharmacy. Itching can also result from systemic diseases such as chronic renal failure, liver disease, or systemic lymphoma. Workup of pruritus should include a careful examination of the skin, hair, nails, and mucous membranes to establish a primary dermatologic diagnosis. If no dermatologic cause is found, a systemic cause or medication-related etiology should be sought. Idiopathic HIV pruritus is a diagnosis of exclusion and should only be considered when a specific diagnosis cannot be established. The management of HIV-associated pruritus should be directed at the underlying condition. Phototherapy has been found to be useful in the treatment of several HIV-associated dermatoses and idiopathic pruritus as well. Unfortunately, some of the treatments that have been suggested for patients with HIV are anecdotal or based on small uncontrolled studies. The last decade has seen a surge in the utilization of HAART which, to some degree, reconstitutes the immune system and ameliorates some dermatologic diseases. On the other hand, some skin diseases flare temporarily when HAART is started. Unless frank drug allergy is suspected, HAART does not need to be stopped.

AIDS-Related Opportunistic Infections↗

PubMed2005

Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia.

Beyond allopurinol and the well-established uricosuric drugs, several other agents can decrease serum uric acid (SUA) levels, such as losartan, fenofibrate and some non-steroidal anti-inflammatory drugs (NSAIDs). Some of these drugs increase renal urate excretion. Hyperuricaemia and gout are common problems (at least 1% of Western men are affected by gout). Raised SUA levels increase the incidence of acute gout and renal calculi. Hyperuricaemia may also predict an increased risk of vascular events. Therefore, lowering SUA levels is of clinical relevance. In this review we consider the effect on SUA levels of drugs that are prescribed for indications other than treating hyperuricaemia. These drugs may obviate the need for specific treatment (e.g. allopurinol) aimed at lowering SUA levels. Furthermore, because hyperuricaemic patients may already be on several drugs (e.g. due to associated dyslipidaemia, hypertension and/or arthritis) compliance may be improved by avoiding additional medication. The potential for adverse effects associated with polypharmacy would also be decreased.

Angiotensin II Type 1 Receptor Blockers↗

PubMed1997

Evidence based health care in old age psychiatry.

OBJECTIVE: The purpose of this article is to present the current status and future needs of old age psychiatry in relation to evidence-based health care. METHOD: The opportunities and difficulties of evidence-based medicine as applied to old age psychiatry are described. Depression is used as a specific example. The role of the Cochrane Collaboration and of clinical guidelines in dealing with these difficulties are discussed. RESULTS: There has been a tendency for drug studies to focus on younger age groups and to exclude patients with comorbidity or polypharmacy. Aspects of clinical management separate from drugs are given insufficient attention. The generalizability of current studies is a problem in old age psychiatry. CONCLUSIONS: Psychiatry is no less part of medicine than any other specialty. Increased attention to studies of effectiveness, as opposed to efficacy, is indicated. The Cochrane Collaboration is an international network which promotes and conducts systematic reviews of the effectiveness of health care. Systematic reviews can increase the generalizability of the current knowledge base and better define the needs for future research.

Aged↗

PubMed2002

Behavioral characteristics in delusional pregnancy: a matched control group study.

OBJECTIVE: False pregnancy or delusional pregnancy, is the condition of believing one is pregnant despite factual evidence to the contrary. This is the first study to utilize a standardized mental disorder assessment tool, The Brief Psychiatric Rating Scale (BPRS) to evaluate a group of women with delusional pregnancy compared to a group of controls. METHOD: Eleven-women with delusional pregnancy (DP) were compared to a control group matched for age, race and DSM-IV psychiatric diagnosis. All patients were receiving care in a state psychiatric hospital setting. RESULTS: Compared to matched controls, women with DP had significantly higher levels of hostility (p < .05), higher rates of prescribed polypharmacy (p < .05) and a trend toward higher antipsychotic medication dosages (t = 1.48, df = 20, p = .08). These findings may be suggestive of greater resistance to treatment in women with DP. CONCLUSIONS: Biologic and psychotherapeutic treatment interventions for women with DP may need to address factors of hostility and treatment resistance. Preliminary treatment issues include selection of specific categories of psychotropic agents, as well as psychotherapies that are cognitive and lead to modification of belief paradigm.

Adult↗

PubMed2005

Determinants of natriuretic peptide production by the heart: basic and clinical implications.

The cardiac natriuretic peptides (NPs) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are polypeptide hormones synthesized, stored, and secreted by cardiac muscle cells (cardiocytes). The NPs modulate extracellular fluid volume and blood pressure and have potent growth-regulating properties, which make them of great interest for cardiac remodeling in acute myocardial infarction and congestive heart failure. We have observed that the production of NP can be coordinately or discoordinately regulated. In the former type, muscle stretch-elicited secretion triggers signals mediated by Gi/o protein, whereas agonists such as endothelin 1 independently signal through Gq. Discoordinated regulation is observed following stimulations by some cytokines, which selectively up-regulate BNP. This regulation takes place at the translational and transcriptional levels and is dependent on a p38 signaling pathway. Further details of processes regulating NP secretion need to be defined to develop a comprehensive view of the endocrine function of the heart. Nevertheless, translational research in the area of NPs has demonstrated the usefulness of these hormones as a marker of disease and as potential therapeutic agents. The latter application of NP is particularly attractive given that ANF and BNP possess pharmacologic actions that require polypharmacy in the treatment of acute myocardial infarction and congestive heart failure.

Animals↗

PubMed2006

Action or inaction? Decision making in patients with diabetes and elevated blood pressure in primary care.

OBJECTIVE: Hypertension increases micro- and macrovascular complications of diabetes. The goal for blood pressure is <130/80 mmHg. In primary care, however, blood pressure in many patients exceeds this goal. In this study, we evaluated the clinical decision-making process when a patient with diabetes presents with elevated blood pressure. RESEARCH DESIGN AND METHODS: Twenty-six primary care practices in two practice-based research networks in Colorado participated. Questionnaires were completed after each encounter with an adult with type 2 diabetes. Data obtained from the survey included 1) demographic information, 2) blood pressure results, 3) action taken, 4) type of action if action was taken, and 5) reasons for inaction if action was not taken. Bivariate and multivariate analyses were performed to identify predictors of action. RESULTS: Completed surveys totaled 778. Blood pressure was 130/74 +/- 18.8/12.0 mmHg (mean +/- SD). Sixty-two percent of patients exceeded goals. Action was taken to lower blood pressure in 34.9% of those. Predictors of action were 1) blood pressure level, 2) total number of medicines the patient was taking, and 3) patient already taking medicines for blood pressure. As blood pressure rose, providers attributed inaction more often to "competing demands" and reasons other than "blood pressure being at or near goal." CONCLUSIONS: No evidence was found for patterns of poor care among primary care physicians. Providers balance the clinical circumstances, including how elevated the blood pressure is, and issues of polypharmacy, medication side effects, and costs when determining the best course of action. Knowledge deficit is not a common cause of inaction.

Diabetic Angiopathies↗

PubMed1993

Gynecological problems of mentally retarded women. A case-control study from southern Finland.

Two hundred and fifty-five mentally retarded women (cases) and their age-matched control women with no mental retardation (controls) requiring the assistance of a gynecological consultant were studied. Reasons for consultation, heights, weights, blood pressures, smoking histories, medications, gynecological findings and therapeutic measures recommended after examination were recorded. In comparison to the group of non-mentally retarded control women the group of mentally retarded women had no deliveries at all, the number of pregnancies was 118.3 times less (p < 0.001), abortion 20 times less (p < 0.01), gynecological laparotomies 4.3 times less (p < 0.05) and diagnostic curettages 25.7 times less often (p < 0.001), but the number of lynestrenol induced therapeutic amenorrhea (TA) 123 times more (p < 0.001), anticonvulsive drug therapy 91 times more (p < 0.001), polypharmacy 22 times more (p < 0.01) and virginal gynecological status 11.7 times more often (p < 0.001). Further, among the mentally retarded cases than non-mentally retarded controls, contraception was 58 times less (p < 0.05), not smoking 1.2 times (p < 0.001), the incidence of genital infections 2.9 times and tumors of all kind 4.6 times less common (p < 0.001). Of the present mentally retarded women 67.5% had at least once in their life received lynestrenol for TA. Autopsy confirmed arterial diseases occurred in two out of four mentally retarded patients aged 44 and 45 years, who were current lynestrenol users and died during the study period. Therapeutic amenorrhea exhibited a clinical picture of depressed pituitary gonadal axis.

Adult↗

PubMed1982

Monitoring and interpretation of antidepressant plasma concentrations.

A brief review of the factors influencing plasma tricyclic concentrations and the relationship between clinical response and plasma concentration is presented. It is concluded that routine monitoring of tricyclics is unwarranted. In some specific instances monitoring tricyclic antidepressant plasma concentrations may be indicated: in cases of therapeutic failure a low level may indicate poor compliance or rapid metabolism and the need to increase the dose; for the management of side effects, especially when cardiac abnormalities exist prior to therapy; in cases of polypharmacy when drug interactions can occur; the management of overdoses and in patients with physical illnesses especially renal and hepatic disease. The elderly also constitute a group of patients in whom drug monitoring may be advisable. This group of patients tends to develop higher plasma levels than younger patients on equivalent doses. Some guidelines for the interpretation of laboratory results are presented and discussed.

Age Factors↗

PubMed1986

An outpatient survey of antidepressant prescription habits.

A review of case notes of patients attending a general hospital psychiatric outpatient clinic revealed that 75% of patients with depressive disorders and 38% of patients with neurotic disorders were prescribed antidepressants. Antidepressants were often prescribed for long periods in low doses and in combination with benzodiazepines. There was less polypharmacy, however, with more sedating antidepressants. The results indicate that clinical prescription habits for antidepressants may still be at some variance with recommendations from the literature.

Adolescent↗