Nutritional management in head and neck cancer: United Kingdom National Multidisciplinary Guidelines.

Nutritional support and intervention is an integral component of head and neck cancer management. Patients can be malnourished at presentation, and the majority of patients undergoing treatment for head and neck cancer will need nutritional support. This paper summarises aspects of nutritional considerations for this patient group and provides recommendations for the practising clinician. Recommendations • A specialist dietitian should be part of the multidisciplinary team for treating head and neck cancer patients throughout the continuum of care as frequent dietetic contact has been shown to have enhanced outcomes. (R) • Patients with head and neck cancer should be nutritionally screened using a validated screening tool at diagnosis and then repeated at intervals through each stage of treatment. (R) • Patients at high risk should be referred to the dietitian for early intervention. (R) • Offer treatment for malnutrition and appropriate nutrition support without delay given the adverse impact on clinical, patient reported and financial outcomes. (R) • Use a validated nutrition assessment tool (e.g. scored Patient Generated-Subjective Global Assessment or Subjective Global Assessment) to assess nutritional status. (R) • Offer pre-treatment assessment prior to any treatment as intervention aims to improve, maintain or reduce decline in nutritional status of head and neck cancer patients who have malnutrition or are at risk of malnutrition. (G) • Patients identified as well-nourished at baseline but whose treatment may impact on their future nutritional status should receive dietetic assessment and intervention at any stage of the pathway. (G) • Aim for energy intakes of at least 30 kcal/kg/day. As energy requirements may be elevated post-operatively, monitor weight and adjust intake as required. (R) • Aim for energy and protein intakes of at least 30 kcal/kg/day and 1.2 g protein/kg/day in patients receiving radiotherapy or chemoradiotherapy. Patients should have their weight and nutritional intake monitored regularly to determine whether their energy requirements are being met. (R) • Perform nutritional assessment of cancer patients frequently. (G) • Initiate nutritional intervention early when deficits are detected. (G) • Integrate measures to modulate cancer cachexia changes into the nutritional management. (G) • Start nutritional therapy if undernutrition already exists or if it is anticipated that the patient will be unable to eat for more than 7 days. Enteral nutrition should also be started if an inadequate food intake (60 per cent of estimated energy expenditure) is anticipated for more than 10 days. (R) • Use standard polymeric feed. (G) • Consider gastrostomy insertion if long-term tube feeding is necessary (greater than four weeks). (R) • Monitor nutritional parameters regularly throughout the patient's cancer journey. (G) • Pre-operative: ○ Patients with severe nutritional risk should receive nutrition support for 10-14 days prior to major surgery even if surgery has to be delayed. (R) ○ Consider carbohydrate loading in patients undergoing head and neck surgery. (R) • Post-operative: ○ Initiate tube feeding within 24 hours of surgery. (R) ○ Consider early oral feeding after primary laryngectomy. (R) • Chyle Leak: ○ Confirm chyle leak by analysis of drainage fluid for triglycerides and chylomicrons. (R) ○ Commence nutritional intervention with fat free or medium chain triglyceride nutritional supplements either orally or via a feeding tube. (R) ○ Consider parenteral nutrition in severe cases when drainage volume is consistently high. (G) • Weekly dietetic intervention is offered for all patients undergoing radiotherapy treatment to prevent weight loss, increase intake and reduce treatments interruptions. (R) • Offer prophylactic tube feeding as part of locally agreed guidelines, where oral nutrition is inadequate. (R) • Offer nutritional intervention (dietary counselling and/or supplements) for up to three months after treatment. (R) • Patients who have completed their rehabilitation and are disease free should be offered healthy eating advice as part of a health and wellbeing clinic. (G) • Quality of life parameters including nutritional and swallowing, should be measured at diagnosis and at regular intervals post-treatment. (G).

Neurokinin-1 expression and co-localization with glutamate and GABA in the hypothalamus of the cat.

Recent behavioral studies using pharmacological techniques have demonstrated that the high affinity substance P (SP) receptor, neurokinin-1 receptor (NK-1), in the medial hypothalamus could be important in mediating defensive rage behavior in the cat. These observations prompted us to use molecular techniques to determine the distribution of NK-1 in the hypothalamus and in other regions of the forebrain relevant to the control of rage behavior. We cloned a 650 bp fragment of the cat NK-1 cDNA. Partial DNA sequence analyses of this fragment indicate 90% homology with the human cDNA. By in situ hybridization (ISH), we showed that NK-1 mRNA was localized in the cytoplasm but not nuclei of cat forebrain neurons. Furthermore, NK-1 mRNA was co-localized in neurons that displayed positive immunolabeling for glutamate or GABA. Moderate labeling was visualized in the anterior medial hypothalamus which receives significant SP input via the stria terminalis from the medial amygdala. Strong labeling was also observed in the basal amygdaloid complex. The functional significance of this labeling pattern is suggested from the observation that both the medial and basal complex of amygdala serve as powerful modulators of defensive rage behavior. Weaker labeling was seen over the posterior medial and lateral hypothalamus. The distribution of NK-1 in the hypothalamus was matched by that of SP-immunoreactive axons and pre-terminals that were observed in the hypothalamus. The overall findings provide anatomical evidence to show that the high affinity SP receptor, NK-1, is linked to glutamate and GABA neurons in the anterior medial hypothalamus and further suggests its likely role in the regulation of feline aggression.

Pressor and subpressor doses of angiotensin II increase insulin sensitivity in NIDDM. Dissociation of metabolic and blood pressure effects.

There is evidence that the renin-angiotensin system may be involved in the metabolic as well as the cardiovascular features of diabetes and that pressor doses of angiotensin II (ANG II) increase insulin sensitivity in parallel with blood pressure (BP) in healthy subjects, but the effects of ANG II on insulin sensitivity have not been previously reported in patients with non-insulin-dependent diabetes mellitus (NIDDM). In a randomized, double-blind, placebo-controlled, crossover study, 11 patients with NIDDM attended 3 study days to evaluate the effects of a 3-h infusion of subpressor and pressor doses of ANG II on whole body insulin sensitivity using the euglycemic hyperinsulinemic clamp. BP and heart rate were recorded, and blood samples were collected for serum insulin, C-peptide, potassium, catecholamines, plasma renin activity, and plasma ANG II concentrations. Plasma levels of ANG II (means +/- SD) were 9 +/- 4, 29 +/- 9, and 168 +/- 47 pmol/ml after placebo, low dose infusion, and high dose infusion, respectively. The higher dose of ANG II was associated with significant increases in BP (e.g., 18 mmHg systolic BP at 150 min) and plasma aldosterone. Whole body insulin sensitivity was 23.8 +/- 12.7 mumol glucose.kg-1.min-1 after placebo and 30.6 +/- 12.7 and 27.2 +/- 13.3 following low and high dose ANG II infusions, respectively (P < 0.05, analysis of variance). In summary, acute infusion of ANG II, with or without an increase in BP, increases insulin sensitivity in normotensive patients with NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Prediction and optimisation of the antihypertensive response to nifedipine.

The predictability of the long term antihypertensive response to nifedipine in individual patients has been assessed by an analysis based upon the concentration-effect parameters defined following the first dose administration of 20 mg nifedipine (Retard). The predicted and measured reductions in blood pressure during steady state nifedipine treatment were compared for the trough and peak responses and there was reasonable agreement for the group of patients as a whole. However, when the measured and predicted blood pressure profiles were compared for each individual patient there was close agreement for the majority of patients but there were significant discrepancies in a few cases. Further analysis of the steady state concentrations in these cases revealed that there was no change in their responsiveness to nifedipine and that discrepancies were directly attributable to inappropriate compliance with the drug regimen. The analysis was further extended to simulate the blood pressure responses to alternative fixed dosage regimens. Assessment of these simulations suggests that blood pressure control with nifedipine Retard is significantly improved by three times daily drug administration.

Effects of angiotensin II on insulin sensitivity: a placebo-controlled study.

1. There is evidence that hyperinsulinaemia increases the aldosterone response to angiotensin II, and that angiotensin-converting enzyme inhibitor drugs enhance peripheral glucose utilization, but the direct effects of angiotensin II on insulin sensitivity have not been reported previously. 2. In a randomized, double-blind, placebo-controlled, cross-over study, 12 healthy male subjects attended on 3 study days for the evaluation of the effects of a subpressor (1 ng min-1kg-1) and pressor (5 ng min-1kg-1) infusion of angiotensin II on whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. Frequent measurements of blood pressure and heart rate were recorded and blood samples were collected for determination of serum insulin, C-peptide and K+ concentration, plasma renin activity and plasma angiotensin II concentration. 3. Plasma angiotensin II concentrations (means +/- SD) were 11 +/- 5 pg/ml after placebo, and 27 +/- 9 and 125 +/- 28 pg/ml after low and high dose angiotensin II, respectively. The higher dose of angiotensin II was associated with significant increases in blood pressure (e.g. 13 mmHg systolic blood pressure at 150 min) and serum aldosterone concentration. Whole-body insulin sensitivity was 10.5 +/- 2 mg of glucose min-1kg-1 after placebo, and 10.5 +/- 2.2 and 10.9 +/- 3.4 mg of glucose min-1kg-1 after low and high dose angiotensin II (not significant). 4. Angiotensin II had no effect on hyperinsulinaemia-induced reductions in serum potassium and triacylglycerol concentrations. 5. Thus, acute infusion of angiotensin II for 3 h, with or without an increase in blood pressure, has no effect on whole-body insulin sensitivity.

Combination of nifedipine and doxazosin in essential hypertension.

Pharmacodynamic and pharmacokinetic interactions have been reported when an alpha 1-antagonist is combined with a calcium antagonist. We evaluated the clinical usefulness of the combination of nifedipine (20 mg twice daily, b.i.d.) and doxazosin (2 mg once daily, o.d.) in hypertensive patients in whom blood pressure (BP) control was suboptimal after doxazosin (group A) or nifedipine (group B) as monotherapy and investigated the underlying kinetic and dynamic interactions, including changes in vascular responsiveness to i.v. infusions of angiotensin II (ANGII) and phenylephrine (PE). The combination was well tolerated and associated with further significant reductions in BP. After 4 weeks of combined therapy, average supine BP over 8 h was 122/77 in group A and 137/80 in group B as compared with 140/86 and 150/88 mm Hg, respectively, during monotherapy + placebo. The combination attenuated both phenylephrine and ANG-induced pressor responses: e.g., the mean PD15 values (dose of agonist required to increase systolic BP by 15 mm Hg) for group A at 1.5-3 h were 3.5 micrograms/kg/min for PE and 7.5 ng/kg/min for ANGII as compared with 2.9 and 2.3, respectively, during treatment with doxazosin and placebo. There was no evidence of a significant kinetic interaction between the two drugs and, in particular, addition of nifedipine had no effect on the steady-state kinetics of doxazosin. In conclusion, doxazosin and nifedipine are an effective antihypertensive combination in patients who require treatment with more than one drug.

Vascular pressor responses in treated and untreated essential hypertension.

Thirty-seven essential hypertensives received placebo for 3 weeks followed by nifedipine retard (n = 14) or enalapril (n = 13) or doxazosin (n = 10) as monotherapy for 6 weeks and attended study days to evaluate the effects of placebo, first dose, and chronic (1-6 weeks) treatment. On each study day, pressor responses to i.v. infusions of phenylephrine (PE) and angiotensin II (AII) were measured 1.5-3 h after drug administration and the derived PD20 values (dose required to increase mean blood pressure by 20 mm Hg) compared. Each treatment produced comparable reductions in BP. Nifedipine significantly attenuated the pressor responses to AII and PE: for AII, the mean PD20 (ng/kg/min) increased from 8.2 (placebo) to 9.9 (first dose), 13.9 (1 week), and 17.4 (6 weeks). Pressor responsiveness to both AII and PE was unchanged following enalapril: for PE, the mean PD20 (micrograms/kg/min) was 2.1 (placebo), 1.5 (first dose), and 1.5 (6 weeks). Doxazosin produced rightward shifts of the PE pressor dose-response curves but had no effect on responses to AII. The relationship between the simultaneous BP and HR changes during the infusion of PE was used as an index of cardiac baroreflex activity. In contrast to enalapril and doxazosin, which had no effect, nifedipine reduced the slope of the HR/BP relationship from -0.62 (placebo) to -0.38 (first dose) and -0.31 beats/min/mm Hg (6 weeks). For comparable reductions in BP, doxazosin only affects adrenergic mechanisms whereas nifedipine affects both adrenergic and non-adrenergically mediated vasoconstriction. The ACE inhibitor enalapril had no effect on pressor responses to AII and PE.

Prediction of response to antihypertensive therapy with enalapril and nifedipine.

We evaluated the usefulness of an integrated concentration-effect modelling technique in predicting the long-term response to antihypertensive therapy with enalapril and nifedipine. Two groups of essential hypertensives were given monotherapy with 20 mg nifedipine twice a day (n = 14) or 20 mg enalapril once a day (n = 13), and were studied following the administration of the drugs and after at least 6 weeks' treatment. For both drugs the predicted responses (predose and 4 h postdose) were in close agreement with the observed responses. With enalapril the observed and predicted profiles over a 12-h study period were well correlated in all subjects. In contrast, with nifedipine, although there was generally good agreement, the model over-predicted the profile of response in one patient and under-predicted the profile in one patient. Thus, there is evidence that application of concentration-effect analysis is useful in predicting the steady-state antihypertensive effect from the first dose-response to the drug.

Factors determining the response to calcium antagonists in hypertension.

Pharmacokinetic and pharmacodynamic variability account for the large interindividual differences in the antihypertensive response to treatment with a calcium antagonist. Using an integrated kinetic-dynamic model, the acute and chronic (4-6 weeks) responses to nifedipine (n = 14) and verapamil (n = 14) were characterized for individual hypertensive patients in terms of fall in blood pressure per unit drug concentration. The responsiveness to nifedipine, as the mean of the group, was -0.48 mm Hg/ng/ml following the first dose and -0.49 mm Hg/ng/ml after chronic dosing. The corresponding values for verapamil were -0.13 and -0.12 mm Hg/ng/ml, respectively. For nifedipine and verapamil, the responsiveness to the first dose was significantly correlated both with the height of the pretreatment blood pressure (p less than 0.001) and the responsiveness after 4-6 weeks of treatment (p less than 0.001). Parameters derived from an individual approach to concentration-effect analysis are useful for evaluating the determinants of response to calcium antagonists and form a potential basis for optimizing drug therapy in individual patients.

Dietary ascorbic acid and resistance to experimental renal candidiasis.

Guinea pigs were maintained for various periods of time on low (0.5 mg/day), intermediate (20 mg/day), or high (100 and 500 mg/day) levels of dietary ascorbic acid. Animals in each experimental group were challenged with Candida albicans via cardiac injection, and the course of infection in the kidneys was assessed. The results show that the animals receiving only 0.5 mg of ascorbic acid per day were significantly more susceptible to the infection than animals maintained on any higher level of dietary ascorbic acid. The greater susceptibility of the guinea pigs in the 0.5-mg level group was evident, however, only during "early" stages of the infection (until about day 3). Guinea pigs receiving high levels of dietary ascorbic acid were no more resistant at any time after infection, or with any challenge dose, than those receiving an intermediate dietary level. Although these data suggest that vitamin C may be involved in resistance to candidiasis, tissue levels of ascorbic acid do not change significantly with time after infection. These results indicate that low levels of dietary ascorbic acid increase susceptibility to candidiasis, yet high (or "megadose") levels of dietary vitamin C do not show any effect on resistance to this microorganism.