Oral galactagogues (natural therapies or drugs) for increasing breast milk production in mothers of non-hospitalised term infants.

BACKGROUND: Many women express concern about their ability to produce enough milk, and insufficient milk is frequently cited as the reason for supplementation and early termination of breastfeeding. When addressing this concern, it is important first to consider the influence of maternal and neonatal health, infant suck, proper latch, and feeding frequency on milk production, and that steps be taken to correct or compensate for any contributing issues. Oral galactagogues are substances that stimulate milk production. They may be pharmacological or non-pharmacological (natural). Natural galactagogues are usually botanical or other food agents. The choice between pharmacological or natural galactagogues is often influenced by familiarity and local customs. Evidence for the possible benefits and harms of galactagogues is important for making an informed decision on their use. OBJECTIVES: To assess the effect of oral galactagogues for increasing milk production in non-hospitalised breastfeeding mother-term infant pairs. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), Health Research and Development Network - Phillippines (HERDIN), Natural Products Alert (Napralert), the personal reference collection of author LM, and reference lists of retrieved studies (4 November 2019). SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (including published abstracts) comparing oral galactagogues with placebo, no treatment, or another oral galactagogue in mothers breastfeeding healthy term infants. We also included cluster-randomised trials but excluded cross-over trials. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two to four review authors independently selected the studies, assessed the risk of bias, extracted data for analysis and checked accuracy. Where necessary, we contacted the study authors for clarification. MAIN RESULTS: Forty-one RCTs involving 3005 mothers and 3006 infants from at least 17 countries met the inclusion criteria. Studies were conducted either in hospitals immediately postpartum or in the community. There was considerable variation in mothers, particularly in parity and whether or not they had lactation insufficiency. Infants' ages at commencement of the studies ranged from newborn to 6 months. The overall certainty of evidence was low to very low because of high risk of biases (mainly due to lack of blinding), substantial clinical and statistical heterogeneity, and imprecision of measurements. Pharmacological galactagogues Nine studies compared a pharmacological galactagogue (domperidone, metoclopramide, sulpiride, thyrotropin-releasing hormone) with placebo or no treatment. The primary outcome of proportion of mothers who continued breastfeeding at 3, 4 and 6 months was not reported. Only one study (metoclopramide) reported on the outcome of infant weight, finding little or no difference (mean difference (MD) 23.0 grams, 95% confidence interval (CI) -47.71 to 93.71; 1 study, 20 participants; low-certainty evidence). Three studies (metoclopramide, domperidone, sulpiride) reported on milk volume, finding pharmacological galactagogues may increase milk volume (MD 63.82 mL, 95% CI 25.91 to 101.72; I² = 34%; 3 studies, 151 participants; low-certainty evidence). Subgroup analysis indicates there may be increased milk volume with each drug, but with varying CIs. There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints, such as tiredness, nausea, headache and dry mouth (very low-certainty evidence). No adverse effects were reported for infants. Natural galactagogues Twenty-seven studies compared natural oral galactagogues (banana flower, fennel, fenugreek, ginger, ixbut, levant cotton, moringa, palm dates, pork knuckle, shatavari, silymarin, torbangun leaves or other natural mixtures) with placebo or no treatment. One study (Mother's Milk Tea) reported breastfeeding rates at six months with a concluding statement of "no significant difference" (no data and no measure of significance provided, 60 participants, very low-certainty evidence). Three studies (fennel, fenugreek, moringa, mixed botanical tea) reported infant weight but could not be meta-analysed due to substantial clinical and statistical heterogeneity (I2 = 60%, 275 participants, very low-certainty evidence). Subgroup analysis shows we are very uncertain whether fennel or fenugreek improves infant weight, whereas moringa and mixed botanical tea may increase infant weight compared to placebo. Thirteen studies (Bu Xue Sheng Ru, Chanbao, Cui Ru, banana flower, fenugreek, ginger, moringa, fenugreek, ginger and turmeric mix, ixbut, mixed botanical tea, Sheng Ru He Ji, silymarin, Xian Tong Ru, palm dates; 962 participants) reported on milk volume, but meta-analysis was not possible due to substantial heterogeneity (I2 = 99%). The subgroup analysis for each intervention suggested either benefit or little or no difference (very low-certainty evidence). There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints such as mothers with urine that smelled like maple syrup and urticaria in infants (very low-certainty evidence). Galactagogue versus galactagogue Eight studies (Chanbao; Bue Xue Sheng Ru, domperidone, moringa, fenugreek, palm dates, torbangun, moloco, Mu Er Wu You, Kun Yuan Tong Ru) compared one oral galactagogue with another. We were unable to perform meta-analysis because there was only one small study for each match-up, so we do not know if one galactagogue is better than another for any outcome. AUTHORS' CONCLUSIONS: Due to extremely limited, very low certainty evidence, we do not know whether galactagogues have any effect on proportion of mothers who continued breastfeeding at 3, 4 and 6 months. There is low-certainty evidence that pharmacological galactagogues may increase milk volume. There is some evidence from subgroup analyses that natural galactagogues may benefit infant weight and milk volume in mothers with healthy, term infants, but due to substantial heterogeneity of the studies, imprecision of measurements and incomplete reporting, we are very uncertain about the magnitude of the effect. We are also uncertain if one galactagogue performs better than another. With limited data on adverse effects, we are uncertain if there are any concerning adverse effects with any particular galactagogue; those reported were minor complaints. High-quality RCTs on the efficacy and safety of galactagogues are urgently needed. A set of core outcomes to standardise infant weight and milk volume measurement is also needed, as well as a strong basis for the dose and dosage form used.

[Levosulpiride in the management of functional dyspepsia and delayed gastric emptying]. / Levosulpirida en el manejo de la dispepsia funcional y la gastroparesia.

Levosulpiride is a sulpiride isomer that exerts its prokinetic action through a dual mechanism: 1) as a D(2) dopamine receptor antagonist and 2) as a serotonin 5HT(4) receptor agonist, conferring this drug with a cholinergic effect. At a dosage of 25mg three times daily, levosulpiride accelerates gastric and gallbladder emptying. Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia, while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists. The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D(2) dopamine antagonists. Therefore, this drug is a useful therapeutic option in the management of patients with functional dyspepsia, as well as in those with delayed gastric emptying.

Sensorimotor gating and habituation of the startle response in schizophrenic patients randomly treated with amisulpride or olanzapine.

BACKGROUND: Schizophrenic patients exhibit impairments in prepulse inhibition (PPI) and habituation of the acoustic startle response (ASR). Recent studies suggested that PPI deficits and habituation deficits are normalized after antipsychotic treatment. Despite clear evidence of gating and habituation mechanisms in animal models, it is still unknown which neurotransmitter systems are involved in schizophrenic patients. Thus, we compared the effects of a combined 5-HT2A/D2 and a pure D2/D3 antagonist on PPI and habituation of ASR in patients with schizophrenia. METHODS: The ASR was measured in 37 acute schizophrenic patients who were randomized and double-blinded as to treatment with amisulpride or olanzapine. Patients were assessed during the first week and after four and eight weeks of treatment. Twenty healthy matched control subjects were examined likewise. RESULTS: Schizophrenic patients showed a significant PPI deficit and significantly decreased startle amplitude at baseline. The gating deficit disappeared after antipsychotic treatment in both treatment groups. Amisulpride sensitized the startle amplitude, whereas startle amplitude was not changed by olanzapine. After correcting for startle amplitude, patients did not show a habituation deficit; however, amisulpride accelerated habituation, whereas olanzapine had no effect. CONCLUSIONS: Our findings suggest that the PPI-restoring effect of antipsychotics is probably attributed to a dopamine D2 receptor blockade.

Effects of amisulpride, risperidone and chlorpromazine on auditory and visual latent inhibition, prepulse inhibition, executive function and eye movements in healthy volunteers.

In view of the evidence that cognitive deficits in schizophrenia are critically important for long-term outcome, it is essential to establish the effects that the various antipsychotic compounds have on cognition, particularly second-generation drugs. This parallel group, placebo-controlled study aimed to compare the effects in healthy volunteers (n = 128) of acute doses of the atypical antipsychotics amisulpride (300 mg) and risperidone (3 mg) to those of chlorpromazine (100 mg) on tests thought relevant to the schizophrenic process: auditory and visual latent inhibition, prepulse inhibition of the acoustic startle response, executive function and eye movements. The drugs tested were not found to affect auditory latent inhibition, prepulse inhibition or executive functioning as measured by the Cambridge Neuropsychological Test Battery and the FAS test of verbal fluency. However, risperidone disrupted and amisulpride showed a trend to disrupt visual latent inhibition. Although amisulpride did not affect eye movements, both risperidone and chlorpromazine decreased peak saccadic velocity and increased antisaccade error rates, which, in the risperidone group, correlated with drug-induced akathisia. It was concluded that single doses of these drugs appear to have little effect on cognition, but may affect eye movement parameters in accordance with the amount of sedation and akathisia they produce. The effect risperidone had on latent inhibition is likely to relate to its serotonergic properties. Furthermore, as the trend for disrupted visual latent inhibition following amisulpride was similar in nature to that which would be expected with amphetamine, it was concluded that its behaviour in this model is consistent with its preferential presynaptic dopamine antagonistic activity in low dose and its efficacy in the negative symptoms of schizophrenia.

The effects of sulpiride on psychomotor performance and subjective tolerance.

In many European countries, the substituted benzamide sulpiride is used with antidepressant indication in the dosage range of 150-300 mg on an outpatient population. This raises the concern of possible impairments of psychomotor performance in this dosage range. To address this question, the psychometric effects of 300 mg of sulpiride in comparison with placebo in 12 healthy volunteers was evaluated in this study. In a randomised, double-blind, two-way, within-subjects (cross-over) design, visuomotor performance was assessed using time estimation, critical flicker fusion, and choice reaction time tasks at baseline and 4 h after oral administration of either 300 mg of sulpiride or placebo. In addition, self-ratings on subjective well-being were obtained. Results were evaluated using analysis of covariance (ANCOVA) with baseline levels as covariates. In healthy subjects, 300 mg of sulpiride caused no alteration in time estimation and choice reaction movement time, whereas critical flicker fusion frequency was lower and choice-reaction decision time were prolonged under medication. Self-rating scales showed no significant differences between sulpiride and placebo. Subjects were not able to tell whether they received placebo or sulpiride. This study indicates that sulpiride is subjectively well tolerated at a dosage of 300 mg. However, using psychometric methods, effects are demonstrable that can be interpreted as a reduction of excitatory arousal without causing the subjective experience of sedation. These results call for caution when prescribing the drug to outpatients.

Amantadine in the treatment of neuroleptic-induced obesity in rats: behavioral, endocrine and neurochemical correlates.

The efficacy of the antiviral agent Amantadine (AM, 5-100 mg/kg/sc, ip or intrahypothalamically, 12.5-100 micrograms bilaterally) in influencing body weight and food intake in drug-free rats, and in preventing neuroleptic-induced weight gain, was assessed in adult female rats. In drug-free rats, acute administration of systemic AM or directly injected in the lateral hypothalamus (LH) displayed a significant dose-dependent anorectic effect (p < 0.001). This effect could be mediated by the brain monoaminergic system, because systemic or local injections of AM increased dopamine and serotonin overflow in the nucleus accumbens and in the LH. Chronic administration of AM significantly decreased body weight gain in drug-free rats only at the dose of 100 mg/kg/sc. Similarly, obesity induced by the neuroleptic drug sulpiride (SUL, 20 mg/kg/ip for 21 days) was prevented by AM only at the dose of 100 mg/kg. AM did not prevent SUL-induced hyperprolactinemia, disruption of the vaginal cycle and a decrement in the weight of the uterus and ovaries at any dosage. This lack of efficacy of AM contrasts with that of bromocriptine, which completely prevented SUL-induced weight gain and hyperprolactinemia. The results show that despite a potent acute anorectic effect, AM displays a weak antagonistic action on SUL-induced obesity in rats, in contrast to the preliminary results obtained in humans. As AM metabolism differs in humans and rats, additional research is needed before its systematic testing in counteracting neuroleptic-induced obesity in patients with mental disorders.

Effects of different dopamine agonists and antagonists on post-menopausal hot flushes.

The dopaminergic system seems to be involved in both pulsatile luteinizing hormone (LH) secretion and hot flushes in post-menopausal women. With the aim of further clarifying its role, the effectiveness of dopaminergic and antidopaminergic drugs in the treatment of hot flushes was studied. Self-assessed scores for vasomotor symptoms were evaluated in 5 groups of 15 patients treated for 20 days with one of the following agents: placebo; the dopamine receptor agonist, bromocriptine; the indirect dopaminergic agent, Liposom; the antidopaminergic drug, veralipride or the peripheral antidopaminergic agent, domperidone. All of these treatment regimens were effective in alleviating hot flushes, but the pharmacological agents proved to be more effective than the placebo. A direct dopaminergic action is hypothesized in the case of bromocriptine and Liposom, while the antidopaminergic drugs might act through different indirect mechanisms such as the short-loop feedback exerted by hyperprolactinaemia on tuberoinfundibular dopamine (TIDA) neurons with a secondary dopamine-like activity, or stimulation of the opioid system.

[A previously unpublished indication for sulpiride: functional uterine hemorrhages]. / Une indication inédite du sulpiride: les hémorragies utérines fonctionnelles.

Sulpiridin has been shown to be remarkably efficient in treating functional uterine haemorrhage (70 per cent success). It is especially so in the pre-menopause. Its mode of action takes place on three levels: the hypothalamus, where it works on the clonic centre for the release of gonadotrophins (the tonic centre not being affected); the ovaries, where it lessens the sensitivity of the reaction of the ovary to gonadotrophins; the uterus, where there is direct action on the thickness of the mucous lining of the uterus and on its blood supply.

An evaluation of a unique new antipsychotic agent, sulpiride: effects on serum prolactin and growth hormone levels.

Sulpiride is a new and chemically different neuroleptic. In a study of 16 severely ill schizophrenic patients, this compound displayed definite evidence of antipsychotic activity while producing few adverse reactions. The relative absence of extrapyramidal side effects may indicate that sulpride has a low potential for producing tardive dyskinesia. Two patients who did not develop significant increases in prolactin levels did show a definite therapeutic response to sulpiride. Thus it appears that central dopaminergic blockade in the hypothalamic area is not a prerequisite for antipsychotic activity.